WO2022212655A1 - Compositions comprenant de l'epa et de la colchicine et leurs procédés d'utilisation pour réduire le risque d'accidents cardiovasculaires chez un sujet - Google Patents

Compositions comprenant de l'epa et de la colchicine et leurs procédés d'utilisation pour réduire le risque d'accidents cardiovasculaires chez un sujet Download PDF

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WO2022212655A1
WO2022212655A1 PCT/US2022/022760 US2022022760W WO2022212655A1 WO 2022212655 A1 WO2022212655 A1 WO 2022212655A1 US 2022022760 W US2022022760 W US 2022022760W WO 2022212655 A1 WO2022212655 A1 WO 2022212655A1
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subject
colchicine
patients
study
visit
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PCT/US2022/022760
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English (en)
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Richard Mason
Sephy PHILIP
Richard Dunbar
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Amarin Pharmaceuticals Ireland Limited
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Publication of WO2022212655A1 publication Critical patent/WO2022212655A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • Cardiovascular disease is one of the leading causes of death in the United States and most European countries. It is estimated that over 70 million people in the United States alone suffer from a cardiovascular disease or disorder including but not limited to high blood pressure, coronary heart disease, dyslipidemia, congestive heart failure and stroke.
  • Lovaza® a lipid regulating agent
  • Lovaza® is indicated as an adjunct to diet to reduce triglyceride levels in adult patients with very high triglyceride levels.
  • Lovaza® can significantly increase LDL-C and/or non-HDL-C levels in some patients.
  • compositions comprising ethyl icosapentate and colchicine.
  • the composition is encapsulated in a capsule shell.
  • the ethyl icosapentate and colchicine are present in the composition in equimolar amounts.
  • the icosapent ethyl is present in amount of at least about 90%, by weight, of total fatty acids in the composition. In yet another embodiment, the icosapent ethyl is present in amount of at least about 96%, by weight, of total fatty acids in the composition.
  • the present disclosure provides methods of treating, preventing, and/or reducing a cardiovascular event in a subject, the method comprising administering to said subject ethyl icosapentate and colchicine.
  • the cardiovascular events are selected from the group consisting of cardiovascular death, myocardial infarction, stroke, coronary revascularization, and unstable angina.
  • the ethyl icosapentate and colchicine are coadministered to the subject.
  • the colchicine is co-formulated in a pharmaceutical composition with the ethyl icosapentate.
  • the ethyl icosapentate and colchicine are co-formulated in a dosage unit.
  • the ethyl icosapentate and colchicine are individual formulated in separate dosage units.
  • administration ethyl icosapentate and colchicine reduces LPS-induced macrophage activation in the subject. In some embodiments, administration of ethyl icosapentate and colchicine reduced iNOS activity in the subject. In yet another embodiment, administration ethyl icosapentate and colchicine decreased nitrite production in the subject.
  • cytokine is IL-1 [3, TNF- ⁇ , or both.
  • the subject is on statin therapy. In some embodiments, the subject has a baseline triglyceride level of at least 135 mg/dL.
  • the ethyl icosapentate is present in a pharmaceutical composition and comprises at least about 90 wt. % of all omega-3 fatty acids in the pharmaceutical composition. In some embodiments, the ethyl icosapentate is present in a pharmaceutical composition and comprises at least about 96 wt. % of all omega-3 fatty acids in the pharmaceutical composition. In some embodiments, about 1 g of the pharmaceutical composition is present in each of 4 capsules. [0014] In some embodiments, the subject has an established cardiovascular disease. In some embodiments, the established cardiovascular disease is determined by the presence of any one of: documented coronary artery disease, documented cerebrovascular disease, documented carotid disease, documented peripheral arterial disease, or combinations thereof.
  • the subject has diabetes and at least one additional risk factor for cardiovascular disease.
  • the at least one additional risk factor for cardiovascular disease is selected from the group consisting of (a) a male gender of at least 55 years of age or a female gender of at least 65 years of age, (b) smokes cigarettes or has stopped smoking cigarettes within three months before administration of the composition, (c) blood pressure of at least 140 mmHg systolic or at least 90 mmHg diastolic, (d) on antihypertensive medication, (e) a male gender with HDL-cholesterol level 40 mg/dL or less or a female gender with HDL-cholesterol level 40 mg/dL or less, (f) has a hsCRP level of greater than 3 mg/L, (g) a creatine clearance between 30 mL/min and 60 mL/min, (h) has non-proliferative retinopathy, (i) pre-proliferative retinopathy, (
  • Figure 1 is a schematic of the study design according to an embodiment of the present disclosure.
  • Figure 2 is a schematic showing disposition of patients according to an embodiment of the present disclosure.
  • Figures 3A and 3B are representative Kaplan-Meier event curves for the cumulative incidence of the primary composite endpoints. Figures 3A and 3B indicate a 25% relative risk reduction for the primary composite endpoint over the course of 5 years.
  • Figure 4 is a representative forest plot of individual components of primary endpoints analyzed as time to first event of each individual endpoint and indicates that each component, individually, was reduced.
  • Figures 5A and 5B are representative Kaplan-Meier event curves for the cumulative incidence of the key secondary composite endpoints. Figures 5A and 5B indicate that there was a 26% RRR for the key secondary composite endpoint over the course of 5 years.
  • Figures 6 and 7 are representative forest plots of primary efficacy outcomes in select prespecified subgroups. Figures 6 and 7 indicate that a subject’s baseline triglyceride levels (e.g., ⁇ 150 vs. ⁇ 150 mg/dL or ⁇ 200 or ⁇ 200 mg/dL) did not influence the primary endpoint outcomes.
  • baseline triglyceride levels e.g., ⁇ 150 vs. ⁇ 150 mg/dL or ⁇ 200 or ⁇ 200 mg/dL
  • Figure 8 and 9 are representative forest plots of secondary efficacy outcomes in select prespecified subgroups.
  • Figures 8 and 9 indicate that a subject’s baseline triglyceride levels (e.g., ⁇ 150 vs. ⁇ 150 mg/dL or ⁇ 200 or ⁇ 200 mg/dL) did not influence the key secondary endpoint outcomes.
  • Figures 10A and 10B are representative Kaplan-Meier curves of primary and key secondary endpoints by achieved triglyceride level at 1 year.
  • Figures 10A and 10B indicate that patient’s triglyceride levels had no influence on the efficacy of icosapent ethyl as compared with placebo with respect to the primary or key secondary efficacy endpoint outcomes.
  • Figure 11 is a representative forest plot of prespecified hierarchical testing of endpoints and indicates that all individual and composite ischemic endpoints were significantly reduced by icosapent ethyl (AMR101).
  • Figure 12 is a schematic of the study design according to an embodiment of the present disclosure.
  • Figure 13 is a representative bar graph depicting the distribution of first, second, and recurrent ischemic events in patients.
  • Figure 13 indicates that the first, second, and recurrent ischemic events were reduced in patients randomized to icosapent ethyl (I PE) compared to placebo.
  • Figure 14 is a representative overall cumulative event Kaplan-Meier event curve for the primary endpoint indicating that overall cumulative primary endpoints were reduced in patients randomized to icosapent ethyl.
  • Figure 15 is a representative cumulative event Kaplan-Meier event curve for the primary endpoint for patients in the secondary prevention cohort, which, similar to Figure 14, indicates that cumulative primary endpoints were also reduced in patients in the secondary prevention cohort randomized to icosapent ethyl.
  • Figure 16 is a representative cumulative event Kaplan-Meier event curve for the primary endpoint for patients in the primary prevention cohort, which, similar to Figures 14 and 15, indicates that cumulative primary endpoints were also reduced in patients in the primary prevention cohort randomized to icosapent ethyl.
  • Figure 17 is a representative forest plot of the total event for each occurrence of the primary endpoint.
  • Figure 17 indicates that the times to first, second, third, or fourth occurrences of the primary composite endpoint were consistently reduced in the icosapent ethyl group as compared to placebo.
  • Figure 18 includes representative pie charts for the proportion of first and subsequent primary endpoint events, overall and by component.
  • Figure 19 is a representative graph depicting the risk difference in 100 patients treated for five years with icosapent ethyl versus placebo of the composite primary endpoint.
  • Figure 20 is a representative forest plot of the total event for each occurrence of the primary and key secondary efficacy endpoints. Figure 20 indicates that the total events for each component of the primary endpoint events were significantly reduced.
  • Figure 21 is a representative overall cumulative event Kaplan-Meier curve for the key secondary endpoint indicating that overall cumulative key secondary endpoints were reduced in patients randomized to icosapent ethyl.
  • Figure 22 is a representative cumulative event Kaplan-Meier curve for the key secondary endpoint for patients in the secondary prevention cohort, which similar to Figure 21 indicates that cumulative key secondary endpoints were also reduced in patients in the secondary prevention cohort randomized to icosapent ethyl.
  • Figure 23 is representative cumulative event Kaplan-Meier curve for the key secondary endpoint for patients in the primary prevention cohort, which, similar to Figures 21 and 22, indicates that cumulative secondary endpoints were also reduced in patients in the primary prevention cohort randomized to icosapent ethyl.
  • Figure 24 is a representative overall cumulative Kaplan-Meier event curve as a function of years since randomization for the primary endpoint indicating that overall cumulative primary endpoints were reduced in patients randomized to icosapent ethyl.
  • Figure 25 is a representative overall cumulative event Kaplan-Meier curve as a function of years since randomization for the key secondary endpoint indicating that overall cumulative key secondary endpoints were reduced in patients randomized to icosapent ethyl.
  • Figure 26 is a representative Kaplan-Meier curve for recurrent events as a function of years since randomization of the primary endpoint for patients in the secondary prevention cohort indicating that cumulative primary endpoints were reduced in patients in the secondary prevention cohort randomized to icosapent ethyl.
  • Figure 27 is a representative Kaplan-Meier curve as a function of years since randomization for recurrent events of the key secondary endpoint for patients in the secondary prevention cohort indicating that cumulative key secondary endpoints were also reduced in patients in the secondary prevention cohort randomized to icosapent ethyl.
  • Figure 28 is a representative Kaplan-Meier curve as a function of years since randomization for recurrent events of the primary endpoint for patients in the primary prevention cohort indicating that cumulative primary endpoints were also reduced in patients in the primary prevention cohort randomized to icosapent ethyl.
  • Figure 29 is a representative Kaplan-Meier curve as a function of years since randomization for recurrent events of the key secondary endpoint for patients in the primary prevention cohort indicating that cumulative key secondary endpoints were reduced in patients in the primary prevention cohort randomized to icosapent ethyl.
  • Figure 30 are representative plots of the total events by number of events per patient for the primary composite endpoints and for each individual component for patients randomized to icosapent ethyl and placebo.
  • Figures 31 A and 31 B are representative flow charts of the total primary and secondary composite endpoint events for patients randomized to AMR101 and placebo, respectively.
  • Figure 32 includes representative pie charts for a proportion of first and subsequent primary endpoint events, overall and by component.
  • Figure 33 is a representative bar graph depicting a distribution of total (i.e., first and subsequent) primary composite endpoint events in patients. Figure 33 indicates that there was a 30% relative risk reduction in total events for the primary composition endpoint in patients randomized to icosapent ethyl.
  • Figures 34A and 34B are representative Kaplan-Meier curves over time for total (i.e., first and subsequent) and time to first primary composite events and secondary composite endpoint events, respectively.
  • Figures 34A and 34B indicate that both primary and key secondary endpoints were significantly reduced in patients randomized to icosapent ethyl compare to placebo.
  • Figure 35 is a representative forest plot of total primary and key secondary composite endpoint events and indicates that times to first, second, and third occurrence of the primary and secondary endpoints were significantly reduced in patients randomized to icosapent ethyl compared placebo.
  • Figure 36 is a representative forest plot of total primary and key secondary composite endpoints and each individual component or endpoint for patients randomized to icosapent ethyl and placebo indicating that not only was there a significant reduction in the composite of the primary and key secondary endpoints, but also, each individual component was also significantly reduced.
  • Figure 37A and 37B are representative forest plots of total primary and secondary composite endpoints in selected subgroups by the negative binomial model, respectively, for patients randomized to icosapent ethyl and placebo.
  • Figure 38 is a representative graph depicting the risk difference in patients treated for five years with icosapent ethyl versus placebo for total components of the composite primary endpoint and indicates that approximately 159 total primary endpoint events could be prevented within that time frame to include 12 cardiovascular deaths, 42 myocardial infarctions, 14 strokes, 76 coronary revascularizations, and 16 episodes of hospitalization for unstable angina.
  • Figures 39 and 40 show the forest plot for total primary and key secondary composite endpoint events and first second, and third occurrences for the reduced dataset with unadjusted and adjusted values, respectively.
  • Figures 41 and 42 show the forest plots for the total primary composite endpoint events and total key secondary composite endpoint events and first, second, and third occurrences for the reduced data with unadjusted values, respectively.
  • Figures 43 and 44 show the total primary composite endpoint events and key secondary composite endpoint events and first, second, and third occurrences for the reduced data set with adjusted values, respectively.
  • Figures 45 and 46 show the total primary and key secondary composite endpoint events and first, second, and third occurrences for the full data set for the unadjusted and adjusted values, respectively.
  • Figure 47 is a representative forest plot depicting the reduction of total primary composite endpoint events in subjects as a function of triglyceride level. Figure 47 indicates that total primary composite endpoints were reduced in all patients across the entire triglyceride range and within each of the defined triglyceride tertiles.
  • Figure 48 is a representative forest plot depicting time to first event of primary composite endpoint events in subjects as a function of triglyceride level. Figure 48 demonstrates that the time to first event of the primary composite endpoint was reduced across the entire triglyceride range.
  • Figure 49 is a representative bar graph for a placebo-corrected reduction in blood pressure in patients administered icosapent ethyl 4 g per day.
  • Figure 50 is a representative bar graph for the study drug adherence over time for each of the first, second, third, and fourth events.
  • Figure 51 is a representative showing that EPA treatment reduced LPS-induced nitrite production in a concentration-dependent manner with statistically significant reductions.
  • Figure 52 is a representative forest plot of total primary and key secondary composite endpoints in the REDUCE-IT study for patients randomized to icosapent ethyl alone (i.e., without colchicine use), received icosapent ethyl with colchicine as currently claimed, and placebo, respectively.
  • Figure 52 indicates that both primary and key secondary endpoints were reduced in patients received icosapent ethyl with or without colchicine compared to placebo.
  • Figure 52 also indicates that, surprisingly, the composite of key secondary endpoint was significantly reduced in patients received icosapent ethyl with colchicine compared to icosapent ethyl alone.
  • Figure 53 is a bar graph summarizing Number Needed to Treat (NNT) and Absolute Risk Reduction (ARR) data in the REDUCE-IT study for patients randomized to icosapent ethyl alone (i.e., “No Colchicine”), received icosapent ethyl with colchicine (i.e., “On colchicine”) as currently claimed, and the overall pooled populations, respectively.
  • Figure 53 shows that there was a remarkable difference in the NNT of primary and key secondary composite endpoints between patients received icosapent ethyl with colchicine and those received icosapent ethyl alone or the pooled populations.
  • a ratio in the range of about 1 to about 200 should be understood to include the explicitly recited limits of about 1 and about 200, but also to include individual ratios such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100, and so forth. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.
  • fatty acid derivative is meant to encompass any modified form of the fatty acid that was derived for example, by a chemical reaction from the fatty acid in free acid form (i.e., terminal carboxylic acid functional group).
  • fatty acid derivatives include alkyl esters such as methyl esters, propyl esters, butyl esters, or ethyl esters, a salt of the fatty acid such as a lithium, sodium, or potassium salt, or glyceride form of the fatty acid such as a mono-, di-, or triglyceride fatty acid.
  • the free fatty acid of eicosapentaenoic acid is administered to the subject and the amount administered is the gram weight sufficient to substantially match the pharmacokinetic profile produced by administration of 4 g of E-EPA per day to a human subject.
  • a derivative of eicosapentaenoic acid is administered to the subject and the amount administered is the gram weight sufficient to substantially match the pharmacokinetic profile produced by administration of 4 g of E-EPA per day to a human subject.
  • a dose-equivalent amount of E-EPA is about 4 g of E-EPA per day.
  • control subject refers to any subject used as a basis for comparison to the test subject.
  • a control subject includes, but is not limited to, any subject who has not been administered the composition, administered a composition other than the test composition (e.g., Lovaza® comprised of 365 mg of E-EPA and 375 mg of E- DHA), or administered a placebo.
  • a composition other than the test composition e.g., Lovaza® comprised of 365 mg of E-EPA and 375 mg of E- DHA
  • cardiovascular risk category 1 refers to subjects categorized as having an established cardiovascular disease. Patients from cardiovascular risk category 1 were stratified to the secondary prevention cohort. The designations for patients defined by cardiovascular risk category 1 are collectively referred to as: secondary prevention stratum, secondary prevention cohort, and the primary risk category.
  • cardiovascular risk category 2 refers to a subject categorized as having diabetes (which itself is a risk factor for cardiovascular disease) and at least one additional risk factor for cardiovascular disease but who does not have an established cardiovascular disease. Patients from cardiovascular risk category 2 were stratified to the primary prevention cohort. The designations for patients defined by cardiovascular risk category 1 are collectively referred to as: primary prevention stratum, primary prevention cohort, and secondary risk category.
  • ranges is intended as a continuous range including every value between the minimum and maximum values recited as well as any ranges that can be formed by such values. Also disclosed herein are any and all ratios (and ranges of any such ratios) that can be formed by dividing a disclosed numeric value into any other disclosed numeric value. Accordingly, the skilled person will appreciate that many such ratios, ranges, and ranges of ratios can be unambiguously derived from the numerical values presented herein and in all instances such ratios, ranges, and ranges of ratios represent various embodiments of the present disclosure.
  • statistical significance refers to a result from data generated by testing or experimentation is not likely to occur randomly or by chance, but is instead likely to be attributable to a specific cause. Statistical significance is evaluated from a calculated probability (p-value), where the p-value is a function of the means and standard deviations of the data samples and indicates the probability under which a statistical result occurred by chance or by sampling error. A result is considered statistically significant if the p-value is 0.05 or less, corresponding to a confidence level of 95%.
  • compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
  • a composition of the disclosure is administered to a subject in an amount sufficient to provide a daily dose of eicosapentaenoic acid of about 1 mg to about 10,000 mg, about 25 mg to about about 5000 mg, about 50 mg to about 3000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about
  • a composition for use in methods of the disclosure comprises eicosapentaenoic acid, or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof, or mixtures of any of the foregoing, collectively referred to herein as "EPA.”
  • EPA pharmaceutically acceptable
  • derivatives of EPA include, but are not limited to, methyl or other alkyl esters, re-esterified monoglycerides, re-esterified diglycerides and re-esterified triglycerides or mixtures thereof.
  • such derivatives of EPA are administered daily in amounts containing the same number of moles of EPA contained in 4 grams of ethyl icosapentate.
  • the EPA comprises an eicosapentaenoic acid ester.
  • the EPA comprises a C 1 - C 5 alkyl ester of eicosapentaenoic acid.
  • the EPA comprises eicosapentaenoic acid ethyl ester (E-EPA), eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl ester.
  • the EPA is in the form of ethyl-EPA, methyl-EPA, lithium EPA, mono-, di- or triglyceride EPA or any other ester or salt of EPA, or the free acid form of EPA.
  • the EPA may also be in the form of a 2-substituted derivative or other derivative which slows down its rate of oxidation but does not otherwise change its biological action to any substantial degree. Where any particular form of EPA (e.g.
  • eicosapentaenoic acid ethyl ester icosapent ethyl or E-EPA
  • any pharmaceutically acceptable derivative of EPA can be substituted in its place including icosapent methyl or eicosapentaenoic acid in free acid form.
  • Eicosapentaenoic acid ethyl ester, icosapent ethyl, and E-EPA are referenced interchangeably.
  • EPA is present in a composition useful in accordance with methods of the disclosure in an amount of about 50 mg to about 5000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg,
  • a composition useful in accordance with the disclosure contains not more than about 10%, not more than about 9%, not more than about 8%, not more than about 7%, not more than about 6%, not more than about 5%, not more than about 4%, not more than about 3%, not more than about 2%, not more than about 1 %, or not more than about 0.5%, by weight, docosahexaenoic acid (DHA), if any.
  • DHA docosahexaenoic acid
  • a composition of the disclosure contains substantially no DHA.
  • a composition useful in the present disclosure contains no DHA and/or derivative thereof.
  • derivatives of DHA include, but are not limited to, methyl or other alkyl esters, re-esterified monoglycerides, re-esterified diglycerides and re-esterified triglycerides or mixtures thereof.
  • EPA comprises at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 1 about 100%, by weight, of all fatty acids present in a composition that is useful in methods of the present disclosure.
  • the composition comprises at least 96% by weight of eicosapentaenoic acid ethyl ester and less than about 2% by weight of a preservative.
  • the preservative is a tocopherol such as all-racemic a-tocopherol.
  • a composition useful in accordance with methods of the disclosure contains less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1 %, less than about 0.5% or less than about 0.25%, by weight of the total composition or by weight of the total fatty acid content, of any fatty acid other than EPA.
  • fatty acid other than EPA examples include linolenic acid (LA), arachidonic acid (AA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), stearadonic acid (STA), eicosatrienoic acid (ETA) and/or docosapentaenoic acid (DPA).
  • a composition useful in accordance with methods of the disclosure contains about 0.1% to about 4%, about 0.5% to about 3%, or about 1% to about 2%, by weight, of total fatty acids other than EPA and/or DHA.
  • fatty acids other than EPA include derivatives of those fatty acids.
  • Derivatives of the fatty acids include, but are not limited to, methyl or other alkyl esters, re-esterified monoglycerides, re-esterified diglycerides and re-esterified triglycerides or mixtures thereof of the fatty acids.
  • a composition useful in accordance with the disclosure has one or more of the following features: (a) eicosapentaenoic acid ethyl ester represents at least about 96%, at least about 97%, or at least about 98%, by weight, of all fatty acids present in the composition; (b) the composition contains not more than about 4%, not more than about 3%, or not more than about 2%, by weight, of total fatty acids other than eicosapentaenoic acid ethyl ester; (c) the composition contains not more than about 0.6%, not more than about 0.5%, or not more than about 0.4% of any individual fatty acid other than eicosapentaenoic acid ethyl ester; (d) the composition has a refractive index (20 °C) of about 1 to about 2, about 1 .2 to about 1 .8 or about 1 .4 to about 1 .5; (e) the composition has a specific gravity (20 °
  • a composition for use in accordance with the disclosure is a self-emulsifying composition.
  • the self-emulsifying composition comprises at least one compound selected from the group consisting of an omega-3 fatty acid and derivative thereof (e.g., pharmaceutically acceptable salt and/or ester).
  • the composition comprises an emulsifier.
  • the emulsifier has a hydrophilic lipophilic balance (HLB) of at least about 10.
  • Non-limiting examples of emulsifiers include polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, and lecithin.
  • the omega-3 fatty acids or derivative thereof are present in an amount of about 50% to about 95% by weight of the total weight of the composition or by weight of the total fatty acids of the total composition.
  • the omega-3 fatty acid is EPA and/or DHA.
  • the EPA is present in amount at least about 95%, by weight, of all fatty acids present in the self-emulsifying composition.
  • the composition contains substantially no DHA.
  • the composition contains substantially no ethanol.
  • the composition is a self-emulsifying composition comprising about 50% to about 95% by weight of the total weight of the composition at least one compound selected from the group consisting of omega-3 polyunsaturated fatty acids and derivative thereof (e.g., pharmaceutically acceptable salt and/or ester).
  • the composition comprises about 1% to about 20% by weight of the total weight of the composition, a sucrose fatty acid ester as an emulsifier having a hydrophilic lipophilic balance of at least about 10.
  • the composition comprises glycerin.
  • the composition comprises about 0% to about 5% by weight of the total composition, ethanol.
  • the self-emulsifying composition comprises about 50% to about 95% by weight of the total weight of the composition, at least one compound selected from the group consisting of omega-3 polyunsaturated fatty acids and derivative thereof; about 1% to about 20%, by weight of the total weight of the composition, a sucrose fatty acid ester as an emulsifier having a HLB of at least about 10; glycerin; and about 0% to about 4% by weight of the total weight of the composition, ethanol.
  • the sucrose fatty acid ester is one or more of: sucrose laurate, sucrose myristate, sucrose palmitate, sucrose stearate, or sucrose oleate.
  • the omega-3 polyunsaturated fatty acid is one or more of EPA, DHA, or derivative thereof. In yet another embodiment, the omega-3 polyunsaturated fatty acid is ethyl-EPA and/or ethyl-DHA.
  • the composition is a self-emulsifying composition comprising about 50% to about 95% by weight of the total weight of the composition, at least one compound selected from the group consisting of omega-3 polyunsaturated fatty acids and derivative thereof (e.g., pharmaceutically acceptable salt and ester); and about 5% to about 50%, by weight, of the total weight of the composition an emulsifier having a HLB of at least about 10; wherein ethanol content is up to about 4% by weight of the total weight of the composition.
  • the omega-3 polyunsaturated fatty acid is EPA and/or DHA.
  • the composition does not contain ethanol.
  • the emulsifier is at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, and lecithin.
  • the emulsifier is at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, and sucrose fatty acid ester.
  • the hydrogenated castor oil is at least one member selected from the group consisting of include polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, or polyoxyethylene (100) hydrogenated castor oil.
  • the polyoxyethylene sorbitan fatty acid ester is at least one member selected from the group consisting of polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, and polyoxyethylene sorbitan monolaurate.
  • the sucrose fatty acid ester is at least one member selected from the group consisting of sucrose laurate, sucrose myristate, sucrose palmitate, sucrose stearate, and sucrose oleate.
  • the composition contains a lecithin selected from the group consisting of soybean lecithin, enzymatically decomposed soybean lecithin, hydrogenated soybean lecithin, and egg yolk lecithin.
  • the composition contains a polyhydric alcohol, wherein the polyhydric alcohol is propylene glycol or glycerin.
  • the composition contains at least one member selected from the group consisting of EPA, DHA, and/or derivative thereof (e.g., their pharmaceutically acceptable salt and ester), wherein the composition contains ethyl-EPA and/or ethyl-DHA.
  • the composition comprises an emulsifier having a HLB of at least about 10 and is about 10 to about 100 parts by weight in relation to 100 parts by weight of the at least one compound selected from the group consisting of omega- 3 polyunsaturated fatty acids and/or derivative thereof (e.g., pharmaceutically acceptable salt and/or ester).
  • the self-emulsifying composition comprises about 70% to about 90%, by weight, eicosapentaenoic acid ethyl ester as a first medicinal component.
  • the composition further comprises about 0.5 to about 0.6%, by weight, water.
  • the composition comprises about 1% to about 29%, by weight, polyoxyethylene sorbitan fatty acid ester as an emulsifier.
  • the composition comprises about 1 to about 25 parts, by weight, lecithin in relation to about 100 parts, by weight, eicosapentaenoic acid ethyl ester.
  • the composition comprises pitavastatin, rosuvastatin, or a salt thereof as a second medicinal component.
  • ethanol and/or polyhydric alcohol constitutes up to about 4% by weight of the total weight of the composition.
  • the composition comprises about 0.01 to about 1 part, by weight, of pitavastatin or its salt in relation to about 100 parts, by weight, of the eicosapentaenoic acid ethyl ester, or about 0.03 to about 5 parts, by weight, rosuvastatin or its salt in relation to about 100 parts, by weight, eicosapentaenoic acid ethyl ester as a second medicinal component.
  • the composition is encapsulated in a hard capsule and/or a soft capsule, wherein a capsule film of the soft capsule may contain gelatin.
  • the self-emulsifying composition further comprises polyoxyethylene hydrogenated castor oil and/or polyoxyethylene castor oil.
  • the emulsifier comprises polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil.
  • the pitavastatin, rosuvastatin, or a salt thereof is pitavastatin calcium or rosuvastatin calcium.
  • the lechtin is soybean lechtin.
  • the polyoxyethylene sorbitan fatty acid ester is polyoxyethylene (20) sorbitan monooleate.
  • the self-emulsifying composition comprising E-EPA has improved bioavailability compared as compared to a standard E-EPA formulation.
  • a standard E-EPA formulation is a formulation that is not self-emulsifying.
  • a self-emulsifying composition comprising about 1 .8 to about 3.8 g of E-EPA has substantially equivalent bioavailability to about 4 g E-EPA that is not formulated as a self-emulsifying composition.
  • the self-emulsifying comprising E-EPA is assessed for a bioequivalence to about 4 g E-EPA that is not formulated as a selfemulsifying using for example, U.S. Food and Drug Administration (FDA) guidelines.
  • FDA Food and Drug Administration
  • compositions useful in accordance with methods of the disclosure are orally deliverable.
  • oral administration include any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth of the subject, whether or not the agent or composition is swallowed.
  • oral administration includes buccal and sublingual as well as esophageal administration.
  • the composition is present in a capsule, for example a soft gelatin capsule.
  • a composition for use in accordance with the disclosure can be formulated as one or more dosage units.
  • dose unit and “dosage unit” herein refer to a portion of a pharmaceutical composition that contains an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect.
  • dosage units may be administered one to a plurality (i.e., 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of times per day, or as many times as needed to elicit a therapeutic response.
  • compositions of the disclosure upon storage in a closed container maintained at room temperature, refrigerated (e.g.
  • a composition (or co-administration regimen) of the present disclosure comprises colchicine.
  • the colchicine can be co-formulated with icosapent ethyl or can be co-administered with icosapent ethyl.
  • Icosapent ethyl and colchicine can be co-formulated in the same dosage unit, or can be individually formulated in separate dosage units.
  • a composition of the disclosure comprises colchicine dispersed or suspended in the icosapent ethyl, wherein the dispersion or suspension is present in a capsule (for example gelatin or HPMC capsule), sachet, or other dosage form or carrier as described herein.
  • the dispersion or suspension is substantially uniform.
  • the icosapent ethyl is present in a first dosage unit, for example a suspension in a capsule, and colchicine is present in second dosage unit, for example a tablet.
  • icosapent ethyl and colchicine are present in a composition of the disclosure, or are co-administered in equimolar amounts (e.g., 1 :1 molar ratio).
  • a weight ratio of icosapent ethyl and colchicine present in a composition of the disclosure, or co-administered is in a range of about 0.75:1 to about 1 .25:1 , about 0.8:1 to about 1 :1 , or about 0.825:1 .
  • a weight ratio of icosapent ethyl and colchicine present in a composition of the disclosure, or co-administered is in a range of about 20,000:1 to about 2:1 , about 15,000:1 to about 10:1 , about 12,000:1 to about 100:1 , about 10,000:1 to about 1000:1 , about 8,000:1 to about 2000:1 , about 6,000:1 to about 4,000:1 , or about 5000:1.
  • colchicine if desired, can be present in a composition of the disclosure (or may be co-administered with icosapent ethyl according to other embodiments of the disclosure) in an amount corresponding to the recommended or suggested dosage colchicine.
  • colchicine may be present in a composition of the disclosure (or may be co-administered with icosapent ethyl according to other embodiments of the disclosure) in an amount less than the recommended or suggested dosage for colchicine.
  • a composition of the disclosure may comprise colchicine in an amount of about 0.2 mg to about 3 mg, or about 0.3 mg to about 2.5 mg, for example, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 .0 mg, about 1.1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1.5 mg, about 1 .6 mg, about 1 .7 mg, about 1 .8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, or about 3.0 mg.
  • the composition as described herein may be administered to a subject once, twice, or three times per day.
  • a composition of the disclosure is administered to a subject in an amount sufficient to provide a daily dose of colchicine of about 0.2 mg to about 3 mg, or about 0.5 mg to about 2.5 mg, for example, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 .0 mg, about 1.1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .6 mg, about 1 .7 mg, about 1 .8 mg, about 1 .9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, or about 3.0 mg.
  • a composition of the disclosure is administered to a subject in an amount sufficient to provide a daily dose of colchicine of about 0.6 mg to about 1.2 mg.
  • a composition of the disclosure is administered to a subject in an amount sufficient to provide a daily dose of colchicine of about 3 mg to about 12,500 mg, about 5 mg to about 10,000 mg, about 10 mg to about 5000 mg, about 50 to about 3000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example about 0.125 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about
  • the disclosure provides a method for treatment and/or prevention of cardiovascular-related disease and disorders.
  • cardiovascular-related disease and disorders refers to any disease or disorder of the heart or blood vessels (i.e., arteries and veins) or any symptom thereof.
  • Non-limiting examples of cardiovascular-related disease and disorders include hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, vascular disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction, and other cardiovascular events.
  • the disclosure also provides methods for treatment and/or prevention of a viral infection (e.g., COVID-19).
  • treatment in relation a given disease, disorder, or viral infection, includes, but is not limited to, inhibiting the disease, disorder, or viral infection, for example, arresting the development of the disease, disorder, or viral infection; relieving the disease, disorder, or viral infection, for example, causing regression of the disease, disorder, or viral infection; or relieving a condition caused by or resulting from the disease, disorder, or viral infection, for example, relieving or treating symptoms of the disease, disorder, or viral infection.
  • prevention in relation to a given disease, disorder, or viral infection means: preventing the onset of disease, disorder, or viral infection development if none had occurred, preventing the disease, disorder, or viral infection from occurring in a subject that may be predisposed to the disorder, disease, or viral infection but has not yet been diagnosed as having the disorder, disease, or viral infection, and/or preventing further disease/disorder/infection development if already present.
  • the present disclosure provides methods of preventing, treating, and/or reducing a risk of a cardiovascular-related disease in a subject.
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of preventing a cardiovascular-related disease in a subject.
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of treating a cardiovascular-related disease in a subject.
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of reducing a risk of a cardiovascular-related disease in a subject.
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of reducing nitric oxide synthase (iNOS) activity in a subject.
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods for decreasing nitrite production in a subject.
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of reducing
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units). In some embodiments, the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of reducing cytokine production in a subject.
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the cytokines are IL-1 ⁇ , TNF- ⁇ , or both.
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of slowing progression of or promoting regression of ASCVD (i.e., atherosclerotic cardiovascular diseases) in a subject.
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of halting or slowing arterial plaque progression in a subject in need thereof.
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of reducing the number or size of arterial plaques in a subject in need thereof.
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of preventing and/or reducing the occurrence of coronary artery stent restenosis (e.g., in-stent restenosis, intracoronary stent restenosis) and/or neoatherosclerosis in a subject.
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units),
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of preventing and/or reducing the occurrence of carotid artery restenosis in a subject.
  • the carotid artery restenosis may occur after procedures such as carotid endarterectomy (CEA) and carotid artery stenting (CAS).
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of preventing and/or reducing the risk of heart failure in a subject.
  • the heart failure is new heart failure.
  • the heart failure is new heart failure requiring hospitalization.
  • the methods comprise administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the present disclosure provides methods of reducing a risk of a cardiovascular event in a subject on statin therapy.
  • the methods comprise (a) identifying a subject on statin therapy and having a fasting baseline triglyceride level of about 135 mg/dL to about 500 mg/d, wherein said subject has established cardiovascular disease or has a high risk of developing cardiovascular disease; and (b) administering to the subject a composition comprising about 1 g to about 4 g of eicosapentaenoic acid (free acid) or derivative thereof (ethyl or methyl ester) and colchicine per day.
  • composition and “pharmaceutical composition” as provided herein are referenced interchangeably.
  • the present disclosure provides methods of reducing a risk of a cardiovascular event in a subject on statin therapy.
  • the methods comprise (a) identifying a subject on statin therapy and having a fasting baseline triglyceride level of about 80 mg/dL to about 1500 mg/dL, wherein said subject has established cardiovascular disease or has a high risk of developing cardiovascular disease; and (b) administering to the subject about 1 g to about 4 g of eicosapentaenoic acid (free acid) or derivative thereof (ethyl or methyl ester) and colchicine (either as a single dosage unit or as multiple dosage units) daily.
  • the reduction in a risk of a cardiovascular event is not correlated to a reduction in the subject’s triglyceride levels.
  • the present disclosure provides methods of reducing a risk of a cardiovascular event in a subject on statin therapy with or without an associated in reduction a baseline triglyceride level of the subject.
  • a reduction of cardiovascular events is not correlated to a reduction in the subject’s triglyceride levels. Accordingly, regardless of whether the subject exhibits a reduction in triglyceride levels, the subject experiences a reduction in a risk of a cardiovascular event.
  • the methods comprise administering to the subject eicosapentaenoic acid or derivative thereof and colchicine (either as a single dosage unit or as multiple dosage units), wherein the subject does not exhibit a statistically significant change in fasting triglyceride levels for a period of time after administration of the composition.
  • the period of time is about 1 year to about 5 years, about 1 year to about 6 years, about 1 year to about 7 years, about 1 year to about 8 years, or about 1 year to about 9 years.
  • the subject exhibits a reduction in fasting triglycerides at a period time of greater than about 5 years, greater than about 6 years, greater than about 7 years, greater than about 8 years, greater than about 9 years, or greater than about 10 years.
  • the present disclosure provides methods of reducing a risk of total cardiovascular events in a subject on statin therapy.
  • the methods comprise administering to the subject a eicosapentaenoic acid or derivative thereof and colchicine (either as a single dosage unit or as multiple dosage units).
  • Total cardiovascular events include a first, second, third, fourth, fifth, sixth, eight, ninth, tenth or more cardiovascular event.
  • the subject has not experienced a cardiovascular event, but is at a high risk for experiencing a cardiovascular event.
  • the subject has experienced multiple cardiovascular events (i.e., a second, third, fourth, or more) and a reduction in a risk of any subsequent cardiovascular event.
  • the total cardiovascular events are reduced by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In some embodiments, the total cardiovascular events are reduced regardless of the subject’s fasting baseline triglyceride level. For example, total cardiovascular events are reduced in a subject having a fasting baseline triglyceride level in a low, medium, or high tertile.
  • Subjects in the low baseline fasting triglyceride tertile have triglyceride levels between about 80 mg/dL to about 190 mg/dL (median triglyceride level of 160 mg/dL), subjects in the medium baseline fasting triglyceride tertile have triglyceride levels between about 191 mg/dL to about 250 mg/dL (median triglyceride level of 215 mg/dL), and lastly, subjects in the high baseline fasting triglyceride tertile have triglyceride levels between about 251 mg/dL to about 1400 mg/dL (median triglyceride level of 304 mg/dL).
  • the present disclosure provides methods of reducing a cardiovascular event in a subject on statin therapy, the methods comprising instructing or having instructed a caregiver of the subject to inquire if the subject has or previously has had atrial fibrillation and/or flutter, assessing or having assessed whether the subject has or has previously had symptoms of atrial fibrillation and/or flutter, monitoring or having monitored the subject for symptoms of atrial fibrillation and/or flutter, and/or providing or having provided guidance to a caregiver of the subject to monitor the subject for symptoms of atrial fibrillation and/or flutter.
  • the methods further comprise administering or having administered to the subject eicosapentaenoic acid or derivative thereof and colchicine (either as a single dosage unit or as multiple dosage units) daily.
  • the present disclosure provides methods of reducing an incidence of a cardiovascular event in a subject on statin therapy.
  • the methods comprise administering to the subject eicosapentaenoic acid or derivative thereof and colchicine (either as a single dosage unit or as multiple dosage units) daily, wherein the subject experiences atrial fibrillation and/or flutter and a reduction in or no cardiovascular event.
  • administration of the eicosapentaenoic acid or derivative thereof and colchicine shifts the cardiovascular event to a less medically severe outcome of atrial fibrillation and/or flutter.
  • the subject experiences atrial fibrillation and/or flutter instead of a cardiovascular event.
  • the subject exhibits an increase in the symptoms of atrial fibrillation and/or flutter and a reduction in a cardiovascular event as compared to baseline or a placebo control.
  • the increase in the symptoms of atrial fibrillation and/or flutter are statistically significant as compared to baseline or a placebo control.
  • the symptoms of atrial fibrillation and/or flutter increase by at least about 1%, at least about 2%, at least about 3%, at least about 4%, or at least about 5%.
  • an incidence of atrial fibrillation and/or flutter requiring hospitalization is greater in the subject as compared to baseline or a placebo control.
  • the subject experiences a reduction in heart rate.
  • the present disclosure provides methods of reducing a risk of a cardiovascular event in a subject on low, medium, or high statin therapy.
  • the methods comprise administering to the subject eicosapentaenoic acid or derivative thereof, colchicine (either as a single dosage unit or as multiple dosage units) daily, and a low, medium, or high intensity statin therapy.
  • the low intensity statin therapy includes about 5 mg to about 10 mg of simvastatin.
  • the medium intensity statin therapy includes about 5 mg to about 10 mg of rosuvastatin, about 10 mg to about 20 mg of atorvastatin, about 20 mg to 40 mg of simvastatin, or about 10 mg to about 20 mg of simvastatin plus about 5 mg to about 10 mg of ezetimibe.
  • the high intensity statin therapy includes about 20 mg to about 40 mg rosuvastatin, about 40 mg to about 80 mg of atorvastatin, about 80 mg of simvastatin, or about 40 mg to about 80 mg of simvastatin plus about 5 mg to about 10 mg of ezetimibe.
  • the subject administered the high statin therapy a greater reduction in a cardiovascular event as compared to a subject in either a low or medium statin therapy.
  • the subject on a medium statin therapy exhibits a greater reduction in a cardiovascular event as compared to a subject on either a high or low statin therapy.
  • the subject on a low statin therapy exhibits a greater reduction in a cardiovascular evet as compared to a subject of a high or a medium statin therapy.
  • the greater reduction is a reduction of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, or more.
  • the present disclosure provides methods of delaying an onset of: (a) non-fatal myocardial infarction; (b) fatal or non-fatal stroke; (c) cardiovascular death; (d) unstable angina; (e) coronary revascularization; (f) hospitalization for unstable angina; (g) composite of cardiovascular death or nonfatal myocardial infarction; (h) fatal or nonfatal myocardial infarction; (i) non-elective coronary revascularization represented the composite of emergent or urgent classifications; (j) cardiovascular death; (k) unstable angina determined to be caused by myocardial ischemia by invasive or non-invasive testing and requiring emergent hospitalization; and/or (I) a composite of total mortality, nonfatal myocardial infarction, and/or nonfatal stroke.
  • An onset of a disease and/or cardiovascular event refers to a first appearance of a sign and/or symptom of the cardiovascular event. In some embodiments, delaying an onset of a cardiovascular event prevents the subject from experiencing the cardiovascular event and/or developing any further symptoms of the cardiovascular event. In some embodiments, the methods comprise administering eicosapentaenoic acid or derivative thereof and colchicine (either as a single dosage unit or as multiple dosage units) daily.
  • the present disclosure provides methods of reducing risk of occurrence of one or more components of a 3-point composite endpoint composed of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke in a subject on statin therapy or reducing risk occurrence of one or more components of a 5- point composite endpoint composed of cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, coronary revascularization, or unstable angina requiring hospitalization in a subject on statin therapy.
  • each of the individual components of 3-point composite and 5-poinst composite endpoints is reduced. For example, each of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke are reduced within the combination.
  • the methods comprise administering eicosapentaenoic acid or derivative thereof and colchicine (either as a single dosage unit or as multiple dosage units) daily.
  • the 3-point composite endpoint or the 5-point composite endpoint is reduced by at least about 20%, at least about 30%, at least about 40%, or at least about 50%.
  • each of the individual components of the 3-point composite endpoint or the 5-point composite endpoint is reduced by at least about 20%, at least about 30%, at least about 40%, or at least about 50%.
  • the present disclosure provides methods of reducing a cardiovascular event, the methods comprising administering a composition comprising EPA or derivative thereof that is formulated such that when administered to the subject, the composition provides an amount of EPA or derivative thereof effective to achieve an efficacy equivalent dose to about a 4 g dose of EPA or derivative thereof but at a lower daily dose of EPA or derivative thereof.
  • the lower daily dose of the EPA or derivative thereof of is not more than about 3.8 g, not more than about 3.6 g, not more than about 3.4 g, not more than about 3.2 g, not more than about 3 g, not more than about 2.8 g, not more than about 2.6 g, or not more than about 2.5 g.
  • the lower daily dose of the EPA or derivative thereof is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40% in the subject as compared to a baseline or placebo control.
  • administering the composition to the subject results in an improved pharmacokinetic profile in the subject as compared a control subject, wherein the subject and control subject are in either or fed or fasting state, and wherein the pharmacokinetic profile is defined by maximum serum concentration (Cmax) and area under the curve (AUG).
  • the control subject is on a statin therapy and administered a placebo or other fatty acid composition such as Lovaza comprised of 365 mg of E-EPA and 375 mg of E-DHA.
  • the present disclosure provides methods of reducing a cardiovascular event in a subject on a statin therapy, the methods comprising administering EPA or derivative thereof and colchicine (either as a single dosage unit or as multiple dosage units), wherein the subject does not experience an adverse event.
  • Non-limiting examples of adverse events include back pain, nasopharyngitis, arthralgia, bronchitis, oedema peripheral, dyspnea, osteoarthritis, cataract, fatigue, constipation, musculoskeletal pain, gout, fall, type 2 diabetes mellitus, gastroesophageal reflux disease, insomnia, acute kidney injury, hepatic disorders, bleeding related disorders (e.g., gastrointestinal or central nervous system bleeding), newly diagnosed diabetes, newly diagnosed neoplasms (e.g., benign or malignant neoplasms), upper respiratory tract infection, chest pain, peripheral edema, pneumonia, influenza, urinary tract infection, cough, dizziness, pain in an extremity, angina pectoris, and anemia.
  • back pain nasopharyngitis, arthralgia, bronchitis, oedema peripheral, dyspnea, osteoarthritis, cataract, fatigue, constipation, musculoskeletal pain,
  • the present disclosure provides methods of reducing a cardiovascular event in a subject on a statin therapy and less than about 65 years of age or greater than about 65 years of age, the method comprising administering to the subject EPA or derivative thereof and colchicine (either as a single dosage unit or as multiple dosage units).
  • the degree by which the cardiovascular event is reduced is dependent upon the age of the subject. For example, in some embodiments, the subject less than about 65 years of age exhibits a statistically significant reduction in a cardiovascular event as compared to a subject greater than about 65 years of age.
  • the subject greater than about 65 years of age exhibits a statistically significant reduction in a cardiovascular event as compared to a subject less than about 65 years of age.
  • the methods for reducing a cardiovascular event are correlated to the age of the subject.
  • the present disclosure provides methods of reducing a cardiovascular event in a subject on a statin therapy, the methods comprising administering to the subject a self-emulsifying composition.
  • the self-emulsifying composition comprises at least one compound selected from the group consisting of an omega-3 fatty acid and derivative thereof (e.g., pharmaceutically acceptable salt and/or ester).
  • the composition comprises an emulsifier.
  • the emulsifier has a hydrophilic lipophilic balance (HLB) of at least about 10.
  • Non-limiting examples of emulsifiers include polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, and lecithin.
  • the omega-3 fatty acids or derivative thereof are present in an amount of about 50% to about 95% by weight of the total weight of the composition or by weight of the total fatty acids of the total composition.
  • the omega- 3 fatty acid is EPA and/or DHA.
  • the EPA is present in amount at least about 95%, by weight, of all fatty acids present in the self-emulsifying composition.
  • the composition contains substantially no DHA.
  • the composition contains substantially no ethanol.
  • the subject has symptoms of atrial fibrillation and/or flutter.
  • symptoms of atrial fibrillation and/or flutter include heart rate greater than about 100 beats per minute (bpm); heart palpitations; shortness of breath; pain, pressure, tightness or discomfort in chest; dizziness; lightheadedness; or fainting.
  • the subject has a risk factor for atrial fibrillation and/or flutter including (a) heart failure; (b) previous heart attack; (c) heat valve abnormalities; (d) high blood pressure; (e) thyroid dysfunction; (f) chronic lung disease; (g) diabetes; (h) obesity; and (i) congenital heart disease.
  • the methods further comprising monitoring a subject for atrial fibrillation and/or flutter or for symptoms of atrial fibrillation and/or flutter.
  • methods to monitor atrial fibrillation and/or flutter include electrocardiograms (ECGs), implantable pacemakers, implantable cardioverter defibrillators, and/or subcutaneous implantable cardiac monitors.
  • the subject has atrial fibrillation and/or flutter or has symptoms of atrial fibrillation and/or flutter and has been determined to have a heart rate of about 80 bpm, about 85, bpm, about 90 bpm, about 95 bpm, about 100 bpm, about 105 bpm, about 110 bpm, about 115 bpm, about 120 bpm, about 125 bpm, about 130 bpm, about 135 bmp, about 140 bmp, about 145 bmp, about 150 bpm, about 155 bpm, about 160 bpm, about 165 bpm, about 170 bpm, about 175 bpm, about 180 bpm, about 185, bpm, about 190 bpm or a heart rate between about 80 bpm to about 100 bpm, about 90 bpm to about 200 bpm, about 100 bpm to about 175 bpm, about 120 bpm to about 180 bpm, or
  • the present disclosure provides methods of reducing blood pressure in a subject.
  • administration of 4 g per day of EPA or derivative thereof (e.g., E-EPA) and colchicine (either as a single dosage unit or as multiple dosage units) for a period at least 1 , 2, 3 or 4 year reduces systolic blood pressure by at least about 1 mm Hg and reduces diastolic blood pressure aby at least about 0.5 mm Hg, compared to baseline or a placebo control subject.
  • the subject has a fasting baseline triglyceride level of about 135 mg/dL to about 500 mg/dL, for example about 135 mg/dL to about 500 mg/dL, about 150 mg/dL to about 500 mg/dL, about 200 mg/dL to about 499 mg/dL or about 200 mg/dL to ⁇ 500 mg/dL.
  • the subject has a fasting baseline triglyceride level of about 50 mg/dL to about 1500 mg/dL, for example about 50 mg/dL to about 1500 mg/dL, about 80 mg/dL to about 1500 mg/dL, about 50 mg/dL to about 190 mg/dl, about 80 mg/dL to about 190 mg/dl, about 190 mg/dL to about 250 mg/dL, about 250 mg/dL to about 1400 mg/dL. In one embodiment, the subject has a fasting baseline triglyceride level of about 80 mg/dL to about 1400 mg/dL.
  • the subject or subject group has a baseline triglyceride level (or median baseline triglyceride level in the case of a subject group), fed or fasting, of about 50 mg/dL, about 55 mg/dL, about 60 mg/dL, about 65 mg/dL, about 70 mg/dL, about 75 mg/dL, about 80 mg/dL, about 85 mg/dL, about 90 mg/dL, about 95 mg/dL, about 100 mg/dL, about 105 mg/dL, about 110 mg/dL, about 115 mg/dL, about 120 mg/dL, about 125 mg/dL, about 130 mg/dL, about 135 mg/dL, about 140 mg/dL, about 145 mg/dL, about 150 mg/dL, about 155 mg/dL, about 160 mg/dL, about 165 mg/dL, about 170 mg/dL, about 175 mg/dL, about 180 mg/dL, about 185 mg/dL, about 50 mg/dL
  • the subject or subject group has a baseline triglyceride level (or median baseline triglyceride level in the case of a subject group), fed or fasting, greater than or equal to 80 mg/dL, greater than or equal to about 100 mg/dL, greater than or equal to about 120 mg/dL greater than or equal to about 150 mg/dL, greater than or equal to about 175 mg/dL, greater than or equal to about 250 mg/dL, or greater than equal to about 500 mg/dL, for example about 190 mg/dL to about 250 mg/dL, about 80 mg/dL to about 190 mg/dL, about 250 mg/dL to about 1400 mg/dL, about 200 mg/dL to about 500 mg/dL, about 300 mg/dL to about 1800 mg/dL, about 500 mg/dL to about 1500 mg/dL, or about 80 mg/dL to about 1500 mg/dL.
  • a baseline triglyceride level or median baseline triglyceride level in the case of
  • the subject or subject group is also on stable therapy with a statin (with or without ezetimibe).
  • the subject or subject group also has established cardiovascular disease, or is at high risk for establishing cardiovascular disease.
  • the subject's statin therapy includes administration of one or more statins.
  • the subject's statin therapy may include one or more of: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.
  • the subject is additionally administered one or more of: amlodipine, ezetimibe, niacin, and sitagliptin.
  • the subject's statin therapy includes administration of a statin and ezetimibe.
  • the subject's statin therapy includes administration of a statin without ezetimibe.
  • the statin therapy is classified as monotherapies, combinations, and or 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor combinations.
  • the monotherapies include simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, or pitavastatin.
  • the combinations include lovastatin and nicotinic acid, simvastatin and ezetimibe, pravastatin and fenofibrate, simvastatin and fenofibrate, atorvastatin and ezetimibe, or rosuvastatin and ezetimibe.
  • the HMG CoA inhibitor combinations include simvastatin and acetylsalicylic acid; pravastatin and acetylsalicylic acid; atorvastatin and amlodipine; simvastatin, acetylsalicylic acid, and ramipril; rosuvastatin and acetylsalicylic acid; atorvastatin, acetylsalicylic acid, and ramipril; rosuvastatin, amlodipine, and lisinopril; atorvastatin and acetylsalicylic acid; rosuvastatin and amlodipine; rosuvastatin and valsartan; atorvastatin, amlodipine, and perindopril; atorvastatin, acetylsalicylic acid, and perindopril; rosuvastatin, perindopril; rosuvastatin, perindopril;
  • the statin therapy is a low, medium (i.e., moderate), or high intensity statin therapy.
  • the low intensity statin therapy includes about 5 mg to about 10 mg of simvastatin.
  • the medium intensity statin therapy includes about 5 mg to about 10 mg of rosuvastatin, about 10 mg to about 20 mg of atorvastatin, about 20 mg to about 40 mg of simvastatin, or about 10 mg to about 20 mg of simvastatin plus about 5 mg to about 10 mg of ezetimibe.
  • the high intensity statin therapy includes about 20 mg to about 40 mg rosuvastatin, about 40 mg to about 80 mg of atorvastatin, about 80 mg of simvastatin, or about 40 mg to about 80 mg of simvastatin plus about 5 mg to about 10 mg of ezetimibe.
  • the subject's statin therapy does not include administration of 200 mg or more per day of niacin and/or fibrates.
  • the subject is not on concomitant omega-3 fatty acid therapy (e.g., is not being administered or co-administered a prescription and/or over-the-counter composition comprising an omega-3 fatty acid active agent).
  • the subject is not administered or does not ingest a dietary supplement comprising an omega-3 fatty acid.
  • the subject has established cardiovascular (CV) disease ("CV disease” or "CVD”).
  • CV disease cardiovascular disease
  • CVD cardiovascular disease
  • the status of a subject as having CV disease can be determined by any suitable method known to those skilled in the art.
  • a subject is identified as having established CV disease by the presence of any one of: documented coronary artery disease, documented cerebrovascular disease, documented carotid disease, documented peripheral arterial disease, or combinations thereof.
  • a subject is identified as having CV disease if the subject is at least 45 years old and: (a) has one or more stenosis of greater than 50% in two major epicardial coronary arteries; (b) has had a documented prior Ml; (c) has been hospitalized for high-risk NSTE ACS with objective evidence of ischemia (e.g., ST-segment deviation and/or biomarker positivity); (d) has a documented prior ischemic stroke; (e) has symptomatic artery disease with at least 50% carotid arterial stenosis; (f) has asymptomatic carotid artery disease with at least 70% carotid arterial stenosis per angiography or duplex ultrasound; (g) has an ankle- brachial index ("ABI") of less than 0.9 with symptoms of intermittent claudication; and/or (h) has a history of aorto-iliac or peripheral arterial intervention (catheter-based or surgical).
  • ABSI ankle- brachial index
  • the subject or subject group being treated in accordance with methods of the disclosure has a high risk for developing CV disease.
  • a subject or subject group has a high risk for developing CV disease if the subject or subject in a subject group is age about 50 or older, has diabetes mellitus (Type 1 or Type 2), and at least one of: (a) is a male age about 55 or older or a female age about 65 or older; (b) is a cigarette smoker or was a cigarette smoker who stopped less than about 3 months prior; (c) has hypertension (e.g., a blood pressure of about 140 mmHg systolic or higher, or greater than about 90 mmHg diastolic); (d) has an HDL-C level of ⁇ about 40 mg/dL for men or ⁇ about 50 mg/dL for women; (e) has an hsCRP level of > about 3.0 mg/L; (f) has renal dysfunction (e.g., a creatin
  • the subject's baseline lipid profile is measured or determined prior to administering the composition to the subject.
  • Lipid profile characteristics can be determined by any suitable method known to those skilled in the art including, for example, by testing a fasting or non-fasting blood sample obtained from the subject using standard blood lipid profile assays.
  • the subject has one or more of: a baseline non-HDL-C value of about 200 mg/dL to about 300 mg/dL; a baseline total cholesterol value of about 250 mg/dL to about 300 mg/dL; a baseline VLDL-C value of about 140 mg/dL to about 200 mg/dL; a baseline HDL-C value of about 10 mg/dL to about 30 mg/dL; a baseline LDL-C value of about 40 mg/dL to about 100 mg/dL; and/or a baseline hsCRP level of about 2 mg/dL or less.
  • the cardiovascular event for which risk is reduced is one or more of: cardiovascular death; nonfatal myocardial infarction; nonfatal stroke; coronary revascularization; unstable angina (e.g., unstable angina determined to be caused by myocardial ischemia by, for example, invasive or non-invasive testing, and requiring hospitalization); cardiac arrest; peripheral cardiovascular disease requiring intervention, angioplasty, bypass surgery or aneurysm repair; death; sudden cardiac death, sudden death, and onset of new congestive heart failure.
  • the cardiovascular event is a first, second, third, fourth, or more cardiovascular event experienced by the subject.
  • the subject is administered about 1 g to about 4 g of the composition per day for about 4 months, about 1 year, about 1 .25 years, about 1 .5 years, about 1 .75 years, about 2 years, about 2.25 years, about 2.5 years, about 2.75 years, about 3 years, about 3.25 years, about 3.5 years, about 3.75 years, about 4 years, about 4.25 years, about 4.5 years, about 4.75 years, about 5 years, or more than about 5 years. Thereafter, in some embodiments the subject exhibits one or more of
  • methods of the present disclosure comprise measuring baseline levels of one or more markers set forth in (a) - (jj) above prior to dosing the subject or subject group.
  • the methods comprise administering a composition as disclosed herein to the subject after baseline levels of one or more markers set forth in (a) - (jj) are determined, and subsequently taking an additional measurement of said one or more markers.
  • composition of the present disclosure upon treatment with a composition of the present disclosure, the subject exhibits one or more of:
  • VLDL-C levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% compared to baseline or control; [0193] (i) a reduction in total cholesterol levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% as compared to baseline or control; and/or
  • a reduction in total cardiovascular events of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% as compared to baseline or control;
  • a reduction of total mortality i.e., death from any cause of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% as compared to baseline or control;
  • a reduction in cardiac arrhythmias of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% as compared to baseline or control;
  • [0215] (ee) a reduction in LPS-induced macrophage activation of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% as compared to baseline or control;
  • (gg) a reduction in nitrite production of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% as compared to baseline or control;
  • a reduction in TNF- ⁇ levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% as compared to baseline or control; and/or
  • the subject or subject group being treated has a baseline EPA blood level on a (mol%) basis of less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1 , less than 2, less than 1 .9, less than 1 .8, less than 1 .7, less than 1 .6, less than 1 .5, less than 1 .4, less than 1 .3, less than 1 .2, less than 1 .1 or less than 1.
  • the subject or subject group being treated has a baseline triglyceride level (or median baseline triglyceride level in the case of a subject group), fed or fasting, of about 135 mg/dL to about 500 mg/dL. In some embodiments, the subject or subject group being treated has a baseline triglyceride level (or median baseline triglyceride level in the case of a subject group), fed or fasting, of about 80 mg/dL to about 1500 mg/dL. In some embodiments, the subject or subject group being treated in accordance with methods of the disclosure is on stable therapy with a statin (with or without ezetimibe).
  • the phrase "on stable therapy with a statin” means that the subject or subject group has been on the same daily dose of the same statin for at least 28 days and, if applicable, the same daily dose of ezetimibe for at least 28 days.
  • the subject or subject group on stable statin therapy has an LDL-C level of about 40 mg/dL to about 100 mg/dL.
  • safety laboratory tests of subject blood samples include one or more of: hematology with complete blood count (“CBC"), including RBC, hemoglobin (Hgb), hematocrit (Het), white cell blood count (WBC), white cell differential, and platelet count; and biochemistry panel including total protein, albumin, alkaline phosphatase, alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), total bilirubin, glucose, calcium, electrolytes, (sodium, potassium, chloride), blood urea nitrogen (BUN), serum creatinine, uric acid, creatine kinase, and HbAic.
  • CBC hematology with complete blood count
  • Hgb hemoglobin
  • Het hematocrit
  • WBC white cell blood count
  • platelet count and platelet count
  • biochemistry panel including total protein, albumin, alkaline phosphatase, alanine aminotransferase (ALT/SGPT
  • a fasting lipid panel associated with a subject includes TG, TC, LDL-C, HDL-C, non-HDL-C, and VLDL-C.
  • LDL-C is calculated using the Friedewald equation, or is measured by preparative ultracentrifugation (Beta Quant) if the subject's triglyceride level is greater than 400 mg/dL.
  • LDL-C is measured by ultracentrifugation (Beta Quant) at randomization and again after about one year after randomization.
  • a biomarker assay associated with blood obtained from a subject includes hsCRP, Apo B and hsTnT.
  • a medical history associated with a subject includes family history, details regarding all illnesses and allergies including, for example, date(s) of onset, current status of condition(s), and smoking and alcohol use.
  • demographic information associated with a subject includes day, month and year of birth, race, and gender.
  • vital signs associated with a subject include systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature (e.g., oral body temperature).
  • a physical examination of a subject includes assessments of the subject's general appearance, skin, head, neck, heart, lung, abdomen, extremities, and neuromusculature.
  • the subject's height and weight are measured. In some embodiments, the subject's weight is recorded with the subject wearing indoor clothing, with shoes removed, and with the subject's bladder empty.
  • a waist measurement associated with the subject is measured.
  • the waist measurement is determined with a tape measure at the top of the subject's hip bone.
  • an electrocardiogram associated with the subject is obtained.
  • an ECG is obtained every year during the treatment/follow- up portion of the study.
  • the ECG is a 12-lead ECG.
  • the ECG is analyzed for detection of silent Ml.
  • subjects randomly assigned to the treatment group receive 4 g per day of a composition comprising at least 96% by weight of eicosapentaenoic acid ethyl ester.
  • the composition is encapsulated in a gelatin capsule.
  • subjects in this treatment group continue to take 4 g per day of the composition for about 1 year, about 2 years, about 3 years, about 4 years, about 4.75 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, or more than about 10 years.
  • a median treatment duration is planned to be about 4 years.
  • the present disclosure provides a method of reducing a risk of cardiovascular events in a subject.
  • the method comprises administering to the subject a composition comprising at least 96% by weight of eicosapentaenoic acid ethyl ester and colchicine (either as a single dosage unit or as multiple dosage units).
  • the subject is administered about 1 g to about 4 g of the composition per day.
  • the reduced risk of CV events is indicated or determined by comparing an amount of time (e.g., an average amount of time) associated with a subject or subject group from first dosing to a first CV event selected from the group consisting of: CV death, nonfatal Ml, nonfatal stroke, coronary revascularization, and hospitalization (e.g., emergent hospitalization) for unstable angina determined to be caused by myocardial ischemia (e.g., by invasive or non-invasive testing), to an amount of time (e.g., an average amount of time) associated with a placebo or untreated subject or group of subjects from first dosing with a placebo to a first CV event selected from the group consisting of: CV death, nonfatal Ml, nonfatal stroke, coronary revascularization, and hospitalization (e.g., emergent hospitalization) for unstable angina determined to be caused by myocardial ischemia (e.g., by invasive or non-invasive testing), wherein said
  • the amount of time associated with the subject or group of subjects are compared to the amount of time associated with the placebo or untreated subject or group of subjects are compared using a log-rank test.
  • the log-rank test includes one or more stratification factors such as CV Risk Category, use of ezetimibe, and/or geographical region.
  • the present disclosure provides a method of reducing risk of CV death in a subject on stable statin therapy and having CV disease or at high risk for developing CV disease, comprising administering to the subject a composition as disclosed herein.
  • the present disclosure provides a method of reducing risk of recurrent nonfatal myocardial infarction (including silent Ml) in a subject on stable statin therapy and having CV disease or at high risk for developing CV disease, comprising administering to the patient one or more compositions as disclosed herein.
  • the present disclosure provides a method of reducing risk of nonfatal stroke in a subject on stable statin therapy and having CV disease or at high risk for developing CV disease, comprising administering to the subject a composition as disclosed herein.
  • the present disclosure provides a method of reducing risk of coronary revascularization in a subject on stable statin therapy and having CV disease or at high risk for developing CV disease, comprising administering to the subject a composition as disclosed herein.
  • the present disclosure provides a method of reducing risk of developing unstable angina caused by myocardial ischemia in a subject on stable statin therapy and having CV disease or at high risk for developing CV disease, comprising administering to the subject a composition as disclosed herein.
  • the present disclosure provides a method of reducing risk of cardiac arrest in a subject on stable statin therapy and having CV disease or at high risk for developing CV disease, comprising administering to the subject a composition as disclosed herein.
  • the present disclosure provides a method of reducing risk of sudden cardiac death and/or sudden death in a subject on stable statin therapy and having CV disease or at high risk for developing CV disease, comprising administering to the subject a composition as disclosed herein.
  • the present disclosure provides a method of reducing risk of first, second, third, fourth, or more cardiovascular event in a subject on stable statin therapy and having CV disease or at high risk for developing CV disease, comprising administering to the subject a composition as disclosed herein
  • any of the methods disclosed herein are used in treatment or prevention of a subject or subjects that consume a traditional Western diet.
  • the methods of the disclosure include a step of identifying a subject as a Western diet consumer or prudent diet consumer and then treating the subject if the subject is deemed a Western diet consumer.
  • the term "Western diet” herein refers generally to a typical diet consisting of, by percentage of total calories, about 45% to about 50% carbohydrate, about 35% to about 40% fat, and about 10% to about 15% protein.
  • a Western diet may alternately or additionally be characterized by relatively high intakes of red and processed meats, sweets, refined grains, and desserts, for example more than 50%, more than 60% or more or 70% of total calories come from these sources.
  • a composition as described herein is administered to a subject once or twice per day.
  • 1 , 2, 3 or 4 capsules, each containing about 1 g of a composition as described herein, are administered to a subject daily.
  • 1 or 2 capsules, each containing about 1 g of a composition as described herein, are administered to the subject in the morning, for example between about 5 am and about 11 am, and 1 or 2 capsules, each containing about 1 g of a composition as described herein, are administered to the subject in the evening, for example between about 5 pm and about 11 pm.
  • the risk of a cardiovascular event in a subject is reduced compared to a control population.
  • a plurality of control subjects to a control population wherein each control subject is on stable statin therapy, has a fasting baseline triglyceride level of about 135 mg/dL to about 500 mg/dL, and has established cardiovascular disease or a high risk of developing cardiovascular disease, and wherein the control subjects are not administered eicosapentaenoic acid ethyl ester and colchicine (either as a single dosage unit or as multiple dosage units) daily.
  • the risk of a cardiovascular event in a subject is reduced compared to a control population.
  • a plurality of control subjects to a control population wherein each control subject is on stable statin therapy, has a fasting baseline triglyceride level of about 80 mg/dL to about 1500 mg/dL, and has established cardiovascular disease or a high risk of developing cardiovascular disease, and wherein the control subjects are not administered eicosapentaenoic acid ethyl ester and colchicine (either as a single dosage unit or as multiple dosage units) daily.
  • a first time interval beginning at (a) an initial administration of a composition as disclosed herein to the subject to (b) a first cardiovascular event of the subject is greater than or substantially greater than a first control time interval beginning at (a') initial administration of a placebo to the control subjects to (b') a first cardiovascular event in the control subjects.
  • the first cardiovascular event of the subject is a major cardiovascular event selected from the group consisting of: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and unstable angina caused by myocardial ischemia.
  • the first cardiovascular event of the control subjects is a major cardiovascular event selected from the group consisting of: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and unstable angina caused by myocardial ischemia.
  • the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is any of: death (from any cause), nonfatal myocardial infarction, or nonfatal stroke.
  • the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is any of: death from a cardiovascular cause, nonfatal myocardial infarction, coronary revascularization, unstable angina, peripheral cardiovascular disease, or cardiac arrhythmia requiring hospitalization.
  • the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is any of: death from a cardiovascular cause, nonfatal myocardial infarction, and coronary revascularization, unstable angina. In some embodiments, the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is any of: death from a cardiovascular cause and nonfatal myocardial infarction. In some embodiments, the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is death (from any cause). In some embodiments, the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is any of: fatal myocardial infarction and nonfatal myocardial infarction (optionally including silent Ml).
  • the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is coronary revascularization.
  • the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is hospitalization (e.g. emergent hospitalization) for unstable angina (optionally unstable angina caused by myocardial ischemia).
  • the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is any one of: fatal stroke or nonfatal stroke.
  • the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is any one of: new coronary heart failure, new coronary heart failure leading to hospitalization, transient ischemic attack, amputation for coronary vascular disease, and carotid revascularization.
  • the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is any one of: elective coronary revascularization and emergent coronary revascularization.
  • the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is an onset of diabetes.
  • the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is cardiac arrhythmia requiring hospitalization.
  • the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is cardiac arrest.
  • the first cardiovascular event of the subject and the first cardiovascular event of the control subjects is sudden cardiac death and/or sudden death.
  • a second time interval beginning at (a) an initial administration of the composition to the subject to (c) a second cardiovascular event of the subject is greater than or substantially greater than a second control time interval beginning at (a') initial administration of a placebo to the control subjects to (o') a second cardiovascular event in the control subjects.
  • the second cardiovascular event of the subject and the second cardiovascular event of the control subjects is a major cardiovascular event selected from the group consisting of: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and unstable angina caused by myocardial ischemia.
  • the major cardiovascular event(s) is further selected from the group consisting of: cardiac arrest, sudden cardiac death, and/or sudden death.
  • the subject has diabetes mellitus and the control subjects each have diabetes mellitus.
  • the subject has metabolic syndrome and the control subjects each have metabolic syndrome.
  • the subject exhibits one or more of (a) reduced triglyceride levels compared to the control population; (b) reduced Apo B levels compared to the control population; (c) increased HDL-C levels compared to the control population; (d) no increase in LDL-C levels compared to the control population; (e) a reduction in LDL-C levels compared to the control population; (f) a reduction in non-HDL-C levels compared to the control population; (g) a reduction in VLDL levels compared to the control population; (h) a reduction in total cholesterol levels compared to the control population; (i) a reduction in high sensitivity C-reactive protein (hsCRP) levels compared to the control population; and/or (j) a reduction in high sensitivity troponin (hsTnT) levels compared to the control population.
  • hsCRP high sensitivity C-reactive protein
  • the subject's weight after administration of the composition is less than a baseline weight determined before administration of the composition. In some embodiments, the subject's waist circumference after administration of the composition is less than a baseline waist circumference determined before administration of the composition.
  • the time interval may be for example an average, a median, or a mean time interval.
  • the first control time interval is an average, a median, or a mean of a plurality of first control time intervals associated with each control subject.
  • the second control time interval is an average, a median, or a mean of a plurality of second control time intervals associated with each control subject.
  • the reduced risk of cardiovascular events is expressed as a difference in incident rates between a study group and a control population.
  • the subjects in the study group experience a first major cardiovascular event after an initial administration of a composition as disclosed herein at a first incidence rate which is less than a second incidence rate, wherein the second incidence rate is associated with the rate of cardiovascular events in the subjects in the control population.
  • the first major cardiovascular event is any one of: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and hospitalization for unstable angina (optionally determined to be caused by myocardial ischemia).
  • the first and second incidence rates are determined for a time period beginning on the date of the initial administration and ending about 4 months, about 1 year, about 2 years, about 3 years, about 4 years, or about 5 years after the date of initial administration.
  • the disclosure provides use of any composition described herein for treating hypertriglyceridemia in a subject in need thereof, comprising: providing a subject having a fasting baseline triglyceride level of about 135 mg/dL to about 500 mg/dL and administering to the subject a composition as described herein.
  • the composition comprises about 1 g to about 4 g of eicosapentaenoic acid ethyl ester, wherein the composition contains substantially no docosahexaenoic acid.
  • the disclosure provides use of any composition described herein for treating hypertriglyceridemia in a subject in need thereof, comprising: providing a subject having a fasting baseline triglyceride level of about 80 mg/dL to about 1500 mg/dL and administering to the subject a composition as described herein.
  • the composition comprises about 1 g to about 4 g of eicosapentaenoic acid ethyl ester, wherein the composition contains substantially no docosahexaenoic acid.
  • the present disclosure provides methods of preventing and/or treating a viral infection in a subject.
  • the viral infection is SARS- CoV-2 infection (e.g., COVID-19).
  • the disclosure also provides methods of treating and/or preventing a disease or symptoms thereof caused by a virus in a subject.
  • the virus is a coronavirus, such as SARS-CoV-2.
  • Exemplary symptoms of SARS-CoV-2 infection and/or COVID-19 include, but are not limited to, coughing, wheezing, fever, tiredness, and difficulty in breathing.
  • the subject infected with SARS-CoV-2 have COVID-19, and/or symptoms of COVID-19 is an elderly subject (e.g., 60 years or greater), an infant, or an immunocompromised subject.
  • the methods include administering to the subject icosapent ethyl and colchicine (either as a single dosage unit or as multiple dosage units).
  • the methods include administering to the subject icosapent ethyl and colchicine in a 1 :1 molar ratio.
  • the methods further include administering to the subject an additional agent that is chemically distinct from icosapent ethyl and colchicine.
  • the additional agent is an anti-viral agent, an anti-malaria agent, and/or a biologic agent.
  • the additional agent is an agent used to treat malaria (e.g., an anti-malaria agent), SARS, MERS, and/or autoimmune disorder.
  • the anti-viral agent is remdesivir, and/or vitamin C.
  • the anti-malaria agent is hydroxychloroquine and/or chloroquine.
  • the biologic agent includes a peptide and/or a nucleic acid.
  • the peptide is an antibody.
  • the biologic agent is a vaccine, such as an antiviral vaccine (e.g., COVID-19 vaccines).
  • Colchicine has a narrow therapeutic window. That is, toxic levels of colchicine are not very far from the therapeutic levels. Therefore, colchicine is associated with a wide range of adverse side effects and overdosing can be a significant risk. Colchicine causes gastrointestinal upset such as diarrhea, fever, muscle pain, low blood cell counts, and other adverse effects, particularly at higher doses. Additional complications may arise for patients taking other drugs that interact with colchicine. There are hundreds of drugs (e.g., P- glycoprotein transporter, CYP3A4 enzyme inhibitors such as erythromycin and clarithromycin, macrolide antibiotics, and many other drugs including statins) that have reported showing various drug-drug-interactions with colchicine.
  • drugs e.g., P- glycoprotein transporter, CYP3A4 enzyme inhibitors such as erythromycin and clarithromycin, macrolide antibiotics, and many other drugs including statins
  • Colchicine touts anti-inflammatory effects via attenuating nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complex.
  • eicosapentaenoic acid (EPA) and derivatives are ligands of the peroxisome proliferator-activated receptor alpha (PPAR alpha), which is a potent modulator of inflammatory reactions.
  • PPAR alpha peroxisome proliferator-activated receptor alpha
  • colchicine and eicosapentaenoic acid (EPA) function as anti-inflammatory agents via different pharmacological pathways.
  • PPAR alpha and NLRP3 a complementary mechanism of action appears to exist between PPAR alpha and NLRP3 mediated suppression of inflammation.
  • the molecular mechanisms responsible for PPAR alpha-mediated suppression of proinflammatory signaling pathways may modulate and interfere with the NLRP3 inflammasome activation.
  • Such an interaction between the PPAR alpha and NLRP3 underpins the enhanced or even synergistic therapeutic benefits of a combined administration of both agents (i.e., EPA and colchicine).
  • NNT Number Needed to Treat
  • NNT data summarized in Figure 53 further demonstrate the synergistic effect of currently claimed administration of a combination of icosapent ethyl and colchicine.
  • the fold changes in Figure 53 indicate that NNTs for therapy without colchicine (e.g., icosapent ethyl alone) were more than doubled compared to the combination (e.g., on colchicine) for the primary composite endpoint, and more than tripled for the secondary composite endpoint.
  • the NNTs were greatly decreased among participants who were taking the combination of icosapent ethyl and colchicine, indicating greater absolute risk reductions (ARRs).
  • ARRs absolute risk reductions
  • the NNTs of the group taking icosapent ethyl alone were more than doubled that of the group taking the combination of icosapent ethyl and colchicine.
  • the ARRs of the group taking icosapent ethyl alone were around 12%, compared to ARRs of around 5% for those taking icosapent ethyl alone (without colchicine) (see e.g., Figure 53).
  • the NNTs of the group taking icosapent ethyl alone were more than triple that of the group taking the combination of icosapent ethyl and colchicine.
  • the ARRs of the group taking icosapent ethyl alone were around 12%, compared to ARRs of around 4% for those taking icosapent ethyl alone (without colchicine) (see e.g., Figure 53).
  • EPA produces a plethora of bioactive oxylipins that moderate excessive inflammation; among these are oxylipins that inhibit neutrophil recruitment and activation, which could enhance similar effects from colchicine, either improving the impact of both drugs on neutrophil recruitment and/or sparing colchicine dose;
  • the drug distribution of colchicine may be very different than icosapent ethyl, because colchicine is much more hydrophilic than icosapent ethyl.
  • the logP indicates the lipophilicity of a given drug, with higher numbers indicating greater lipophilicity.
  • Many approved drugs cluster between a logP of 1 to 4.
  • the logP of colchicine is around 1 .46 to 1 .59, which is on the low end of the spectrum. This has a major impact on colchicine’s distribution, especially in terms of the mix of various organs and tissues colchicine affects.
  • icosapent ethyl has a very high logP of around 6.7 to 6.8.
  • both drugs might be delivered to some identical tissues, the combination of the two will cover a much wider lipophilicity spectrum. This may potentiate the benefits of either one as monotherapy, because they provide complementary and synergistic therapeutic effects against the inflammatory and tissue-injury response; and
  • Colchicine’s efficacy may be less even than icosapent ethyl over the 24-hour period, resulting from “tidal” variations in tissue exposure owing to acute dosing; this can result in weaker effects at trough and more toxicity at peak.
  • icosapent ethyl’s efficacy for inflammation depends on phospholipid-EPA integrating into cell membranes; this results in an increasing reservoir of anti-inflammatory substrates that are always present and available to the cell. This provides a more steady and reliable source of antiinflammatory substrates as compared to colchicine. As such, icosapent ethyl can “even out” any “tidal” variations in colchicine effects vis-a-vis anti-inflammatory actions.
  • EXAMPLE 1 Impact of Icosapent Ethyl on Reducing Cardiovascular Events in High Risk Statin-Treated Patients
  • CV cardiovascular
  • a multi-center, prospective, randomized, double-blind, placebo-controlled, parallel-group study was performed to evaluate the effect of AMR101 (4g per day) on cardiovascular health and mortality in hypertriglyceridemic patients with cardiovascular disease or at high risk for cardiovascular disease.
  • the intended expanded indication of the study was treatment with AMR101 as an add-on to statin therapy to reduce the risk of cardiovascular events in patients with clinical cardiovascular disease or with multiple risk factors for cardiovascular disease.
  • a subgroup of patients in the REDUCE-IT clinical trial were taking colchicine at a daily dosage ranging from about 0.5 mg to about 1 .8 mg, or from about 0.6 mg to about 1.2 mg.
  • a post hoc analysis of this subgroup was performed to evaluate the therapeutic effect of combined administration of icosapent ethyl (i.e., AMR101 ) and colchicine (see e.g., Figures 52 and 53).
  • the primary objective of this study was, in patients at LDL-C goal while on statin therapy, with established cardiovascular disease (CVD) or at high risk for CVD, and hypertriglyceridemia (e.g., fasting triglycerides(TG) ⁇ 200 mg/dL and ⁇ 500 mg/dL), to evaluate the effect of AMR101 4 g daily on time from randomization to first occurrence of any component of the composite of the following major CV events: CV death; nonfatal Ml; (including silent Ml; electrocardiograms (ECGs) were performed annually for the detection of silent Mis); nonfatal stroke; coronary revascularization; and unstable angina determined to be caused by myocardial ischemia by invasive/non-invasive testing and requiring emergent hospitalization.
  • CVD cardiovascular disease
  • hypertriglyceridemia e.g., fasting triglycerides(TG) ⁇ 200 mg/dL and ⁇ 500 mg/dL
  • Total CV events analysis defined as the time from randomization to occurrence of the first and all recurrent major CV events defined as CV death, nonfatal Ml (including silent Ml), nonfatal stroke, coronary revascularization, or unstable angina determined to be caused by myocardial ischemia by invasive/non-invasive testing and requiring emergent hospitalization; • Primary composite endpoint in the subset of patients with diabetes mellitus at baseline;
  • New onset diabetes defined as Type 2 diabetes newly diagnosed during the treatment/follow-up period
  • New onset hypertension defined as blood pressure ⁇ 140 mmHg systolic or ⁇ 90 mmHg diastolic newly diagnosed during the treatment/follow-up period;
  • the population for this study were men and women ⁇ 45 years of age with established CVD, or men and women ⁇ 50 years of age with diabetes in combination with one additional risk factor for CVD.
  • all patients had atherogenic dyslipidemia defined as on treatment for hypercholesterolemia (but at treatment goal for LDL-C, by treatment with a statin) and hypertriglyceridemia. More details regarding the patient population are listed in the inclusion criteria below.
  • the patients needed to provide consent to participate in the study and were willing and able to comply with the protocol and the study procedures.
  • Screening Period During the screening period, patients were evaluated for inclusion and exclusion criteria.
  • Treatment/Follow-Up Period Within 42 days after the first screening visit (Visit 1 ) or within 60 days after the first screening visit (Visit 1 ) for those patients that had a second screening visit (Visit 1.1), eligible patients entered the treatment/follow-up period. During this period, the patients received study drug during the planned visits at the Research Site and took the study drug while away from the Research Site.
  • Group 1 AMR101 (>96% E-EPA) 4 g daily (four 1000 mg capsules daily)
  • CV risk category e.g., Westernized, Eastern European, and Asia Pacific countries.
  • geographical region e.g., Westernized, Eastern European, and Asia Pacific countries.
  • CV Risk Category 1 patients with established CVD defined in the inclusion criteria. Patients with diabetes and established CVD were included in this category. These patients are defined as the secondary prevention stratum, primary risk category, and/or secondary prevention cohort.
  • CV Risk Category 2 patients with diabetes and at least one additional risk factor for CVD, but no established CVD. These patients are defined as the primary prevention stratum, secondary risk category, and/or primary prevention cohort.
  • Inclusion Criteria A detailed list of the inclusion criteria for this study is provided in Tables 3-5. Specifically, Table 3 outlines the inclusion criteria for patients in this study whereas Tables 4 and 5 further outline the inclusion criteria based on whether that patient is part of the primary prevention risk category or the secondary prevention risk category of patients, respectively.
  • Stable therapy was 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 had their statin therapy or use of ezetimibe initiated at Visit 1 or had their statin, statin dose and/or ezetimibe dose changed at Visit 1 , needed to go through a stabilization period of at least 28 days since initiation/change and had their qualifying lipid measurements measured (TG and LDL-C) after the washout period (at Visit 1.1).
  • Statins may have been administered with or without ezetimibe.
  • FSH follicle-stimulating hormone
  • CV Risk Category 2 Patients at high risk for CVD (in CV Risk Category 2) were defined as detailed in Table 5.
  • Screening Visit 1 During Visit 1 , patients came to the Research Site for and were instructed to fast for at least 10 hours before their visit. If patients qualified for randomization based on the procedures at Visit 1 , they needed to be randomized within 42 days after Visit 1 . The following procedures were performed at the screening Visit 1 : • Obtained signed informed consent;
  • Visit 1.1 Screening Visit: Patients who qualified for study participation after Visit 1 because they meet all inclusion criterion and none of the exclusion criteria, skipped Visit 1.1 and returned to the Research Site for Visit 2 to be randomized and to start the treatment/follow-up period of the study. For these patients, Visit 2 occurred soon after Visit 1 . Patients, who did not qualify at Visit 1 , returned to the Research Site for a second qualifying visit (Visit 1 .1 ) at the discretion of the investigator. At Visit 1.1 , procedures that caused failure of eligibility at Visit 1 were repeated. Patients were eligible for randomization after Visit 1.1 if they meet all inclusion criteria and if they no longer failed the exclusion criteria.
  • Visit 1.1 was mandatory at least 28 days after Visit 1 in order to check eligibility. These were patients who at Visit 1 started treatment with a statin, changed their statin, changed the daily dose of their statin, started to washout prohibited medications or started a stabilization period with certain medications (See inclusion/exclusion criteria above for details). Any of these changes at Visit 1 may have affected the qualifying lipid levels and therefore, patients needed to have Visit 1.1 to determine whether they qualified based on lipid level requirements (TG and LDL-C) determined at Visit 1 . Other procedures that caused failure of eligibility at Visit 1 were also repeated at Visit 1.1. The following procedures were performed at the screening Visit 1.1 :
  • Visit 3 (Dav 120; ⁇ 4 Months): Patients returned to the Research Site for Visit 3 on Day 120 ⁇ 10 days. The following procedures were performed:
  • Visits 4, 5, 6, 7, 8, and 9 At Visit 4: Day 360 ⁇ 10; Visit 5: Day 720 ⁇ 10; Visit 6: Day 1080 ⁇ 10; and Visit 7: Day 1440 ⁇ 10: Visit 8: Day 1800 ⁇ 10, Visit 9: Day 2160 ⁇ 10, the following procedures were performed:
  • Last Visit - End of Study All patients completed the study at the same time (within a 30-day window after the study end date), irrespective of the date that they were randomized. The end date of the study was planned for Day 2160 but the actual end date was dependent on the determination of the study end date by the DMC when approximately 1612 primary efficacy events had occurred (event-driven trial). For each patient, the last visit may have occurred within 30 days after the actual study end date as determined by the DMC. However, for the efficacy endpoints based on CV events, only events occurring up to and including the scheduled actual study end date were included in the efficacy analyses. A final follow-up visit was required for all patients. In a rare case that a final follow-up visit did not occur within the 30-day timeframe following the study end date, any attempt to contact the patient was recorded on a special contact form, until/unless appropriate information was obtained. At the Last Visit, the following procedures were performed:
  • Telephoned Follow-up Contact Site personnel contacted each patient by telephone on the following study days: Day 60 ⁇ 3 days; Day 180 ⁇ 5 days; Day 270 ⁇ 5 days; Day 450 ⁇ 5 days; Day 540 ⁇ 5 days; Day 630 ⁇ 5 days; Day 810 ⁇ 5 days; Day 900 ⁇ 5 days; Day 990 ⁇ 5 days; Day 1170 ⁇ 5 days; Day 1260 ⁇ 5 days; Day 1350 ⁇ 5 days; Day 1530 ⁇ 5 days; Day 1620 ⁇ 5 days; Day 1710 ⁇ 5 days; Day 1890 ⁇ 5 days; Day 1980 ⁇ 5 days; and Day 2070 ⁇ 5 days.
  • Clinical Laboratory Procedures and Evaluations All clinical laboratory determinations for screening and safety were performed by a certified clinical laboratory under the supervision of the Sponsor or its designee. Whenever possible and appropriate, samples for the clinical laboratory procedures were collected after fasting for at least 10 hours. For the purposes of this study, fasting was defined as nothing by mouth except water (and any essential medications). The investigator reviewed and signed all laboratory test reports. At screening, patients who had laboratory values that are outside the exclusionary limits specified in the exclusion criteria were not enrolled in the study (patients would have been considered for the study if values were classified as not clinically significant by the investigator). After randomization, the investigator was notified if laboratory values were outside of their normal range. In this case, the investigator was required to conduct clinically appropriate follow-up procedures.
  • Safety Laboratory Tests The safety parameters were analyzed by a certified clinical laboratory at screening (Visit 1 or Visit 1 .1 ), Randomization visit (Visit 2; Day 0), Visit 3 (Day 120; ⁇ 4 Months) and all other follow-up visits including the Last Visit.
  • the safety laboratory tests included: • Hematology with complete blood count (CBC), including RBC, hemoglobin (Hgb), hematocrit (Het), white cell blood count (WBC), white cell differential, and platelet count; and
  • Biochemistry panel including total protein, albumin, alkaline phosphatase, alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), total bilirubin, glucose, calcium, electrolytes (sodium, potassium, chloride), blood urea nitrogen (BUN), serum creatinine, uric acid, creatine kinase, and HbA1c.
  • Each laboratory result was classified as low (L), normal (N), and high (H) at each visit according to the laboratory-supplied normal range.
  • the shift from baseline was presented for each post-baseline visit and overall post-baseline visits. If multiple measurements for a test parameter were available for a post-baseline patient-visit, the most extreme value was included in the shift table. For shift from baseline to overall post-baseline visits, values from all visits (including unscheduled measurements) were included.
  • the chemistry shift table included fasting lipid parameters. The continuous lipid values were presented as part of the efficacy analysis.
  • the fasting lipid panel included: TG, TC, LDL-C, HDL-C, non-HDL-C, and VLDL-C.
  • LDL-C was calculated using the Friedewald equation.
  • Visit 1 and Visit 1.1 direct LDL-C were used if at the same visit TG >400 mg/dL (4.52 mmol/L).
  • LDL-C values were used for the evaluation of the LDL-C inclusion criterion (LDL-C qualifying measurements for randomization) and for the assessment of changes in the statin therapy when LDL-C was not at goal.
  • LDL-C was measured by direct LDL cholesterol or by preparative ultracentrifugation if at the same visit TG >400 mg/dL (4.52 mmol/L).
  • TG >400 mg/dL (4.52 mmol/L).
  • LDL-C were measured by preparative ultracentrifugation. These preparative ultracentrifugation LDL-C measurements were used in the statistical analysis including the calculation of the percent change from baseline (1 year versus baseline). Hopkins LDL-C was calculated for each visit.
  • Genetic Testing A fasting blood sample was stored for future genetic testing at the discretion of the Sponsor. The specifics of this test were determined at a later date. This sample was optional as local regulations may prohibit genetic samples to be collected or shipped outside the country, or patients may not have consented. Research on genetic testing looked for links between genes and certain diseases, including their treatment(s) such as medicines and medical care. The blood samples were collected in the study center with the regular protocol-required labs. Each patient tube with a sample for genetic testing were labeled with patient number only. The site maintained a Subject Code Identification List for cross-reference. The patient number did not contain any identifiable information (i.e., patient initials, date of birth, etc.).
  • Un-analyzed samples were stored frozen by the Sponsor for a period of up to 2 years following the end of the study, at which time they were destroyed. If samples were tested, results were not reported to the patient, parents, relatives, or attending physician and were not recorded in the patient's medical records. There was no follow-up contact with the sites or patients regarding this sample.
  • the subject could withdraw their consent for genetic testing at any time up to analysis, even after the sample had been obtained.
  • the subject could notify the site in writing that they withdraw their consent for the genetic testing portion of the study, and it was documented by the site in the subject chart, as well as captured in the CRF. The lab was notified to pull the sample and destroy it.
  • Potential genetic bioassays may have been performed and may have been as broad as a genome-wide association study (GWAS) or as limited as a single gene-target approach; potential target genes include, but are not limited to the genes encoding: Apo C3, Apo A5, CETP, LPL, PCSK9, TNF ⁇ , TNF
  • GWAS genome-wide association study
  • Biomarkers Assays The biomarker assays included: hsCRP, Apo B and hsTnT.
  • a urine pregnancy test was administered to women of childbearing potential at certain visits as listed in schedule of procedures (Table 1).
  • the urine pregnancy tests was performed at the Research Site utilizing marketed test kits, or at a certified clinical laboratory; • A fasting blood sample (10 mL) for archiving. This sample was collected only at sites in countries where allowed by local regulations and at sites for which approved by the IRB or IEC.
  • the plasma from the archiving sample was stored frozen in 2 separate equal aliquots, and was used at the Sponsor's discretion to perform repeat analyses described in the protocol or to perform other tests related to cardiovascular health; and
  • Critical lab values are values that may have warranted medical intervention to avoid possible harm to a patient.
  • Critical lab values were defined in the Laboratory Manual for the study, and the Research Site was notified of the occurrence of a critical lab value (critical high or critical low) by a special annotation (flag) in the laboratory reports provided to the Research Sites.
  • TG values were confirmed critically high patients could be discontinued from study drug with the option to remain on study.
  • LDL-C values were confirmed critically high the investigator needed to take appropriate medical action which included: reinforcing/intensifying therapeutic lifestyle changes (including diet and physical activity), increasing the dose of the present statin therapy, adding ezetimibe, or prescribing a more potent statin to lower LDL-C. The investigator used the best clinical judgment for each patient.
  • Medical, Surgical and Family History Medical history, including family history and details regarding all illnesses and allergies, date(s) of onset, status of current condition, and smoking and alcohol use were collected on all patients.
  • Demographics Demographic information including day, month, and year of birth, race, and gender were collected for all patients.
  • Vital Signs and Patient Measurements included systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature. Blood pressure was measured using a standardized process:
  • Blood pressure was recorded to the nearest 2 mmHg mark on the manometer or to the nearest whole number on an automatic device. A blood pressure reading was repeated 1 to 2 minutes later, and the second reading recorded to the nearest 2 mmHg mark.
  • Phvsical Examination A physical examination included source documentation of general appearance, skin, and specific head and neck, heart, lung, abdomen, extremities, and neuromuscular assessments.
  • Height, Weight and Body Mass Index Height and weight were measured. Measurement of weight was performed with the patient dressed in indoor clothing, with shoes removed, and bladder empty.
  • Waist Circumference Waist circumference was measured with a tape measure, as follows: Start at the top of the hip bone then bring the tape measure all the way around - level with the navel. Make sure the tape measure is snug, but without compressing the skin, and that it is parallel with the floor. Patients should not have held their breath while measuring waist circumference.
  • ECG 12-Lead Electrocardiogram
  • ECGs All post-randomization ECGs (protocol-specified and other) were sent to the CEC for evaluation of silent Ml.
  • the 12-lead ECG parameters included Heart Rate (bpm), PR Interval (msec), QRS Interval (msec), QT Interval (msec), and QTc Interval (msec) were measured, and Overall Interpretation and Silent Ml (Yes/No) were summarized for all patients at Screening (Visit 1 ), Randomization visit (Visit 2; Day 0) and all other follow-up visits including the last visit of the study.
  • a treatment-emergent PCS high value at any time was defined as a change from a value less than or equal to the defined PCS value at baseline to a PCS high value at any post-baseline measurement.
  • a treatment-emergent PCS low value at any time was defined as a change from a value greater than or equal to the lower PCS value at baseline to a PCS low value at any post-baseline measurement.
  • Table 8 provides the PCS ECG values.
  • Treatment Regimen, Dosage, and Duration Eligible study patients were randomly assigned on Day 0 to one of the 2 treatment groups. Patients in each group received either 4 g/day AMR101 or placebo for up to 6.5 years, depending on individual date of randomization and overall study stop date according to Table 9. The daily dose of study drug was 4 capsules per day taken as two capsules taken on two occasions per day (2 capsules were given twice daily).
  • Identification Number A unique patient identification number (patient number) was established for each patient at each site. The patient number was used to identify the patient throughout the study and was entered on all documentation. If a patient was not eligible to receive treatment, or if a patient discontinued from the study, the patient number could not be reassigned to another patient. The patient number was used to assign patients to one of the 2 treatment groups according to the randomization schedule.
  • Concomitant Medications during Treatment/Follow-Up Period Any medications administered during the study period were documented on the Concomitant Medication CRF. Patients had not taken any investigational agent within 90 days prior to screening. Patients could not participate in any other investigational medication trial while participating in this study. The following non-study drug related, non-statin, lipid-altering medications and supplements, and foods were prohibited during the study (from Visit 1 until after the Last Visit-End of Study), except for compelling medical reasons in ODIS patients:
  • omega-3 fatty acid medications • prescription omega-3 fatty acid medications; • dietary supplements containing omega-3 fatty acids (e.g., flaxseed, fish, krill, or algal oils);
  • simvastatin 80 mg was used only in patients who had been taking this dose for 12 months or more and had not experienced any muscle toxicity.
  • FDA Drug Safety Communication Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury. (http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetylnformationforPatie ntsandProviders/ucm204882.htm); and • Changing of the type of statin or the statin dose during the treatment/follow-up period of the study was only done for compelling medical reasons and was documented in the CRF.
  • statin therapy maintained throughout the study was important and, in the rare circumstance that it became medically compelling to discontinue statin use, the patient could remain in the study and on study medication with approval from the Medical Monitor. Under such conditions, resumption of statin therapy was attempted when/if medically appropriate.
  • LDL-C Rescue If the level of LDL-C exceeded 130 mg/dL (3.37 mmol/L) during the study (initial measurement and confirmed by a second determination at least 1 week later), the investigator either increased the dose of the present statin therapy or added ezetimibe to lower LDL-C. The investigator used the best clinical judgment for each patient.
  • medically warranted i.e., tamoxifen, estrogens, progestins, thyroid hormone therapy, systemic corticosteroids and HIV-protease inhibitors.
  • Patient Restrictions Beginning at the screening visit, all patients were instructed to refrain from excessive alcohol consumption, to follow a physician recommended diet and to maintain it through the duration of the study. Excessive alcohol consumption is on average 2 units of alcohol per day or drinking 5 units or more for men or 4 units or more for women in any one hour (episodic excessive drinking or binge drinking).
  • a unit of alcohol is defined as a 12-ounce (350 ml) beer, 5-ounce (150 ml) wine, or 1.5-ounce (45 ml) of 80- proof alcohol for drinks.
  • AMR101 1000 mg and placebo capsules (paraffin) were provided in liquid-filled, oblong, gelatin capsules. Each capsule was filled with a clear liquid (colorless to pale yellow in color). The capsules were approximately 25.5 mm in length with a diameter of approximately 9.5 mm.
  • Labeling and Packaging Study medication was packaged in high-density polyethylene bottles. Labeling and packaging was performed according to GMP guidelines and all applicable country-specific requirements. The bottles were numbered for each patient based on the randomization schedule. The patient randomization number assigned by IWR or a designee of the Sponsor for the study (if no IWR system was used), corresponds to the number on the bottles. The bottle number for each patient was recorded in the Electronic Data Capture (EDC) system for the study.
  • EDC Electronic Data Capture
  • Dispensing Procedures At Visit 2 (Day 0), patients were assigned a study drug according to their treatment group determined by the randomization schedule. Once assigned to a treatment group, patients received study drug supplies. At each visit, patients brought unused drug supplies dispensed to them earlier. From the drug supplies assigned to each patient, site personnel administered the drug while the patients were at the Research Site. The investigator or designee contacted the IWR system or a designee of the Sponsor for the study (if no IWR system is used) when any unscheduled replacements of study medication were needed. During the last visit of the treatment period, patients brought the unused drug supplies for site personnel to calculate the final study medication compliance by unused capsule count.
  • the primary efficacy endpoint was time from randomization to the first occurrence of the composite of the following clinical events: CV death; nonfatal Ml (including silent Ml; ECGs were performed annually for the detection of silent Mis); nonfatal stroke; coronary revascularization; and unstable angina determined to be caused by myocardial ischemia by invasive/non-invasive testing and requiring emergent hospitalization. The first occurrence of any of these major adverse vascular events during the follow-up period of the study were included in the incidence.
  • Secondary Efficacy Endpoints The key secondary efficacy endpoint was the time from randomization to the first occurrence of the composite of CV death, nonfatal Ml (including silent Ml), or nonfatal stroke. Other secondary efficacy endpoints were time from randomization to the first occurrence of the individual or composite endpoints as follows (tested in the order listed):
  • Non-elective coronary revascularization represented as the composite of emergent or urgent classifications
  • Total CV events analysis defined as the time from randomization to occurrence of the first and all recurrent major CV events defined as CV death, nonfatal Ml (including silent Ml), nonfatal stroke, coronary revascularization, or unstable angina determined to be caused by myocardial ischemia by invasive/non-invasive testing and requiring emergent hospitalization;
  • TAA Transient ischemic attack
  • New onset diabetes defined as Type 2 diabetes newly diagnosed during the treatment/follow-up period
  • New onset hypertension defined as blood pressure ⁇ 140 mmHg systolic OR ⁇ 90 mm Hg diastolic newly diagnosed during the treatment/follow-up period;
  • CHF congestive heart failure
  • Adverse Events An adverse event is defined as any untoward medical occurrence, which does not necessarily have a causal relationship with the medication under investigation. An adverse event can therefore be any unfavorable and/or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational medication product, whether or not related to the investigational medication product. All adverse events, including observed or volunteered problems, complaints, or symptoms, were recorded on the appropriate CRF. Each adverse event was evaluated for duration, intensity, and causal relationship with the study medication or other factors.
  • Adverse events which included clinical laboratory test variables, were monitored from the time of informed consent until study participation was complete. Patients were instructed to report any adverse event that they experienced to the investigator. Beginning with Visit 2, investigators assessed for adverse events at each visit and recorded the event on the appropriate adverse event CRF.
  • Unexpected Adverse Events An unexpected adverse event is an adverse event either not previously reported or where the nature, seriousness, severity, or outcome is not consistent with the current Investigator's Brochure.
  • SAE serious adverse event
  • life-threatening in the definition of "serious” refers to an event in which the patient was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe;
  • Is an important medical event Important medical events that may not result in death, be life threatening, or require hospitalization were considered an SAE when, based upon appropriate medical judgment, they may have jeopardized the patient and may have required medical or surgical intervention to prevent one of the outcomes listed above. Examples of such medical events included allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that did not result in inpatient hospitalizations, or the development of drug dependency.
  • Adverse Events of Special Interest Bleeding-related adverse events, glucose control (fasting blood glucose and HbA1 c), and indicators of hepatic disorders (e.g., ALT or AST increases >3 x ULN, total bilirubin increases of ⁇ 2 x ULN) were summarized separately and compared between treatment groups.
  • Exposure In Utero During Clinical Trials If a patient became pregnant during the study, the investigator reported the pregnancy to the Sponsor or designee within 24 hours of being notified. The Sponsor or designee then forwarded the Exposure In Utero form to the investigator for completion. The patient was followed by the investigator until completion of the pregnancy. If the pregnancy ended for any reason before the anticipated date, the investigator notified the Sponsor or designee. At the completion of the pregnancy, the investigator documented the outcome of the pregnancy. If the outcome of the pregnancy met the criteria for immediate classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the investigator followed the procedures for reporting an SAE.
  • SAE i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly
  • a TG value was flagged as critically high, i.e., >1000 mg/dL (11.29 mmol/L), and confirmed as critically high by a repeat measurement (new fasting blood sample) within 7 days. In this case, a patient could be discontinued from study drug (with the option to remain GDIS) and other lipid-altering medications may be (re)initiated. If the TG value was flagged as >2000 mg/dL (22.58 mmol/L) then appropriate medical action was taken by the investigator as soon as possible.
  • Occurrence of an outcome event according to the judgment of the investigator was not considered a valid reason for study drug discontinuation.
  • Patients that continued in the study after ⁇ 30 days cessation of therapy were characterized as Off Drug In Study (ODIS).
  • ODIS patients were asked to return to the study site for an interim visit once the patient had been off study drug for >30 days. Procedures at this visit were consistent with those at Visit 5. If not contraindicated, patients also had the option to restart study medication at any point once characterized as ODIS.
  • a brief therapy interruption could have been followed with a re-challenge (re-initiating study medication) as soon as clinically appropriate; thereby allowing a causative role for study medication to be confirmed or ruled out and continuing a patient in the study and on study drug if appropriate.
  • the reason for study drug discontinuation or interruption was recorded on the CRF.
  • Randomized Population The randomized population included all patients who sign the informed consent form and are assigned a randomization number at Visit 2 (Day 0).
  • Intent-to-Treat Population The ITT population included all patients who were randomized via the IRWS (Interactive Web Response System). All efficacy analyses were performed on the ITT population. Patients were analyzed according to the randomized treatment.
  • IRWS Interactive Web Response System
  • Modified Intent-to-Treat Population The Modified Intent-to-Treat (mITT) population included all randomized patients who had the study drug dispensed after randomization. Groups were defined based on the randomized treatment.
  • Per-Protocol Population The per-protocol (PP) population included all mITT patients without any major protocol deviations, and who had ⁇ 80% compliance while on treatment. To be included in the PP population the minimum time on therapy was 90 days.
  • Safety Population All safety analyses were conducted based on the safety population, which is defined as all randomized patients. This was the same as the ITT population.
  • ITT overall and by stratification factors (CV risk, ezetimibe use, and geographical region); • mITT population; overall and by stratification factors (CV risk, ezetimibe use, and geographical region);
  • Concomitant therapies Concomitant medication/therapy verbatim terms were coded using the latest available version, prior to data base lock, of the World Health Organization Drug Dictionary and the Anatomical Therapeutic Chemical classification system. The numbers and percentages of patients in each treatment group taking concomitant medications were summarized. All verbatim descriptions and coded terms were listed for all non-study medications.
  • Summary Statistics Summary statistics (n, mean, standard deviation, median, minimum, and maximum) for the baseline and post-baseline measurements, the percent changes, or changes from baseline were presented by treatment group and by visit for all efficacy variables analyzed. The summary statistics included changes in body weight and body mass index from baseline by treatment group and by visit.
  • the primary endpoint for patients who had a non-CV death within 90 days of last contact without having had an earlier CV event was censored at the time of death.
  • the primary endpoint for patients who had a non- CV death more than 90 days after last contact without having had an earlier CV event were censored at the time of last contact.
  • the primary analysis assumed that all silent Mis occurred on the date of the first tracing indicative of a silent Ml; a second (sensitivity) analysis assumed that all silent Mis occurred on the day after the last prior normal ECG; and a third (sensitivity) analysis assumed that all silent Mis occurred at the mid-point between the last normal ECG and the ECG with the new Ml. All deaths causally adjudicated as “undetermined” were combined with those adjudicated as “CV deaths” for the primary analysis. A sensitivity analysis of the CV death category was performed that excluded the “undetermined cause of death” cohort.
  • the primary efficacy analysis was performed on the ITT population.
  • a sensitivity analysis was performed using the mITT and PP populations.
  • patients who discontinued study drug prematurely were censored for the primary composite endpoint analysis on the date of drug discontinuation.
  • the primary analysis was repeated using this censoring rule for the mITT population.
  • a multivariable, stratified Cox proportional hazards model was constructed for the primary endpoint to evaluate the treatment effect adjusting for important covariates.
  • Kaplan-Meier estimated the log-rank test stratified by stratification factors used at randomization, and the Cox proportional hazards model including the stratification factors as specified above for the primary efficacy endpoint, were summarized by treatment group.
  • the key secondary endpoint for patients who had a non-CV death within 90 days of last contact without having had an earlier CV event was censored at the time of death.
  • the key secondary endpoint for patients who had a non-CV death more than 90 days after last contact without having had an earlier CV event was censored at the time of last contact.
  • Kaplan-Meier curves stratified by each stratification factor were presented. These analyses were conducted for the ITT population.
  • tertiary endpoints for patients who gad a non-CV death more than 90 days after last contact without having had an earlier CV event were censored at the time of last contact.
  • LDL-C preparative ultracentrifugation values were missing, then another LDL-C value was used, with prioritization of values obtained from LDL-C Direct measurements, followed by LDL-C derived by the Friedewald calculation (only for subjects with TG ⁇ 400 mg/dL), and finally LDL-C derived using the calculation published by Hopkins University investigators (Martin SS, Blaha MJ, Elshazly MB, et al. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA. 2013; 310:2061 -8.).
  • the randomization visit was considered Baseline. If a baseline value was not available from the randomization visit, then the latest screening value was used. For measurements of lipids, lipoproteins and inflammatory markers, the change and the percent change were summarized at each visit. Since these biomarkers are typically not normally distributed, the Wilcoxon rank-sum test was used for treatment comparisons of the percent change from baseline, and medians and quartiles were provided for each treatment group. The medians of the differences between the treatment groups and 95% Cis were estimated with the Hodges-Lehmann method. In addition, shift -tables were generated as appropriate.
  • NAFLD NAFLD Fibrosis Score
  • CVD cardiovascular disease
  • Sensitivity analyses for endpoints comprised of coronary revascularizations which exclude early elective revascularizations (e.g., within 30-90 days postrandomization)
  • o LDL-P Using archived frozen biosamples (e.g., serum and whole blood); potential analyses of treatment effects on biomarkers and genetic markers and associations with outcomes, including but not limited to the following: o LDL-P; o RLP-C (measured); o LDL-TG; o Ox-LDL; o Galectin-3; o Lp(a) at baseline, as a predictor of OVD benefit; o LpPLA2; o HDL2, HDL3, apo A-l, apo A-ll, HDL-P, apo C-lll (and apo C-lll in apo-B containing proteins), apo A-V, Apo E subtypes (2, 3, 4), IL-6, lipoprotein lipase (LPL); and o Analyses may include change (and percent change) from baseline, on- treatment comparisons between treatment groups with testing as predictors of CV risk.
  • o Analyses may include change (and percent change) from baseline, on-
  • FPG Fasting plasma glucose
  • eGFR 141 x min (Scr/ ⁇ , 1 ) ⁇ x max(Scr/ ⁇ , 1) -1.209 x 0.993 Age x 1 .018 [if female] x
  • Scr is serum creatinine in mg/dL
  • K is 0.7 for females and 0.9 for males
  • ⁇ is -0.329 for females and -0.411 for males
  • min indicates the minimum of Scr/K or 1
  • max indicates the maximum of S cr / ⁇ or 1 .
  • a Cox proportional hazard (PH) model as mentioned above but additionally with baseline TG as a covariate were fitted to the data at each interim. Diagnostic plots for the PH assumption were evaluated. The consistency of the treatment effects in subgroups was assessed for the primary and key secondary efficacy endpoints. For each subgroup variable, a Cox PH model with terms for treatment, stratification factors (with the exception of those subgroup variables related to the stratification factors, i.e., CV risk category), subgroup, and treatment-by-subgroup interaction were performed. The main treatment effect was tested with this model. P-values for testing the interaction terms ⁇ 0.15 were considered significant. Results were presented in a Forest plot.
  • Subgroup analyses of the primary and key secondary endpoints were performed as described for the primary endpoint. For each subgroup, Kaplan-Meier estimates, the log-rank test stratified by stratification factors used at randomization (except where the subgroup was a stratification factor), and HRs and Cis from the Cox proportional hazards model as specified for the primary efficacy endpoint, were summarized by treatment group. All subgroup analyses were conducted for the ITT, mITT and PR populations.
  • Interim Efficacy Analysis Two interim analyses were planned for the primary efficacy endpoint using adjudicated events when approximately 60% (967 events) and approximately 80% (1290 events) of the total number of primary endpoint events planned (1612) was reached. The planned interim analyses were based on a group-sequential design.
  • the alpha-levels for the two protocol prespecified interim analyses and the final analysis are based on a group sequential design (GSD) with O’Brien-Fleming boundaries generated using the Lan-DeMets alpha spending function.
  • GSD group sequential design
  • the one-sided alpha-levels and boundaries based on a Z-test and the achieved p-values for each of the two interim analyses and the final analysis are given in Table 10.
  • Table 10 Group Sequential P-Values Boundaries According to Two Actual Interim Analyses Information Fractions
  • Treatment-emergent adverse events were summarized by system organ class and preferred term, and by treatment. This included overall incidence rates (regardless of severity and relationship to study drug), and incidence rates for moderate or severe adverse events.
  • a summary of SAEs and adverse events leading to early discontinuation (for ⁇ 30 days) were presented through data listings. Patients who restarted study drug were included in the summary of AEs leading to discontinuation.
  • Safety laboratory tests and vital signs were summarized by post-treatment change from baseline for each of the parameters using descriptive statistics by treatment group. Those patients with significant laboratory abnormalities were identified in data listings. Additional safety parameters were summarized in data listings.
  • All AEs included: treatment-emergent adverse event (TEAE) by high level group term (HLGT); TEAE by high level term (HLT); and TEAE by system organ class (SOO), HLGT, HLT, and preferred term (PT) (4-level table).
  • All SAEs included: treatment emergent SAE by HLGT ; treatment emergent SAE by HLT; and treatment emergent SAE by SOC, HLGT, HLT, and PT (4-level table).
  • PCS clinically significant
  • DILI Drug-Induced Liver Injury
  • a graph of distribution of peak values of alanine aminotransferase (ALT) versus peak values of total bilirubin (TBL) during the treatment period was prepared, using a logarithmic scale.
  • the peak TBL times the Upper Limit of Normal (ULN) were plotted against the peak ALT times the ULN, where the peak TBL and peak ALT may or may not have happened on the same day of liver testing.
  • the graph was divided into 4 quadrants with a vertical line corresponding to 3x ULN for ALT and a horizontal line corresponding to 2x ULN for TBL.
  • the upper right quadrant was referred to as the potential Hy’s Law quadrant, including potentially DILI cases.
  • liver function tests ALT, AST, alkaline phosphatase [ALP] and TBL
  • the recruitment period was assumed to be 4.2 years with 20% recruitment in the first year, 40% in the second year, 20% in the third year, 19% in the fourth year and the remaining 1% in the last 0.2 years.
  • the estimated maximum study duration was 6.5 years unless the trial was terminated early for efficacy or safety issues.
  • the 'sample size' was the number of events rather than the number of patients. The number of events that occurred depends primarily on three factors: how many patients were enrolled; the combined group event rate; and how long the patients were followed. Because of the difficulty in predicting the combined event rate, the Sponsor monitored the event rate as the trial progressed. If the combined event rate was less than anticipated, either increasing the number of patients, extending the length of follow-up, or a balance of adjusting both factors was necessary to achieve the sample size of 1612 events.
  • the actual number of patients randomized may have varied from the target number (either original or revised) as a result of the inherent lag between the date the last patient started screening and the date the last patient was randomized.
  • Cardiovascular death includes death resulting from an acute myocardial infarction, sudden cardiac death, death due to congestive heart failure (CHF), death due to stroke, death due to cardiovascular (CV) procedures, death due to CV hemorrhage, and death due to other cardiovascular causes.
  • CHF congestive heart failure
  • CV cardiovascular
  • Death due to acute myocardial infarction refers to a death by any mechanism (e.g., arrhythmia, CHF) within 30 days after a Ml related to the immediate consequences of the Ml, such as progressive CHF or recalcitrant arrhythmia.
  • a “break” e.g., a CHF and arrhythmia-free period of at least a week
  • CV or non-CV death should be classified as CV or non-CV death, and if classified as a CV death, should be attributed to the immediate cause, even though the Ml may have increased the risk of that event (e.g., the risk of arrhythmic death is increased for many months after an acute Ml).
  • Acute Ml should be verified to the extent possible by the diagnostic criteria outlined for acute Ml (see Definition of Ml) or by autopsy findings showing recent Ml or recent coronary thrombosis. Death resulting from a procedure to treat a Ml (percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG)), or to treat a complication resulting from Ml, should also be considered death due to acute Ml. Death resulting from an elective coronary procedure to treat myocardial ischemia (i.e., chronic stable angina) or death due to a Ml that occurs as a direct consequence of a CV investigation/procedure/operation should be considered as a death due to a CV procedure.
  • PCI percutaneous coronary intervention
  • CABG coronary artery bypass graft surgery
  • complication resulting from Ml should also be considered death due to acute Ml.
  • Sudden Cardiac Death refers to a death that occurs unexpectedly, not within 30 days of an acute Ml, and includes the following deaths: death witnessed and instantaneous without new or worsening symptoms; death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms, unless the symptoms suggest an acute Ml; death witnessed and attributed to an identified arrhythmia (e.g., captured on an electrocardiographic (ECG) recording, witnessed on a monitor, or unwitnessed but found on implantable cardioverter-defibrillator review); death after unsuccessful resuscitation from cardiac arrest; death after successful resuscitation from cardiac arrest and without identification of a non-cardiac etiology; and/or unwitnessed death without other cause of death (information regarding the patient’s clinical status preceding death should be provided, if available)
  • ECG electrocardiographic
  • Death due to Congestive Heart Failure refers to a death in association with clinically worsening symptoms and/or signs of heart failure (See Definition of Heart Failure Event, for full details below). Deaths due to heart failure can have various etiologies, including single or recurrent myocardial infarctions, ischemic or non-ischemic cardiomyopathy, hypertension, or valvular disease.
  • Death due to Stroke refers to death after a stroke that is either a direct consequence of the stroke or a complication of the stroke. Acute stroke should be verified to the extent possible by the diagnostic criteria outlined for stroke (See Definition of Transient Ischemic Attack and Stroke, for full details below).
  • Death due to Cardiovascular Procedures refers to death caused by the immediate complications of a cardiac procedure.
  • Death due to Cardiovascular Hemorrhage refers to death related to hemorrhage such as a non-stroke intracranial hemorrhage (see Definition of Transient Ischemic Attack and Stroke, for full details below), non-procedural or non-traumatic vascular rupture (e.g., aortic aneurysm), or hemorrhage causing cardiac tamponade.
  • Death due to Other Cardiovascular Causes refers to a CV death not included in the above categories (e.g., pulmonary embolism or peripheral arterial disease).
  • Non-cardiovascular death is defined as any death that is not thought to be due to a cardiovascular cause. The following is a suggested list of non-cardiovascular causes of death for this trial.
  • Non-infectious e.g., systemic inflammatory response syndrome (SIRS)
  • SIRS systemic inflammatory response syndrome
  • Prescription Drug Error e.g., prescribed drug overdose, use of inappropriate drug, or drug-drug interaction
  • Malignancy Malignancy is coded as cause of death, if:
  • Cancer deaths may arise from cancers that were present prior to randomization or which developed subsequently. It may be helpful to distinguish these two scenarios (i.e. worsening of prior malignancy; new malignancy).
  • Suggested categorization includes the following organ systems; Lung/larynx, breast, leukemia/lymphoma, upper Gl, melanoma, central nervous system, colon/rectum, renal, bladder, prostate, other/unspecified, or unknown.
  • Undetermined Cause of Death refers to a death not attributable to one of the above categories of cardiovascular death or to a non-cardiovascular cause.
  • the inability to classify the cause of death is generally due to lack of information (e.g., the only available information is “patient died”) or when there is insufficient supporting information or detail to assign the cause of death.
  • a cause of death was not readily apparent (e.g., found dead at home)
  • the cause was assumed to be cardiovascular in origin, unless one of the following two scenarios occur: there is no information or data available regarding the circumstances of death other than that a death has occurred; or the available data are conflicting regarding whether the death was cardiovascular or non-cardiovascular.
  • Ml myocardial infarction
  • evidence of myocardial necrosis either changes in cardiac biomarkers or postmortem pathological findings
  • supporting information derived from the clinical presentation electrocardiographic changes, or the results of myocardial or coronary artery imaging.
  • the totality of the clinical, electrocardiographic, and cardiac biomarker information should be considered to determine whether or not a Ml has occurred. Specifically, timing and trends in cardiac biomarkers and electrocardiographic information require careful analysis. The adjudication of Ml should also take into account the clinical setting in which the event occurs. Ml may be adjudicated for an event that has characteristics of a Ml, but which does not meet the strict definition because biomarker or electrocardiographic results are not available. [0476] The Criteria for myocardial infarction include clinical presentation, biomarker evaluation, and ECG changes.
  • Clinical Presentation The clinical presentation is consistent with diagnosis of myocardial ischemia and infarction. Other findings that might support the diagnosis of Ml should be take into account because a number of conditions are associated with elevations in cardiac biomarkers (e.g., trauma, surgery, pacing, ablation, congestive heart failure, hypertrophic cardiomyopathy, pulmonary embolism, severe pulmonary hypertension, stroke or subarachnoid hemorrhage, infiltrative and inflammatory disorders of cardiac muscle, drug toxicity, burns, critical illness, extreme exertion, and chronic kidney disease). Supporting information can also be considered from myocardial imaging and coronary imaging. The totality of the data may help differentiate acute Ml from the background disease process.
  • cardiac biomarkers e.g., trauma, surgery, pacing, ablation, congestive heart failure, hypertrophic cardiomyopathy, pulmonary embolism, severe pulmonary hypertension, stroke or subarachnoid hemorrhage, infiltrative and inflammatory disorders of cardiac muscle, drug toxicity, burn
  • ECG Changes ECG changes can be used to support or confirm a Ml. Supporting evidence may be ischemic changes and confirmatory information may be new Q waves.
  • Criteria for acute myocardial ischemia include:
  • ST elevation New ST elevation at the J point in two anatomically contiguous leads with the cut-off points: ⁇ 0.2 mV in men (> 0.25 mV in men ⁇ 40 years) or ⁇ 0.15 mV in women in leads V2-V3 and/or ⁇ 0.1 mV in other leads.
  • ST depression and T-wave changes new horizontal or down-sloping ST depression ⁇ 0.05 mV in two contiguous leads; and/or new T inversion ⁇ 0.1 mV in two contiguous leads.
  • ECG criteria illustrate patterns consistent with myocardial ischemia.
  • ECG abnormalities may represent an ischemic response and may be accepted under the category of abnormal ECG findings.
  • Criteria for pathological Q-wave include: any Q-wave in leads V2-V3 ⁇ 0.02 seconds or QS complex in leads V2 and V3; Q-wave ⁇ 0.03 seconds and ⁇ 0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V6; V4-V6; II, III, and aVF); and R-wave 0.04 s in V1-V2 and R/S ratio >1 with a concordant positive T-wave in the absence of a conduction defect.
  • Criteria for Prior Myocardial Infarction include: pathological Q-waves, as defined above; and R-wave ⁇ 0.04 seconds in V1-V2 and R/S ⁇ 1 with a concordant positive T-wave in the absence of a conduction defect.
  • Myocardial Infarction Subtypes Several Ml subtypes are commonly reported in clinical investigations and each is defined below:
  • Spontaneous Ml • Detection of rise and/or fall of cardiac biomarkers with at least one value above the URL with at least one of the following: o Clinical presentation consistent with ischemia; o ECG evidence of acute myocardial ischemia; o New pathological Q waves; o Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality; and/or o Autopsy evidence of acute Ml
  • a spontaneous myocardial infarction is defined as one of the following: o Clinical presentation consistent with ischemia; o ECG evidence of acute myocardial ischemia; o New pathological Q waves; o Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality; and/or o Autopsy evidence of acute Ml; and
  • Percutaneous Coronary Intervention-Related Myocardial Infarction is defined by any of the following criteria. Ml associated with and occurring within 48 hours of PCI, with elevation of cardiac biomarker values to > 5 x 99 th percentile of the URL in patients with normal baseline values ( ⁇ 99 th percentile URL), or a rise of [cardiac biomarker] values ⁇ 20% if baseline values are elevated and are stable or falling. This classification also requires at least 1 of the following:
  • Coronary Artery Bypass Grafting-Related (CABG) Myocardial Infarction is defined by the following criteria. Symptoms of cardiac ischemia were not required and data was collected in such a way that analyses using ⁇ 20% or ⁇ 50% could both be performed.
  • Biomarker elevations within 48 hours of CABG o Troponin or CK-MB (preferred) > 10 x 99 th percentile of the URL; and o No evidence that cardiac biomarkers were elevated prior to the procedure; or o Both of the following are true:
  • o New pathological Q-waves A confirmatory ECG is recommended if there have been no clinical symptoms or history of myocardial infarction; o Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause; and/or o Autopsy evidence of a healed or healing Ml.
  • the universal Ml definition includes clinical classification of different types of Ml, electrocardiographic features, and by biomarker evaluation, with the definition of each provided below.
  • Clinical Classification of Different Types of Myocardial Infarction include the following:
  • Type 1 Spontaneous myocardial infarction related to ischemia due to a primary coronary event such as plaque erosion and/or rupture, fissuring, or dissection;
  • Type 2 Myocardial infarction secondary to ischemia due to either increased oxygen demand or decreased supply, e.g., coronary artery spasm, coronary embolism, anemia, arrhythmias, hypertension, or hypotension;
  • Type 3 Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of myocardial ischemia, accompanied by presumably new ST elevation, or new LBBB, or evidence of fresh thrombus in a coronary artery by angiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood;
  • Type 4a Myocardial infarction associated with Percutaneous Coronary Intervention (PCI);
  • Type 4b Myocardial infarction associated with stent thrombosis as documented by angiography or at autopsy;
  • Type 4c Myocardial infarction associated with stent restenosis as detected by angiography or at autopsy;
  • Type 5 Myocardial infarction associated with CABG.
  • Electrocardiographic Features include:
  • STEMI ST-Elevation Ml
  • the additional categories of STEMI include: Q wave, non-Q-wave, or unknown (no ECG or ECG non-interpretable);
  • NSTEMI Non-ST-Elevation Ml
  • Biomarker Elevation per Universal Ml Definition: The magnitude of cardiac biomarker elevation can be calculated as a ratio of the peak biomarker value divided by the 99th percentile URL. The biomarker elevation can be provided for various Ml subtypes.
  • Unstable angina requiring hospitalization is defined as: Ischemic discomfort (angina, or symptoms thought to be equivalent) ⁇ 10 minutes in duration occurring at rest or in an accelerating pattern with frequent episodes associated with progressively decreased exercise capacity;
  • Hospitalization is defined as an admission to an inpatient unit or a visit to an emergency department that results in at least a 24-hour stay (or a date change if the time of admission/discharge is not available);
  • Transient ST elevation (duration ⁇ 20 minutes): New ST elevation at the J point in two anatomically contiguous leads with the cut-off points: ⁇ 0.2 mV in men (>0.25 mV in men ⁇ 40 years) or ⁇ 0.15 mV in women in leads V2-V3 and/or ⁇ 0.1 mV in other leads
  • An early positive exercise stress test defined as ST elevation or ⁇ 2 mm ST depression prior to 5 mets; or at least one of the following: stress echocardiography (reversible wall motion abnormality); myocardial scintigraphy (reversible perfusion defect); or MRI (myocardial perfusion deficit under pharmacologic stress.
  • stress echocardiography reversible wall motion abnormality
  • myocardial scintigraphy reversible perfusion defect
  • MRI myocardial perfusion deficit under pharmacologic stress.
  • o Angiographic evidence of new or worse ⁇ 70% lesion and/or thrombus in an epicardial coronary artery that is believed to be responsible for the myocardial ischemic symptoms/signs
  • PCI or CABG coronary revascularization procedure
  • Escalation of pharmacotherapy for ischemia should be considered supportive of the diagnosis of unstable angina.
  • pharmacotherapy for ischemia such as intravenous nitrates or increasing dosages of
  • Planned hospitalization or re-hospitalization for performance of an elective revascularization in patients who did not fulfill the criteria for unstable angina should not have been considered a hospitalization for unstable angina.
  • hospitalization of a patient with stable exertional angina for coronary angiography and PCI that is prompted by a positive outpatient stress test should not be considered hospitalization for unstable angina; or re-hospitalization of a patient meeting the criteria for unstable angina who was stabilized, discharged, and subsequently readmitted for revascularization, does not constitute a second hospitalization for unstable angina.
  • Transient Ischemic Attack Transient ischemic attack (TIA) is defined as a transient episode ( ⁇ 24 hours) of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.
  • Stroke Stroke is defined as an acute episode of neurological dysfunction caused by focal or global brain, spinal cord, or retinal vascular injury.
  • Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused by an infarction of central nervous system tissue. Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an ischemic stroke with hemorrhagic transformation and not a hemorrhagic stroke.
  • Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal dysfunction caused by a nontraumatic intraparenchymal, intraventricular, or subarachnoid hemorrhage.
  • microhemorrhages seen on T2- weighted MRI imaging, subdural and epidural hemorrhages are not considered hemorrhagic strokes.
  • Undetermined Stroke Undetermined stroke is defined as an acute episode of focal or global neurological dysfunction caused by presumed brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction but with insufficient information to allow categorization as ischemic or hemorrhagic.
  • Stroke Disability should be measured by a reliable and valid scale in all cases, typically at each visit and 90 days after the event.
  • the modified Rankin Scale show below in Table 13 may be used to address this requirement:
  • Heart Failure Event is defined as an event that meets all of the following criteria:
  • the patient’s length-of-stay in hospital extends for at least 24 hours (or a change in calendar date if the hospital admission and discharge times are unavailable);
  • the patient exhibits documented new or worsening symptoms due to HF on presentation, including at least one of the following: dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, paroxysmal nocturnal dyspnea), decreased exercise tolerance, fatigue, or other symptoms of worsened end-organ perfusion or volume overload (must be specified and described by the protocol);
  • the patient has objective evidence of new or worsening HF, consisting of at least two physical examination findings or one physical examination finding and at least one laboratory criterion), including: o Physical examination findings considered to be due to heart failure, including new or worsened: Peripheral edema, increasing abdominal distention or ascites (in the absence of primary hepatic disease), S3 gallop, clinically significant or rapid weight gain thought to be related to fluid retention; or o Laboratory evidence of new or worsening HF, if obtained within 24 hours of presentation, including: increased B-type natriuretic peptide (BNP)/ N- terminal pro-BNP (NT-proBNP) concentrations consistent with decompensation of heart failure (such as BNP > 500 pg/mL or NT- proBNP > 2,000 pg/mL).
  • BNP B-type natriuretic peptide
  • NT-proBNP N- terminal pro-BNP
  • echocardiographic criteria could include: E/e’ > 15 or D-dominant pulmonary venous inflow pattern, plethoric inferior vena cava with minimal collapse on inspiration, or decreased left ventricular outflow tract (LVOT) minute stroke distance (time velocity integral [TVI]) OR right heart catheterization showing a pulmonary capillary wedge pressure (pulmonary artery occlusion pressure) ⁇ 18 mmHg, central venous pressure ⁇ 12 mmHg, or a cardiac index ⁇ 2.2 L/min/m 2 .
  • LVOT left ventricular outflow tract
  • TVI time velocity integral
  • the patient receives initiation or intensification of treatment specifically for HF, including at least one of the following: significant augmentation in oral diuretic therapy, intravenous diuretic, inotrope, or vasodilator therapy, or Mechanical or surgical intervention.
  • the mechanical or surgical intervention including mechanical circulatory support (e.g., intra-aortic balloon pump, ventricular assist device) and/or mechanical fluid removal (e.g., ultrafiltration, hemofiltration, dialysis).
  • New Heart Failure/Heart Failure Not Requiring Hospitalization is defined as an event that meets all of the following: the patient has an urgent, unscheduled office/practice or emergency department visit for a primary diagnosis of HF, but not meeting the criteria for a HF hospitalization; all signs and symptoms for HF hospitalization must be met as defined in A Heart Failure Hospitalization above; and the patient receives initiation or intensification of treatment specifically for HF, as detailed in the above section with the exception of oral diuretic therapy, which was not sufficient.
  • Clinically-Driven Target Lesion Revascularization Revascularization is clinically-driven if the target lesion diameter stenosis is > 50% by quantitative coronary angiography (QCA) and the subject has clinical or functional ischemia which cannot be explained by another native coronary or bypass graft lesion.
  • Clinical or functional ischemia includes any of the following: a history of angina pectoris, presumably related to the target vessel; objective signs of ischemia at rest (electrocardiographic changes) or during exercise test (or equivalent), presumably related to the target vessel; and abnormal results of any invasive functional diagnostic test (e.g., coronary flow reserve [CFR] or fractional flow reserve [FFR]).
  • Non-Target Lesion and Non-Target Lesion Revascularization A lesion for which revascularization is not attempted or one in which revascularization is performed using a non-study device, respectively.
  • Non-Target Vessel and Non-Target Vessel Revascularization A vessel for which revascularization is not attempted or one in which revascularization is performed using a non-study device, respectively.
  • PCI Percutaneous Coronary Intervention
  • Urgent The procedure should be performed on an inpatient basis and prior to discharge because of significant concerns that there is risk of myocardial ischemia, Ml, and/or death. Patients who are outpatients or in the emergency department at the time that the cardiac catheterization is requested would warrant hospital admission based on their clinical presentation.
  • the patient is in cardiogenic shock when the PCI begins (i.e., the time at which the first guide wire or intracoronary device is introduced into a coronary artery or bypass graft for the purpose of mechanical revascularization) or within the last ten minutes prior to the start of the case or during the diagnostic portion of the case, the patient has also received chest compressions or has been on unanticipated circulatory support (e.g., intra-aortic balloon pump, extracorporeal mechanical oxygenation, or cardiopulmonary support).
  • unanticipated circulatory support e.g., intra-aortic balloon pump, extracorporeal mechanical oxygenation, or cardiopulmonary support.
  • PCI Percutaneous Coronary Intervention
  • Peripheral vascular intervention is a catheter-based or open surgical procedure designed to improve peripheral arterial or venous blood flow or otherwise modify or revise vascular conduits. Procedures may include, but are not limited to, balloon angioplasty, stent placement, thrombectomy, embolectomy, atherectomy, dissection repair, aneurysm exclusion, treatment of dialysis conduits, placement of various devices, intravascular thrombolysis or other pharmacotherapies, and open surgical bypass or revision. In general, the intention to perform percutaneous peripheral vascular intervention is denoted by the insertion of a guide wire into a peripheral artery or vein.
  • the target vessel(s) and the type of revascularization procedure should be specified and recorded.
  • this definition applies to the extracranial carotid artery and other noncardiac arteries and veins and excludes the intracranial vessels and lymphatics.
  • Procedural Status includes: • Non-Elective: Non-elective procedures include emergent and urgent procedures. A non-elective procedure is a procedure that is performed without delay, because there is clinical consensus that the procedure should occur imminently. Non- elective procedures imply a degree of instability of the patient, urgency of the medical condition, or instability of the threatening lesion. o Emergent: A procedure that is performed immediately because of the acute nature of the medical condition (e.g., acute limb ischemia, acute aortic dissection), and the increased morbidity or mortality associated with a temporal delay in treatment.
  • o Urgent An urgent procedure is one that is not emergent but required to be performed on a timely basis 24 hrs) (e.g., a patient who has been stabilized following initial treatment of acute limb ischemia, and there is clinical consensus that a definitive procedure should occur within the next 24 hours).
  • An elective procedure is one that is scheduled and is performed on a patient with stable disease, or in whom there is no urgency and/or increased morbidity or mortality associated with a planned procedure.
  • Any revascularization includes any arterial vascular intervention done to treat ischemia or prevent major ischemic events, including percutaneous or surgical intervention of the coronary, peripheral, or carotid arteries. Aneurysm repairs, dissection repairs, arterial-venous fistula or graft placement or repairs, or renal arterial intervention for hypertension or renal dysfunction are not included.
  • Bradyarrhythmia - High-level AV block (defined as third-degree AV block or second-degree AV block), junctional or ventricular escape rhythm, or severe sinus bradycardia (typically with heart rate ⁇ 30 bpm).
  • the bradycardia must require temporary or permanent pacing.
  • Cardiac Arrest Sudden Cardiac Death: A sudden, unexpected death due to the cessation of cardiac mechanical activity, confirmed by the absence of a detectable pulse, unresponsiveness, and apnea (or agonal, gasping respirations) of presumed cardiac etiology. An arrest is presumed to be cardiac (i.e., related to heart disease) if this is likely, based on the available information, including hospital records and autopsy data.
  • the cardiac arrest is further sub-classified into either: witnessed, occurring within 60 min from the onset of new symptoms, in the absence of a clear cause other than cardiovascular; or unwitnessed, within 24 hours of being observed alive, in the absence of pre-existing other non-cardiovascular causes of death;
  • Non-cardiac causes of cardiac arrest, such as drug overdose, suicide, drowning, hypoxia, exsanguination, cerebrovascular accident, subarachnoid hemorrhage, or trauma must not be present.
  • Resuscitated Cardiac Arrest is present when there is restoration of both: organized electrical activity and organized mechanical activity resulting in restoration of spontaneous circulation (defined as the documented presence of a measurable pulse and blood pressure at any time after initiation of resuscitative efforts).
  • Criteria for the Diagnosis of Metabolic Syndrome The diagnosis of metabolic syndrome requires the presence of three out of the following five specific components using the following criteria with cut points of parameters as defined in Table 1 and listed below, and waist circumference cut points further guided by the Table 14.
  • HDL-C • Reduced HDL-C (HDL-C ⁇ 40 mg/dL if male; HDL-C ⁇ 50 mg/dL if female);
  • Elevated blood pressure (systolic ⁇ 130 mmHg and/or diastolic ⁇ 85 mmHg, or an antihypertensive therapy with medical history of hypertension;
  • Subject Disposition The subject disposition by treatment group is depicted in Figure 2. A total of 19,212 patients were screened of whom 8,179 (43%) were randomized. At the time of database lock, vital status was available in 99.8%; 152 (1 .9%) patients did not complete final study visits and 578 (7.1%) patients withdrew consent.
  • Demographic and Baseline Disease Characteristics Among the patients who underwent randomization, 70.7% were enrolled on the basis of secondary prevention (i.e., patients had established cardiovascular disease) and 29.3% for primary prevention (i.e., patients had diabetes mellitus and at least one additional risk factor). The median age was 64 years, 28.8% were female, and 38.5% were from the United States. At baseline, the median LDL-cholesterol was 75.0 mg/dL, HDL-cholesterol was 40.0 mg/dL, and triglycerides were 216.0 mg/dL. The baseline characteristics of the patients are provided below in Table 16.
  • the median change in LDL cholesterol level from baseline was an increase of 3.1% (2.0 mg/dL [0.05 mmol/L]) in the AMR101 group and an increase of 10.2% (7.0 mg /dL [0.18 mmol/L]) in the placebo group — a 6.6% (5.0 mg/dL [0.13 mmol/L]) lower increase with AMR101 than with placebo (P ⁇ 0.001).
  • Figure 3A shows the Kaplan-Meier event curves for the primary efficacy endpoint of time to first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina in the AMR101 and placebo groups with the inset showing the data on an expanded y axis. All patients were included in the analysis and patients experiencing more than one type of endpoint event were counted for their first occurrence in each event type.
  • Figure 3A The primary endpoint as shown in Figure 3A occurred in 17.2% of AMR101 patients versus in 22.0% of placebo patients (HR, 0.75; 95% Cl, 0.68- 0.83; P ⁇ 0.001 ) for an absolute risk reduction (AAR) of 4.8% (95% Cl, 3.1 -6.5%) and number needed to treat (NNT) of 21 (95% Cl, 15-33) over median follow up 4.9 years.
  • AAR absolute risk reduction
  • NNT number needed to treat
  • Figure 3B shows the Kaplan-Meier estimates of the cumulative incidence of the primary composition endpoints over time.
  • Figure 3B indicates a 25% relative risk reduction for the primary composite endpoint over the course of 5 years.
  • Figure 4 lists the individual components of the primary endpoint analyzed as time to first event of each individual endpoint. Shown first in Figure 4 is the HR and 95% Cl for the primary composite endpoint event (time to first occurrence of either cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina). Shown separately beneath Figure 4 are HRs and 95% Cis for time to first occurrence of each type of individual primary endpoint component event, irrespective of whether contributing to the primary composite endpoint event or not. [0534] Analyses of Key Secondary Endpoints:
  • Figure. 5A shows the Kaplan-Meier event curves for the key secondary efficacy endpoint of time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in the AMR101 and placebo groups with the inset showing the data on an expanded y axis. All patients were included in the analysis and patients experiencing more than one type of endpoint event were counted for their first occurrence in each event type.
  • Figure 5A occurred in 11 .2% of AMR101 patients versus 14.8% of placebo patients (HR, 0.74, 95% Cl 0.65-0.83, P ⁇ 0.001 ) for an absolute risk reduction of 3.6% (95% Cl, 2.1 -5.0%) and a number needed to treat of 28 (95% Cl, 20-47) over median follow up 4.9 years.
  • Figure 5B shows the Kaplan-Meier estimates of the cumulative incidence of the key secondary composition endpoints over time. Significantly, Figure 5B indicates a 26% relative risk reduction for the key secondary composite endpoint over the course of 5 years.
  • FIGS 8 and 9 The key secondary efficacy outcomes in select prespecified subgroups are shown in Figures 8 and 9 with corresponding HRs and 95% Cis for the key secondary efficacy endpoint of time to first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina from select prespecified subgroups in the AMR101 and placebo groups.
  • Figures 6-9 indicate that a subject’s baseline triglyceride levels (e.g., ⁇ 150 vs. ⁇ 150 mg/dL or ⁇ 200 or ⁇ 200 mg/dL) had no influence on the primary or key secondary efficacy endpoints.
  • Figures 10A and 10B show that achievement of on-treatment triglyceride levels above or below 150 mg/dL at one year did not influence the efficacy of AMR101 versus placebo.
  • Figures 10A and 10B show the primary and key secondary endpoints by achieved triglyceride level (e.g., above or below 150 mg/dL) at 1 year (e.g., patients with a triglyceride level above or below 150 mg/dL after 1 year of having received the AMR101).
  • Figure 10A are the Kaplan-Meier curves for the primary endpoint of time to first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina in the AMR101 treatment group for patients with achieved triglycerides, and the placebo group at year 1 .
  • Figure 10B are the Kaplan-Meier event curves for the key secondary endpoint of time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in the AMR101 treatment group for patients with achieved triglycerides, and the placebo group at year 1 .
  • Figures 10A and 10B indicate that regardless of the subject’s triglyceride levels at year 1 , the subject experienced a statistically significant reduction in time to first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina.
  • the attainment of triglyceride levels of 150 mg/dL or higher or below 150 mg/dL at 1 year after randomization also had no influence on the efficacy of AMR101 as compared with placebo with respect to the primary or key secondary efficacy endpoint.
  • icosapent ethyl 4g per day provide a RRR of 25% for the primary composite endpoint, 26% for the secondary composite endpoint, 25% for the composite of cardiovascular death or nonfatal myocardial infarction, 31% for fatal or nonfatal myocardial infarction, 35% for urgent or emergent revascularization, 20% for cardiovascular death, 32% for hospitalization for unstable angina, 28% for fatal or nonfatal stroke, 23% reduction in the composite of total mortality, nonfatal myocardial infarction, or nonfatal stroke, and lastly, a 13% reduction in total mortality.
  • Results for selected tertiary outcomes are shown in Table 17.
  • a tertiary endpoint, adjudicated sudden cardiac death was 2.1% versus 1 .5% (HR, 0.69; 95% Cl, 0.50- 0.96).
  • Adverse events occurring in ⁇ 5% are reported in Table 22.
  • AMR101 was associated with a significantly higher rate of atrial fibrillation (5.3% versus 3.9%), and peripheral edema (6.5% vs 5%), but a lower rate of diarrhea (9% vs 11.1 %), anemia (4.7% vs 5.8%), and gastrointestinal adverse events (33.0% to 35.1%).
  • a triglyceride level ⁇ 150 mg/dL was required for inclusion in this study however, owing to initial allowance for variability in these levels and differences between qualifying and randomization measurements, 10.3% of enrolled patients had triglycerides less than 150 mg/dL on study entry. Cardiovascular benefits appeared similar across baseline levels of triglycerides (e.g., 135-149, 150 to 199, and 200 mg/dL or greater).
  • the goal of the following study was to determine if icosapent ethyl administered at 4 g per day (e.g., 2 g twice daily) reduces total major adverse cardiovascular events in patients with fasting triglycerides ⁇ 150 and ⁇ 500 mg/dL and LDL-cholesterol >40 and ⁇ 100 mg/dL who are at increased cardiovascular risk despite statin therapy.
  • established cardiovascular disease i.e., secondary prevention stratum
  • ⁇ 50 years old with type 2 or type 1 diabetes mellitus requiring treatment with medication and at least one additional risk factor i.e., primary prevention stratum.
  • the secondary prevention stratum consisted of patients with documented coronary artery disease ( ⁇ 50% stenosis in at least two major epicardial coronary arteries with or without prior revascularization; prior Ml; hospitalization for non-ST-segment elevation acute coronary syndrome with ST-segment deviation or positive biomarkers); documented cerebrovascular disease (prior ischemic stroke; symptomatic ⁇ 50% carotid stenosis; asymptomatic carotid disease with ⁇ 70% stenosis; history of carotid revascularization); or documented peripheral artery disease (ankle-brachial index ⁇ 0.9 with symptoms of intermittent claudication; history of aorto-iliac or peripheral surgery or intervention).
  • documented coronary artery disease ⁇ 50% stenosis in at least two major epicardial coronary arteries with or without prior revascularization; prior Ml; hospitalization for non-ST-segment elevation acute coronary syndrome with ST-segment deviation or positive biomarkers
  • the primary prevention stratum consisted of patients with no documented cardiovascular disease as defined above, with diabetes, and with at least one of the following cardiovascular risk factors: men ⁇ 55 years of age or women ⁇ 65 years of age; cigarette smoker or stopped smoking within 3 months before first visit; blood pressure ⁇ 140 mmHg systolic or ⁇ 90 mmHg diastolic or on antihypertensive medication; HDL-cholesterol ⁇ 40 mg/dL for men or ⁇ 50 mg/dL for women; hsCRP >3 mg/L; creatinine clearance >30 and ⁇ 60 mL/min; non-proliferative retinopathy, pre-proliferative retinopathy, proliferative retinopathy, maculopathy, advanced diabetic eye disease or a history of photocoagulation; micro- or macro-albuminuria; or asymptomatic ankle-brachial index ⁇ 0.9.
  • Exclusion criteria for the study participants included severe heart failure or liver disease, hemoglobin A1c levels >10.0%, planned coronary intervention, familial lipoprotein lipase deficiency, intolerance or hypersensitivity to statins, history of acute or chronic pancreatitis, and hypersensitivity to fish, shellfish, or ingredients of icosapent ethyl or placebo.
  • the primary outcome for the study was total recurrent events consisting of the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. Recurrent event analyses were also performed for the key secondary endpoint, a composite of cardiovascular death, nonfatal myocardial infarction, or non-fatal stroke. For each of these composite endpoints, the effects of icosapent ethyl in the secondary and primary prevention strata were examined separately.
  • Demographic and baseline disease characteristics are presented using frequencies and percentages for categorical variables and medians with interquartile ranges for continuous variables. Between treatment group comparisons were derived using the chi- square test for categorical variables and Wilcoxon rank test for continuous variables. All clinical endpoint events used in the efficacy analyses were adjudicated by an independent Clinical Endpoint Committee (CEC) who were blinded to the treatment assignment. Since the primary efficacy endpoint was the time from randomization to the first occurrence of any component of the composite endpoint, and recurrence of such events within each patient is possible, a pre-specified analysis using a Cox proportional-hazard with the counting-process formulation of Andersen and Gill was performed to model the first and all recurrent cardiovascular events.
  • CEC Clinical Endpoint Committee
  • Table 26 Secondary and Primary Prevent Per Adjusted Stratification for Patients Randomized to Placebo or Icosapent Ethyl.
  • Table 27 Baseline Characteristics of Patients with No Events, a Single Event, or Multiple Events.
  • Total Events for Primary Efficacy Endpoint The total events for the primary efficacy endpoint showed that of 8,179 patients, there were 1 ,606 (i.e., 55.2% of the endpoints) first primary endpoints and 1 ,303 (i.e., 44.8% of the endpoints) additional primary endpoints, for a total of 2,909 endpoint events among the 1 ,606 patients. There were 762 second events, 272 third events, and 269 fourth or more events.
  • Figure 13 shows a distribution of first and recurrent events in the patients randomized to icosapent ethyl or placebo before and after the trial.
  • Figures 14-16 depict the overall cumulative event curves from the primary endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and unstable angina. The overall cumulative events are shown in Figure 14, the secondary prevention stratum events are shown in Figure 15, and the primary prevention stratum events are shown in Figure 16.
  • FIGS 21 -23 depict the cumulative event curves from the key secondary endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The overall cumulative events are shown in Figure 21 , the secondary prevention stratum events are shown in Figure 22, and the primary prevention stratum events are shown in Figure 23.
  • Total key secondary endpoints were significantly reduced from 861 to 590 (HR 0.71 , 95% Cl 0.63-0.79, P ⁇ 0.0001) with icosapent ethyl versus placebo as shown in Figure 21.
  • Figures 24-29 show the total events for the primary and key secondary efficacy endpoints as a function of the total cumulative incidence vs years since randomization.
  • Figures 14-16 and Figures 21 -23 which report the total events for the primary and key secondary efficacy endpoints as a function of the mean cumulative function vs follow up time in days from randomization.
  • Figures 24 and 25 show the overall mean cumulative recurrent events of the primary composite endpoint and key secondary endpoint, respectively.
  • Figures 26 and 27 depict the recurrent events of primary and key secondary endpoints for the secondary prevention stratum, respectively.
  • Figures 28 and 29 further depict the recurrent events of primary and key secondary endpoints for the primary prevention stratum, respectively.
  • Icosapent ethyl was well tolerated with no significant difference in rates of serious adverse events versus placebo. Although overall rates were low in both treatment groups, and none of the events were fatal, there was a trend towards increased serious bleeding with no significant increases in adjudicated hemorrhagic stroke, serious central nervous system bleeding, or gastrointestinal bleeding. There was a small, but statistically significant increase in hospitalization for atrial fibrillation or flutter noted in the REDUCE-IT study as described in Example 1 . Nevertheless, the large number of important ischemic events averted, including a significant reduction in cardiovascular death, provides a very favorable risk-benefit profile. Given the broad inclusion criteria and relatively few exclusion criteria, these results are likely generalizable to a large proportion of statin-treated patients with atherosclerosis or diabetes.
  • icosapent ethyl 4 g per day significantly reduces total ischemic events in patients with established atherosclerosis or with diabetes and additional cardiovascular risk factors already being treated with statin therapy, with consistent benefits across a variety of individual ischemic endpoints.
  • icosapent ethyl reduces total ischemic events in both secondary and primary prevention.
  • icosapent ethyl should be considered in order to reduce the total burden of atherosclerotic events.
  • Example 2 As described above in Example 1 , in time-to-first-event analyses, icosapent ethyl significantly reduced the risk of ischemic events, including cardiovascular death, among patients with elevated triglycerides receiving statins. However, these patients remain at risk for first and subsequent ischemic events. Results from Example 2 indicated that the use icosapent ethyl was superior as compared to a placebo in reducing total ischemic events, with a consistent benefit in secondary as well as primary prevention. The objective of the study described in this example was to use pre-specified analyses to determine the extent to which icosapent ethyl reduced total ischemic events in patients from the REDUCE- IT trial.

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Abstract

Dans divers modes de réalisation, la présente divulgation concerne des procédés réduisant le risque d'accidents cardiovasculaires chez un sujet traité par statines grâce à l'administration au sujet d'un acide eicosapentaénoïque ou d'un dérivé de celui-ci et de colchicine.
PCT/US2022/022760 2021-03-31 2022-03-31 Compositions comprenant de l'epa et de la colchicine et leurs procédés d'utilisation pour réduire le risque d'accidents cardiovasculaires chez un sujet WO2022212655A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10278936B2 (en) * 2012-06-29 2019-05-07 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of a cardiovascular event in a subject on statin therapy
US10842762B2 (en) * 2012-11-02 2020-11-24 Murray And Poole Enterprises Ltd Method of treating cardiovascular events using colchicine concurrently with an antiplatelet agent

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10278936B2 (en) * 2012-06-29 2019-05-07 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of a cardiovascular event in a subject on statin therapy
US10842762B2 (en) * 2012-11-02 2020-11-24 Murray And Poole Enterprises Ltd Method of treating cardiovascular events using colchicine concurrently with an antiplatelet agent

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