Methods of reducing risk of cardiovascular events in subject with atrial fibrillation and / or atrial flutter

Abstract

To provide methods for treating and preventing cardiovascular diseases and disorders.SOLUTION: The present disclosure provides methods for reducing the risk of cardiovascular events in a subject receiving statin therapy and having atrial fibrillation and / or flutter by administering to the subject a pharmaceutical composition comprising about 1 g to about 4 g of eicosapentaenoic acid ethyl ester or a derivative thereof.SELECTED DRAWING: Figure 1

Description

Detailed Description of the Invention

[0001] Priority claims This application claims priority to U.S. Provisional Patent Application No. 62 / 934,121, filed November 12, 2019, U.S. Provisional Patent Application No. 62 / 934,637, filed November 13, 2019, U.S. Provisional Patent Application No. 62 / 934,952, filed November 13, 2019, U.S. Provisional Patent Application No. 62 / 934,879, filed November 13, 2019, U.S. Provisional Patent Application No. 62 / 976,683, filed February 14, 2020, and U.S. Provisional Patent Application No. 62 / 948,058, filed December 13, 2019, the entire contents of which are incorporated herein by reference.

[0002] [Background technology] 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 cardiovascular diseases or disorders, including, but not limited to, hypertension, coronary heart disease, dyslipidemia, congestive heart failure, and stroke.

[0003] Lovaza®, a lipid-regulating agent, is indicated as a dietary supplement to reduce triglyceride levels in adult patients with very high triglyceride levels. Unfortunately, Lovaza® can significantly increase LDL-C and / or non-HDL-C levels in some patients. There is a need for improved treatments for cardiovascular diseases and disorders.

[0004] [Summary of the Invention] In various embodiments, the present disclosure provides methods of treating and preventing cardiovascular diseases and disorders.

[0005] In various embodiments, the present disclosure provides methods of treating and preventing cardiovascular diseases and disorders.

[0006] In one aspect, the disclosure provides a method for treating a patient, comprising determining, or determining whether the patient has a triglyceride level of at least 150 mg / dl and a history of atrial fibrillation and / or atrial flutter by obtaining, or having obtained, information indicating that the patient has a triglyceride level of at least 150 mg / dl, previously had symptoms of atrial fibrillation and / or atrial flutter, and / or has been previously diagnosed as suffering from atrial fibrillation and / or atrial flutter, and / or monitoring, or having monitored, the subject for triglyceride levels of at least 150 mg / dl and symptoms of atrial fibrillation and / or atrial flutter; and (a) determining that the patient previously had symptoms of atrial fibrillation and / or atrial flutter, previously was diagnosed as suffering from atrial fibrillation and / or atrial flutter, and / or has a history of atrial fibrillation and / or atrial flutter during monitoring. and / or symptoms of atrial fibrillation and / or atrial flutter, (i) determining whether the risk of the patient experiencing symptoms of atrial fibrillation and / or atrial flutter is greater than the reduction in the risk of one or more cardiovascular events in the patient when the patient is administered about 4 g of eicosapentaenoic acid (EPA) per day, or (ii) determining whether the reduction in risk of one or more cardiovascular events is greater than the risk of the patient experiencing symptoms of atrial fibrillation and / or atrial flutter when the patient is administered about 4 g of EPA per day; (b) if the patient in (i) is at greater risk of experiencing symptoms of atrial fibrillation and / or atrial flutter, administering to the patient an atrial fibrillation flutter and / or atrial flutter therapeutic agent instead of about 4 g of EPA per day; and (c) if the patient in (ii) is at greater risk of having a reduced risk of one or more cardiovascular events, administering about 4 g of EPA per day to the patient.

[0007] In some embodiments, if a subject in (c) is administered about 4 g of EPA per day, they are likely to experience both (1) an increase in the frequency of atrial fibrillation and / or atrial flutter episodes, and (2) a decrease in the frequency of cardiovascular events. In some embodiments, if the subject is being treated with a statin, they will continue to be treated with the statin regardless of whether they are in (a) or (b).

[0008] In another aspect, the disclosure provides a method for treating a subject, comprising determining or having determined whether the subject has a triglyceride level of at least 150 mg / dl and a history of atrial fibrillation and / or atrial flutter by (i) obtaining or having obtained information indicating that the subject has a triglyceride level of at least 150 mg / dl and has previously had symptoms of atrial fibrillation and / or atrial flutter and / or has been previously diagnosed as suffering from atrial fibrillation and / or atrial flutter, and / or (ii) monitoring or having monitored the subject for a triglyceride level of at least 150 mg / dl and symptoms of atrial fibrillation and / or atrial flutter, and (a) determining whether the subject has previously had symptoms of atrial fibrillation and / or atrial flutter and has previously been diagnosed with atrial fibrillation and / or atrial flutter. and / or atrial flutter, and / or symptoms of atrial fibrillation and / or atrial flutter are determined during monitoring, administering an atrial fibrillation and / or atrial flutter therapeutic agent to the subject; and (b) if the subject does not have previous symptoms of atrial fibrillation and / or atrial flutter, has not previously been diagnosed as having atrial fibrillation and / or atrial flutter, and / or symptoms of atrial fibrillation and / or atrial flutter are not determined during monitoring, administering about 4 g of eicosapentaenoic acid (EPA) to the subject per day to reduce the risk of a cardiovascular event, wherein after administration of the atrial fibrillation and / or atrial flutter therapeutic agent, the risk of atrial fibrillation and / or atrial flutter in the subject in (a) is lower than if the subject in (a) were administered about 4 g of EPA per day.

[0009] In some embodiments, a subject in (a) is likely to experience both (1) an increase in the frequency of atrial fibrillation and / or atrial flutter episodes and (2) a decrease in the frequency of cardiovascular events when administered about 4 g of EPA per day. In some embodiments, the subject is being treated with a statin, and continues to be treated with the statin regardless of whether the subject is in (a) or (b).

[0010] In another aspect, the disclosure provides a method of treatment comprising: identifying subjects with measured triglyceride levels greater than 150 mg / dl who have previously experienced symptoms of atrial fibrillation or atrial flutter; determining that individuals with triglyceride levels greater than 150 mg / dl who have previously experienced episodes of atrial fibrillation or atrial flutter are likely to experience both (1) an increase in the frequency of episodes of atrial fibrillation or atrial flutter and (2) a decrease in the frequency of cardiovascular events other than atrial fibrillation or atrial flutter upon treatment with 4 g of eicosapentaenoic acid (EPA) per day; and determining whether or not the individuals have a high risk of developing atrial fibrillation or atrial flutter. provides a method of treatment comprising treating the subject with either (a) determining that the subject's reduction in frequency of cardiovascular events other than atrial fibrillation or atrial flutter is worth the risk of increasing the frequency of atrial fibrillation or atrial flutter in the subject, and therefore treating the subject with 4 g of EPA per day, or (b) determining that the subject's reduction in frequency of cardiovascular events other than atrial fibrillation or atrial flutter is not worth the risk of increasing the frequency of atrial fibrillation or atrial flutter in the subject, and therefore selecting to exclude the subject from treatment with EPA and instead treat the subject with a statin.

[0011] In some embodiments, the disclosure provides a method of treatment, comprising identifying subjects with measured triglyceride levels greater than 150 mg / dl who are being treated with a statin and who have previously experienced symptoms of atrial fibrillation or atrial flutter, and determining that individuals with triglyceride levels greater than 150 mg / dl who are being treated with a statin and who have previously experienced episodes of atrial fibrillation or atrial flutter are likely to experience both (1) an increase in the frequency of episodes of atrial fibrillation or atrial flutter and (2) a decrease in the frequency of cardiovascular events other than atrial fibrillation or atrial flutter upon treatment with 4 g of eicosapentaenoic acid (EPA) per day. and treating with either (a) or (b): (a) determining that the subject's reduction in frequency of cardiovascular events other than atrial fibrillation or atrial flutter is worth the risk of increasing the frequency of atrial fibrillation or atrial flutter in the subject, and therefore treating the subject with 4 g of EPA per day and a statin; or (b) determining that the subject's reduction in frequency of cardiovascular events other than atrial fibrillation or atrial flutter is not worth the risk of increasing the frequency of atrial fibrillation or atrial flutter in the subject, and therefore selecting to exclude the subject from treatment with EPA and instead continue treating the subject with a statin.

[0012] In yet another aspect, the disclosure provides a method of treatment comprising identifying subjects with measured triglyceride levels greater than 150 mg / dl who are being treated with a statin and who have a prior history of atrial fibrillation or atrial flutter, and determining that individuals with triglyceride levels greater than 150 mg / dl who are being treated with a statin and who have a prior history of atrial fibrillation or atrial flutter, upon treatment with 4 g of eicosapentaenoic acid (EPA) per day, experience both: (1) an increase in the frequency of episodes of atrial fibrillation or atrial flutter; and (2) an increase in the predicted cardiovascular benefits resulting from EPA treatment. and selecting treatment with either (a) or (b): (a) determining that the predicted cardiovascular benefit is worth the risk of increased frequency of atrial fibrillation or atrial flutter in the subject, and therefore treating the subject with 4 g of EPA per day; or (b) determining that the predicted cardiovascular benefit is not worth the risk of increased frequency of atrial fibrillation or atrial flutter in the subject, and therefore excluding the subject from treatment with EPA and treating the subject with a statin instead.

[0013] In another aspect, the disclosure provides a method for reducing the risk of a cardiovascular event in a subject having a triglyceride level of at least about 150 mg / dl, comprising administering to the subject at least about 4 g of eicosapentaenoic acid (EPA) per day for a period of time that is effective to reduce a cardiovascular event, wherein the subject develops atrial fibrillation and / or atrial flutter during the period of time that is effective to reduce the risk of a cardiovascular event.

[0014] In some embodiments, the present disclosure provides a method for reducing the risk of cardiovascular events in a subject under the age of 65 years and having a triglyceride level of at least about 150 mg / dl, comprising administering to the subject at least about 4 g of eicosapentaenoic acid (EPA) per day for a period of time that is effective to reduce cardiovascular events, wherein the subject does not exhibit increased symptoms of atrial fibrillation and / or atrial flutter.

[0015] In some embodiments, the atrial fibrillation and / or atrial flutter medication is one or more of warfarin, a beta-blocker, and a calcium channel blocker. In some embodiments, warfarin is administered at a dose of about 25 mg per day.

[0016] In some embodiments, reducing the subject's risk of a cardiovascular event further comprises determining that one or more cardiovascular benefits are predicted to occur. In some embodiments, the cardiovascular event does not include atrial fibrillation and / or atrial flutter.

[0017] In some embodiments, the subject does not have a history of atrial fibrillation and / or atrial flutter before administering 4g of EPA.In some embodiments, the subject has established cardiovascular disease.In some embodiments, established cardiovascular disease is determined by the existence of any one of documented coronary artery disease, documented cerebrovascular disease, documented carotid artery disease, documented peripheral artery disease, or a combination thereof.In some embodiments, the subject does not have established cardiovascular disease, but has at least two risk factors for cardiovascular disease.

[0018] In some embodiments, EPA is administered to a subject in dosage units 1 to 4 times per day, hi some embodiments, the subject is administered EPA for at least about 4 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.

[0019] In some embodiments, the subject has one or more of a baseline non-HDL-C level of about 200 mg / dL to about 300 mg / dL, a baseline total cholesterol level of about 250 mg / dL to about 300 mg / dL, a baseline VLDL-C level of about 140 mg / dL to about 200 mg / dL, a baseline HDL-C level of about 10 to about 30 mg / dL, and / or a baseline LDL-C level of about 40 to about 100 mg / dL. [Brief explanation of the drawings]

[0020] [Figure 1] FIG. 1 is a schematic diagram of a study design according to an embodiment of the present disclosure. [Figure 2] FIG. 1 is a schematic diagram illustrating a patient breakdown according to an embodiment of the present disclosure. [Figure 3A] Representative Kaplan-Meier event curves for the cumulative incidence of the primary composite endpoint. Figures 3A and 3B show a 25% relative risk reduction for the primary composite endpoint over 5 years. [Figure 3B] Representative Kaplan-Meier event curves for the cumulative incidence of the primary composite endpoint. Figures 3A and 3B show a 25% relative risk reduction for the primary composite endpoint over 5 years. [Figure 4] Representative forest plot of the individual components of the primary endpoint analyzed as time to first event for each individual endpoint, showing that each component was reduced individually. [Figure 5A] Representative Kaplan-Meier event curves for the cumulative incidence of the key secondary composite endpoint. Figures 5A and 5B show that there was a 26% RRR for the key secondary composite endpoint over 5 years. [Figure 5B] Representative Kaplan-Meier event curves for the cumulative incidence of the key secondary composite endpoint. Figures 5A and 5B show that there was a 26% RRR for the key secondary composite endpoint over 5 years. [Figure 6] Representative forest plot analysis of the individual components of the primary and key secondary endpoints in the ITT population. [Figure 7]Representative forest plots of the primary efficacy outcome in certain pre-specified subgroups. Figures 6 and 7 show that the subject's baseline triglyceride level (e.g., ≥ 150 vs < 150 mg / dL or ≥ 200 vs < 200 mg / dL) did not affect the primary endpoint outcome. [Figure 8] Representative forest plots of the primary efficacy outcome in certain pre-specified subgroups. Figures 6 and 7 show that the subject's baseline triglyceride level (e.g., ≥ 150 vs < 150 mg / dL or ≥ 200 vs < 200 mg / dL) did not affect the primary endpoint outcome. [Figure 9] Representative forest plots of secondary efficacy outcomes in certain pre-specified subgroups. Figures 9 and 10 show that a subject's baseline triglyceride level (e.g., ≥ 150 vs < 150 mg / dL or ≥ 200 vs < 200 mg / dL) did not affect the key secondary endpoint outcomes. [Figure 10] Representative forest plots of secondary efficacy outcomes in certain pre-specified subgroups. Figures 9 and 10 show that a subject's baseline triglyceride level (e.g., ≥ 150 vs < 150 mg / dL or ≥ 200 vs < 200 mg / dL) did not affect the key secondary endpoint outcomes. [Figure 11] Representative Kaplan-Meier curves of the primary and key secondary endpoints by achieved triglyceride levels at 1 year. Figures 11A and 11B show that a patient's triglyceride levels did not affect the efficacy of icosapent ethyl compared to placebo for the primary or key secondary efficacy outcomes. [Figure 12] Representative forest plot of pre-specified hierarchical testing of endpoints showing that all individual and composite ischemic endpoints were significantly reduced by icosapent ethyl (AMR101). [Figure 13] 1 is a representative plot of median triglycerides over time for the ITT population. [Figure 14] 1 is a representative plot of median LDL-C (Hopkins approximation) for the ITT population. [Figure 15] 1 is a representative Kaplan-Meier curve of time from date of randomization to early termination of the study for the ITT population. [Figure 16] FIG. 1 is a schematic diagram of a study design according to an embodiment of the present disclosure. [Figure 17] Figure 13 is a representative bar graph showing the distribution of first, second, and recurrent ischemic events in patients randomized to icosapent ethyl (IPE) compared to placebo. [Figure 18] 1 is a representative Kaplan-Meier event curve for the primary endpoint, overall cumulative events, showing a reduction in the overall cumulative primary endpoint in patients randomized to icosapent ethyl. [Figure 19] 16 is a representative Kaplan-Meier event curve of cumulative events for the primary endpoint for patients in the secondary prevention cohort, similar to FIG. 18, showing that the cumulative primary endpoint was also reduced in patients in the secondary prevention cohort randomized to icosapent ethyl. [Figure 20] 16 is a representative Kaplan-Meier event curve of cumulative events for the primary endpoint for patients in the primary prevention cohort, showing that similar to Figures 18 and 19, the cumulative primary endpoint was also reduced in patients in the primary prevention cohort randomized to icosapent ethyl. [Figure 21] Figure 21 is a representative forest plot of total events for each occurrence of the primary endpoint. Figure 21 shows that the time to the first, second, third, or fourth occurrence of the primary composite endpoint was consistently reduced in the icosapent ethyl group compared to placebo. [Figure 22] Representative pie charts of the rates of first and subsequent primary endpoint events overall and by component are included. [Figure 23] 1 is a representative graph showing the difference in risk for the composite primary endpoint for 100 patients treated with icosapent ethyl versus placebo for 5 years. [Figure 24] Representative forest plot of total events for each occurrence of the primary and key secondary efficacy endpoints. Figure 24 shows that total events for each component of the primary endpoint were significantly reduced. [Figure 25] 1 is a representative Kaplan-Meier curve of overall cumulative events for a key secondary endpoint showing a reduction in the overall cumulative key secondary endpoint in patients randomized to icosapent ethyl. [Figure 26] 26 is a representative Kaplan-Meier curve of cumulative events for key secondary endpoints for patients in the secondary prevention cohort, similar to FIG. 25, showing that the cumulative key secondary endpoint was also reduced in patients in the secondary prevention cohort randomized to icosapent ethyl. [Figure 27] 26 is a representative Kaplan-Meier curve of cumulative events of key secondary endpoints for patients in the primary prevention cohort, similar to Figures 25 and 26, showing that the cumulative primary endpoint was also reduced in patients in the primary prevention cohort randomized to icosapent ethyl. [Figure 28] FIG. 1 is a representative overall cumulative Kaplan-Meier event curve as a function of years from randomization of the primary endpoint showing reduction in the overall cumulative primary endpoint in patients randomized to icosapent ethyl. [Figure 29] 1 is a representative Kaplan-Meier curve of overall cumulative events as a function of years from randomization for key secondary endpoints, showing that the overall cumulative key secondary endpoint was reduced in patients randomized to icosapent ethyl. [Figure 30] 1 is a representative Kaplan-Meier curve of the key secondary endpoint of recurrent events as a function of years from randomization for patients in the secondary prevention cohort, showing that the cumulative primary endpoint was also reduced in patients in the secondary prevention cohort randomized to icosapent ethyl. [Figure 31]1 is a representative Kaplan-Meier curve of recurrent events of the key secondary endpoint as a function of years from randomization for patients in the secondary prevention cohort, showing that the cumulative key secondary endpoint was also reduced in patients in the secondary prevention cohort randomized to icosapent ethyl. [Figure 32] 1 is a representative Kaplan-Meier curve of primary endpoint recurrent events as a function of years since randomization for patients in the primary prevention cohort, showing that the cumulative primary endpoint was also reduced in patients in the primary prevention cohort randomized to icosapent ethyl. [Figure 33] 1 is a representative Kaplan-Meier curve of recurrent events of the key secondary endpoint as a function of years since randomization for patients in the primary prevention cohort, showing that the cumulative key secondary endpoint was reduced in patients in the primary prevention cohort randomized to icosapent ethyl. [Figure 34] 1 is a representative plot of total events by number of events per patient for the primary composite endpoint and each individual component for patients randomized to icosapent ethyl and placebo. [Figure 35] Figures 35A and 36B are representative flow charts of the total primary and secondary composite endpoint events for patients randomized to AMR101 and placebo, respectively. [Figure 36] Representative pie charts of the rates of first and subsequent primary endpoint events overall and by component are included. [Figure 37A] 37A-37C are representative bar graphs showing the distribution of patients' total (i.e., first and subsequent) primary composite endpoint events. Figure 37A shows that there was a 30% relative risk reduction in the primary composite endpoint total events for patients randomized to icosapent ethyl. [Figure 37B] 1 is a representative plot showing the distribution of first and subsequent primary composite endpoint events in the complete dataset of patients randomized 1:1 to AMR101 versus placebo in the ITT population. [Figure 38A]Representative Kaplan-Meier curves for the sum (i.e., first and subsequent) and time to first primary and secondary composite endpoint events, respectively, over time. Figures 38A and 38B show that both the primary and key secondary endpoints were significantly reduced in patients randomized to icosapent ethyl compared to placebo. [Figure 38B] Representative Kaplan-Meier curves for the sum (i.e., first and subsequent) and time to first primary and secondary composite endpoint events, respectively, over time. Figures 38A and 38B show that both the primary and key secondary endpoints were significantly reduced in patients randomized to icosapent ethyl compared to placebo. [Figure 39] Representative forest plot of total primary composite endpoint events and ranked secondary composite endpoint events, showing that the time to the first, second, and third occurrence of the primary and secondary endpoints was significantly reduced in patients randomized to icosapent ethyl compared to placebo. [Figure 40] Representative forest plots of the total primary and key secondary composite endpoints and each individual component or endpoint for patients randomized to icosapent ethyl and placebo, showing that not only was there a significant reduction in the composite of the primary and key secondary endpoints, but the individual components were also significantly reduced. [Figure 41A] 10A-10C are representative forest plots of the overall primary composite endpoint and secondary composite endpoints for selected subgroups by binomial model for patients randomized to icosapent ethyl and placebo, respectively. [Figure 41B] 10A-10C are representative forest plots of the overall primary composite endpoint and secondary composite endpoints for selected subgroups by binomial model for patients randomized to icosapent ethyl and placebo, respectively. [Figure 42]Representative graph showing the difference in risk for patients treated with icosapent ethyl versus placebo for 5 years for all components of the composite primary endpoint, demonstrating that approximately 159 total primary endpoint events were prevented during that time period, including 12 cardiovascular deaths, 42 myocardial infarctions, 14 strokes, 76 coronary revascularizations, and 16 episodes of hospitalization for unstable angina. [Figure 43] Forest plots of total primary and secondary composite endpoint events, and first, second, and third occurrences for the reduced dataset of unadjusted and adjusted values, respectively. [Figure 44] Forest plots of total primary and secondary composite endpoint events, and first, second, and third occurrences for the reduced dataset of unadjusted and adjusted values, respectively. [Figure 45] The total primary and secondary key composite endpoint events, and first, second, and third occurrences, respectively, are shown for data reduced using unadjusted values. [Figure 46] The total primary and secondary key composite endpoint events, and first, second, and third occurrences, respectively, are shown for data reduced using unadjusted values. [Figure 47] The total primary and secondary composite endpoint events, and first, second, and third occurrences, respectively, for the reduced dataset using adjusted values ​​are shown. [Figure 48] The total primary and secondary composite endpoint events, and first, second, and third occurrences, respectively, for the reduced dataset using adjusted values ​​are shown. [Figure 49] Shown are the total primary and secondary composite endpoint events, and the first, second, and third occurrences for the complete dataset in unadjusted and adjusted values, respectively. [Figure 50]Shown are the total primary and secondary composite endpoint events, and the first, second, and third occurrences for the complete dataset in unadjusted and adjusted values, respectively. [Figure 51] 1 is a representative bar graph showing the risk difference for 1000 patients treated with AMR101 versus placebo for 5 years for all components of the composite primary endpoint in the ITT population. [Figure 52] Figure 52 is a representative forest plot showing the reduction in subject total primary composite endpoint events as a function of triglyceride level. Figure 52 shows that the total primary composite endpoint was reduced in all patients across the triglyceride range and within each defined triglyceride tertile. [Figure 53] Figure 53 is a representative forest plot showing the time to first event of the primary composite endpoint of subjects as a function of triglyceride level. Figure 53 shows that the time to first event of the primary composite endpoint was reduced across the triglyceride range. [Figure 54] 1 is a representative forest plot showing the effect of icosapent ethyl on the primary composite endpoint by LDL-C percent change from baseline in quartiles at 1 year in the ITT population. [Figure 55] 1 is a representative bar graph of placebo-corrected blood pressure reduction in patients receiving 4 g of icosapent ethyl per day. [Figure 56] Representative bar graphs of study drug adherence over time for the first, second, third, and fourth events. [Figure 57A] Representative Kaplan-Meier curves of time from the date of randomization to the primary and key secondary endpoints for AMR101 versus placebo by increase or unchanged / reduction in LDL-C at year 1 in the placebo arm of the ITT population, respectively. [Figure 57B]Representative Kaplan-Meier curves of time from the date of randomization to the primary and key secondary endpoints for AMR101 versus placebo by increase or unchanged / reduction in LDL-C at year 1 in the placebo arm of the ITT population, respectively. [Figure 58A] Representative Kaplan-Meier curves of time from the date of randomization to the primary and key secondary endpoints for AMR101 versus placebo by increase or unchanged / decrease in hsCRP at year 2 in the placebo arm of the ITT population, respectively. [Figure 58B] Representative Kaplan-Meier curves of time from the date of randomization to the primary and key secondary endpoints for AMR101 versus placebo by increase or unchanged / decrease in hsCRP at year 2 in the placebo arm of the ITT population, respectively. [Figure 59] Representative forest plot analysis of the primary endpoint by subgroups of the ITT population (geographic region, cardiovascular risk category, baseline ezetimibe use, sex, and age group). [Figure 60] Representative forest plot analysis of the primary endpoint by subgroups of the ITT population (white vs. non-white, baseline diabetes, baseline statin intensity, TG ≥ 200 vs. < 200 mg / dL, TG ≥ 150 vs. < 150 mg / dL, and TG ≥ 200 and HDL-C ≤ 35 mg / dL). [Figure 61] Representative forest plot analysis of the primary endpoint by subgroups of the ITT population (US vs. non-US, hsCRP ≤ 2 vs. > 2 mg / L, hsCRP ≤ 3 vs. > 3 mg / L, baseline eGFR, LDL-C (derived) by tertiles, and HDL-C by tertiles). [Figure 62] Representative forest plot analysis of the primary endpoint by subgroups of the ITT population (apoB by tertiles, Non-HDL-C by tertiles, and TG by tertiles). [Figure 63]Representative forest plot of the analysis of key secondary endpoints by subgroups of the ITT population (geographic region, cardiovascular risk category, baseline ezetimibe use, sex, and age group). [Figure 64] Representative forest plot analysis of key secondary endpoints by subgroups of the ITT population (white vs. non-white, baseline diabetes, baseline statin intensity, TG ≥ 200 vs. < 200 mg / dL, TG ≥ 150 vs. < 150 mg / dL, and TG ≥ 200 and HDL-C ≤ 35 mg / dL). [Figure 65] Representative forest plot analysis of key secondary endpoints by subgroups of the ITT population (US vs. non-US, hsCRP ≤ 2 vs. > 2 mg / L, hsCRP ≤ 3 vs. > 3 mg / L, baseline eGFR, LDL-C (derived) by tertiles, and HDL-C by tertiles). [Figure 66] Representative forest plot analysis of key secondary endpoints by subgroups of the ITT population (apoB by tertiles, Non-HDL-C by tertiles, and TG by tertiles). [Figure 67] 1 is a representative forest plot showing a pre-specified hierarchical endpoint study highlighting the relative risk reduction (RRR) for each endpoint. [Figure 68] 1 is a representative forest plot showing patients from both the icosapent ethyl and placebo groups who required hospitalization for ≥24 hours from atrial fibrillation and / or flutter at baseline in the ITT population. [Figure 69A] 1 is a representative plot showing the overlap of atrial fibrillation and / or flutter and bleeding between the placebo and icosapent ethyl groups, and the risk difference between the two groups in the ITT population. [Figure 69B] 1 is a representative plot showing the overlap of atrial fibrillation and / or flutter and bleeding between the placebo and icosapent ethyl groups in the secondary prevention cohort. [Figure 69C] 1 is a representative plot showing the overlap between atrial fibrillation and / or flutter and bleeding between the placebo and icosapent ethyl groups in a high-risk primary prevention cohort. [Figure 70A] Representative Kaplan-Meier curves showing time to endpoints of atrial fibrillation and / or flutter requiring hospitalization of 24 hours or more by treatment group in the ITT population. [Figure 70B] Representative Kaplan-Meier curves showing time to endpoints of atrial fibrillation and / or flutter requiring hospitalization of 24 hours or more by treatment group in the ITT population. [Figure 71] Representative forest plot summarizing endpoints by history of atrial fibrillation and / or flutter in the ITT population. [Figure 72] Representative forest plot showing endpoints with on-study atrial fibrillation and / or flutter in the ITT population. [Figure 73] 1 is a representative forest plot summarizing endpoints based on patients with a history of atrial fibrillation and / or flutter from the ITT population. [Figure 74] 1 is a representative forest plot showing atrial fibrillation or flutter specifically adjudicated by baseline history of atrial fibrillation and / or flutter in a high-risk primary prevention cohort. [Figure 75] 1 is a representative forest plot showing atrial fibrillation or flutter specifically adjudicated by baseline history of atrial fibrillation or flutter in the secondary prevention cohort. [Figure 76] Forest plot showing atrial fibrillation and / or flutter requiring hospitalization for more than 24 hours by baseline in the ITT population. [Figure 77] Representative bar graph showing benefit and risk considerations for patients under 65 years of age, demonstrating the reduced risk of developing atrial fibrillation in this patient population. [Figure 78] Representative bar graph illustrating benefit and risk considerations for patients aged 65 years and older, demonstrating the increased risk of developing atrial fibrillation in this patient population. [Figure 79] 1 is a representative plot showing the change in median hemoglobin levels over time for the safety population. [Figure 80]1 is a representative plot showing the median platelet count over time for the safety population. [Figure 81] 1 is a representative plot showing the change in median alanine aminotransferase (ALT) levels over time in the safety population. [Figure 82] 1 is a representative plot showing the change in median aspartate aminotransferase (AST) levels over time in the safety population. [Figure 83] 1 is a representative plot showing the distribution of peak ALT or AST values ​​versus peak total bilirubin values ​​to assess serious drug-induced hepatotoxicity in the ITT population.

[0021] [Mode for Carrying Out the Invention] While the present disclosure may be embodied in various forms, the following description of several embodiments is made with the understanding that the present disclosure should be considered as an exemplification of the invention and is not intended to limit the invention to the particular embodiments shown. Headings are provided for convenience only and should not be construed as limiting the invention in any way. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

[0022] The use of numerical values ​​in the various quantitative values ​​specified in this application, unless expressly stated otherwise, is described as approximations, as if both the minimum and maximum values ​​within the specified range were preceded by the word "about." It is understood, although not always explicitly stated, that all numerical designations are preceded by the term "about." Such range formats are used for convenience and brevity and should be understood flexibly to include the numerical values ​​explicitly specified as range limits, but also to include all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were expressly specified. For example, 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, as well as subranges such as about 10 to about 50, about 20 to about 100, etc. It is also understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0023] As used herein, the term "about," when referring to a measurable value such as an amount or concentration, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or 0.1% of the specified amount.

[0024] As used herein, the term "derivative," when referring to a fatty acid, is meant to encompass any modified form of a fatty acid, for example, derived by chemical reaction (i.e., a terminal carboxylic acid functional group) from a fatty acid in its free acid form. Non-limiting examples of fatty acid derivatives as used herein include fatty acids such as alkyl esters, such as methyl esters, propyl esters, butyl esters, or ethyl esters; salts of fatty acids, such as lithium salts, sodium salts, or potassium salts; or glyceride forms of fatty acids, such as mono-, di-, or triglyceride fatty acids.

[0025] In one embodiment, when a derivative of EPA is administered in place of EPA, the amount of the EPA derivative administered to a subject per day is determined to be the maximum serum EPA concentration (C max The amount is sufficient to substantially match the pharmacokinetic profile of EPA produced by administering 4 g of E-EPA per day to human subjects, in terms of ATP (relative ATP concentration) and area under the curve (AUC), and is referred to herein as a "dose-equivalent amount of EPA derivative." For a 3.7 g dose of EPA per day, the dose-equivalent amount of E-EPA is approximately 4 g of E-EPA per day.

[0026] In one embodiment, eicosapentaenoic acid free fatty acid is administered to a subject, and the amount administered is sufficient in gram weight to substantially match the pharmacokinetic profile produced by administering 4g of E-EPA to a human subject per day.In another embodiment, eicosapentaenoic acid derivative is administered to a subject, and the amount administered is sufficient in gram weight to substantially match the pharmacokinetic profile produced by administering 4g of E-EPA to a human subject per day.For a dose of 3.7g of eicosapentaenoic acid per day, the dose equivalent of E-EPA is about 4g of E-EPA per day.

[0027] As used herein, the phrase "control subject" refers to any subject used as a standard for comparison with a test subject. Control subjects include, but are not limited to, any subject who does not receive a composition, who receives a composition other than the test composition (e.g., Lovaza®, which consists of 365 mg E-EPA and 375 mg E-DHA), or who receives a placebo.

[0028] As used herein, the phrase "cardiovascular risk category 1" refers to subjects classified as having established cardiovascular disease. Patients in cardiovascular risk category 1 were stratified into a secondary prevention cohort. The designation of patients defined by cardiovascular risk category 1 is collectively referred to as the secondary prevention stratum, secondary prevention cohort, and primary risk category.

[0029] As used herein, the phrase "cardiovascular risk category 2" refers to subjects who are classified as having diabetes (which is itself a risk factor for cardiovascular disease) and at least one additional risk factor for cardiovascular disease, but who do not have established cardiovascular disease. Patients in cardiovascular risk category 2 were stratified into a primary prevention cohort. The designation of patients defined in cardiovascular risk category 1 is collectively referred to as the primary prevention stratum, primary prevention cohort, and secondary risk category.

[0030] The disclosure of ranges is also intended as a continuous range, including every value between the minimum and maximum values ​​recited, and any range that can be formed by such values. Also disclosed herein are any and all ratios (and any such ratio ranges) that can be formed by dividing a disclosed numerical value into any other disclosed numerical value. Accordingly, one of ordinary skill in the art will understand that many such ratios, ranges, and ratio ranges are clearly obtainable from the numerical values ​​presented herein, and that in all cases, such ratios, ranges, and ratio ranges represent various embodiments of the present disclosure.

[0031] As used herein, the phrase "statistical significance" refers to a result from data generated by a test or experiment that is unlikely to have occurred randomly or by chance, but instead is likely to be attributable to a specific cause. Statistical significance is assessed from a calculated probability (p-value), where the p-value is a function of the mean and standard deviation of the data sample and indicates the probability that the statistical result occurred by chance or sampling error. A p-value of 0.05 or less is considered statistically significant, corresponding to a 95% confidence level.

[0032] "Comprising" or "comprise" is intended to mean that compositions and methods include the recited elements, but do not exclude others. "Consisting essentially of," when used to define compositions and methods, is intended to mean excluding other elements of any essential importance to the combination for the stated purpose. Thus, a composition consisting essentially of elements as defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" is intended to mean excluding more than trace amounts of other components and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0033] List of abbreviations: ANOVA, analysis of variance; ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; RRR, relative risk reduction; HR, hazard ratio; CV, cardiovascular; DM, diabetes; HDL-C, high-density lipoprotein cholesterol; HIV / AIDS, human immunodeficiency virus / acquired immunodeficiency syndrome; ICD-9, International Classification of Diseases, Ninth Revision; TG, triglycerides; TC, total cholesterol; VLDL-C, very-low-density lipoprotein cholesterol, apoB; apolipoprotein B; hsCRP, high-sensitivity C-reactive protein; hsTnT, high-sensitivity troponin; RLP-C, remnant particle cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; non-HDL-C, non-high-density lipoprotein cholesterol; PAD, peripheral arterial disease; REDUCE-IT, Reduction of Cardiovascular Events with Icosapent Ethyl Intervention Trial; SD, standard deviation; TG, triglycerides; and HLB, hydrophilic-lipophilic balance.

[0034] composition In one embodiment, the composition of the present disclosure has an amount of about 1 mg to about 10,000 mg, 25 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 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 62 5mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1025mg, 1050mg , approx. 1075 mg, approx. 1100 mg, approx. 1025 mg, approx. 1050 mg, approx. 1075 mg, approx. 1200 mg, approx. 1225 mg, approx. 1250 mg, approx. 1275 mg, approx. 0mg, approx. 1475mg, approx. 1500mg, approx. 1525mg, approx. 1550mg, approx. 1575mg, approx. 1600mg, approx. 1625mg, approx. 1650mg, approx. 1850mg, 1875mg, 1900mg, 1925mg, 1950mg, 1975mg, 2000mg, 2025mg, 2050mg, 2075mg, 2100mg, 2125mg, 2150mg, 2175mg, 2200mg, 2225m g, approx. 2250 mg, approx. 2275 mg, approx. 2300 mg, approx. 2325 mg, approx. 2350 mg, approx. 2375 mg, approx. 2400 mg, approx. 25mg, about 2650mg, about 2675mg, about 2700mg, about 2725mg, about 2750mg, about 2775mg, about 2800mg, about 2825mg, about 2850mg, about 2875mg, about 2900mg, about 2925mg, about 2950mg, about 2975mg, about 3000mg,Approximately 3025mg, approximately 3050mg, approximately 3075mg, approximately 3100mg, approximately 3125mg, approximately 3150mg, approximately 3175mg, approximately 3200mg, approximately 3225mg, approximately 3250mg, approximately 3275mg, approximately 3300mg, approximately 3325mg, approximately 3350mg, approximately 3375mg, approximately 3400mg, approximately 3425mg, approximately 3450mg, approximately 3475mg, approximately 3500mg, approximately 3525mg, approximately 3550mg, approximately 3575mg, approximately 3600mg, approximately 3625mg, approximately 3650mg, approximately 3675mg, approximately 3700mg, approximately 3725mg, approximately 3750mg, approximately 3775mg, approximately 3 800mg, approximately 3825mg, approximately 3850mg, approximately 3875mg, approximately 3900mg, approximately 3925mg, approximately 3950mg, approximately 3975mg, approximately 4000mg, approximately 4025mg, approximately 4050mg, approximately 4075mg, approximately 4100mg, approximately 4125mg, approximately 4150mg, approximately 4175mg, approximately 4200mg, approximately 4225mg, approximately 4250mg, approximately 4275mg, approximately 4300mg, approximately 4325mg, approximately 4350mg, approximately 4375mg, approximately 4400mg, approximately 4425mg, approximately 4450mg, approximately 4475mg, approximately 4500mg, approximately 4525mg, approximately 4550mg, approximately 457 5mg, approximately 4600mg, approximately 4625mg, approximately 4650mg, approximately 4675mg, approximately 4700mg, approximately 4725mg, approximately 4750mg, approximately 4775mg, approximately 4800mg, approximately 4825mg, approximately 4850mg, approximately 4875mg, approximately 4900mg, approximately 4925mg, approximately 4950mg, approximately 4975mg, approximately 5000mg, approximately 5025mg, approximately 5050mg, approximately 5075mg, approximately 5100mg, approximately 5125mg, approximately 5150mg, approximately 5175mg, approximately 5200mg, approximately 5225mg, approximately 5250mg, approximately 5275mg, approximately 5300mg, approximately 5325mg, approximately 5350mg g, approximately 5375mg, approximately 5400mg, approximately 5425mg, approximately 5450mg, approximately 5475mg, approximately 5500mg, approximately 5525mg, approximately 5550mg, approximately 5575mg, approximately 5600mg, approximately 5625mg, approximately 5650mg, approximately 5675mg, approximately 5700mg, approximately 5725mg, approximately 5750mg, approximately 5775mg, approximately 5800mg, approximately 5825mg, approximately 5850mg, approximately 5875mg, approximately 5900mg, approximately 5925mg, approximately 5950mg, approximately 5975mg, approximately 6000mg, approximately 6025mg, approximately 6050mg, approximately 6075mg, approximately 6100mg, approximately 6125mgApproximately 6150mg, approximately 6175mg, approximately 6200mg, approximately 6225mg, approximately 6250mg, approximately 6275mg, approximately 6300mg, approximately 6325mg, approximately 6350mg, approximately 6375mg, approximately 6400mg, approximately 6425mg, approximately 6450mg, approximately 6475mg, approximately 6500mg, approximately 6525mg, approximately 6550mg, approximately 6575mg, approximately 6600mg, approximately 6625mg, approximately 6650mg, approximately 6675mg, approximately 6700mg, approximately 6725mg, approximately 6750mg, approximately 6775mg, approximately 6800mg, approximately 6825mg, approximately 6850mg, approximately 6875mg, approximately 6900mg, approximately 6 925mg, approximately 6950mg, approximately 6975mg, approximately 7000mg, approximately 7025mg, approximately 7050mg, approximately 7075mg, approximately 7100mg, approximately 7125mg, approximately 7150mg, approximately 7175mg, approximately 7200mg, approximately 7225mg, approximately 7250mg, approximately 7275mg, approximately 7300mg, approximately 7325mg, approximately 7350mg, approximately 7375mg, approximately 7400mg, approximately 7425mg, approximately 7450mg, approximately 7475mg, approximately 7500mg, approximately 7525mg, approximately 7550mg, approximately 7575mg, approximately 7600mg, approximately 7625mg, approximately 7650mg, approximately 7675mg, approximately 770 0mg, approximately 7725mg, approximately 7750mg, approximately 7775mg, approximately 7800mg, approximately 7825mg, approximately 7850mg, approximately 7875mg, approximately 7900mg, approximately 7925mg, approximately 7950mg, approximately 7975mg, approximately 8000mg, approximately 8025mg, approximately 8050mg, approximately 8075mg, approximately 8100mg, approximately 8125mg, approximately 8150mg, approximately 8175mg, approximately 8200mg, approximately 8225mg, approximately 8250mg, approximately 8275mg, approximately 8300mg, approximately 8325mg, approximately 8350mg, approximately 8375mg, approximately 8400mg, approximately 8425mg, approximately 8450mg, approximately 8475mg g, approximately 8500mg, approximately 8525mg, approximately 8550mg, approximately 8575mg, approximately 8600mg, approximately 8625mg, approximately 8650mg, approximately 8675mg, approximately 8700mg, approximately 8725mg, approximately 8750mg, approximately 8775mg, approximately 8800mg, approximately 8825mg, approximately 8850mg, approximately 8875mg, approximately 8900mg, approximately 8925mg, approximately 8950mg, approximately 8975mg, approximately 9000mg, approximately 9025mg, approximately 9050mg, approximately 9075mg, approximately 9100mg, approximately 9125mg, approximately 9150mg, approximately 9175mg, approximately 9200mg, approximately 9225mg, approximately 9250mgThe compound is administered to a subject in an amount sufficient to provide a daily dose of about 9275 mg, about 9300 mg, about 9325 mg, about 9350 mg, about 9375 mg, about 9400 mg, about 9425 mg, about 9450 mg, about 9475 mg, about 9500 mg, about 9525 mg, about 9550 mg, about 9575 mg, about 9600 mg, about 9625 mg, about 9650 mg, about 9675 mg, about 9700 mg, about 9725 mg, about 9750 mg, about 9775 mg, about 9800 mg, about 9825 mg, about 9850 mg, about 9875 mg, about 9900 mg, about 9925 mg, about 9950 mg, about 9975 mg, or about 10,000 mg of eicosapentaenoic acid.

[0035] In one embodiment, a composition for use in the disclosed methods comprises eicosapentaenoic acid, or a pharmaceutically acceptable ester, derivative, complex, or salt thereof, or a mixture of any of the foregoing, collectively referred to herein as "EPA." The term "pharmaceutically acceptable" in this context means that the substance in question does not produce unacceptable toxicity to the subject or interact with other components of the composition. In one embodiment, EPA derivatives include, but are not limited to, methyl or other alkyl esters, re-esterified monoglycerides, re-esterified diglycerides, and re-esterified triglycerides, or mixtures thereof. In one embodiment, such EPA derivatives are administered daily in an amount containing the same number of moles of EPA as contained in 4 grams of ethyl eicosapentaenoate.

[0036] In another embodiment, the EPA comprises an eicosapentaenoic acid ester. In another embodiment, the EPA comprises a C1-C5 alkyl ester of eicosapentaenoic acid. In another embodiment, the EPA comprises eicosapentaenoic acid ethyl ester (E-EPA), eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl ester.

[0037] In another embodiment, EPA is ethyl-EPA, methyl-EPA, lithium EPA, mono-, di-, or triglyceride EPA, or any other ester or salt form of EPA, or the free acid form of EPA. EPA may be in the form of a 2-substituted or other derivative that slows its oxidation rate but does not substantially alter its biological activity. Where any specific form of EPA (eicosapentaenoic acid ethyl ester, icosapent ethyl, or E-EPA) is referred to throughout this application, any pharmaceutically acceptable derivative of EPA can be substituted in its place, including the free acid forms of icosapentaenoic acid or eicosapentaenoic acid. Eicosapentaenoic acid ethyl ester, icosapent ethyl, and E-EPA are referred to interchangeably.

[0038] In another embodiment, the EPA is from about 50 mg to about 5000 mg, from about 75 mg to about 2500 mg, or from 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, about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, about 2500 mg, about 2525 mg, about 2550 mg, about 2575 mg, about 2600 mg, about 2625 mg, about 2650 mg, about 2675 mg, about 2700 mg, about 2725 mg, about 2750 mg, about 2775 mg, about 2800 mg, about 2825 mg, about 2850 mg, about 2875 mg, about 2900 mg, about 2925 mg, about 2950 mg, about 2975 mg, about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg,About 3100mg, about 3125mg, about 3150mg, about 3175mg, about 3200mg, about 3225mg, about 3250mg, about 3275mg, about 3300mg, about 3325mg, About 3350mg, about 3375mg, about 3400mg, about 3425mg, about 3450mg, about 3475mg, about 3500mg, about 3525mg, about 3550mg, about 3575mg, about 3600mg, about 3625mg, about 3650mg, about 3675mg, about 3700mg, about 3725mg, about 3750mg, about 3775mg, about 3800mg, about 3825mg, about 3850mg, about 3875mg, about 3900mg, about 3925mg, about 3950mg, about 3975mg, about 4000mg, about 4025mg, about 4050mg, about 4075mg, about 4 100mg, approximately 4125mg, approximately 4150mg, approximately 4175mg, approximately 4200mg, approximately 4225mg, approximately 4250mg, approximately 4275mg, approximately 4300mg, approximately 4325mg, approximately 4350mg, approximately 4375mg, approximately 4400mg, approximately 4425mg, approximately 4450mg, approximately 4475mg, approximately 4500mg, approximately 4525mg, approximately 4550mg, approximately 4575mg, approximately 46 The compound may be present in compositions useful according to the methods of the present disclosure in an amount of about 4000 mg, about 4625 mg, about 4650 mg, about 4675 mg, about 4700 mg, about 4725 mg, about 4750 mg, about 4775 mg, about 4800 mg, about 4825 mg, about 4850 mg, about 4875 mg, about 4900 mg, about 4925 mg, about 4950 mg, about 4975 mg, or about 5000 mg.

[0039] In another embodiment, compositions useful according to the present invention, when present, contain about 10% by weight or less, about 9% by weight or less, about 8% by weight or less, about 7% by weight or less, about 6% by weight or less, about 5% by weight or less, about 4% by weight or less, about 3% by weight or less, about 2% by weight or less, about 1% by weight or less, or about 0.5% by weight or less of docosahexaenoic acid (DHA). In another embodiment, the compositions of the present disclosure are substantially free of DHA. In yet another embodiment, the compositions useful in the present disclosure are free of DHA and / or its derivatives. In one embodiment, 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.

[0040] In another embodiment, EPA comprises at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 96% by weight, at least about 97% by weight, at least about 98% by weight, at least about 99% by weight, or about 100% by weight of all fatty acids present in the compositions useful in the methods of the present disclosure.

[0041] In some embodiments, the composition comprises at least 96% by weight of eicosapentaenoic acid ethyl ester and less than about 2% by weight of a preservative, hi some embodiments, the preservative is a tocopherol, such as fully racemic α-tocopherol.

[0042] In another embodiment, compositions useful according to the methods of the present disclosure contain less than about 10% by weight, less than about 9% by weight, less than about 8% by weight, less than about 7% by weight, less than about 6% by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, less than about 1% by weight, less than about 0.5% by weight, or less than about 0.25% by weight of the total composition or total fatty acid content of any fatty acid other than EPA. Specific examples of "fatty acids other than EPA" 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). In another embodiment, compositions useful according to the methods of the present disclosure contain between about 0.1% by weight and about 4% by weight, between about 0.5% by weight and about 3% by weight, or between about 1% by weight and about 2% by weight of total fatty acids other than EPA and / or DHA. In one embodiment, the fatty acids other than EPA include derivatives of those fatty acids, including, but not limited to, methyl or other alkyl esters, re-esterified monoglycerides, re-esterified diglycerides, and re-esterified triglycerides, or mixtures thereof of fatty acids.

[0043] In another embodiment, a composition useful according to the present disclosure has one or more of the following characteristics: (a) eicosapentaenoic acid ethyl esters represent 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 no more than about 4%, no more than about 3%, or no more than about 2% by weight of total fatty acids other than eicosapentaenoic acid ethyl esters; (c) the composition contains no more than about 0.6%, no more than about 0.5%, or no more than about 0.4% of any individual fatty acid other than eicosapentaenoic acid ethyl esters; (d) the composition (e) 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°C) of about 0.8 to about 1.0, about 0.85 to about 0.95, or about 0.9 to about 0.92; (e) the composition contains about 20 ppm or less, about 15 ppm or less, or about 10 ppm or less of heavy metals; (f) the composition contains about 5 ppm or less, about 4 ppm or less, about 3 ppm or less, or about 2 ppm or less of arsenic; and / or (g) the composition has a peroxide value of about 5 meq / kg or less, about 4 meq / kg or less, about 3 meq / kg, or about 2 meq / kg or less.

[0044] In some embodiments, the composition for use according to the present disclosure is a self-emulsifying composition. In some embodiments, the self-emulsifying composition comprises at least one compound selected from the group consisting of omega-3 fatty acids and derivatives thereof (e.g., pharmaceutically acceptable salts and / or esters). In another embodiment, the composition comprises an emulsifier. In some embodiments, 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 esters, polyoxyethylene castor oil, polyethylene glycol fatty acid esters, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters, and lecithin. In another embodiment, the omega-3 fatty acid or a derivative thereof is present in an amount of about 50% to about 95% by weight of the total weight of the composition or of the total fatty acids of the total composition. In some embodiments, the omega-3 fatty acid is EPA and / or DHA. In some embodiments, EPA is present in an amount of at least about 95% by weight of all fatty acids present in the self-emulsifying composition. In another embodiment, the composition is substantially free of DHA. In yet another embodiment, the composition is substantially free of ethanol.

[0045] In another embodiment, the composition is a self-emulsifying composition comprising from about 50% to about 95% by weight of at least one compound selected from the group consisting of omega-3 polyunsaturated fatty acids and derivatives thereof (e.g., pharmaceutically acceptable salts and / or esters) based on the total weight of the composition. In another embodiment, the composition comprises from about 1% to about 20% by weight of the total weight of the composition of a sucrose fatty acid ester as an emulsifier having a hydrophilic-lipophilic balance of at least about 10. In another embodiment, the composition comprises glycerin. In another embodiment, the composition comprises from about 0% to about 5% by weight of the total composition of ethanol. In another embodiment, the self-emulsifying composition comprises from about 50% to about 95% by weight of the total weight of the composition of at least one compound selected from the group consisting of omega-3 polyunsaturated fatty acids and derivatives thereof, from about 1% to about 20% by weight of the total weight of the composition of a sucrose fatty acid ester as an emulsifier having an HLB of at least about 10, glycerin, and from about 0% to about 4% by weight of the total weight of the composition of ethanol. In another embodiment, sucrose fatty acid ester is one or more of sucrose laurate, sucrose myristate, sucrose palmitate, sucrose stearate or sucrose oleate.In another embodiment, omega-3 polyunsaturated fatty acid is one or more of EPA, DHA or their derivatives.In yet another embodiment, omega-3 polyunsaturated fatty acid is ethyl-EPA and / or ethyl-DHA.

[0046] In another embodiment, the composition is a self-emulsifying composition comprising about 50% to about 95% by weight of the total weight of the composition of at least one compound selected from the group consisting of omega-3 polyunsaturated fatty acids and derivatives thereof (e.g., pharmaceutically acceptable salts and / or esters); and about 5% to about 50% by weight of the total weight of the composition of an emulsifier having an HLB of at least about 10, wherein the ethanol content is up to about 4% by weight of the total weight of the composition. In some embodiments, the omega-3 polyunsaturated fatty acid is EPA and / or DHA. In another embodiment, the composition is ethanol-free. In another embodiment, 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. In another embodiment, 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.

[0047] In another embodiment, the hydrogenated castor oil is at least one member selected from the group consisting of 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. In another embodiment, 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. In another embodiment, 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.

[0048] In some embodiments, the composition comprises a lecithin selected from the group consisting of soybean lecithin, enzymatically hydrolyzed soybean lecithin, hydrogenated soybean lecithin, and egg yolk lecithin. In another embodiment, the composition comprises a polyhydric alcohol, wherein the polyhydric alcohol is propylene glycol or glycerin. In another embodiment, the composition comprises at least one member selected from the group consisting of EPA, DHA, and / or derivatives thereof (e.g., pharmaceutically acceptable salts and esters thereof), and the composition comprises ethyl-EPA and / or ethyl-DHA. In another embodiment, the composition comprises about 10 to about 100 parts by weight of an emulsifier having an HLB of at least about 10 and per 100 parts by weight of at least one compound selected from the group consisting of omega-3 polyunsaturated fatty acids and / or derivatives thereof (e.g., pharmaceutically acceptable salts and / or esters).

[0049] In another embodiment, the self-emulsifying composition comprises about 70% to about 90% by weight of eicosapentaenoic acid ethyl ester as a first pharmaceutical ingredient. In some embodiments, the composition further comprises about 0.5 to about 0.6% by weight of water. In some embodiments, the composition comprises about 1% to about 29% by weight of a polyoxyethylene sorbitan fatty acid ester as an emulsifier. In another embodiment, the composition comprises about 1 to about 25 parts by weight of lecithin per about 100 parts by weight of eicosapentaenoic acid ethyl ester. In yet another embodiment, the composition comprises pitavastatin, rosuvastatin, or a salt thereof as a second pharmaceutical ingredient. In another embodiment, ethanol and / or polyhydric alcohols comprise up to about 4% by weight of the total weight of the composition. In another embodiment, the composition comprises, as a second pharmaceutical ingredient, about 100 parts by weight of eicosapentaenoic acid ethyl ester, about 0.01 to about 1 part by weight of pitavastatin or a salt thereof, or about 0.03 to about 5 parts by weight of rosuvastatin or a salt thereof relative to about 100 parts by weight of eicosapentaenoic acid ethyl ester. In some embodiments, the composition is encapsulated in a hard capsule and / or a soft capsule, and the capsule film of the soft capsule may contain gelatin. In another embodiment, the self-emulsifying composition further comprises polyoxyethylene hydrogenated castor oil and / or polyoxyethylene castor oil. In another embodiment, the emulsifier comprises a polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil. In some embodiments, the pitavastatin, rosuvastatin, or a salt thereof is pitavastatin calcium or rosuvastatin calcium. In another embodiment, the lechthin is soybean lechthin. In another embodiment, the polyoxyethylene sorbitan fatty acid ester is polyoxyethylene (20) sorbitan monooleate.

[0050] In some embodiments, a self-emulsifying composition containing E-EPA has improved bioavailability compared to a standard E-EPA formulation, which is a formulation that is not self-emulsifying. In some embodiments, a self-emulsifying composition containing about 1.8 to about 3.8 g of E-EPA has substantially the same bioavailability as about 4 g of E-EPA not formulated as a self-emulsifying composition. In some embodiments, a self-emulsifying composition containing E-EPA is evaluated for bioequivalence to about 4 g of E-EPA not formulated as a self-emulsifying composition, for example, using U.S. Food and Drug Administration (FDA) guidelines.

[0051] In another embodiment, the composition useful in accordance with the method of the present disclosure is orally deliverable. As used herein, the term "orally deliverable" or "oral administration" includes any form of delivery of a therapeutic agent or composition thereof to a subject, in which the agent or composition is placed in the subject's mouth, regardless of whether the agent or composition is swallowed. Thus, "oral administration" includes buccal, sublingual, and esophageal administration. In one embodiment, the composition is present in a capsule, for example, a soft gelatin capsule.

[0052] Compositions for use according to the present disclosure may be formulated as one or more dosage units. As used herein, the terms "dose unit" and "dosage unit" refer to a portion of a pharmaceutical composition containing an amount of a therapeutic agent suitable for single administration to provide a therapeutic effect. Such dosage units may be administered one to multiple times (i.e., 1 to about 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 2) per day, or as many times as necessary to elicit a therapeutic response.

[0053] In one embodiment, a composition of the present disclosure exhibits at least about 90%, at least about 95%, at least about 97.5%, or at least about 99% of the active ingredient originally present therein upon storage in a sealed container maintained at room temperature, refrigerated (e.g., about 5 to about 5-10°C) temperature, or frozen for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0054] Treatment method In one embodiment, the present disclosure provides a method for treating and / or preventing cardiovascular-related diseases and disorders.The term "cardiovascular-related diseases and disorders" herein refers to any disease or disorder of the heart or blood vessels (i.e., arteries and veins), or any symptoms thereof.Non-limiting examples of cardiovascular-related diseases and disorders include hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, vascular disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction, and other cardiovascular events.

[0055] The term "treatment" in relation to a given disease or disorder includes, but is not limited to, inhibiting the disease or disorder, for example, halting the progression of the disease or disorder; alleviating the disease or disorder, for example, causing the regression of the disease or disorder; alleviating the condition caused by or resulting from the disease or disorder, for example, alleviating or treating the symptoms of the disease or disorder. The term "prevention" in relation to a given disease or disorder means preventing the onset of disease if none has occurred, preventing the disease or disorder from occurring in a subject who may have a predisposition to the disorder or disorder but has not yet been diagnosed with the disorder or disorder, and / or preventing further onset of the disease / disorder if already present.

[0056] In various embodiments, the present disclosure provides methods for reducing the risk of cardiovascular events in a subject receiving statin therapy. In some embodiments, the method includes (a) identifying a subject receiving statin therapy and having a fasting baseline triglyceride level of about 135 mg / dL to about 500 mg / d, wherein the subject has established cardiovascular disease or is at high risk for developing cardiovascular disease, and (b) administering to the subject a composition comprising about 1 g to about 4 g per day of eicosapentaenoic acid (free acid) or a derivative thereof (ethyl or methyl ester). As provided herein, the terms "composition" and "pharmaceutical composition" are referred to interchangeably.

[0057] In various embodiments, the present disclosure provides a method of reducing the risk of a cardiovascular event in a subject, comprising determining, or having determined, whether the subject has a triglyceride level of at least 150 mg / dl and a history of atrial fibrillation and / or atrial flutter.

[0058] In some embodiments, determining whether a subject has a triglyceride level of at least 150 mg / dl and a history of atrial fibrillation and / or atrial flutter comprises obtaining or having obtained information indicating that the patient has a triglyceride level of at least 150 mg / dl, previously had symptoms of atrial fibrillation and / or atrial flutter, and / or has previously been diagnosed with atrial fibrillation and / or atrial flutter. In another embodiment, determining whether a subject has a triglyceride level of at least 150 mg / dl and a history of atrial fibrillation and / or atrial flutter comprises monitoring or having monitored the subject for a triglyceride level of at least 150 mg / dl and symptoms of atrial fibrillation and / or atrial flutter. In some embodiments, the subject is determined to have a triglyceride level of at least about 150 mg / dl by measuring the triglyceride level in a blood sample obtained from the subject. In some embodiments, the history of atrial fibrillation and / or atrial flutter is determined by determining whether the subject has or has had the symptoms of atrial fibrillation and / or flutter.Non-limiting examples of the symptoms of atrial fibrillation and / or atrial flutter include: heart rate above about 100 beats per minute (bpm); palpitations; shortness of breath; chest pain, pressure, narrowing or discomfort; dizziness; lightheadedness; or fainting.In some embodiments, the risk factors of atrial fibrillation and / or atrial flutter include: (a) heart failure; (b) previous heart attack; (c) heart valve abnormality; (d) high blood pressure; (e) thyroid dysfunction; (f) chronic lung disease; (g) diabetes; (h) obesity; and (i) congenital heart disease. In some embodiments, the subject is monitored for symptoms of atrial fibrillation and / or flutter using one or more of an electrocardiogram (ECG), an implantable pacemaker, an implantable cardioverter-defibrillator, and / or a subcutaneous implantable cardiac monitor.

[0059] In some embodiments, the method further comprises determining the risk of the subject experiencing symptoms of atrial fibrillation and / or atrial flutter if the subject previously had symptoms of atrial fibrillation and / or atrial flutter, previously diagnosed with atrial fibrillation and / or atrial flutter, and / or had symptoms of atrial fibrillation and / or atrial flutter during monitoring. In some embodiments, the method comprises determining the risk of the subject experiencing symptoms of atrial fibrillation and / or atrial flutter if the subject is administered EPA. In some embodiments, the method comprises determining whether the risk of the subject experiencing symptoms of atrial fibrillation and / or atrial flutter if the subject is administered EPA is greater than the reduction in the risk of a cardiovascular event in the subject. In some embodiments, the method comprises determining whether the reduction in risk of one or more cardiovascular events is greater than the risk of the subject experiencing symptoms of atrial fibrillation and / or atrial flutter if the subject is administered about 4 g of EPA per day.

[0060] In some embodiments, determining whether the risk of a subject experiencing symptoms of atrial fibrillation and / or atrial flutter when the subject is administered EPA is greater than the risk of reducing the risk of cardiovascular events comprises evaluating the risk benefit of reducing one or more cardiovascular events compared to the risk of increasing symptoms of atrial fibrillation and / or atrial flutter.Atrial fibrillation and / or flutter are caused by abnormal electrical signals that start in the upper chambers of the heart.When abnormal signals pass through the heart, the subject may experience cardiac flutter (e.g., rapid heartbeat), in addition to shortness of breath, fatigue, or mild headache.However, although atrial fibrillation and / or flutter may cause chest discomfort when the heart is beating rapidly, atrial fibrillation and / or flutter are generally less serious than the subject experiencing cardiovascular events (e.g., cardiovascular death, coronary revascularization, unstable angina, myocardial infarction, and / or stroke). Therefore, in some embodiments, the benefit of reducing the risk of one or more cardiovascular events in a subject outweighs the risk associated with an increase in symptoms of atrial fibrillation and / or atrial flutter.In some embodiments, if the benefit of administering EPA to a subject is greater than the associated increase in symptoms of atrial fibrillation and / or atrial flutter that the subject experiences as a result of administering EPA, the subject is administered EPA to reduce the risk of one or more cardiovascular events.

[0061] In some embodiments, if the benefit of administering EPA to a subject to reduce one or more cardiovascular events is less than the risk that the subject will experience symptoms associated with atrial fibrillation and / or atrial flutter, the subject will not be administered EPA. For example, in some embodiments, the symptoms of atrial fibrillation and / or atrial flutter are so severe that they suggest that the subject will experience a cardiovascular event if the subject is administered EPA. In some embodiments, if the risk associated with an increase in symptoms of atrial fibrillation and / or atrial flutter is greater than the benefit of administering EPA to the subject, the subject will not be administered EPA. In some embodiments, the subject will instead be administered a statin, and / or, if already receiving statin therapy, will continue to receive the statin.

[0062] In some embodiments, the risk associated with symptoms of atrial fibrillation and / or atrial flutter is determined by monitoring the subject for symptoms of atrial fibrillation and / or atrial flutter and determining whether the symptoms are severe enough to cause a cardiovascular event if the subject were administered EPA. In some embodiments, the risk is based on assessing the subject for consistency of heart rate, heart contractions, blood pooling in the atria, increased risk of blood clotting, and / or increased blood clots.

[0063] In some embodiments, if the patient has previously had symptoms of atrial fibrillation and / or atrial flutter and has previously been diagnosed with atrial fibrillation and / or atrial flutter and / or symptoms of atrial fibrillation and / or atrial flutter, the method includes administering an atrial fibrillation and / or atrial flutter therapeutic agent to the patient instead of EPA. In some embodiments, the subject's risk of atrial fibrillation and / or atrial flutter after administration of the atrial fibrillation and / or atrial flutter therapeutic agent is lower than if the subject were administered EPA. In some embodiments, the risk of atrial fibrillation and / or atrial flutter after administration of the atrial fibrillation and / or atrial flutter therapeutic agent is lower than if the subject were administered 4 g of EPA per day.

[0064] In some embodiments, if the subject is at greater risk of experiencing symptoms of atrial fibrillation and / or atrial flutter, the method includes administering to the patient an atrial fibrillation and / or atrial flutter therapeutic agent instead of EPA. In some embodiments, the subject is administered an atrial fibrillation and / or atrial flutter therapeutic agent instead of about 4 g of EPA per day.

[0065] In some embodiments, the atrial fibrillation and / or atrial flutter therapeutic agent administered to the subject is one or more of a beta-blocker, anticoagulant, antithrombotic, calcium channel blocker, antiplatelet, sodium channel blocker, or potassium channel blocker. Non-limiting examples of beta-blockers include acebutolol, metoprolol, nadolol, pindolol, betapace, and propranolol. Non-limiting examples of anticoagulants include rivaroxaban, dabigatran, apixaban, and edoxaban. Non-limiting examples of antithrombotic agents include warfarin, heparin, aspirin, ticlopidine, and dipyridamole. Non-limiting examples of calcium channel blockers include diltiazem hydrochloride, verapamil hydrochloride, and verapamil hydrochloride. Non-limiting examples of antiplatelet agents include aspirin, anagrelide, dipyridamole, vorapaxar, apixaban, rivaroxaban, dalteparin, and fondaparinux. Non-limiting examples of sodium channel blockers include procainamide, disopyramide, quinidine, and flecainide. Non-limiting examples of potassium channel blockers include dronedarone, ibutilide, and sotalol.

[0066] In some embodiments, the atrial fibrillation and / or atrial flutter therapeutic agent is administered to the subject at a standard dose. In some embodiments, the subject is administered a beta-blocker at a dose of about 20 mg to about 80 mg. In some embodiments, the subject is administered an anticoagulant at a dose of about 2.5 mg to about 250 mg. In some embodiments, the subject is administered a calcium channel blocker at a dose of about 2.5 mg to about 10 mg. In some embodiments, the subject is administered an antiplatelet agent at a dose of about 30 mg to about 300 mg. In some embodiments, the subject is administered a sodium channel blocker at a dose of about 20 mg to about 150 mg. In some embodiments, the subject is administered a potassium channel blocker at a dose of about 20 mg to about 150 mg. In some embodiments, the subject is administered warfarin at a dose of 25 mg.

[0067] In yet another embodiment, if the subject has not previously had symptoms of atrial fibrillation and / or atrial flutter, has not previously been diagnosed with atrial fibrillation and / or atrial flutter, and / or has not been diagnosed with symptoms of atrial fibrillation and / or atrial flutter during monitoring, the method comprises administering EPA to the subject to reduce the risk of cardiovascular events. In some embodiments, about 4 g of EPA is administered to the subject per day.

[0068] In some embodiments, if the patient is at a higher risk of having one or more reduced cardiovascular events, the method comprises administering EPA to the patient.In some embodiments, when the subject is administered EPA, the subject experiences both an increase in the frequency of atrial fibrillation and / or atrial flutter symptoms and a reduction in the frequency of cardiovascular events.In some embodiments, about 4g of EPA is administered to the subject per day.

[0069] In some embodiments, if the subject is being treated with a statin, the method comprises continuing to treat the subject with the statin, regardless of whether the subject is at risk for experiencing symptoms of atrial fibrillation and / or flutter. In some embodiments, if the subject is being treated with a statin, the method comprises continuing to treat the subject with the statin, regardless of whether the subject is at risk for having a reduced risk of one or more cardiovascular events. In some embodiments, if the subject is being treated with a statin, the method comprises continuing to treat the subject with the statin, regardless of whether the subject is likely to experience and increase atrial fibrillation and / or atrial flutter symptoms and a reduced frequency of cardiovascular events.

[0070] In some embodiments, the method includes reducing the risk of a cardiovascular event in a subject, including determining that an individual with a triglyceride level greater than 150 mg / dl and who has previously experienced an episode of atrial fibrillation or atrial flutter is likely to experience both (1) an increase in the frequency of episodes of atrial fibrillation or atrial flutter, and (2) a decrease in the frequency of cardiovascular events other than atrial fibrillation or atrial flutter, upon treatment with 4 g of EPA per day. In some embodiments, the method further includes identifying a subject with a measured triglyceride level greater than 150 mg / dl who has previously experienced symptoms of atrial fibrillation and / or atrial flutter.

[0071] In some embodiments, the method further comprises determining that the reduction in the frequency of cardiovascular events other than atrial fibrillation or atrial flutter in the subject is worth the risk of increasing the frequency of atrial fibrillation or atrial flutter in the subject.In some embodiments, after this determination, the method comprises administering EPA to the subject.In some embodiments, the method comprises administering about 4g of EPA to the subject per day.

[0072] In yet another embodiment, the method further comprises determining that the reduction in the frequency of cardiovascular events other than atrial fibrillation or atrial flutter in the subject is not worth the risk of increasing the frequency of atrial fibrillation or atrial flutter in the patient. In some embodiments, after this determination, the subject is not administered EPA, but instead is administered a statin. In some embodiments, if the subject is already receiving statin therapy, the method comprises continuing to administer the statin to the patient.

[0073] In some embodiments, the method further comprises determining that one or more cardiovascular benefits are predicted to occur, thereby reducing the risk of one or more cardiovascular events. In some embodiments, the cardiovascular events do not include atrial fibrillation and / or atrial flutter. In some embodiments, the cardiovascular events are one or more of cardiovascular death, coronary revascularization, unstable angina, stroke, and myocardial infarction. In some embodiments, the cardiovascular events are sudden cardiac death, cardiac arrest, or both.

[0074] In some embodiments, the method comprises reducing the risk of cardiovascular events in a subject, wherein the subject develops atrial fibrillation and / or atrial flutter during the course of treatment. In some embodiments, the method comprises administering EPA to the subject for a period that is effective in reducing the risk of cardiovascular events, wherein the subject develops atrial fibrillation and / or atrial flutter during the period that is effective in reducing the risk of cardiovascular events. In some embodiments, it is determined that before treatment, the subject has not previously had symptoms of atrial fibrillation and / or atrial flutter, has not previously been diagnosed with atrial fibrillation and / or atrial flutter, and / or has not exhibited symptoms of atrial fibrillation and / or atrial flutter. In some embodiments, the subject is administered about 4 g of EPA per day.

[0075] In some embodiments, the method includes reducing the risk of cardiovascular events in a subject under 65 years of age. In some embodiments, the method includes administering EPA to the subject for a period effective to reduce cardiovascular events, and the subject does not exhibit an increase in symptoms of atrial fibrillation and / or atrial flutter. In some embodiments, prior to treatment, the subject under 65 years of age is determined to have no previous symptoms of atrial fibrillation and / or atrial flutter, not been previously diagnosed with atrial fibrillation and / or atrial flutter, and / or not exhibited symptoms of atrial fibrillation and / or atrial flutter. In some embodiments, the subject is administered about 4 g of EPA per day. In some embodiments, the subject is under 65 years of age, under 60 years of age, under 55 years of age, under 50 years of age, under 45 years of age, under 40 years of age, under 35 years of age, under 30 years of age, or younger.

[0076] In some embodiments, the method includes reducing the risk of sudden cardiac death in a subject with a history of atrial fibrillation and / or atrial flutter. In some embodiments, the method includes reducing the risk of cardiac arrest in a subject with a history of atrial fibrillation and / or atrial flutter. In some embodiments, the method includes determining whether a subject has a history of atrial fibrillation and / or atrial flutter based on whether the subject has previously had symptoms of atrial fibrillation and / or atrial flutter, has previously been diagnosed with atrial fibrillation and / or atrial flutter, and / or has had symptoms of atrial fibrillation and / or atrial flutter.

[0077] In various embodiments, the present disclosure provides methods for reducing the risk of cardiovascular events in a subject receiving antithrombotic therapy. In some embodiments, the methods include (a) identifying a subject receiving antithrombotic therapy and having a fasting baseline triglyceride level of about 135 mg / dL to about 500 mg / d, identifying the subject as having established cardiovascular disease or at high risk for developing cardiovascular disease, and (b) administering to the subject a composition comprising about 1 g to about 4 g per day of eicosapentaenoic acid (free acid) or a derivative thereof (ethyl or methyl ester). As provided herein, the terms "composition" and "pharmaceutical composition" are referred to interchangeably.

[0078] In various embodiments, the present disclosure provides methods for reducing the risk of cardiovascular events in a subject receiving antithrombotic therapy. In some embodiments, the methods include (a) identifying a subject receiving antithrombotic therapy and having a fasting baseline triglyceride level of about 80 mg / dL to about 1500 mg / dL, the subject having established cardiovascular disease or being at high risk for developing cardiovascular disease, and (b) administering to the subject a composition comprising about 1 g to about 4 g per day of eicosapentaenoic acid (free acid) or a derivative thereof (ethyl or methyl ester). In some embodiments, the reduced risk of cardiovascular events is not correlated with a reduction in the subject's triglyceride level.

[0079] In some embodiments, the present disclosure provides a method for reducing the risk of cardiovascular events in a subject receiving antithrombotic therapy with or without a reduction in the subject's baseline triglyceride level. Thus, the reduction in cardiovascular events is not correlated with a reduction in the subject's triglyceride level. Thus, the subject experiences a reduced risk of cardiovascular events regardless of whether the subject exhibits a reduction in triglyceride level. In some embodiments, the method includes administering to the subject a composition comprising eicosapentaenoic acid or a derivative thereof, wherein the subject does not exhibit a statistically significant change in fasting triglyceride level for a period of time following administration of the composition. In some embodiments, the period 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. In other embodiments, the subject exhibits a reduction in fasting triglyceride levels for a period of more than about 5 years, more than about 6 years, more than about 7 years, more than about 8 years, more than about 9 years, or more than about 10 years.

[0080] In some embodiments, the present disclosure provides a method for reducing the risk of total cardiovascular events in a subject receiving antithrombotic therapy. In some embodiments, the method comprises administering a composition comprising eicosapentaenoic acid or a derivative thereof to the subject. Total cardiovascular events include the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or more cardiovascular events. In some embodiments, the subject has not experienced a cardiovascular event but is at high risk for experiencing a cardiovascular event. In some embodiments, the subject has experienced multiple cardiovascular events (i.e., the second, third, fourth, or more) and a reduced risk of any subsequent cardiovascular events. In some embodiments, 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, total cardiovascular events are reduced regardless of the subject's fasting baseline triglyceride level. For example, total cardiovascular events are reduced in subjects with low, middle or high fasting baseline triglyceride levels.The subjects in the low baseline fasting triglyceride tertile have triglyceride levels of about 80mg / dL to about 190mg / dL (median triglyceride level of 160mg / dL), the subjects in the middle baseline fasting triglyceride tertile have triglyceride levels of about 191mg / dL to about 250mg / dL (median triglyceride level of 215mg / dL), and finally, the subjects in the high baseline fasting triglyceride tertile have triglyceride levels of about 251mg / dL to about 1400mg / dL (median triglyceride level of 304mg / dL).

[0081] In some embodiments, the present disclosure provides a method for reducing cardiovascular events in a subject receiving antithrombotic therapy, the method comprising instructing or instructing the subject's caregiver to ask whether the subject has or has previously had atrial fibrillation and / or atrial flutter, assessing or assessing whether the subject has or has previously had symptoms of atrial fibrillation and / or atrial flutter, monitoring or monitoring the subject for symptoms of atrial fibrillation and / or atrial flutter, and / or providing or providing guidance to the subject's caregiver to monitor the subject for symptoms of atrial fibrillation and / or atrial flutter.In some embodiments, the method further comprises administering or administering to the subject a composition comprising eicosapentaenoic acid or a derivative thereof per day.

[0082] In some embodiments, the present disclosure provides a method for reducing the incidence of cardiovascular events in a subject receiving antithrombotic therapy. In some embodiments, the method comprises administering to the subject a composition comprising eicosapentaenoic acid or a derivative thereof per day, wherein the subject experiences reduced atrial fibrillation and / or atrial flutter and cardiovascular events, or no cardiovascular events. For example, administration of the composition shifts cardiovascular events to less serious medical consequences of atrial fibrillation and / or atrial flutter. Thus, in some embodiments, the subject experiences atrial fibrillation and / or atrial flutter instead of cardiovascular events. In another embodiment, the subject experiences an increase in symptoms of atrial fibrillation and / or atrial flutter and a reduction in cardiovascular events compared to baseline or placebo control. In some embodiments, the increase in symptoms of atrial fibrillation and / or atrial flutter is statistically significant compared to baseline or placebo control. For example, the symptoms of atrial fibrillation and / or atrial flutter increase by at least about 1%, at least about 2%, at least about 3%, at least about 4%, or at least about 5%.In yet another embodiment, the incidence of atrial fibrillation and / or atrial flutter requiring hospitalization is greater in the subject compared to baseline or placebo control.In some embodiments, the subject experiences a decrease in heart rate.

[0083] In various embodiments, the present disclosure provides methods for reducing the risk of cardiovascular events in subjects receiving antithrombotic and / or statin therapy. In some embodiments, the methods include (a) identifying a subject receiving antithrombotic and / or statin therapy and having a fasting baseline triglyceride level of about 135 mg / dL to about 500 mg / d, wherein the subject has established cardiovascular disease or is at high risk for developing cardiovascular disease, and (b) administering to the subject a composition comprising about 1 g to about 4 g per day of eicosapentaenoic acid (free acid) or a derivative thereof (ethyl or methyl ester). As provided herein, the terms "composition" and "pharmaceutical composition" are referred to interchangeably.

[0084] In various embodiments, the present disclosure provides methods for reducing the risk of cardiovascular events in subjects receiving antithrombotic and / or statin therapy. In some embodiments, the methods include (a) identifying a subject receiving antithrombotic and / or statin therapy and having a fasting baseline triglyceride level of about 80 mg / dL to about 1500 mg / dL, wherein the subject has established cardiovascular disease or is at high risk for developing cardiovascular disease, and (b) administering to the subject a composition comprising about 1 g to about 4 g per day of eicosapentaenoic acid (free acid) or a derivative thereof (ethyl or methyl ester). In some embodiments, the reduced risk of cardiovascular events does not correlate with a reduction in the subject's triglyceride level.

[0085] In some embodiments, the present disclosure provides a method for reducing the risk of cardiovascular events in a subject receiving antithrombotic and / or statin therapy, with or without a reduction in the subject's baseline triglyceride level. Thus, the reduction in cardiovascular events is not correlated with a reduction in the subject's triglyceride level. Thus, the subject experiences a reduced risk of cardiovascular events regardless of whether the subject exhibits a reduction in triglyceride level. In some embodiments, the method includes administering to the subject a composition comprising eicosapentaenoic acid or a derivative thereof, wherein the subject does not exhibit a statistically significant change in fasting triglyceride level for a period of time following administration of the composition. In some embodiments, the period 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. In other embodiments, the subject exhibits a reduction in fasting triglyceride levels for a period of more than about 5 years, more than about 6 years, more than about 7 years, more than about 8 years, more than about 9 years, or more than about 10 years.

[0086] In some embodiments, the present disclosure provides a method for reducing the risk of total cardiovascular events in a subject receiving antithrombotic and / or statin therapy. In some embodiments, the method comprises administering to the subject a composition comprising eicosapentaenoic acid or a derivative thereof. Total cardiovascular events include the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or more cardiovascular events. In some embodiments, the subject has not experienced a cardiovascular event but is at high risk for experiencing a cardiovascular event. In some embodiments, the subject has experienced multiple cardiovascular events (i.e., the second, third, fourth, or more) and a reduced risk of any subsequent cardiovascular events. In some embodiments, 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, total cardiovascular events are reduced regardless of the subject's fasting baseline triglyceride level. For example, total cardiovascular events are reduced in subjects with low, middle or high fasting baseline triglyceride levels.The subjects in the low baseline fasting triglyceride tertile have triglyceride levels of about 80mg / dL to about 190mg / dL (median triglyceride level of 160mg / dL), the subjects in the middle baseline fasting triglyceride tertile have triglyceride levels of about 191mg / dL to about 250mg / dL (median triglyceride level of 215mg / dL), and finally, the subjects in the high baseline fasting triglyceride tertile have triglyceride levels of about 251mg / dL to about 1400mg / dL (median triglyceride level of 304mg / dL).

[0087] In some embodiments, the present disclosure provides a method for reducing cardiovascular events in a subject receiving antithrombotic therapy and / or statin therapy, the method comprising instructing or instructing the subject's caregiver to ask whether the subject has or has previously had atrial fibrillation and / or atrial flutter, assessing or assessing whether the subject has or has previously had symptoms of atrial fibrillation and / or atrial flutter, monitoring or monitoring the subject for symptoms of atrial fibrillation and / or atrial flutter, and / or providing or providing guidance to the subject's caregiver to monitor the subject for symptoms of atrial fibrillation and / or atrial flutter. In some embodiments, the method further comprises administering or administering to the subject a composition comprising eicosapentaenoic acid or a derivative thereof per day.

[0088] In some embodiments, the present disclosure provides a method for reducing the incidence of cardiovascular events in a subject receiving antithrombotic and / or statin therapy. In some embodiments, the method includes administering a composition containing eicosapentaenoic acid or a derivative thereof to a subject per day, wherein the subject experiences reduced atrial fibrillation and / or atrial flutter and cardiovascular events, or no cardiovascular events. For example, administration of the composition shifts cardiovascular events to less serious medical consequences of atrial fibrillation and / or atrial flutter. Thus, in some embodiments, the subject experiences atrial fibrillation and / or atrial flutter instead of cardiovascular events. In another embodiment, the subject experiences an increase in symptoms of atrial fibrillation and / or atrial flutter and a reduction in cardiovascular events compared to baseline or a placebo control. In some embodiments, the increase in symptoms of atrial fibrillation and / or atrial flutter is statistically significant compared to baseline or a placebo control. For example, the symptoms of atrial fibrillation and / or atrial flutter increase by at least about 1%, at least about 2%, at least about 3%, at least about 4%, or at least about 5%.In yet another embodiment, the incidence of atrial fibrillation and / or atrial flutter requiring hospitalization is greater in the subject compared to baseline or placebo control.In some embodiments, the subject experiences a decrease in heart rate.

[0089] In some embodiments, the present disclosure provides methods for reducing the risk of cardiovascular events in subjects receiving low-, moderate-, or high-intensity statin therapy. In some embodiments, the methods include administering to the subject a composition containing eicosapentaenoic acid or a derivative thereof and low-, moderate-, or high-intensity statin therapy per day. In some embodiments, the low-intensity statin therapy includes about 5 mg to about 10 mg of simvastatin. In some embodiments, 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. In some embodiments, the high-intensity statin therapy comprises about 20 mg to about 40 mg of 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. In some embodiments, subjects receiving high-intensity statin therapy exhibit a greater reduction in cardiovascular events compared to subjects receiving low- or moderate-intensity statin therapy. In some embodiments, subjects receiving moderate-intensity statin therapy exhibit a greater reduction in cardiovascular events compared to subjects receiving either high- or low-intensity statin therapy. In some embodiments, subjects receiving low-intensity statin therapy exhibit a greater reduction in cardiovascular events compared to subjects receiving high- or moderate-intensity statin therapy. In some embodiments, the greater reduction is 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.

[0090] In some embodiments, the antithrombotic therapy includes one or more antiplatelet therapies and / or one or more anticoagulant therapies. In some embodiments, the antiplatelet therapy is aspirin and / or clopidogrel. In some embodiments, the anticoagulant therapy is warfarin. In some embodiments, aspirin, clopidogrel, or warfarin is the antithrombotic monotherapy. In some embodiments, the antithrombotic therapy includes one or more antiplatelet therapies and one or more anticoagulant therapies. In some embodiments, subjects administered one or more antiplatelet therapies exhibit a greater reduction in cardiovascular events compared to subjects receiving either anticoagulant therapy or one or more antiplatelet therapies and anticoagulant therapy. In some embodiments, subjects administered one or more anticoagulant therapies exhibit a greater reduction in cardiovascular events compared to subjects receiving either antiplatelet therapy or one or more antiplatelet therapies and anticoagulant therapy. In some embodiments, subjects administered one or more antiplatelet therapies and anticoagulant therapy exhibit a greater reduction in cardiovascular events compared to subjects receiving either anticoagulant therapy or antiplatelet therapy. In some embodiments, the greater reduction is 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.

[0091] In various embodiments, the present disclosure provides methods for reducing the risk of cardiovascular events in a subject receiving statin therapy. In some embodiments, the methods include (a) identifying a subject receiving statin therapy and having a fasting baseline triglyceride level of about 80 mg / dL to about 1500 mg / dL, the subject having established cardiovascular disease or at high risk for developing cardiovascular disease, and (b) administering to the subject a composition comprising about 1 g to about 4 g per day of eicosapentaenoic acid (free acid) or a derivative thereof (ethyl or methyl ester). In some embodiments, the reduced risk of cardiovascular events does not correlate with a reduction in the subject's triglyceride level.

[0092] In various embodiments, the present disclosure provides methods for reducing the risk of cardiovascular events in subjects receiving statin therapy and having fasting triglyceride levels, LDL-C levels, RLP-C levels, HDL-C levels, non-HDL-C levels, apoB levels, hsCRP levels, or eGFR levels in one or more of the low, middle, or high tertiles. In some embodiments, the subject exhibits a reduced risk of cardiovascular events regardless of whether the subject's LDL-C levels, RLP-C levels, HDL-C levels, non-HDL-C levels, apoB levels, hsCRP levels, and / or eGFR levels are in the low, middle, or high tertiles. For example, in some embodiments, a subject can have any combination of low, moderate, or high LDL-C levels, RLP-C levels, HDL-C levels, non-HDL-C levels, apoB levels, hsCRP levels, and / or eGFR levels and can exhibit a reduced risk of cardiovascular events.

[0093] In some embodiments, the risk of a cardiovascular event is reduced in subjects with fasting baseline triglyceride levels in the low, middle, or high tertiles. Subjects in the low baseline fasting triglyceride tertile have triglyceride levels of about 80 mg / dL to about 190 mg / dL, subjects in the middle baseline fasting triglyceride tertile have triglyceride levels of about 191 mg / dL to about 250 mg / dL, and finally, subjects in the high baseline fasting triglyceride tertile have triglyceride levels of about 251 mg / dL to about 1400 mg / dL. In some embodiments, the risk of a cardiovascular event is reduced by at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0094] In some embodiments, the risk of cardiovascular events is reduced in subjects with fasting baseline LDL-C levels in the low, middle, or high tertiles. Subjects in the low baseline fasting LDL-C tertile have LDL-C levels of about 1 mg / dL to about 67 mg / dL, subjects in the middle baseline fasting LDL-C tertile have triglyceride levels of about 67 mg / dL to about 84 mg / dL, and finally, subjects in the high baseline fasting LDL-C tertile have triglyceride levels of about 84 mg / dL to about 208 mg / dL. In some embodiments, the risk of cardiovascular events is reduced by at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0095] In some embodiments, the risk of a cardiovascular event is reduced in subjects with fasting baseline RLP-C levels in the low, middle, or high tertiles. Subjects in the low baseline fasting RLP-C tertile have RLP-C levels of about 12 mg / dL to about 28 mg / dL, subjects in the middle baseline fasting RLP-C tertile have RLP-C levels of about 28 mg / dL to about 34 mg / dL, and finally, subjects in the high baseline fasting RLP-C tertile have RLP-C levels of about 34 mg / dL to about 106 mg / dL. In some embodiments, the risk of a cardiovascular event is reduced by at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0096] In some embodiments, the risk of a cardiovascular event is reduced in subjects with fasting baseline HDL-C levels in the low, middle, or high tertiles. Subjects in the low baseline fasting HDL-C tertile have HDL-C levels of about 17 mg / dL to about 36 mg / dL, subjects in the middle baseline fasting HDL-C tertile have HDL-C levels of about 36 mg / dL to about 43 mg / dL, and finally, subjects in the high baseline fasting HDL-C tertile have HDL-C levels of about 43 mg / dL to about 107 mg / dL. In some embodiments, the risk of a cardiovascular event is reduced by at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0097] In some embodiments, the risk of a cardiovascular event is reduced in subjects with fasting baseline apoB levels in the low, middle, or high tertiles. Subjects in the low baseline fasting apoB tertile have apoB levels of about 17 mg / dL to about 76 mg / dL, subjects in the middle baseline fasting apoB tertile have apoB levels of about 76 mg / dL to about 89 mg / dL, and finally, subjects in the high baseline fasting apoB tertile have apoB levels of about 89 mg / dL to about 207 mg / dL. In some embodiments, the risk of a cardiovascular event is reduced by at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0098] In some embodiments, the risk of a cardiovascular event is reduced in subjects with fasting baseline non-HDL-C levels in the low, middle, or high tertiles. Subjects in the low baseline fasting non-HDL-C tertile have non-HDL-C levels of about 60 mg / dL to about 109 mg / dL, subjects in the middle baseline fasting non-HDL-C tertile have non-HDL-C levels of about 109 mg / dL to about 127 mg / dL, and finally, subjects in the high baseline fasting non-HDL-C tertile have non-HDL-C levels of about 127 mg / dL to about 244 mg / dL. In some embodiments, the risk of a cardiovascular event is reduced by at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0099] In some embodiments, the risk of a cardiovascular event is reduced in subjects with fasting baseline hsCRP levels in the low, middle, or high tertiles. Subjects in the low baseline fasting hsCRP tertile have hsCRP levels of about 2 mg / dL to about 109 mg / dL, subjects in the middle baseline fasting hsCRP tertile have hsCRP levels of about 109 mg / dL to about 127 mg / dL, and finally, subjects in the high baseline fasting hsCRP tertile have hsCRP levels of about 127 mg / dL to about 244 mg / dL. In some embodiments, the risk of a cardiovascular event is reduced by at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0100] In some embodiments, the risk of a cardiovascular event is reduced in subjects with fasting baseline eGFR levels in the low, middle, or high tertiles. Subjects in the low baseline fasting eGFR tertile have a fasting eGFR of 60 mL / min / 1.73 m 2 Subjects in the middle baseline fasting eGFR tertile had eGFR levels below approximately 60 mL / min / 1.73 m 2 ~Approx. 90mL / min / 1.73m 2 and finally, subjects in the high baseline fasting eGFR tertile had an eGFR level of approximately 90 mL / min / 1.73 m 2 In some embodiments, the risk of a cardiovascular event is reduced by at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0101] In some embodiments, the present disclosure provides a method for reducing the risk of cardiovascular events in a subject receiving statin therapy with or without a reduction in the subject's baseline triglyceride level. Thus, the reduction in cardiovascular events is not correlated with a reduction in the subject's triglyceride level. Thus, the subject experiences a reduced risk of cardiovascular events regardless of whether the subject exhibits a reduction in triglyceride level. In some embodiments, the method includes administering to the subject a composition comprising eicosapentaenoic acid or a derivative thereof, wherein the subject does not exhibit a statistically significant change in fasting triglyceride level for a period of time following administration of the composition. In some embodiments, the period 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. In other embodiments, the subject exhibits a reduction in fasting triglyceride levels for a period of more than about 5 years, more than about 6 years, more than about 7 years, more than about 8 years, more than about 9 years, or more than about 10 years.

[0102] In some embodiments, the present disclosure provides a method for reducing the risk of cardiovascular events in a subject receiving statin therapy, with or without a reduction in the subject's baseline LDL-C level. Thus, the reduction in cardiovascular events is not correlated with a change in the subject's LDL-C level. Thus, the subject experiences a reduced risk of cardiovascular events regardless of whether the subject exhibits a reduction in LDL-C level or whether the subject exhibits no statistically significant change in LDL-C level. In some embodiments, the method includes administering to the subject a composition comprising eicosapentaenoic acid or a derivative thereof, wherein the subject does not exhibit a statistically significant change in LDL-C level for a period of time following administration of the composition. In some embodiments, the period 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. In other embodiments, the subject exhibits a reduction in LDL-C level for a period of more than about 5 years, more than about 6 years, more than about 7 years, more than about 8 years, more than about 9 years, or more than about 10 years.

[0103] In some embodiments, the present disclosure provides a method for reducing the risk of total cardiovascular events in a subject receiving statin therapy. In some embodiments, the method comprises administering a composition comprising eicosapentaenoic acid or a derivative thereof to the subject. Total cardiovascular events include the first, second, third, fourth, fifth, sixth, eighth, ninth, tenth, or more cardiovascular events. In some embodiments, the subject has not experienced a cardiovascular event but is at high risk for experiencing a cardiovascular event. In some embodiments, the subject has experienced multiple cardiovascular events (i.e., the second, third, fourth, or more) and a reduced risk of any subsequent cardiovascular events. In some embodiments, 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, total cardiovascular events are reduced regardless of the subject's fasting baseline triglyceride level. For example, total cardiovascular events are reduced in subjects with low, middle or high fasting baseline triglyceride levels.The subjects in the low baseline fasting triglyceride tertile have triglyceride levels of about 80mg / dL to about 190mg / dL (median triglyceride level of 160mg / dL), the subjects in the middle baseline fasting triglyceride tertile have triglyceride levels of about 191mg / dL to about 250mg / dL (median triglyceride level of 215mg / dL), and finally, the subjects in the high baseline fasting triglyceride tertile have triglyceride levels of about 251mg / dL to about 1400mg / dL (median triglyceride level of 304mg / dL).

[0104] In some embodiments, the present disclosure provides a method for reducing cardiovascular events in a subject receiving statin therapy, the method comprising instructing or instructing the subject's caregiver to ask whether the subject has or has previously had atrial fibrillation and / or atrial flutter, assessing or assessing whether the subject has or has previously had symptoms of atrial fibrillation and / or atrial flutter, monitoring or monitoring the subject for symptoms of atrial fibrillation and / or atrial flutter, and / or providing or providing guidance to the subject's caregiver to monitor the subject for symptoms of atrial fibrillation and / or atrial flutter.In some embodiments, the method further comprises administering or administering to the subject a composition comprising eicosapentaenoic acid or a derivative thereof per day.

[0105] In some embodiments, the present disclosure provides a method for reducing the incidence of cardiovascular events in subjects receiving statin therapy. In some embodiments, the method comprises administering to a subject a composition comprising eicosapentaenoic acid or a derivative thereof per day, wherein the subject experiences reduced atrial fibrillation and / or atrial flutter and cardiovascular events, or no cardiovascular events. For example, administration of the composition shifts cardiovascular events to less serious medical consequences of atrial fibrillation and / or atrial flutter. Thus, in some embodiments, the subject experiences atrial fibrillation and / or atrial flutter instead of cardiovascular events. In another embodiment, the subject experiences an increase in symptoms of atrial fibrillation and / or atrial flutter and a reduction in cardiovascular events compared to baseline or placebo control. In some embodiments, the increase in symptoms of atrial fibrillation and / or atrial flutter is statistically significant compared to baseline or placebo control. For example, the symptoms of atrial fibrillation and / or atrial flutter increase by at least about 1%, at least about 2%, at least about 3%, at least about 4%, or at least about 5%.In yet another embodiment, the incidence of atrial fibrillation and / or atrial flutter requiring hospitalization is greater in the subject compared to baseline or placebo control.In some embodiments, the subject experiences a decrease in heart rate.

[0106] In some embodiments, the present disclosure provides methods for reducing the risk of cardiovascular events in subjects receiving low-, moderate-, or high-intensity statin therapy. In some embodiments, the methods include administering to the subject a composition containing eicosapentaenoic acid or a derivative thereof and low-, moderate-, or high-intensity statin therapy per day. In some embodiments, the low-intensity statin therapy includes about 5 mg to about 10 mg of simvastatin. In some embodiments, 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. In some embodiments, the high-intensity statin therapy comprises about 20 mg to about 40 mg of 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. In some embodiments, subjects receiving high-intensity statin therapy exhibit a greater reduction in cardiovascular events compared to subjects receiving low- or moderate-intensity statin therapy. In some embodiments, subjects receiving moderate-intensity statin therapy exhibit a greater reduction in cardiovascular events compared to subjects receiving either high- or low-intensity statin therapy. In some embodiments, subjects receiving low-intensity statin therapy exhibit a greater reduction in cardiovascular events compared to subjects receiving high- or moderate-intensity statin therapy. In some embodiments, the greater reduction is 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.

[0107] In some embodiments, the present disclosure provides methods for delaying the onset of: (a) non-fatal myocardial infarction; (b) fatal or non-fatal stroke; (c) cardiovascular death; (d) unstable angina; (e) coronary revascularization; (f) hospitalization due to unstable angina; (g) a composite of cardiovascular death or non-fatal myocardial infarction; (h) fatal or non-fatal myocardial infarction; (i) non-elective coronary revascularization, representing a composite of urgent or emergency classification; (j) cardiovascular death; (k) unstable angina determined by invasive or non-invasive testing to be caused by myocardial ischemia and requiring emergency hospitalization; and / or (l) a composite of all-cause mortality, non-fatal myocardial infarction, and / or non-fatal stroke. Onset of a disease and / or cardiovascular event refers to the first appearance of signs and / or symptoms of a cardiovascular event. In some embodiments, delaying the onset of cardiovascular events prevents the subject from experiencing a cardiovascular event and / or from developing any further symptoms of a cardiovascular event. In some embodiments, the method comprises administering a composition comprising eicosapentaenoic acid or a derivative thereof per day.

[0108] In yet another embodiment, the present disclosure provides a method for reducing the risk of one or more components of a 3-point composite endpoint consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke in a subject receiving statin therapy, or for reducing the risk of one or more components of a 5-point composite endpoint consisting of cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, coronary revascularization, or unstable angina requiring hospitalization in a subject receiving statin therapy. In some embodiments, each of the individual components of the 3-point composite and 5-point composite endpoints is reduced. For example, each of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke is reduced in combination. In some embodiments, the method comprises administering a composition comprising eicosapentaenoic acid or a derivative thereof per day. In some embodiments, 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%. In some embodiments, each of the individual components of a 3-point composite endpoint or a 5-point composite endpoint is reduced by at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0109] In another embodiment, the present disclosure provides a method for reducing cardiovascular events, the method comprising administering a composition comprising EPA or a derivative thereof, the composition being formulated so that, when administered to a subject, the composition provides an effective amount of EPA or a derivative thereof that achieves efficacy equivalent to about a 4 g dose of EPA or a derivative thereof, but at a lower daily dose of EPA or a derivative thereof. In some embodiments, the lower daily dose of EPA or a derivative thereof is about 3.8 g or less, about 3.6 g or less, about 3.4 g or less, about 3.2 g or less, about 3 g or less, about 2.8 g or less, about 2.6 g or less, or about 2.5 g or less. In some embodiments, the lower daily dose of EPA or a derivative thereof is reduced in the subject by at least about 10%, at least about 20%, at least about 30%, or at least about 40% compared to baseline or a placebo control. In one embodiment, administering the composition to a subject results in an improved pharmacokinetic profile in the subject compared to a control subject, wherein the subject and the control subject are in either a fed or fasted state, and the pharmacokinetic profile is determined by a maximum serum concentration (C max ) and the area under the curve (AUC). In some embodiments, control subjects are receiving statin therapy and are administered a placebo or other fatty acid composition, such as Lovaza, consisting of 365 mg E-EPA and 375 mg E-DHA.

[0110] In some embodiments, the present disclosure provides a method for reducing cardiovascular events in a subject receiving statin therapy, the method comprising administering a composition comprising EPA or a derivative thereof, wherein the subject does not experience any adverse events. Non-limiting examples of adverse events include back pain, nasopharyngitis, arthralgia, bronchitis, peripheral edema, dyspnea, osteoarthritis, cataracts, fatigue, constipation, musculoskeletal pain, gout, falls, type 2 diabetes mellitus, gastroesophageal reflux disease, insomnia, acute kidney injury, liver damage, 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 infections, chest pain, peripheral edema, pneumonia, influenza, urinary tract infections, cough, dizziness, pain in the extremities, angina, and anemia.

[0111] In yet another embodiment, the present disclosure provides a method for reducing cardiovascular events in a subject receiving statin therapy and under or over about 65 years of age, the method comprising administering a composition comprising EPA or a derivative thereof to the subject. In some embodiments, the degree to which cardiovascular events are reduced depends on the age of the subject. For example, in some embodiments, subjects under about 65 years of age exhibit a statistically significant reduction in cardiovascular events compared to subjects over about 65 years of age. Conversely, in some embodiments, subjects over about 65 years of age exhibit a statistically significant reduction in cardiovascular events compared to subjects under about 65 years of age. Thus, in some embodiments, the method for reducing cardiovascular events is correlated with the age of the subject.

[0112] In some embodiments, the present disclosure provides a method for reducing cardiovascular events in a subject receiving statin therapy, the method comprising administering a self-emulsifying composition to the subject. In some embodiments, the self-emulsifying composition comprises at least one compound selected from the group consisting of omega-3 fatty acids and derivatives thereof (e.g., pharmaceutically acceptable salts and / or esters). In another embodiment, the composition comprises an emulsifier. In some embodiments, 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 esters, polyoxyethylene castor oil, polyethylene glycol fatty acid esters, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters, and lecithin. In another embodiment, the omega-3 fatty acid or a derivative thereof is present in an amount of about 50% to about 95% by weight of the total weight of the composition or of the total fatty acids of the total composition. In some embodiments, the omega-3 fatty acid is EPA and / or DHA. In some embodiments, EPA is present in an amount of at least about 95% by weight of all fatty acids present in the self-emulsifying composition.In another embodiment, the composition is substantially free of DHA.In yet another embodiment, the composition is substantially free of ethanol.

[0113] In some embodiments, the subject has the symptom of atrial fibrillation and / or atrial flutter.Non-limiting examples of the symptom of atrial fibrillation and / or atrial flutter include: heart rate more than about 100 beats per minute (bpm); palpitations; shortness of breath; chest pain, pressure, narrowing or discomfort; dizziness; lightheadedness; or fainting.In some embodiments, the subject has the risk factor of atrial fibrillation and / or atrial flutter, including: (a) heart failure; (b) previous heart attack; (c) heart valve abnormality; (d) high blood pressure; (e) thyroid dysfunction; (f) chronic lung disease; (g) diabetes; (h) obesity; and (i) congenital heart disease.

[0114] In some embodiments, the method further includes monitoring the subject for atrial fibrillation and / or atrial flutter, or for symptoms of atrial fibrillation and / or atrial flutter. Non-limiting examples of methods for monitoring atrial fibrillation and / or atrial flutter include an electrocardiogram (ECG), an implantable pacemaker, an implantable cardioverter-defibrillator, and / or a subcutaneous implantable cardiac monitor.

[0115] In some embodiments, the subject has atrial fibrillation and / or atrial flutter or has symptoms of atrial fibrillation and / or atrial flutter and has a cardiac rhythm 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 The patient is determined to have a heart rate of 150 bpm, about 155 bpm, about 160 bpm, about 165 bpm, about 170 bpm, about 175 bpm, about 180 bpm, about 185 bpm, or about 190 bpm, or a heart rate of 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 about 85 bpm to about 200 bpm.

[0116] In some embodiments, the present disclosure provides a method for reducing the blood pressure of a subject.In one embodiment, the administration of 4 g per day of EPA or its derivative (E-EPA) for at least 1, 2, 3 or 4 years reduces systolic blood pressure by at least about 1 mmHg and reduces diastolic blood pressure by at least about 0.5 mmHg compared to baseline or placebo control subjects.

[0117] In some embodiments, the subject has a fasting baseline triglyceride level of about 135 mg / dL to about 500 mg / dL, e.g., 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. In some embodiments, the subject has a fasting baseline triglyceride level of about 50 mg / dL to about 1500 mg / dL, e.g., 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, or 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. In some embodiments, a subject or group of subjects has a blood glucose level 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, dL, about 120mg / dL, about 125mg / dL, about 130mg / dL, about 135mg / dL, about 140mg / dL, about 145mg / dL, about 150mg / dL, about 1 55mg / dL, approx. 160mg / dL, approx. 165mg / dL, approx. 170mg / dL, approx. 175mg / dL, approx. 180mg / dL, approx. 185mg / dL, approx. 190mg / d L, approx. 195 mg / dL, approx. 200 mg / dL, approx. 205 mg / dL, approx. 210 mg / dL, approx. 215 mg / dL, approx. 220 mg / dL, approx. 225 mg / dL, approx. 23 0mg / dL, approx. 235mg / dL, approx. 240mg / dL, approx. 245mg / dL, approx. 250mg / dL, approx. 255mg / dL, approx. 260mg / dL, approx. 265mg / dL , about 270 mg / dL, about 275 mg / dL, about 280 mg / dL, about 285 mg / dL, about 290 mg / dL, about 295 mg / dL, about 300 mg / dL, about 305 mg / dL, approx. 310 mg / dL, approx. 315 mg / dL, approx. 320 mg / dL, approx. 325 mg / dL, approx. 330 mg / dL, approx. 335 mg / dL, approx. 340 mg / dL,Approx. 345 mg / dL, approx. 350 mg / dL, approx. 355 mg / dL, approx. 360 mg / dL, approx. 365 mg / dL, approx. 370 mg / dL, approx. 375 mg / dL, approx. 380mg / dL, approx. 385mg / dL, approx. 390mg / dL, approx. 395mg / dL, approx. 400mg / dL, approx. 405mg / dL, approx. 410m g / dL, approx. 415 mg / dL, approx. 420 mg / dL, approx. 425 mg / dL, approx. 430 mg / dL, approx. 435 mg / dL, approx. 440 mg / dL, approx. 44 5mg / dL, approx. 450mg / dL, approx. 455mg / dL, approx. 460mg / dL, approx. 465mg / dL, approx. 470mg / dL, approx. 475mg / dL, approx. have a fed or fasting baseline triglyceride level (or for a control group, the median baseline triglyceride level) of 480 mg / dL, about 485 mg / dL, about 490 mg / dL, about 495 mg / dL, about 500 mg / dL, about 1000 mg / dL, about 1100 mg / dL, about 1200 mg / dL, about 1300 mg / dL, about 1400 mg / dL, about 1500 mg / dL, about 2000 mg / dL, about 2500 mg / dL, about 3000 mg / dL, about 3500 mg / dL, about 4000 mg / dL, about 4500 mg / dL, about 5000 mg / dL, or greater than about 5000 mg / dL. In some embodiments, the subject or group of subjects has a fed or fasting baseline triglyceride level (or, for a group of subjects, the median baseline triglyceride level) of 80 mg / dL or more, about 100 mg / dL or more, about 120 mg / dL or more, about 150 mg / dL or more, about 175 mg / dL or more, about 250 mg / dL or more, or about 500 mg / dL or more, e.g., 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.

[0118] In some embodiments, the subject or group of subjects is also receiving stable statin therapy (with or without ezetimibe). In some embodiments, the subject or group of subjects also has established cardiovascular disease or is at high risk of establishing cardiovascular disease. In some embodiments, the subject's statin therapy includes administration of one or more statins. For example, without limitation, the subject's statin therapy may include one or more of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. In some embodiments, the subject is further administered one or more of amlodipine, ezetimibe, niacin, and sitagliptin. In some embodiments, the subject's statin therapy includes administration of a statin and ezetimibe. In some embodiments, the subject's statin therapy includes administration of a statin that does not include ezetimibe.

[0119] In some embodiments, statin therapy is classified as monotherapy, combination, and / or combination of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitors. In some embodiments, monotherapy includes simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, or pitavastatin. In some embodiments, combinations include lovastatin and nicotinic acid, simvastatin and ezetimibe, pravastatin and fenofibrate, simvastatin and fenofibrate, atorvastatin and ezetimibe, or rosuvastatin and ezetimibe. In some embodiments, the HMG CoA inhibitor combination comprises 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, and indapamide; rosuvastatin, amlodipine, and perindopril; or atorvastatin and perindopril.

[0120] In some embodiments, the statin therapy is low-intensity, medium-intensity (i.e., moderate), or high-intensity statin therapy. In some embodiments, the low-intensity statin therapy comprises about 5 mg to about 10 mg of simvastatin. In some embodiments, the medium-intensity statin therapy comprises 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. In some embodiments, the high-intensity statin therapy comprises about 20 mg to about 40 mg of 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.

[0121] In some embodiments, the statin therapy of the object does not include the administration of niacin and / or fibrate of 200mg or more per day.In some embodiments, the object is not receiving concomitant omega-3 fatty acid therapy (for example, the prescription and / or commercial composition that comprises omega-3 fatty acid active agent is not administered or simultaneously administered).In some embodiments, the object is not administered or does not take the dietary supplement that comprises omega-3 fatty acid.

[0122] In some embodiments, the subject has established cardiovascular (CV) disease ("CV disease" or "CVD"). A subject's status as having CV disease can be determined by any suitable method known to those skilled in the art. In some embodiments, 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 artery disease, documented peripheral artery disease, or a combination thereof. In some embodiments, a subject is identified as having CV disease if the subject is at least 45 years of age and (a) has one or more stenoses of greater than 50% in the two major epicardial coronary arteries; (b) has a documented previous MI, (c) is hospitalized for a high-risk NSTE ACS with objective evidence of ischemia (e.g., ST-segment deviation and / or positive biomarkers); (d) has a documented previous ischemic stroke; (e) has symptomatic arterial disease with at least 50% carotid artery stenosis; (f) has asymptomatic carotid artery disease with at least 70% carotid artery stenosis on 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 aortoiliac or peripheral arterial intervention (catheter-based or surgical).

[0123] In some embodiments, a subject or group of subjects being treated according to the methods of the present disclosure has an elevated risk of developing CV disease. For example, but not limited to, a subject or group of subjects is at elevated risk of developing CV disease if the subject or group of subjects is about 50 years of age or older, has diabetes mellitus (type 1 or type 2), and at least one of the following: (a) is a male about 55 years of age or older or a female about 65 years of age or older; (b) is a smoker or was a smoker who quit less than about three months ago; (c) has hypertension (e.g., a systolic blood pressure of about 140 mmHg or greater, or a diastolic blood pressure of more than about 90 mmHg); (d) has HDL-C of about 40 mg / dL or less for men and about 50 mg / dL or less for women; (e) has an hsCRP level > about 3.0 mg / L; (f) has impaired renal function (e.g., a creatinine clearance ("CrCL") of greater than about 30 mL / min and less than about 60 mL / min); (g) has retinopathy (e.g., (h) have microalbuminuria (e.g., a positive Mikral or other strip test, an albumin / creatinine ratio of ≥ about 2.5 mg / mmol, all on at least two consecutive occasions, or an albumin excretion rate on timed collections of ≥ about 20 mg / min); (i) have macroalbuminuria (e.g., Albustix or other dipstick evidence of total proteinuria, an albumin / creatinine ratio of ≥ about 25 mg / mmol, all on at least two consecutive occasions, or an albumin excretion rate on timed collections of at least ≥ about 200 mg / min); and / or (j) have an ankle-brachial index of < about 0.9 without symptoms of intermittent claudication.

[0124] In some embodiments, the subject's baseline lipid profile is measured or determined before 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, testing a fasting or non-fasting blood sample obtained from the subject using a standard blood lipid profile assay. In some embodiments, the subject has one or more of a baseline non-HDL-C level of about 200 mg / dL to about 300 mg / dL, a baseline total cholesterol level of about 250 mg / dL to about 300 mg / dL, a baseline VLDL-C level of about 140 mg / dL to about 200 mg / dL, a baseline HDL-C level of about 10 mg / dL to about 30 mg / dL, a baseline LDL-C level of about 40 mg / dL to about 100 mg / dL, and / or a baseline hsCRP level of about 2 mg / dL or less.

[0125] In some embodiments, the cardiovascular event that risk is reduced is one or more of the following: cardiovascular death; non-fatal myocardial infarction; non-fatal stroke; coronary revascularization; unstable angina (for example, unstable angina that is determined to be caused by myocardial ischemia, for example, by invasive or non-invasive testing, and requires hospitalization); cardiac arrest; peripheral cardiovascular disease that requires intervention, angioplasty, bypass surgery, or aneurysm repair; sudden cardiac death, sudden death, and new onset of congestive heart failure.In some embodiments, the cardiovascular event is the first, second, third, fourth, or more cardiovascular events that the subject experiences.

[0126] In some embodiments, 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 (a) reduction in triglyceride levels compared to baseline or control; (b) reduction in apoB levels compared with baseline or control; (c) an increase in HDL-C levels compared with baseline or control; (d) no increase or increase in LDL-C levels compared with baseline or control; (e) reduction in LDL-C levels compared with baseline; (f) reduction in non-HDL-C levels compared with baseline or control; (g) Increase in non-HDL-C levels compared with baseline or control; (h) reduction in VLDL-C levels compared with baseline or control; (i) reduction in total cholesterol levels compared to baseline or control; (j) reduction in high-sensitivity C-reactive protein (hsCRP) levels compared to baseline or control; (k) a reduction in high-sensitivity troponin (hsTnT) levels compared to baseline or control; (l) reduced risk of cardiovascular death, coronary revascularization, unstable angina, myocardial infarction, and / or stroke compared with baseline or control; (m) reduction in risk of cardiac arrest compared with baseline or control; (n) reduction in risk of sudden death compared with baseline or control; (o) Reduction of the first, second, third, fourth, or more cardiovascular events compared to baseline or placebo control; (p) reduction in total cardiovascular events compared with baseline or control; (q) reduction in the three-point composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared with baseline or control; (r) reduction in a 5-point composite endpoint of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, coronary revascularization, or unstable angina compared with baseline or control; (s) an increase in atrial fibrillation and / or atrial flutter compared with baseline or control; (t) an increase in symptoms of atrial fibrillation and / or atrial flutter compared with baseline or control; (u) reduction in total mortality (i.e., death from any cause) compared with baseline or control; (v) reduction in a composite of all-cause mortality, nonfatal myocardial infarction, and stroke compared with baseline or placebo control; (w) reduction in new congestive heart failure (CHF) or new CHF as the primary cause of hospitalization compared with baseline or control; (x) reduction in transient ischemic attacks compared to baseline or control; (y) reduced risk of amputation due to peripheral vascular disease (PVD) compared with baseline or control; (z) reduced risk of carotid revascularization compared with baseline or control; (aa) Reduction in cardiac arrhythmias compared to baseline or control; (bb) reduction in hypertension compared to baseline or control; (cc) reduction in type 1 or type 2 diabetes compared with baseline or control; (dd) a reduction in weight and / or weight circumference compared to baseline or a control; and / or (ee) a decrease in eGFR levels compared to baseline or a control.

[0127] In one embodiment, the disclosed method comprises measuring a baseline level of one or more markers set forth in (a)-(ee) above prior to administering to a subject or group of subjects. In another embodiment, the method comprises administering a composition disclosed herein to a subject after a baseline level of one or more markers set forth in (a)-(ee) has been determined, followed by an additional measurement of the one or more markers.

[0128] In another embodiment, treatment with a composition of the present disclosure causes a subject to: (a) a reduction in triglyceride levels compared to baseline or a control 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 55%; (b) a reduction in apoB 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% compared to baseline or a control; (c) an increase in HDL-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%, at least about 55%, or at least about 75% compared to baseline or a control; (d) no increase in LDL-C levels or an increase in LDL-C levels of less than 30%, less than 20%, less than 10%, or less than 5% compared to baseline or control; and / or (e) a reduction in LDL-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 55% compared to baseline or a control; (f) a reduction in non-HDL-C levels compared to baseline or a control of at least about 1%, at least about 3%, 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%, or at least about 50%; (g) increase in non-HDL-C levels of less than 30%, less than 20%, less than 10%, less than 5% (actual % change or median % change), or no increase in non-HDL-C levels compared with baseline or control; (h) a reduction in VLDL-C levels compared to baseline or a control 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%; (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% compared to baseline or a control; and / or (j) a reduction in hsCRP levels compared to baseline or a control 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%; (k) a reduction in high-sensitivity troponin (hsTnT) levels compared to baseline or a control 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%; (l) a reduction in the risk of cardiovascular death, coronary revascularization, unstable angina, myocardial infarction, and / or stroke 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% compared to baseline or a control; (m) a reduction in the risk of cardiac arrest 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% compared to baseline or a control; (n) a reduction in the risk of sudden cardiac death and / or sudden cardiac death 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% compared to baseline or a control; (o) a reduction in the first, second, third, fourth, or more cardiovascular events experienced by 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% of subjects compared to baseline or a control; (p) 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% compared to baseline or a control; (q) a reduction in a three-point composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke 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% compared to baseline or a control; (r) a reduction in a 5-point composite endpoint of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, coronary revascularization, or unstable angina 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% compared to baseline or control; (s) an increase in atrial fibrillation and / or atrial flutter of at least about 1%, at least about 1.5%, at least about 2%, at least about 2.5%, at least about 3%, at least about 3.5%, at least about 4%, at least about 4.5%, at least about 5%, at least about 5.5%, at least about 6%, at least about 6.5%, at least about 7%, at least about 7.5%, at least about 8%, at least about 8.5%, at least about 9%, at least about 9.5%, or at least about 10% compared to baseline or a control; (t) an increase in symptoms of atrial fibrillation and / or atrial flutter of at least about 1%, at least about 1.5%, at least about 2%, at least about 2.5%, at least about 3%, at least about 3.5%, at least about 4%, at least about 4.5%, at least about 5%, at least about 5.5%, at least about 6%, at least about 6.5%, at least about 7%, at least about 7.5%, at least about 8%, at least about 8.5%, at least about 9%, at least about 9.5%, or at least about 10% compared to baseline or a control; (u) a reduction in 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% compared to baseline or a control; (v) a reduction in a composite of all-cause mortality, non-fatal myocardial infarction, and stroke 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% compared to baseline or a control; (w) a reduction in new CHF or new CHF as a primary cause of hospitalization 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% compared to baseline or a control; (x) a reduction in transient ischemic attacks 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% compared to baseline or a control; (y) a reduction in the risk of amputation due to PVD 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% compared to baseline or a control; (z) a reduction in the risk of coronary revascularization 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% compared to baseline or a control; (aa) a reduction in cardiac arrhythmias compared to baseline or a control 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%; (bb) a reduction in hypertension 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% compared to baseline or a control; (cc) a reduction in type 1 or type 2 diabetes 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% compared to baseline or a control; (dd) a reduction in body weight and / or body weight circumference 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% compared to baseline or a control; and / or (ee) exhibit one or more of a reduction in body weight and / or body weight circumference 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% compared to baseline or a placebo control.

[0129] In one embodiment, the subject or group of subjects being treated has a baseline EPA blood concentration 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.

[0130] In another embodiment, the subject or group of subjects being treated has a fed or fasting baseline triglyceride level (or median baseline triglyceride level, for a group of subjects) of about 135 mg / dL to about 500 mg / dL. In some embodiments, the subject or group of subjects being treated has a fed or fasting baseline triglyceride level (or median baseline triglyceride level, for a group of subjects) of about 80 mg / dL to about 1500 mg / dL. In some embodiments, the subject or group of subjects being treated according to the methods of the present disclosure is receiving stable statin therapy (with or without ezetimibe). As used herein, the phrase "stable statin therapy" refers to a subject or group of subjects receiving 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. In some embodiments, the subject or group of subjects receiving stable statin therapy has an LDL-C level of about 40 mg / dL to about 100 mg / dL.

[0131] In some embodiments, safety laboratory testing of a subject's blood sample includes hematology of a complete blood count ("CBC") including RBC, hemoglobin (Hgb), hematocrit (Hct), white blood cell count (WBC), white blood cell differential, and platelet count; and 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 HbA 1c The biochemistry panel includes one or more of the following:

[0132] In some embodiments, the fasting lipid panel associated with a subject includes TG, TC, LDL-C, HDL-C, non-HDL-C, and VLDL-C. In some embodiments, LDL-C is calculated using the Friedewald equation or measured by preparative ultracentrifugation (Beta Quant) if the subject's triglyceride level is greater than 400 mg / dL. In some embodiments, LDL-C is measured by ultracentrifugation (Beta Quant) at randomization and again about one year after randomization.

[0133] In some embodiments, biomarker assays relating to blood obtained from a subject include hsCRP, apoB, and hsTnT.

[0134] In some embodiments, the medical history associated with the subject includes family history, details regarding all illnesses and allergies, including date of onset, current status of the condition, and smoking and alcohol use.

[0135] In some embodiments, demographic information associated with a subject includes date of birth, race, and gender.

[0136] In some embodiments, the vital signs associated with the subject include systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature (eg, oral temperature).

[0137] In some embodiments, a subject's physical examination includes an evaluation of the subject's general appearance, skin, head, neck, heart, lungs, abdomen, extremities, and neuromuscular system.

[0138] In some embodiments, the subject's height and weight are measured. In some embodiments, the subject's weight is recorded with the subject wearing indoor clothing, with their shoes off, and with their bladder empty.

[0139] In some embodiments, a waist circumference measurement associated with the subject is measured, hi some embodiments, the waist circumference measurement is determined with a tape measure placed above the subject's hip bones.

[0140] In some embodiments, an electrocardiogram associated with the subject is obtained. In some embodiments, the ECG is obtained annually during the treatment / follow-up portion of the study. In some embodiments, the ECG is a 12-lead ECG. In some embodiments, the ECG is analyzed for the detection of silent MI.

[0141] In some embodiments, subjects randomly assigned to a treatment group receive 4g of a composition comprising at least 96% by weight of eicosapentaenoic acid ethyl ester per day. In some embodiments, the composition is encapsulated in a gelatin capsule. In some embodiments, subjects in this treatment group continue to take 4g of the composition per day 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. In some embodiments, the median treatment period is planned to be about 4 years.

[0142] In some embodiments, the present disclosure provides a method for reducing the risk of a cardiovascular event in a subject. In some embodiments, the method includes administering to the subject a composition comprising at least 96% by weight of eicosapentaenoic acid ethyl ester. In some embodiments, the subject is administered about 1 g to about 4 g of the composition per day.

[0143] In some embodiments, the reduced risk of a CV event is demonstrated or determined by comparing the amount of time (e.g., the average amount of time) associated with a subject or group of subjects from first administration to a first CV event selected from the group consisting of CV death, non-fatal MI, non-fatal stroke, coronary revascularization, and hospitalization (e.g., emergency hospitalization) due to unstable angina determined (e.g., by invasive or non-invasive testing) to be caused by myocardial ischemia, with the amount of time (e.g., the average amount of time) associated with a placebo or untreated subject or group of subjects from first administration to a first CV event selected from the group consisting of CV death, non-fatal MI, non-fatal stroke, coronary revascularization, and hospitalization (e.g., emergency hospitalization) due to unstable angina determined (e.g., by invasive or non-invasive testing) to be caused by myocardial ischemia, wherein the placebo does not comprise eicosapentaenoic acid ethyl ester. In some embodiments, the amount of time associated with a subject or group of subjects is compared to the amount of time associated with a placebo or untreated subject or group of subjects using a log-rank test. In some embodiments, the log-rank test includes one or more stratification factors, such as CV risk classification, ezetimibe use, and / or geographic region.

[0144] In some embodiments, the present disclosure provides a method of reducing the risk of CV death in a subject receiving stable statin therapy and having or at high risk for developing CV disease, comprising administering to the subject a composition disclosed herein.

[0145] In another embodiment, the present disclosure provides a method of reducing the risk of recurrent myocardial infarction (including silent MI) in a subject receiving stable statin therapy and having or at high risk of developing CV disease, comprising administering to the patient one or more compositions disclosed herein.

[0146] In some embodiments, the present disclosure provides a method of reducing the risk of non-fatal stroke in a subject receiving stable statin therapy and having or at high risk for developing CV disease, comprising administering to the subject a composition disclosed herein.

[0147] In some embodiments, the present disclosure provides a method of reducing the risk of coronary revascularization in a subject receiving stable statin therapy and having or at high risk for developing CV disease, comprising administering to the subject a composition disclosed herein.

[0148] In some embodiments, the present disclosure provides a method for reducing the risk of developing unstable angina caused by myocardial ischemia in a subject receiving stable statin therapy and having or at high risk for developing CV disease, comprising administering to the subject a composition disclosed herein.

[0149] In some embodiments, the present disclosure provides a method of reducing the risk of cardiac arrest in a subject who is on stable statin therapy and has or is at high risk for developing CV disease, comprising administering to the subject a composition disclosed herein.

[0150] In some embodiments, the present disclosure provides a method of reducing the risk of sudden cardiac death and / or sudden death in a subject receiving stable statin therapy and having or at high risk for developing CV disease, comprising administering to the subject a composition disclosed herein.

[0151] In some embodiments, the present disclosure provides a method of reducing the risk of a first, second, third, fourth, or more cardiovascular events in a subject who is receiving stable statin therapy and has or is at high risk for developing CV disease, comprising administering to the subject a composition disclosed herein.

[0152] In another embodiment, any of the methods disclosed herein is used to treat or prevent a subject or subjects consuming a traditional Western diet. In one embodiment, the disclosed method includes identifying a subject as a Western diet consumer or a sensible diet consumer, and then treating the subject if the subject is considered a Western diet consumer. The term "Western diet" herein generally refers to a typical diet consisting of about 45% to about 50% carbohydrates, about 35% to about 40% fat, and about 10% to about 15% protein, as a percentage of total calories. Alternatively, or additionally, a Western diet may be characterized by a relatively high intake of red and processed meats, sweets, refined grains, and desserts, e.g., greater than 50%, greater than 60%, or 70% or more of total calories from these sources.

[0153] In another embodiment, the compositions described herein are administered to a subject once or twice a day. In another embodiment, one, two, three, or four capsules, each containing about 1 g of the composition described herein, are administered to a subject daily. In another embodiment, one or two capsules, each containing about 1 g of the composition described herein, are administered to a subject in the morning, for example, from about 5:00 AM to about 11:00 AM, and one or two capsules, each containing about 1 g of the composition described herein, are administered to a subject in the afternoon, for example, from about 5:00 PM to about 11:00 PM.

[0154] In some embodiments, the subject's risk of a cardiovascular event is reduced compared to a control population. In some embodiments, a plurality of control subjects for the control population, each of which is receiving stable statin therapy, have fasting baseline triglyceride levels of about 135 mg / dL to about 500 mg / dL, have established cardiovascular disease or are at high risk for developing cardiovascular disease, and are not administered a composition comprising about 1 g to about 4 g of eicosapentaenoic acid ethyl ester per day.

[0155] In some embodiments, the subject's risk of a cardiovascular event is reduced compared to a control population. In some embodiments, a plurality of control subjects for the control population, each of which is receiving stable statin therapy, have fasting baseline triglyceride levels of about 80 mg / dL to about 1500 mg / dL, have established cardiovascular disease or are at high risk for developing cardiovascular disease, and are not administered a composition comprising about 1 g to about 4 g of eicosapentaenoic acid ethyl ester per day.

[0156] In some embodiments, (a) the first time interval beginning with the initial administration of a composition disclosed herein to the subject (b) to the first cardiovascular event is longer or substantially longer than (a') the first control time interval beginning with the initial administration of a placebo to the control subject (b') to the first cardiovascular event in the control subject. In some embodiments, the subject's first cardiovascular event is a major cardiovascular event selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, and unstable angina caused by myocardial ischemia. In some embodiments, the control subject's first cardiovascular event is a major cardiovascular event selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, and unstable angina caused by myocardial ischemia. In some embodiments, the subject's first cardiovascular event and the control subject's first cardiovascular event are death (from any cause), non-fatal myocardial infarction, or non-fatal stroke. In some embodiments, the first cardiovascular event of the subject and the first cardiovascular event of the control subject are any of cardiovascular death, non-fatal myocardial infarction, coronary revascularization, unstable angina, peripheral cardiovascular disease, or cardiac arrhythmia requiring hospitalization.In some embodiments, the first cardiovascular event of the subject and the first cardiovascular event of the control subject are any of cardiovascular death, non-fatal myocardial infarction, coronary revascularization, and unstable angina.In some embodiments, the first cardiovascular event of the subject and the first cardiovascular event of the control subject are any of cardiovascular death and non-fatal myocardial infarction.In some embodiments, the first cardiovascular event of the subject and the first cardiovascular event of the control subject is death (from any cause).In some embodiments, the first cardiovascular event of the subject and the first cardiovascular event of the control subject are any of fatal myocardial infarction and non-fatal myocardial infarction (optionally including silent MI). In some embodiments, the first cardiovascular event in the subject and the first cardiovascular event in the control subject is a coronary revascularization.In some embodiments, the first cardiovascular event of the subject and the control subject is hospitalization (e.g., emergency hospitalization) due to unstable angina (optionally unstable angina caused by myocardial ischemia). In some embodiments, the first cardiovascular event of the subject and the control subject is any one of fatal stroke or non-fatal stroke. In some embodiments, the first cardiovascular event of the subject and the control subject is any one of new coronary heart failure, new coronary heart failure resulting in hospitalization, transient ischemic attack, amputation due to coronary vascular disease, and carotid revascularization. In some embodiments, the first cardiovascular event of the subject and the control subject is any one of elective coronary revascularization and emergency coronary revascularization. In some embodiments, the first cardiovascular event of the subject and the control subject is the onset of diabetes. In some embodiments, the first cardiovascular event of the subject and the control subject is cardiac arrhythmia requiring hospitalization. In some embodiments, the first cardiovascular event of the subject and the first cardiovascular event of the control subject is cardiac arrest.In some embodiments, the first cardiovascular event of the subject and the first cardiovascular event of the control subject is sudden cardiac death and / or sudden death.

[0157] In some embodiments, (a) the second time interval beginning with the initial administration of the composition to the subject (c) to a second cardiovascular event in the subject is longer or substantially longer than (a') the second control time interval beginning with the initial administration of a placebo to the control subject (c') to a second cardiovascular event in the control subject. In some embodiments, the second cardiovascular event in the subject and the second cardiovascular event in the control subject are major cardiovascular events selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, and unstable angina caused by myocardial ischemia. In some embodiments, the major cardiovascular event is further selected from the group consisting of cardiac arrest, sudden cardiac death, and / or sudden death.

[0158] In some embodiments, the subjects have diabetes mellitus and the control subjects each have diabetes mellitus. In some embodiments, the subjects have metabolic syndrome and the control subjects each have metabolic syndrome.

[0159] In some embodiments, the subject exhibits one or more of the following: (a) reduced triglyceride levels compared to a control population; (b) reduced apoB levels compared to a control population; (c) increased HDL-C levels compared to a control population; (d) no increase in LDL-C levels compared to a control population; (e) reduced LDL-C levels compared to a control population; (f) reduced non-HDL-C levels compared to a control population; (g) reduced VLDL levels compared to a control group; (h) reduced total cholesterol levels compared to a control population; (i) reduced high-sensitivity C-reactive protein (hsCRP) levels compared to a control population; and / or (j) reduced high-sensitivity troponin (hsTnT) levels compared to a control population.

[0160] In some embodiments, the subject's weight after administration of the composition is less than the baseline weight determined before administration of the composition, hi some embodiments, the subject's waist circumference after administration of the composition is less than the baseline waist circumference determined before administration of the composition.

[0161] In the method of the present disclosure in which time interval is determined or evaluated, the time interval can be, for example, average, median or average value time interval.For example, in the embodiment in which the first control time interval is related to a plurality of control subjects, the first control time interval is the average, median or average value of the plurality of first control time intervals related to each control subject.Similarly, in the embodiment in which the second control time interval is related to a plurality of control subjects, the second control time interval is the average, median or average value of the plurality of second control time intervals related to each control subject.

[0162] In some embodiments, the reduced risk of cardiovascular events is expressed as the difference in incidence between the study group and the control population. In some embodiments, the subjects in the study group experience a first major cardiovascular event at a first incidence rate lower than a second incidence rate after the first administration of the composition disclosed herein, and the second incidence rate is related to the rate of cardiovascular events in the subjects in the control population. In some embodiments, the first major cardiovascular event is any one of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, and hospitalization due to unstable angina (optionally determined to be caused by myocardial ischemia). In some embodiments, the first and second incidence rates are determined for a period beginning on the date of the first administration and ending about 4 months, about 1 year, about 2 years, about 3 years, about 4 years, or about 5 years from the date of the first administration.

[0163] In another embodiment, the present disclosure provides a use of any of the compositions described herein for treating hypertriglyceridemia in a subject in need thereof, comprising providing to the subject a fasting baseline triglyceride level of about 135 mg / dL to about 500 mg / dL and administering to the subject a composition described herein. In one embodiment, the composition comprises about 1 g to about 4 g of eicosapentaenoic acid ethyl ester, and the composition is substantially free of docosahexaenoic acid.

[0164] In yet another embodiment, the present disclosure provides a use of any of the compositions described herein for treating hypertriglyceridemia in a subject in need thereof, comprising providing to the subject a fasting baseline triglyceride level of about 80 mg / dL to about 1500 mg / dL and administering to the subject a composition described herein. In one embodiment, the composition comprises about 1 g to about 4 g of eicosapentaenoic acid ethyl ester, and the composition is substantially free of docosahexaenoic acid. [Example]

[0165] Example 1: Effect of icosapent ethyl on reducing cardiovascular events in high-risk statin-treated patients The incidence of cardiovascular events remains high among patients with cardiovascular risk factors receiving treatment for secondary or primary prevention. Even patients receiving appropriate statin therapy remain at significant residual cardiovascular risk. In such patients, elevated triglyceride levels serve as an independent marker of increased ischemic risk, as shown in epidemiological and Mendelian randomization studies. Randomized trials have shown that triglyceride-lowering medications, such as sustained-release niacin and fibrates, have not reduced the incidence of cardiovascular events when administered in addition to appropriate medications, including statins. Furthermore, contemporary trials and recent meta-analyses of omega-3 fatty acid products have not shown benefit in patients receiving statin therapy. Therefore, the purpose of this study was to determine whether and how icosapent ethyl (interchangeably referred to as AMR101 or VASCEPA®) reduced cardiovascular events in patients with elevated triglyceride levels on statin therapy.

[0166] The next study, also known as the REDUCE-IT clinical trial, was a large cardiovascular (CV) outcomes trial designed to evaluate the CV risk reduction effects of AMR101 treatment (commercially known as VASCEPA®) versus placebo on a five-point primary composite endpoint of CV death, nonfatal stroke, nonfatal myocardial infarction (MI), coronary revascularization, or unstable angina requiring hospitalization.

[0167] We conducted a multicenter, prospective, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the effects of AMR101 (4 g per day) on cardiovascular health and mortality in patients with hypertriglyceridemia who had or were at high risk for cardiovascular disease. The intended expanded indication for 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 multiple risk factors for cardiovascular disease.

[0168] The primary objective of this study was to evaluate the effect of 4 g of AMR101 daily on time from randomization to the first occurrence of any component of the following major CV events in patients 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) and LDL-C targets: CV death; nonfatal MI (including asymptomatic MI; electrocardiograms (ECGs) were performed annually to detect asymptomatic MI); nonfatal stroke; coronary revascularization; and unstable angina pectoris caused by myocardial ischemia determined by invasive / noninvasive testing and requiring emergency hospitalization.

[0169] The key secondary objective of this study was to evaluate the effect of 4 g daily of AMR101 on the time from randomization to the first occurrence of a composite of the following major CV events: CV death, nonfatal MI (including silent MI), and nonfatal stroke.

[0170] Other secondary objectives of the study were to evaluate the effect of treatment on the time from randomization to the first occurrence of the following individual or composite endpoints: a composite of CV death or nonfatal MI (including asymptomatic MI); fatal or nonfatal MI (including asymptomatic MI); non-elective coronary revascularization expressed as a composite of urgent or emergency classification; CV death; unstable angina caused by invasive or noninvasive testing and requiring emergency hospitalization; fatal or nonfatal stroke; a composite of all-cause mortality, nonfatal MI (including asymptomatic MI), or nonfatal stroke; and all-cause mortality.

[0171] The primary tertiary objective of this study was to evaluate the effect of 4 g of AMR101 and percent change from baseline on fasting triglycerides and LDL-C. Other tertiary objectives of this study, in addition to supporting efficacy and safety analyses, were to evaluate the effect of treatment on: • Total CV event analysis, defined as the time from randomization to the occurrence of the first and all recurrent major CV events, defined as CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, or unstable angina determined by invasive / noninvasive testing to be caused by myocardial ischemia and requiring emergency hospitalization; • The primary composite endpoint in the subset of patients with diabetes mellitus at baseline; • The primary composite endpoint in the subset of patients with metabolic syndrome at baseline, defined as waist circumference ≥ 35 inches (88 cm) for all women and Asian, Hispanic, or Latino men, and ≥ 40 inches (102 cm) for all other men; • Primary composite endpoint in the subset of patients with impaired glucose metabolism at baseline (fasting blood glucose (FBG) of 100–125 mg / dL at Visit 2); • A key secondary composite endpoint in the subset of patients with impaired glucose metabolism at baseline (FBG of 100–125 mg / dL at Visit 2); • composite of CV death, nonfatal MI (including asymptomatic MI), nonfatal stroke, cardiac arrhythmia requiring hospitalization for ≥24 hours, or cardiac arrest; • A composite of CV death, nonfatal MI (including asymptomatic MI), non-elective coronary revascularization (defined as urgent or emergency classification), or unstable angina determined by invasive / non-invasive testing to be caused by myocardial ischemia and requiring emergency hospitalization; • A composite of CV death, nonfatal MI (including asymptomatic MI), non-elective coronary revascularization (defined as urgent or emergency classification), unstable angina determined by invasive / non-invasive testing to be caused by myocardial ischemia and requiring emergency hospitalization, nonfatal stroke, or peripheral vascular disease (PVD) requiring intervention such as angioplasty, bypass surgery, or aneurysm repair; • A composite of CV death, nonfatal MI (including asymptomatic MI), non-elective coronary revascularization (defined as urgent or emergency classification), unstable angina determined to be caused by myocardial ischemia by invasive / non-invasive testing and requiring emergency hospitalization, PVD requiring intervention, or arrhythmia requiring hospitalization for ≥24 hours; • New onset congestive heart failure (CHF); • New CHF as the primary cause of hospitalization; • Transient ischemic attack (TIA); ●Amputation due to PVD; ●Carotid artery revascularization; • All coronary revascularizations defined as a composite of urgent, emergency, elective, or salvage; ● Urgent coronary revascularization; ● Emergency coronary revascularization; • Elective coronary revascularization; ● Salvage coronary revascularization; Cardiac arrhythmias requiring hospitalization for ≥24 hours ●Cardiac arrest; ● Ischemic stroke; ● Hemorrhagic stroke; • Fatal or nonfatal stroke in the subset of patients with a history of stroke before baseline; • New-onset diabetes, defined as type 2 diabetes newly diagnosed during the treatment / follow-up period; • New-onset hypertension, defined as a newly diagnosed systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg during the treatment / follow-up period; Fasting triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B (apoB), high-sensitivity C-reactive protein (hsCRP and log[hsCRP]), high-sensitivity troponin (hsTnT), and remnant-like lipoprotein cholesterol (RLP-C; estimated from a standard lipid panel, RLP-C = TC - HDL-C - LDL-C [Varbo 2014]) (based on ITT estimates): Assessment of the relationship between baseline biomarker levels and treatment effects within the primary and ranked secondary endpoints; Assessment of the effect of AMR101 on each marker; and Assessment of the relationship between post-baseline biomarker values ​​and treatment effect within the primary and key secondary composite endpoints by including post-baseline biomarker values ​​(e.g., at 4 months or 1 year) as covariates. • Change from baseline and percent change from baseline in fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apoB, hsCRP, hsTnT, and RLP-C; Weight changes; and ●Changes in waist circumference.

[0172] Study population The study population was men and women aged ≥ 45 years with established CVD or ≥ 50 years with diabetes combined with one additional risk factor for CVD. In addition, all patients had atherogenic dyslipidemia and hypertriglyceridemia, defined as treatment of hypercholesterolemia (but with a therapeutic goal of LDL-C and treatment with statins). Further details regarding the patient population are listed in the inclusion criteria below. Patients had to provide consent to participate in the study and be willing and able to comply with the protocol and study procedures.

[0173] Research period The study consisted of the following study periods:

[0174] Screening Period: During the screening period, patients were assessed for inclusion and exclusion criteria.

[0175] The first visit to the research unit (Visit 1) involved administering study procedures to assess patient eligibility for the study. At this screening visit, patients signed an informed consent form before any study procedures were administered, and the informed consent form included the treatment / follow-up period. Based on the Visit 1 evaluation, the following situations occurred: Patients who were eligible for participation based on study treatment at Visit 1 returned to the research unit for Visit 2 (randomization visit) to begin the treatment / follow-up period. This included, for example, patients at Visit 1 who were on a stable dose of statin, planned to use the same statin and same dose of statin, and did not need to wash out any non-statin lipid-modifying drugs. Patients who were not eligible to participate based on study treatment at Visit 1 and are unlikely to become eligible within the next 28 days (e.g., unlikely to stabilize statin dose, unable to wash out non-statin lipid-modifying medication, etc.): These patients failed screening after Visit 1. Patients who were not eligible for study participation based on study treatment at Visit 1 could become eligible within the next 28 days. To become eligible, patients returned for a second optional screening visit (Visit 1.1) at the investigator's discretion, at which time any treatment necessary to reassess any previously failed inclusion / exclusion criteria was repeated. This included, for example, patients who started a statin at Visit 1 and whose statin dose was changed and / or who needed to wash out a non-statin lipid-modifying drug at Visit 1. The following applied to these patients: Patients whose statin or statin dose was changed at Visit 1 were required to be on a stable statin dose for at least 28 days before the lipid profile measurement at Visit 1.1. Other concomitant medications (e.g., antidiabetic therapy) may have been optimized or stabilized during this period. Patients who began washout at Visit 1 had a washout period of at least 28 days (only 7 days for bile acid sequestrants) before lipid profile measurements at Visit 1.1. Patients who were on a stable dose of a statin at Visit 1, had plans to maintain the same statin at the same dose, did not require washout of any medication, but were asked to return for Visit 1.1 to repeat one or more of the other study procedures not related to concomitant medications. Patients who became eligible for participation based on additional study treatment at Visit 1.1 returned to the research unit for Visit 2 (randomization visit) to begin the treatment / follow-up period.

[0176] At the end of the screening period, patients were required to meet all inclusion and exclusion criteria before being randomized. Patients who were not eligible to participate after the screening period (based on study treatment at Visit 1 and / or Visit 1.1) could return for rescreening at a later date. These patients were required to resume all treatments beginning at Visit 1. This included patients who needed more time to stabilize one or more conditions or therapies (e.g., statins, antidiabetic agents, antihypertensive agents, thyroid hormones, HIV protease inhibitor therapy).

[0177] Treatment / Follow-up Period: Eligible patients entered the treatment / follow-up period within 42 days of the initial screening visit (Visit 1) or within 60 days of the initial screening visit (Visit 1) for patients who attended the second screening visit (Visit 1.1). During this period, patients received study medication during scheduled visits at the study site and took study medication while away from the study site.

[0178] During the visits, study procedures for efficacy and safety evaluations were performed. A detailed schedule of procedures is provided in Table 1 below. [Table 1-1] [Table 1-2]

[0179] Research period Although patients were randomized at different times during the enrollment period, all completed the study on approximately the same date (i.e., study end date), so follow-up periods varied based on the date of randomization. All randomized patients were planned to receive the study drug and be followed until the study end date. A minimum of approximately 1612 primary endpoint events was expected during the study. 8179 patients were randomized at multiple study sites worldwide over a period of approximately 4.2 years. After randomization, patients were treated and followed for an estimated maximum of 6.5 years. The study end date was determined to be when approximately 1612 primary efficacy events had been determined. Table 2 shows the study milestones, from the first patient screened to the last patient visit and subsequent database lock. [Table 2]

[0180] Research Group At Visit 2 (Day 0), eligible study patients were randomly assigned to the following treatment groups: Group 1: AMR101 (>96% E-EPA) 4g per day (four 1000mg capsules per day) Group 2: Placebo (4 capsules per day)

[0181] Four AMR101 or placebo capsules were taken daily, two capsules in the morning and two capsules in the evening (a two-times-per-day dosing regimen).

[0182] Number of patients This was an event-driven trial, and we anticipated a minimum of 1612 primary efficacy endpoint events would be required during the study. A total of approximately 8179 patients were enrolled in the study to receive either AMR101 or placebo (approximately 4089 patients per treatment group) to observe the estimated 1612 events that comprised the primary composite efficacy endpoint.

[0183] Randomization Eligible patients were randomized to one of two study groups using a computer-generated randomization scheme on day 0. Treatment assignment was provided using the internet (IWR), with randomized patients receiving either AMR101 or placebo in a 1:1 ratio.

[0184] Blinding This was a double-blind study. Patients at the study site, the investigators, pharmacists, and other support personnel, sponsor personnel and designees, study administrators and organizational personnel, and suppliers supporting the study were unaware of the randomization code (i.e., they did not know which study participants received the study drug and which received the placebo). The study drug, AMR101, and placebo capsules were similar in size and appearance to maintain blinding.

[0185] During the double-blind treatment / follow-up period, all persons (patients at the study site, investigators, pharmacists, and other support personnel, sponsor personnel and designees, study administrators and organizational personnel, and suppliers managing / supporting the study) were blinded to the individual results of efficacy laboratory measures (including lipid values), except for laboratory personnel performing the analyses. Individual results from the lipid profile could be unblinded in the event of a patient emergency.

[0186] Stratification Participants were assigned to treatment groups stratified by CV risk classification, ezetimibe use, and geographic region (e.g., Western, Eastern Europe, and Asia-Pacific countries). There were two CV risk classifications. CV Risk Class 1: Patients with established CVD as defined by the inclusion criteria. Patients with diabetes and established CVD were included in this category. These patients were defined as the secondary prevention stratum, primary risk category, and / or secondary prevention cohort. CV Risk Class 2: Patients with diabetes and at least one additional risk factor for CVD, but without established CVD. These patients are defined as the primary prevention stratum, secondary risk class, and / or primary prevention cohort.

[0187] Stratification was recorded in the IWR at the time of enrollment. Approximately 70% of randomized patients were in CV risk category 1, and approximately 30% of randomized patients were in CV risk category 2. Enrollment of patients in a CV risk category was stopped when the planned number of patients in that risk category was reached.

[0188] Study population 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, while Tables 4 and 5 further outline the inclusion criteria based on whether the patient was part of the primary prevention risk classification or secondary prevention risk classification, respectively. [Table 3]

[0189] Stable therapy was defined as the same daily dose of the same statin for at least 28 days prior to lipid-eligible measurements (TG and LDL-C) and, if applicable, the same daily dose of ezetimibe for at least 28 days prior to lipid-eligible measurements (TG and LDL-C). Patients who initiated statin therapy or ezetimibe at Visit 1 or who changed their statin, statin dose, and / or ezetimibe dose at Visit 1 were required to undergo a stabilization period of at least 28 days from initiation / change and have their eligible lipid measurements (TG and LDL-C) measured after the washout period (Visit 1.1). Statins may have been administered with or without ezetimibe.

[0190] If patients were eligible at the first eligibility visit for TG and LDL-C (Visit 1) and met all other inclusion / exclusion criteria, they were randomized at Visit 2. If patients were not eligible at the first eligibility visit (Visit 1), they were allowed a second re-eligibility visit (Visit 1.1). For some patients, a second re-eligibility visit (Visit 1.1) was required after the stabilization / washout period because medications needed to be stabilized and / or washed out.

[0191] Women were not considered to be of childbearing potential if they met one of the following criteria documented by the investigator: they had undergone hysterectomy, tubal ligation, or bilateral oophorectomy before signing informed consent; and / or they were postmenopausal, defined as ≥1 year since their last menstrual period, or had follicle-stimulating hormone (FSH) levels in the menopausal range.

[0192] Patients with established CVD (CV risk category 1) were defined as detailed in Table 4 . [Table 4]

[0193] Patients at high risk of CVD (CV risk category 2) were defined as detailed in Table 5 . [Table 5]

[0194] Exclusion Criteria: Patients who met the following exclusion criteria listed in Table 6 were not eligible for the study. [Table 6-1] [Table 6-2]

[0195] Study Procedures The screening period for this study included two visits: Visit 1 and Visit 1.1.

[0196] Screening Visit (Visit 1): During Visit 1, patients were instructed to come to the study site and fast for at least 10 hours before the visit. If patients were eligible for randomization based on treatment at Visit 1, they had to be randomized within 42 days of Visit 1. The following treatments were administered at Screening Visit 1: ● Signed informed consent was obtained; ● assigned a patient number to the patient; • Medical, surgical, and family history was obtained; ● Demographics recorded; ● Height, weight, and body mass index were obtained; • Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature) were obtained; • A 12-lead electrocardiogram was obtained; ● Inclusion / exclusion criteria were assessed; • This included procedures and (fasting) blood samples (e.g., hsCRP, calculated creatinine clearance) required to determine CV risk classification (see inclusion criteria); • Obtained fasting blood samples for chemistry and hematology testing; • Fasting blood samples for lipid profile (TG, TC, HDL-C, LDL-C, non-HDL-C, VLDL-C) were obtained; • Urine pregnancy tests were performed on women of childbearing potential; • Concomitant medications were recorded; • Patients were instructed to fast for at least 10 hours before their next visit.

[0197] Screening Visit (Visit 1.1): Patients who were eligible for study participation after Visit 1 because they met all inclusion criteria and none of the exclusion criteria skipped Visit 1.1 and returned to the study site for Visit 2 to be randomized and begin the treatment / follow-up period of the study. For these patients, Visit 2 occurred immediately after Visit 1. Patients who were ineligible at Visit 1 returned to the study site for a second eligibility visit (Visit 1.1), at the investigator's discretion. At Visit 1.1, the procedure that caused eligibility failure at Visit 1 was repeated. Patients became eligible for randomization after Visit 1.1 if they met all inclusion criteria and no longer met exclusion criteria. If patients were evaluated at Visit 1.1 and eligible for randomization based on the procedure repeated at Visit 1.1, they were required to be randomized within 60 days of Visit 1. For some patients, Visit 1.1 was required at least 28 days after Visit 1 to confirm eligibility. These were patients who initiated treatment with statins at Visit 1, changed their statins, changed the daily dose of their statins, initiated a washout of prohibited medications, or began a stabilization period on a specific medication (see inclusion / exclusion criteria above for details). Any of these changes at Visit 1 could have affected eligibility lipid levels, so patients were required to attend Visit 1.1 to determine whether they were eligible based on the lipid level requirements (TG and LDL-C) determined at Visit 1. Any other procedures that caused eligibility failure at Visit 1 were also repeated at Visit 1.1. The following procedures were performed at Screening Visit 1.1: • Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature) were obtained; ●Inclusion / exclusion criteria were assessed; only assessments for which patients were deemed ineligible at Visit 1 were repeated; • Fasting blood samples for chemistry and hematology were obtained. Only samples deemed ineligible by patients at Visit 1 were obtained; If patients were deemed ineligible at Visit 1, a fasting blood sample for lipid profile (TG, TC, HDL-C, LDL-C, non-HDL-C, VLDL-C) was obtained. This included patients who initiated treatment with statins at Visit 1, changed their statin, changed the daily dose of their statin, initiated a washout of prohibited medications, or started a stabilization period on a specific medication (see inclusion / exclusion criteria for details). These patients had a fasting blood sample collected at Visit 1.1 for eligible lipid values ​​(TG and LDL-C) to assess the TG and LDL-C inclusion criteria. Concomitant medications were recorded.

[0198] The treatment / follow-up period for this study included Visit 2, Visit 3, and Visits 4 through 9. Every attempt was made to complete follow-up visits during the defined gap period.

[0199] Randomization Visit (Visit 2; Day 0): Eligible patients returned to the study site for Visit 2. The following procedures were performed at Visit 2: ● Performed a physical examination; ● Weight obtained; • Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature) were obtained; ●Waist circumference (one of the factors for diagnosing metabolic syndrome) was measured; • A 12-lead electrocardiogram was obtained; ● Inclusion / exclusion criteria were assessed; Fasting blood samples were obtained for: o Chemistry and hematology tests; Baseline ‡ lipid profile; o Biomarker assays (baseline); Genetic testing (any blood sample); and Stored (in a nationally and IRB / IEC approved laboratory and dependent on national regulations). • A urine pregnancy test was performed for women of childbearing potential (must be negative for randomization); • Dispensed study medication and recorded randomization numbers; • Instructed patients on how to take the study medication; • Study medication was administered - Note: Study medication was taken orally with food after collection of all fasting blood samples; • Assessed and recorded adverse events; • Concomitant medications were recorded; The patient was instructed as follows: ○ Bring all study supplies with the patient to the next visit; Do not take the study drug on the morning of your next visit; and Fast for ≥10 hours before your next visit.

[0200] Visit 3 (Day 120; approximately 4 months): Patients returned to the study site on Day 120 ± 10 days for Visit 3. The following procedures were performed: Physical examination, ● Weight obtained; • Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature) were obtained; Fasting blood samples were obtained for: Chemistry and hematology tests; and Lipid profile. • Compliance with the study drug was reviewed by counting unused capsules, and compliance was discussed and counseled with patients as necessary. • Study medication administered - Note: After collection of all fasting blood samples, study medication should be taken orally with food; ●Efficacy events were assessed and recorded; • Assessed and recorded adverse events; • Concomitant medications were recorded; The patient was instructed as follows: ○ Bring all study supplies with the patient to the next visit; Do not take the study drug on the morning of your next visit; and Fast for ≥10 hours before your next visit.

[0201] The following procedures were performed at Visits 4, 5, 6, 7, 8, and 9: Visit 4: Day 360 ± 10; Visit 5: Day 720 ± 10; Visit 6: Day 1080 ± 10; Visit 7: Day 1440 ± 10; Visit 8: Day 1800 ± 10; Visit 9: Day 2160 ± 10: Physical examination, ● Weight obtained; • Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature) were obtained; ● Waist circumference was measured (taken only at visit 5); • A 12-lead electrocardiogram was obtained; Fasting blood samples were obtained for: o Chemistry and hematology tests; Lipid profile; Biomarker assays (collected only at Visit 5); and Stored (in national and International Review Board (IRB) / Independent Ethics Committee (IEC) approved laboratories and dependent on national regulations); • Reviewed study drug compliance by counting unused capsules and discussed and counseled patients regarding compliance as needed; • Study medication administered - Note: After collection of all fasting blood samples, study medication should be taken orally with food; ●Efficacy events were assessed and recorded; • Assessed and recorded adverse events; • Concomitant medications were recorded; The patient was instructed as follows: ○ Bring all study supplies with the patient to the next visit; Do not take the study drug on the morning of your next visit; and Fast for ≥10 hours before your next visit.

[0202] Additional Visits: The study end date was expected to be day 2160, but the actual end date depended on the DMC's determination of the study end date and when approximately 1612 primary efficacy events occurred. If the actual study end date was later than the expected end date, additional visits were scheduled between Visits 7 and the last visit, with a maximum of 360 ± 10 days between visits. If the actual study end date was earlier than the expected end date, fewer visits occurred, and the last visit (see section below titled "Last Visit - End of Study") occurred earlier. The same procedures were performed at the additional visits. Regardless of the number of additional visits, the last visit occurred after the DMC established the study end date, and the procedures listed below in the section titled "Last Visit - End of Study" were performed.

[0203] Final Visit - End of Study: Regardless of randomization date, all patients completed the study at the same time (within a 30-day window from the study end date). The study end date was planned as day 2160, but the actual end date depended on the DMC's determination of the study end date when approximately 1612 primary efficacy events had occurred (event-driven trial). For each patient, the final visit may have occurred within 30 days of the actual study end date determined by the DMC. However, for efficacy endpoints based on CV events, only events occurring up to and including the planned actual study end date were included in the efficacy analysis. A final follow-up visit was required for all patients. In the rare cases where the final follow-up visit did not occur within the 30-day time frame from the study end date, any attempts to contact the patient were recorded on a special contact form until appropriate information was obtained. At the final visit, the following procedures were performed: Physical examination, ● Weight obtained; • Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature) were obtained; ●Waist circumference was measured; • A 12-lead electrocardiogram was obtained; Fasting blood samples were obtained for: o Chemistry and hematology tests; Lipid profile; Biomarker assays; and Stored (in a nationally and IRB / IEC approved laboratory and dependent on national regulations). • Compliance with the study drug was determined by the number of unused capsules; ●Efficacy events were assessed and recorded; Adverse events were assessed and recorded; and Concomitant medications were recorded.

[0204] Telephone follow-up contact: Site personnel contacted each patient by telephone on the following study days: day 60 ± 3; day 180 ± 5; day 270 ± 5; day 450 ± 5; day 540 ± 5; day 630 ± 5; day 810 ± 5; day 900 ± 5; day 990 ± 5; day 1170 ± 5; day 1260 ± 5; day 1350 ± 5; day 1530 ± 5; day 1620 ± 5; day 1710 ± 5; day 1890 ± 5; day 1980 ± 5; and day 2070 ± 5.

[0205] If the study treatment / follow-up period extended beyond the expected end date (day 2160), additional follow-up calls were made every 3 months between additional visits ± 5 days. If the study treatment / follow-up period was shorter than the expected end date, fewer follow-up calls were necessary. Every attempt was made to speak to each patient within this time frame. The following information was collected from patients: • Possible efficacy endpoints related to CV events. Patients were asked to return to the study site to assess any endpoints or identified events; • adverse events; Concomitant medications; and ● Current address and contact information.

[0206] Patients were reminded of the following: • Take the study medication with food according to the assigned dosing schedule; • When returning to the research center for the next visit; • Bringing unused study medication to the next visit; Do not take the study drug on the morning of your next visit; and Fast for at least 10 hours before your next visit.

[0207] Inspection procedure Clinical Laboratory Procedures and Assessments: All screening and safety-related clinical laboratory decisions were performed by a certified clinical laboratory under the supervision of the sponsor or its designee. Whenever possible and appropriate, samples for clinical laboratory procedures were collected after at least 10 hours of fasting. For the purposes of this study, fasting was defined as abstaining from oral intake except for water (and any essential medications). The investigator reviewed and signed all laboratory test reports. Patients with laboratory values ​​at screening outside the exclusion limits specified in the exclusion criteria were not enrolled in the study (patients would have been considered for the study if the values ​​had been classified by the investigator as clinically insignificant). After randomization, the investigator was notified if laboratory values ​​were outside their normal range. In this case, the investigator was required to implement clinically appropriate follow-up procedures.

[0208] Safety Laboratory Tests: Safety parameters were analyzed by a certified clinical laboratory at screening (Visit 1 or Visit 1.1), the randomization visit (Visit 2; Day 0), Visit 3 (Day 120; approximately 4 months), and all other follow-up visits, including the final visit. Safety laboratory tests included the following: Hematology for complete blood count (CBC) including RBC, hemoglobin (Hgb), hematocrit (Hct), white blood cell count (WBC), white blood 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.

[0209] Each test result was classified as low (L), normal (N), and high (H) at each visit according to the normal range provided by the test. Shifts from baseline were expressed for each post-baseline visit and for the overall post-baseline visit. When multiple measurements of a test parameter were available at a patient's post-baseline visit, the most extreme value was included in the shift table. For shifts from baseline to the overall post-baseline visit, values ​​from all visits (including unscheduled measurements) were included. Fasting lipid parameters were included in the chemical shift table. Continuous lipid values ​​were expressed as part of the efficacy analyses.

[0210] Fasting Lipid Profile: Fasting lipid panel: TG, TC, LDL-C, HDL-C, non-HDL-C, and VLDL-C. At all visits, LDL-C was calculated using the Friedewald equation. At Visits 1 and 1.1, direct LDL-C was used if TG > 400 mg / dL (4.52 mmol / L) at the same visit. These LDL-C values ​​were used to assess the LDL-C inclusion criteria (LDL-C eligibility measure for randomization) and to evaluate changes in statin therapy if LDL-C targets were not met. At all remaining visits (except Visits 2 and 4), LDL-C was measured by direct LDL cholesterol or by preparative ultracentrifugation if TG > 400 mg / dL (4.52 mmol / L) at the same visit. In addition, LDL-C was measured by preparative ultracentrifugation at Visit 2 (0-month follow-up, baseline) and Visit 4 (12-month follow-up), regardless of TG levels. These preparative ultracentrifugation LDL-C measurements were used in statistical analyses, including calculation of percent change from baseline (1 year vs. baseline). Hopkins LDL-C was calculated for each visit.

[0211] Genetic Testing: Fasting blood samples were stored for future genetic testing at the sponsor's discretion. Details of this testing were to be determined at a later date. This sample was optional, as local regulations may prohibit the collection or international shipping of genetic samples or patients may not consent. Studies involving genetic testing explored the association between genes and specific diseases, including their treatments, such as drugs and medical treatments. Blood samples were collected at a research center with a laboratory with routine protocols. Each patient tube containing a sample for genetic testing was labeled with only the patient number. The laboratory maintained a subject code identification list for cross-referencing. The patient number did not contain any identifiable information (e.g., patient initials, date of birth). Unanalyzed samples were frozen and stored by the sponsor for up to two years after the end of the study, at which point the samples were destroyed. If samples were tested, the results were not reported to the patient, parents, relatives, or primary care physician, and were not recorded in the patient's medical record. There was no follow-up communication with the laboratory or patient regarding the samples. Subjects could withdraw consent for genetic testing at any time up until analysis, even after samples were obtained. Subjects could notify the laboratory in writing that they wished to withdraw consent for the genetic testing portion of the study, which was documented by the laboratory in the subject chart and recorded on the CRF. The laboratory was notified to withdraw the sample and discard it. Potential genetic bioassays may be conducted, which may be 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 apoC3, apoA5, ​​CETP, LPL, PCSK9, TNFα, TNFβ, ALOX5, COX2, FABP, haptoglobin 1, and haptoglobin 2.

[0212] Biomarker assays: Biomarker assays included hsCRP, apoB, and hsTnT.

[0213] Additional Laboratory Tests: Additional laboratory tests were performed and included the following: During scheduled procedures, women of childbearing potential underwent a urine pregnancy test at the specific visits listed (Table 1). Urine pregnancy tests were performed in research facilities utilizing commercially available test kits or in certified clinical laboratories. Archival fasting blood samples (10 mL). These samples were collected only at national facilities permitted by local regulations and approved by the IRB or IEC. Plasma from the archival samples was stored frozen in two separate aliquots and used for repeat analyses as described in the protocol or for other testing related to cardiovascular health at the sponsor's discretion. • Perform potential non-genetic bioassays, including but not limited to apoA1, apoC3, apoE, NMR lipid profile (particle size and number), oxidized LDL, Lp(a), Lp-PLA2, serum fatty acid concentrations, and gamma-glutamyltransferase (GGT).

[0214] Blinding of Test Results: All efficacy test results during the double-blind period of the study were kept secret from patients, investigators, pharmacists, and other support staff at the study site, sponsor personnel and designees, organizational research managers and personnel, and suppliers administering and / or supporting the study, except for laboratory personnel performing the assays. To ensure patient safety, hsTnT values ​​were reported to the site.

[0215] Flagging of Critical Laboratory Values: Critical laboratory values ​​were those that could require medical intervention to avoid potential patient harm. Critical laboratory values ​​were defined in the study laboratory manual, and study sites were notified of the occurrence of critical laboratory values ​​(high or low) by special annotations (flags) on the laboratory reports provided to the study sites. Laboratory values ​​that were part of the efficacy endpoints during the double-blind period of the study were not provided to study sites; however, sites were notified if a patient's sample had a TG value >1000 mg / dL (11.29 mmol / L) (highly elevated TG value) or an LDL-C value >130 mg / dL (3.37 mmol / L) (highly elevated LDL-C value). These very elevated values ​​were confirmed by a repeat measurement (new fasting blood sample) within 7 days. TG values ​​>2000 mg / dL (22.58 mmol / L) were also flagged so that appropriate medical treatment could be initiated by the investigator as soon as possible.

[0216] If TG levels were confirmed to be very high, patients could discontinue the study drug and remain in the study using their options. Investigators used their best clinical judgment for each patient, including the use of approved TG-lowering medications after patients discontinued the study drug. If LDL-C levels were confirmed to be very high, investigators were required to implement appropriate medical interventions, including: reinforcing / intensifying therapeutic lifestyle changes (including diet and physical activity), increasing the dose of current statin therapy, adding ezetimibe, or prescribing a more potent statin to lower LDL-C. Investigators used their best clinical judgment for each patient.

[0217] medical treatment Medical, surgical, and family history: Medical history including family history and details of all illnesses and allergies, date of onset, current condition, and tobacco and alcohol use was collected in all patients.

[0218] Demographics: Demographic information was collected for all patients, including date of birth, race, and sex.

[0219] Vital Signs and Patient Measurements: Vital signs included systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature. Blood pressure was measured using a standardized process: The patient sat for ≥ 5 minutes with their feet flat on the floor and the measuring arm supported so that the midpoint of the manometer cuff was at heart level; and • A rubber pouch was placed over the brachial artery and a mercury sphygmomanometer or automated blood pressure device with an appropriately sized cuff was used.

[0220] Blood pressure was recorded to the nearest 2 mmHg mark on the manometer or to the nearest integer on the automated device. The blood pressure reading was repeated 1-2 min later, and the second reading was recorded to the nearest 2 mmHg mark.

[0221] The baseline and post-baseline endpoint value categories shown in Table 7A were measured and displayed. Definitions of treatment-emergent values ​​of potentially clinically significant (PCS) vital signs are defined below in Table 7B. [Table 7] [Table 8]

[0222] The number (%) of patients with post-baseline PCS vital sign values ​​was summarized by treatment group. A list of patients meeting threshold criteria was provided.

[0223] Physical Examination: The physical examination included source documentation of general appearance, skin, and specific head and neck, cardiac, pulmonary, abdominal, extremity, and neuromuscular evaluation.

[0224] Height, weight, and body mass index: Height and weight were measured. Weight measurements were performed with the patient in house clothes, shoes removed, and with an empty bladder.

[0225] Waist circumference: Waist circumference was measured with a tape measure as follows: starting from the top of the hip bone, the tape measure was circled around the waist level with the navel. Ensure that the tape measure is snug but does not compress the skin and is parallel to the floor. Patients should not hold their breath while measuring waist circumference.

[0226] 12-Lead Electrocardiogram (ECG): ECGs (standard 12-lead) were obtained annually. Laboratory personnel made every attempt to perform patient ECGs using the same equipment at each visit. ECGs were reviewed by the laboratory for detection of asymptomatic MI. Asymptomatic MI was sent for event adjudication. All post-randomization ECGs (protocol-specified and other) were sent to the CEC for evaluation of asymptomatic MI. 12-lead ECG parameters, including heart rate (bpm), PR interval (milliseconds), QRS interval (milliseconds), QT interval (milliseconds), and QTc interval (milliseconds), were measured, and an overall interpretation and asymptomatic MI (yes / no) were summarized for all patients at screening (Visit 1), the randomization visit (Visit 2; Day 0), and all other follow-up visits, including the last visit of the study.

[0227] A high PCS value occurring during treatment at any time was defined as a change from a value equal to or less than the defined PCS value at baseline to a high PCS value at any post-baseline measurement. A low PCS value occurring during treatment at any time was defined as a change from a value equal to or greater than the lower PCS value at baseline to a low PCS value at any post-baseline measurement. Table 8 provides PCS ECG values. [Table 9]

[0228] The number (%) of patients with post-baseline PCS ECG values ​​was expressed by treatment group. A list of subjects with potentially clinically important changes in ECG values ​​was included.

[0229] Treatment and Procedures Treatment Regimen, Dosage, and Duration: Eligible study patients were randomly assigned to one of two treatment groups on Day 0. Patients in each group received either 4 g / day of AMR101 or placebo for up to 6.5 years, depending on their individual date of randomization and overall study discontinuation date per Table 9. The daily dose of study drug was four capsules per day, given as two capsules twice daily (two capsules given twice daily). [Table 10]

[0230] Patients were instructed to take the study medication with food (i.e., with or at the end of breakfast and dinner). On the day the patient was scheduled for a study visit, following collection of all fasting blood samples, the daily dose of study medication was administered by site personnel with food provided by the site. For the purposes of this study, fasting was defined as abstaining from anything by mouth except water (and any essential medications) for at least 10 hours. Treatment Assignment

[0231] Identification Numbers: Each patient was assigned a unique patient identification number (patient number) at each site. The patient number was used to identify the patient throughout the study and was fully documented. If a patient was not eligible to receive treatment or if the patient withdrew from the study, the patient number could not be reassigned to another patient. The patient number was used to assign patients to one of two treatment groups according to the randomization schedule.

[0232] Drug Randomization: Only eligible patients who met all inclusion criteria and none of the exclusion criteria were randomized to receive study medication beginning at Visit 2 (Day 0). Eligible study patients were randomly assigned to one of two treatment groups. Participants were stratified by CV risk category, ezetimibe use, and geographic region (Western, Eastern Europe, and Asia-Pacific countries). Approximately 70% of randomized patients were in CV risk category 1, which included patients with established CVD, and approximately 30% of randomized patients were in CV risk category 2, which included patients with diabetes and at least one additional risk factor but without established CVD. Enrollment of patients in a CV risk category was halted when the planned number of patients in that risk category was reached.

[0233] Emergency Unblinding: In an emergency, the investigator could request a patient's treatment assignment for unblinding if knowledge of the patient's treatment assignment was essential to the patient's clinical management or welfare. Before unblinding a patient's individual treatment assignment, the investigator assessed the relationship of the adverse event to administration of the study drug (yes or no). If the blind was broken for any reason, the investigator recorded the date and reason for breaking the blind in the appropriate case report form (CRF) and source documents.

[0234] Compliance Management: Patients were strongly encouraged to adhere to their treatment regimen with the investigational drug throughout the study period unless a clear contraindication arose. Any interruption of treatment was brief (e.g., <4 weeks) when possible and only for clinically indicated reasons, such as adverse events. Discontinuation was discontinuance whenever possible. Any discontinuation was based on compelling clinical reasons. Assessment of compliance with the investigational drug treatment regimen was obtained for all patients at each scheduled visit. Investigational drug was dispensed in amounts exceeding those required for the study. Patients were instructed to return all unused investigational drug at their next visit. Compliance with the investigational drug regimen was assessed at each visit by counting unused capsules. Discrepancies were evaluated and discussed with each patient to assess compliance. If compliance was insufficient, patients were counseled on the importance of compliance with the dosing regimen. At the end of the study, final investigational drug compliance was determined by counting unused capsules.

[0235] Study limitations 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 medications within 90 days prior to screening. While participating in this study, patients could not participate in any other investigational drug trials. Except for compelling medical reasons in ODIS patients, the following non-investigational drug-related, non-statin, lipid-modifying drugs, and nutritional supplements, as well as foods, were prohibited during the study (from Visit 1 to the end of the final study visit): • Niacin >200 mg / day; ●Fibrates; Prescription omega-3 fatty acid medications; • Dietary supplements containing omega-3 fatty acids (e.g., flaxseed, fish, krill, or algae oil); • Bile acid sequestrants; ● PCSK9 inhibitors; cyclophosphamide; and ●Systemic retinoid.

[0236] If any of these products were used during the study treatment / follow-up period, it was for a compelling medical reason in the ODIS patient and documented in the concomitant medication CRF. If the ODIS patient agreed to resume the study medication, the use of excluded medications was discontinued. Foods rich in omega-3 fatty acids were strongly discouraged after Visit 1 during the study period (not applicable only to the Netherlands or Canada; therefore, all centers in the Netherlands and Canada ignored this request). The following products were permitted: statins, ezetimibe, and herbal products and dietary supplements not containing omega-3 fatty acids.

[0237] Statins: The same statin was continued at the same dose until the end of the study unless deemed medically necessary to change due to adverse events or lack of efficacy (LOE). If LOE was a deciding factor, ezetimibe was preferably added to the current dose; • Allowed patients to switch between brand-name statins and generic versions of the same statin at any time during the study; • statins were administered with or without ezetimibe; Based on FDA recommendations, simvastatin 80 mg was used only in patients who had been taking this dose for at least 12 months and had not experienced any muscle toxicity (see the following reference: FDA Drug Safety Communication: Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury. (http: / / www.fda.gov / Drugs / DrugSafety / PostmarketDrugSafetyInformationforPatientsandProviders / ucm204882.htm)); and Changes in statin type or statin dose during the treatment / follow-up period of the study were made only for compelling medical reasons and were documented on the CRF. It was important to maintain statin therapy throughout the study, and in the rare situation where discontinuing statin use was medically compelling, patients could remain in the study and receive the investigational drug with the approval of the medical monitor. Under such conditions, resumption of statin therapy was attempted when / if medically appropriate. If LDL-C levels exceeded 130 mg / dL (3.37 mmol / L) during the study (confirmed by the initial measurement and a second measurement at least 1 week later), the investigator increased the dose of current statin therapy or added ezetimibe to lower LDL-C. The investigator used their best clinical judgment for each patient.

[0238] LDL-C rescue: If LDL-C levels exceeded 130 mg / dL (3.37 mmol / L) during the study (confirmed by the initial measurement and a second measurement at least 1 week later), the investigator either increased the dose of current statin therapy or added ezetimibe to lower LDL-C. The investigator used their best clinical judgment for each patient.

[0239] No data were available regarding the potential interaction between ethyl EPA and oral contraceptives. No studies have suggested that omega-3 fatty acids, including ethyl EPA, reduce the effectiveness of oral contraceptives.

[0240] Medications that were excluded if not on a stable dose for ≥28 days before screening could be initiated after randomization if medically warranted (i.e., tamoxifen, estrogen, progestin, thyroid hormone therapy, systemic corticosteroids, and HIV protease inhibitors).

[0241] Patient Restrictions: Beginning at the screening visit, all patients were instructed to abstain from excessive alcohol consumption, follow a physician-recommended diet, and maintain it for the duration of the study. Excessive alcohol consumption was defined as an average of 2 units of alcohol per day, or 5 or more units for men or 4 or more units for women in any 1-hour period (episodic excessive drinking or binge drinking). One unit of alcohol was defined as 12 ounces (350 mL) of beer, 5 ounces (150 mL) of wine, or 1.5 ounces (45 mL) of 80-proof drinking alcohol.

[0242] investigational drug Clinical Trial Materials: The following clinical materials were supplied by the sponsor. ●AMR101 1000mg capsules ● Placebo capsule (compatible with AMR 101 1g capsule)

[0243] The sponsor provided sufficient quantities of AMR101 1000 mg capsules and placebo capsules to allow for completion of the study. The lot numbers of the supplied medications were recorded in the final study report. Records were maintained showing the receipt and dispensing of all medication supplies. At the end of the study, any unused study medication was destroyed.

[0244] Pharmaceutical Formulation: AMR101 1000 mg and placebo capsules (paraffin) were provided in liquid-filled rectangular gelatin capsules. Each capsule was filled with a clear liquid (colorless to pale yellow). The capsules were approximately 25.5 mm long and 9.5 mm in diameter.

[0245] Labeling and Packaging: Study medication was packaged in high-density polyethylene bottles. Labeling and packaging was performed in accordance with GMP guidelines and all applicable country-specific requirements. Each patient's bottle was numbered based on the randomization schedule. The patient's randomization number, assigned by the IWR or the study sponsor's designee (if the IWR system was not used), corresponds to the bottle number. Each patient's bottle number was recorded in the study's electronic data capture (EDC) system.

[0246] Dispensing procedures and storage conditions Dispensing Procedures: At Visit 2 (Day 0), patients were assigned study medication according to their treatment group, as determined by the randomization schedule. Once assigned to a treatment group, patients received their study medication. At each visit, patients brought in their previously dispensed, unused medication supply. Site personnel administered medication from each patient's assigned medication supply while the patient was at the study site. If an unscheduled exchange of study medication was necessary, the investigator or designee contacted the IWR system or sponsor's designee (if an IWR system was not used) for the study. During the final visit of the treatment period, patients brought their unused medication supply to site personnel, and final study medication compliance was calculated by unused capsule count.

[0247] Storage Conditions: At the study site, the study drug was stored at room temperature (20°C-25°C) between 68°F and 77°F. Storage temperatures did not exceed 59°F (15°C) or 86°F (30°C), and the drug was stored in its original packaging. The study drug was stored in a pharmacy or a locked, secure storage facility, accessible only to individuals authorized by the investigator to dispense the drug. The investigator or designee maintained accurate dispensing records. At the end of the study, study site personnel were responsible for all used and unused study drug. Any unused study drug was destroyed. The investigator agreed not to distribute the study drug to any patients other than those participating in the study.

[0248] Efficacy evaluation Variables and Treatment Specifications: The primary endpoint and most of the secondary and tertiary endpoints were based on clinical events related to CVD and mortality. All events occurring between randomization and the end of the study (inclusive) were recorded. Only adjudicated events were included in the final analysis.

[0249] Primary Efficacy Outcome: The primary efficacy outcome was the time from randomization to the first occurrence of a composite of the following clinical events: CV death, nonfatal MI (including asymptomatic MI; ECG was performed annually to detect asymptomatic MI), nonfatal stroke, coronary revascularization, and unstable angina caused by myocardial ischemia determined by invasive / noninvasive testing and requiring emergency hospitalization. The first occurrence of any of these major vascular adverse events during the study follow-up period was included in the incidence rate.

[0250] Secondary Efficacy Endpoints: The key secondary efficacy endpoint was the time from randomization to the first occurrence of a composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke. Other secondary efficacy endpoints were the time from randomization to the first occurrence of the following individual or composite endpoints (tested in the order listed): • composite of CV death or non-fatal MI (including asymptomatic MI); • Fatal or non-fatal MI (including asymptomatic MI); • Non-elective coronary revascularization representing a composite of urgent or emergency classification; ●CV death; Unstable angina determined by invasive or noninvasive testing to be caused by myocardial ischemia and requiring emergency hospitalization; • Fatal and non-fatal stroke; A composite of all-cause mortality, non-fatal MI (including asymptomatic MI), or non-fatal stroke; and / or ●Total mortality rate.

[0251] For secondary endpoints that counted a single event, the time from randomization to the first occurrence of this type of event was counted for each patient. For secondary efficacy endpoints that were a composite of two or more types of events, the time from randomization to the first occurrence of any of the event types included in the composite was counted for each patient.

[0252] Tertiary Efficacy Endpoints: The following tertiary efficacy endpoints were evaluated to support the efficacy and safety analyses. Where applicable, and unless otherwise specified, endpoint analyses were conducted as follows: time from randomization to the first occurrence of the individual or composite endpoint. • Total CV event analysis, defined as the time from randomization to the occurrence of the first and all recurrent major CV events, defined as CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, or unstable angina determined by invasive / noninvasive testing to be caused by myocardial ischemia and requiring emergency hospitalization; • The primary composite endpoint in the subset of patients with diabetes mellitus at baseline; • The primary composite endpoint in the subset of patients with metabolic syndrome at baseline, with waist circumference cut points specifically set at ≥35 inches (88 cm) for all women and Asian, Hispanic, or Latino men, and ≥40 inches (102 cm) for all other men; • Primary composite endpoint in the subset of patients with impaired glucose metabolism at baseline (FBG of 100–125 mg / dL at Visit 2); • A key secondary composite endpoint in the subset of patients with impaired glucose metabolism at baseline (FBG of 100–125 mg / dL at Visit 2); • composite of CV death, nonfatal MI (including asymptomatic MI), nonfatal stroke, cardiac arrhythmia requiring hospitalization for ≥24 hours, or cardiac arrest; • A composite of CV death, nonfatal MI (including asymptomatic MI), non-elective coronary revascularization (defined as urgent or emergency classification), or unstable angina determined by invasive / non-invasive testing to be caused by myocardial ischemia and requiring emergency hospitalization; • A composite of CV death, nonfatal MI (including asymptomatic MI), non-elective coronary revascularization (defined as urgent or emergency classification), unstable angina determined to be caused by myocardial ischemia by invasive / non-invasive testing and requiring emergency hospitalization, nonfatal stroke, or PVD requiring intervention such as angioplasty, bypass surgery, or aneurysm repair; • A composite of CV death, nonfatal MI (including asymptomatic MI), non-elective coronary revascularization (defined as urgent or emergency classification), unstable angina determined to be caused by myocardial ischemia by invasive / non-invasive testing and requiring emergency hospitalization, PVD requiring intervention, or arrhythmia requiring hospitalization for ≥24 hours; ●New CHF; • New CHF as the primary cause of hospitalization; • Transient ischemic attack (TIA); ●Amputation due to PVD; ●Carotid artery revascularization; • All coronary revascularizations defined as a composite of urgent, emergency, elective, or salvage; ● Urgent coronary revascularization; ● Emergency coronary revascularization; • Elective coronary revascularization; ● Salvage coronary revascularization; Cardiac arrhythmias requiring hospitalization for ≥24 hours ●Cardiac arrest; ● Ischemic stroke; ● Hemorrhagic stroke; • Fatal or nonfatal stroke in the subset of patients with a history of stroke before baseline; • New-onset diabetes, defined as type 2 diabetes newly diagnosed during the treatment / follow-up period; • New-onset hypertension, defined as a newly diagnosed systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg during the treatment / follow-up period; Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apoB, hsCRP (hsCRP and log[hsCRP]), hsTnT, and RLP-C (estimated from a standard lipid panel, RLP-C = TC - HDL-C - LDL-C [Varbo 2014]) (based on ITT estimates): Assessment of the relationship between baseline biomarker levels and treatment effects within the primary and ranked secondary composite endpoints; Assessment of the effect of AMR101 on each marker; and Assessment of the relationship between post-baseline biomarker values ​​and treatment effect within the primary and key secondary composite endpoints by including post-baseline biomarker values ​​(e.g., at 4 months or 1 year) as covariates. Weight changes; and ●Changes in waist circumference.

[0253] Where applicable and unless otherwise specified, for tertiary endpoints that counted a single event, the time from randomization to the first occurrence of this type of event was counted in each patient. Similarly, where applicable and unless otherwise specified, for tertiary endpoints that were a composite of two or more types of event, the time from randomization to the first occurrence of the type of event included in the composite was counted in each patient.

[0254] Other sensitivity, supportive, and exploratory analyses were performed for the primary efficacy endpoint, i.e., on-treatment analyses including the occurrence of major events up to 0 and 30 days after permanent discontinuation of the drug.

[0255] The following clinical events, as adjudicated positively by a clinical endpoint committee, were analyzed as tertiary endpoints in the intention-to-treat (ITT) population: • a composite of all-cause mortality or congestive heart failure (CHF); • composite of CV death or new CHF; ● Sudden cardiac death; Peripheral artery disease (PAD); and ●Atrial fibrillation or atrial flutter.

[0256] The above tertiary endpoints were analyzed in the same manner as the primary endpoint.

[0257] In addition, the following were analyzed as tertiary endpoints in the ITT population: The relationship between high-sensitivity C-reactive protein (hsCRP) during treatment and the key secondary endpoints; and -Relationship between serum eicosapentaenoic acid (EPA) during treatment and primary and ranked secondary endpoints.

[0258] To assess the relationship between on-treatment hsCRP and the primary and key secondary endpoints, subgroup analyses were performed, as was done for the ITT population of patients grouped according to values ​​≥2 mg / dL or <2 mg / dL at baseline and year 2. To assess the relationship between on-treatment serum EPA and the primary and key secondary endpoints, Kaplan-Meier (KM) curves were generated for AMR101-treated patients grouped into tertiles based on their values ​​at year 1 and compared with placebo-treated patients.

[0259] Safety evaluation Variable and Treatment Specifications: Safety assessments included adverse events, clinical laboratory values ​​(chemistry, hematology), 12-lead ECG, vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature), weight, waist circumference, and physical examination according to the study procedures in Table 1. A complete medical, surgical, and family history was completed at Visit 1. All laboratory test results were evaluated by the investigator for their clinical significance. Any observation on physical examination or clinical laboratory value that the investigator deemed clinically significant was considered an adverse event.

[0260] Adverse Events: An adverse event is defined as any untoward medical event not necessarily causally related to the investigational drug. Thus, an adverse event can be any untoward and / or unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of an investigational product, whether or not related to the investigational product. All adverse events, including observed or spontaneous problems, complaints, or symptoms, were recorded on the appropriate CRF. Each adverse event was evaluated for duration, intensity, and causal relationship to the investigational drug or other factors.

[0261] Adverse events, including clinical laboratory test variables, were monitored from the time of informed consent until completion of study participation. Patients were instructed to report any adverse events they experienced to the investigator. Beginning at Visit 2, the investigator assessed adverse events at each visit and recorded the events on the appropriate adverse event CRF.

[0262] Whenever possible, specific diseases and syndromes, rather than individual associated signs and symptoms, were identified by the investigator and recorded on the CRF. However, if an observed or reported sign or symptom was not considered by the investigator to be a component of a specific disease or syndrome, it was recorded as a separate adverse event on the CRF.

[0263] Any medical condition present at baseline that was present when the patient was screened or that did not worsen was reported as an adverse event. However, any medical condition or sign or symptom that was present at baseline and changed in severity or severity at any time during the study was reported as an adverse event.

[0264] Clinically significant abnormal laboratory findings or other abnormal assessments detected during the study or present at baseline and significantly worsening were reported as adverse events or SAEs. Investigators exercised their medical and scientific judgment in determining whether an abnormal laboratory finding or other abnormal assessment was clinically significant.

[0265] The investigator rated the severity (intensity) of each adverse event as mild, moderate, or severe and also classified each adverse event for its possible relationship to the study drug using the categories "yes" or "no." Severity was defined as follows: • Mild - Events that are usually transient in nature and generally do not interfere with normal activities. Moderate - An event that is so bothersome that it interferes with normal activities. • Severe - A disabling event involving the inability to work or perform normal daily activities or the inability to work or perform normal daily activities.

[0266] Assessment of causality: The relationship of the adverse event to the administration of the study drug was assessed according to the following definitions: • No (unrelated, unrelated, unrelated) - The time lapse between administration of the investigational drug and the occurrence or worsening of the adverse event rules out a causal relationship and another cause (e.g., concomitant medication, therapy, comorbidity) is suspected. • Yes (related, possibly related, probably related) - The time course from administration of the investigational drug to the occurrence or worsening of the adverse event is consistent with a causal relationship, and no other causes (concomitant medications, therapies, comorbidities, etc.) can be identified.

[0267] The following factors were also taken into consideration: • Time series from study drug administration; • Events that occurred after the study drug was given. The length of time from exposure to the study drug to the event was assessed in the clinical context of the event; • Underlying, concomitant, and concurrent disorders; • Each report was evaluated in the light of the natural history and course of the disease being treated and any other illnesses the patient may have experienced; ● Concomitant medications; • Examining other medications the patient was taking or treatments the patient received to determine whether any of these may have caused the event in question; • known response patterns to this class of investigational drug; • Clinical and / or preclinical data may have indicated whether a particular response was likely to be a class effect; • exposure to physical and / or mental stress; • Exposure to stress may induce adverse changes in the patient, providing a logical and more complete explanation for the events; • pharmacology and pharmacokinetics of the investigational drug; and • The known pharmacological properties (absorption, distribution, metabolism, and excretion) of the investigational drug were taken into consideration.

[0268] Unexpected Adverse Event: An unexpected adverse event is an adverse event that has not been previously reported or whose nature, severity, severity, or outcome is inconsistent with the current investigator's brief.

[0269] Serious Adverse Events: A serious adverse event (SAE) is defined as an adverse event that meets any of the following criteria: ● Leading to death; • The term "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, not an event that might have caused death if it were more serious; • Requiring hospitalization or prolongation of existing hospitalization. In general, hospitalization for treatment of a pre-existing condition that did not worsen from baseline was not considered an adverse event and was not reported as an SAE; ● causing disability / incapacity; Have a congenital abnormality / birth defect; and Significant medical events. Significant medical events that may have resulted in death, may have been fatal, or may not have required hospitalization were considered SAEs if, based on appropriate medical judgment, they could have endangered the patient and required medical or surgical intervention to prevent one of the outcomes listed above. Examples of such medical events include allergic bronchospasm requiring intensive care in the emergency room or at home, a blood disorder or seizure that did not result in inpatient hospitalization, or the development of a drug dependency.

[0270] Due to the design of this study, SAEs that were endpoint events were recorded for endpoint determination purposes only and were not captured as SAEs. The intent was to report endpoint events as SAEs to the IRB unless the IRB required them to be reported. The investigators specifically notified their institutions / IRBs of this plan and confirmed whether they wanted endpoint events reported. Per agreement with the US FDA, these endpoints were also not reported to the US FDA as SAEs; rather, they were reported as endpoint events. If an event was determined not to meet the criteria for an event, following the determination, the event was evaluated as an SAE, beginning with that day as day 0.

[0271] Adverse events of particular interest: bleeding-related adverse events, glucose control (fasting blood glucose and HbA1c), and indicators of liver damage (e.g., increase in ALT or AST >3 × ULN, increase in total bilirubin ≥ 2 × ULN) were summarized separately and compared between treatment groups.

[0272] Serious Adverse Event Reporting - Investigator Action Initial reporting: All SAEs occurring from the time of informed consent through 28 days after the last dose of investigational drug were reported to the sponsor or designee within 24 hours of becoming aware of their occurrence (this refers to any adverse event that met any of the serious criteria described above). SAEs that the investigator deemed related to the investigational drug after the 28-day follow-up period were also reported to the sponsor or designee. Investigators were required to submit reports of SAEs to the institutional review board (IRB) or independent ethics committee (IEC) according to local requirements. All investigators involved in studies using the same investigational drug (IMP) received reports of any suspected unexpected serious adverse reactions (SUSARs) for subsequent submission to their local IRBs, if required. Investigators were blinded to all reports sent. In addition, regulatory authorities were notified of SAEs in accordance with the regulatory and legal requirements of their specific jurisdictions.

[0273] Follow-up Report: The investigator followed the patient until the SAE subsided, or until the condition became chronic in nature and stable (in the case of persistent impairment), or until the patient died. Within 24 hours of receiving the follow-up information, the investigator electronically updated the SAE form in the EDC system for the study and submitted any supporting documentation (e.g., laboratory test reports, patient discharge summary, or autopsy report) to the sponsor or designee via fax or email.

[0274] Sponsor reporting: The IRB and IEC were notified of SUSARs according to local requirements. Where necessary, cases were unblinded for reporting purposes.

[0275] In utero Exposure 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 In Utero Exposure Form to the investigator for completion. The patient was followed by the investigator until the pregnancy was completed. If the pregnancy terminated prematurely for any reason, the investigator notified the sponsor or designee. Upon completion of the pregnancy, the investigator documented the outcome of the pregnancy. If the outcome of the pregnancy met criteria for immediate classification as an SAE (i.e., postpartum complications, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the investigator followed procedures for reporting the SAE.

[0276] Treatment discontinuation / patient withdrawal Patients could withdraw from the study at any time for any reason. Administration of the study drug could also be discontinued at any time at the discretion of the investigator. In all cases, subjects who discontinued treatment but remained in the study (i.e., patients with ODIS) continued to be followed for efficacy and safety.

[0277] Reasons for early discontinuation of study drug: Discontinuation of study drug was avoided whenever possible, but may have occurred for any of the following reasons: Patients withdrew consent or requested early discontinuation of the study for any reason. Patients were encouraged to continue participating in the study for the entire study period, even if they chose not to take the study drug any longer. ● The occurrence of a clinical or laboratory adverse event, serious or non-serious, at the discretion of the investigator. If a patient discontinued due to an adverse event or laboratory abnormality, the sponsor or designee was notified. It was recommended that patients be strongly encouraged to adhere to their investigational drug treatment regimen for the duration of the study unless a clear contraindication arose. Any interruption of treatment was, where possible, brief (e.g., <4 weeks) and only for clinically indicated reasons, such as an adverse event. The following were considered reasons for discontinuation: ○ ALT>3×ULN and bilirubin>1.5×ULN; ○ALT>5×ULN; ○ALT>3×ULN and emergence or worsening of hepatitis; ALT >3 × ULN persisting for >4 weeks; and / or ALT > 3 × ULN and inability to monitor weekly for 4 weeks • Any medical or personal condition that, in the investigator's opinion, put the patient at risk by continuing in the study or by preventing compliance with the protocol; • The sponsor discontinued the study; ●Clinical trial site closure in the following cases: Another clinical trial site is unable to accommodate the patient, or The patient was unable or unwilling to travel to another study site; and / or TG levels were flagged as very high, i.e., >1000 mg / dL (11.29 mmol / L), and confirmed as very high by a repeat measurement (new fasting blood sample) within 7 days. In this case, the patient could discontinue the study drug (with the option to maintain ODIS) and may (re)initiate another lipid-modifying medication. If TG levels were flagged as >2000 mg / dL (22.58 mmol / L), appropriate medical treatment was initiated by the investigator as soon as possible.

[0278] The occurrence of an outcome event, as determined by the investigator, was not considered a valid reason for discontinuing the study drug. Patients who discontinued study drug treatment prematurely and did not withdraw consent remained in the study and were monitored until the end of the study. Patients who continued in the study after ≥30 days of treatment discontinuation were characterized as Off Drug In Study (ODIS). ODIS patients were asked to return to the study site for an interim visit if they had not taken study drug for >30 days. Disposition at this visit was consistent with disposition at Visit 5. If not contraindicated, patients could also resume study drug at any time after being characterized as ODIS. For patients who discontinued study drug (e.g., due to a potentially drug-related or non-drug-related AE), rechallenge (reinitiating study drug) could be performed as soon as clinically appropriate after a short treatment interruption, allowing for the confirmation or exclusion of a causative role of the study drug and, if appropriate, for the patient to continue on the study and study drug. Reasons for discontinuation or interruption of study drug were recorded on the CRF.

[0279] Follow-up / loss to follow-up after early discontinuation of study drug Patients who discontinued the study drug prematurely were not replaced. All randomized patients were followed until the end of the study or death, regardless of whether the study drug was discontinued prematurely. Any events occurring after early discontinuation of the study drug were recorded until the end of the study. To track the patient's medical status, especially if the patient discontinued the study, investigators were encouraged to obtain information from the patient's primary care practitioner (physician or any other health care provider). Investigators were also requested to recontact these patients at the end of the study and make as many attempts as possible to obtain at least their vital status and their status regarding the primary endpoint, thus avoiding loss to follow-up for efficacy assessments. If a patient was lost to follow-up, the CRF was completed until the last visit or contact.

[0280] statistics Randomized population: The randomized population included all patients who signed an informed consent form and were assigned a randomization number at Visit 2 (Day 0).

[0281] Treated Population: The ITT population included all patients randomized via the IRWS (Automated Web Response System). All efficacy analyses were performed on the ITT population. Patients were analyzed according to their randomized treatment.

[0282] Modified-Treatment Population: The modified-treat-to-treat (mITT) population included all randomized patients who received study medication dispensed after randomization. Groups were defined based on randomized treatment.

[0283] Per-protocol population: The per-protocol (PP) population included all mITT patients who had ≥80% compliance during treatment without any major protocol deviations. The minimum duration of therapy to be included in the PP population was 90 days.

[0284] Safety Population: All safety analyses were performed based on the safety population, defined as all randomized patients, which was the same as the ITT population.

[0285] Statistical Methods: Safety and efficacy variables were analyzed using appropriate statistical methods detailed in a separate Statistical Analysis Plan (SAP), which was finalized prior to study blinding.

[0286] Patient Disposition and Demographics / Baseline Characteristics: The number and percentage of patients were tabulated for each of the following categories in each treatment group: ● Screened (total only); ●Rescreening and reasons for rescreening (total only); • ITT overall and by stratification factors (CV risk, ezetimibe use, and geographic region); mITT population; overall and by stratification factors (CV risk, ezetimibe use, and geographic region); • PP population; overall and by stratification factors (CV risk, ezetimibe use, and geographic region); ●Safety population; • Patients who completed the study; • Patients who terminated the study early and the main reasons for early termination; • Patients who terminated the study early before the primary endpoint event was confirmed; Patients with complete follow-up, defined as patients in whom all components of the primary endpoint were confirmed during the entire observation period (or until death); and • Patients whose investigational drug was discontinued prematurely at study completion but continued within the study period along with the primary reason (e.g., ODIS patients).

[0287] For randomized patients who discontinued study treatment, the primary reasons for discontinuation were listed and summarized by treatment group.Demographic and baseline characteristics, including age, sex, ethnicity, race, height, weight, BMI, diabetes, hypertension, metabolic syndrome, overweight / obese / normal by BMI, and diabetes and obesity, were summarized using descriptive statistics by treatment group for the ITT population.

[0288] Demographic data and baseline characteristics were compared between treatment groups in the ITT and PP populations. Differences in demographic and baseline characteristics were tested using chi-square tests (for categorical variables) or t-tests (for continuous variables). The p-values ​​used were considered descriptive, primarily as an assessment of balance between the two groups. Age in years was calculated using the date of randomization (Visit 2) and date of birth.

[0289] Study Drug Exposure and Compliance: Study drug exposure was summarized by treatment group using descriptive statistics at each time point and overall. Overall study drug compliance was calculated as the number of doses expected to be taken for the scheduled dosing period as follows: Compliance (%) = (total number of capsules dispensed - total number of capsules returned) x 100 (last dose - first dose + 1) x 4 capsules / day

number

[0290] Overall percent compliance was calculated for each patient in the ITT and modified ITT populations and summarized by treatment group using descriptive statistics.

[0291] Concomitant medications: Verbatim terms for concomitant medications / therapies were coded using the latest available versions of the World Health Organization Drug Dictionary and Anatomical Therapeutic Chemical Classification System before database lock. The number and percentage of patients in each treatment group taking concomitant medications were summarized. All verbatim descriptions and coded terms were listed for all non-investigational medications.

[0292] Efficacy Analysis: For efficacy endpoints that included CV events, only adjudicated events were included in the final statistical analysis.

[0293] Summary Statistics: Summary statistics (n, mean, standard deviation, median, minimum, and maximum) of baseline and post-baseline measurements, percent change, or change from baseline were presented by treatment group and visit for all efficacy variables analyzed. Summary statistics included change from baseline in weight and body mass index by treatment group and visit.

[0294] Primary endpoint analysis: The primary efficacy endpoint was analyzed using the log-rank test comparing the two treatment groups (AMR101 and placebo), including the stratification factors "CV risk category," ezetimibe use, and geographic region (Western, Eastern Europe, and Asia-Pacific countries) (each recorded in the IWR at enrollment) as covariates. The two-sided alpha level for the primary analysis was reduced from 0.05 to account for interim analyses based on a group sequential design with O'Brien-Fleming bounds generated using the Lan-DeMets alpha-spending function. Hazard ratios (HRs) by treatment group (AMR101 vs. placebo) from the Cox proportional hazards model, including stratification factors, are also reported, along with associated 95% confidence intervals (CIs). Kaplan-Meier estimates from randomization to time to the primary efficacy endpoint were plotted.

[0295] The size and direction of the treatment effect of the individual components of the composite endpoint, as well as their relative contribution to the composite endpoint, were also determined. All observational data adjudicated positively by the CEC, including data after discontinuation of study treatment for patients who discontinued the investigational drug prematurely, were included in the primary analysis. Patients who did not experience a primary efficacy event before the end of the study or who withdrew early from the study without a preceding primary efficacy event, were censored at the date of their last visit / telephone contact. The maximum prespecified interval between visits (on-site or telephone) was 90 days. Given the maximum 90-day monitoring period for CV events, the primary endpoint was censored for patients without a previous CV event who experienced a non-CV death within 90 days of their last contact at the time of death. The primary endpoint was censored for patients without a previous CV event who experienced a non-CV death more than 90 days after their last contact at the time of their last contact.

[0296] In the primary analysis, we assumed all asymptomatic MIs occurred on the first follow-up day showing an asymptomatic MI; in the secondary (sensitivity) analysis, we assumed all asymptomatic MIs occurred the day after the last normal ECG; and in the tertiary (sensitivity) analysis, we assumed all asymptomatic MIs occurred at the midpoint between the last normal ECG and the ECG containing the new MI. All deaths adjudicated as "undetermined" causally were combined with those adjudicated as "CV deaths" for the primary analysis. We performed a sensitivity analysis of the CV death category that excluded the "undetermined cause of death" cohort.

[0297] The primary efficacy analysis was performed on the intention-to-treat (ITT) population. Sensitivity analyses were performed using the mITT and PP populations. As a sensitivity analysis, patients who prematurely discontinued the study drug 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. As a supplementary analysis, a multivariable stratified Cox proportional hazards model was constructed for the primary endpoint to assess the treatment effect adjusting for important covariates.

[0298] Secondary endpoint analysis: Key secondary hypotheses were tested as part of the confirmatory process only if the primary analysis was statistically significant. In the analysis of secondary efficacy endpoints, type 1 error was controlled by testing each endpoint in turn, starting with the primary endpoint. Testing was performed at a significance level consistent with that used for the primary endpoint and was stopped when a secondary endpoint was found in which treatments were not significantly different. P values ​​were expressed in all analyses, but they were considered descriptive after the first nonsignificant result. Each secondary endpoint was analyzed using the same methods described for the primary efficacy endpoint. Kaplan-Meier estimates, log-rank tests stratified by the stratification factors used at randomization, and Cox proportional hazards models including the stratification factors specified above for the primary efficacy endpoint were summarized by treatment group. Taking into account the 90-day monitoring period for CV events, the key secondary endpoint was censored at the time of death for patients who had no previous CV events and had non-CV death within 90 days of last contact. The key secondary endpoint for patients with no prior CV events and non-CV deaths more than 90 days after last contact was censored at the time of last contact. Kaplan-Meier curves stratified by each stratification factor are presented. These analyses were performed on the intention-to-treat population.

[0299] Tertiary endpoint analysis: The tertiary endpoint of time to event was analyzed using the same methods as described for the primary efficacy endpoint. Kaplan-Meier estimates, log-rank tests stratified by the stratification factors used at randomization, and Cox proportional hazards models specified for the primary efficacy endpoint were summarized by treatment group. Given the 90-day monitoring period for CV events, where applicable, the tertiary endpoint for patients without a previous CV event who had a non-CV death within 90 days of last contact was censored at the time of death. Where applicable, the tertiary endpoint for patients without a previous CV event who had a non-CV death more than 90 days after last contact was censored at the time of last contact. Kaplan-Meier curves stratified by each stratification factor are presented.

[0300] Fasting lipid panels were tested at screening (Visit 1 or Visit 1.1), the randomization visit (Visit 2; Day 0), Visit 3 (Day 120; approximately 4 months), and all other follow-up visits, including the final visit. Preparative ultracentrifugation measurements of LDL-C were analyzed for change from baseline to 1 year, unless this value was missing. If the LDL-C preparative ultracentrifugation value was missing, we used alternative LDL-C values, prioritizing values ​​obtained from direct LDL-C measurement, followed by the Friedewald calculation (only for subjects with triglycerides <400 mg / dL), and finally, by using a published calculation by Hopkins researchers (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). Additionally, changes in LDL-C from baseline to day 120 using the Friedewald and Hopkins methods were analyzed using the arithmetic mean of LDL-C values ​​obtained at Visit 2 (Day 0) and the preceding Visit 1 (or Visit 1.1). If one of these values ​​was missing, the single available LDL-C value was used. Hopkins LDL-C was calculated at each visit.

[0301] The randomization visit was considered the baseline. If baseline values ​​were not available from the randomization visit, the most recent screening value was used. For lipid, lipoprotein, and inflammatory marker measurements, change and percent change were summarized at each visit. Because these biomarkers are typically not normally distributed, treatment comparisons of percent change from baseline used the Wilcoxon rank-sum test, with median and quartile values ​​provided for each treatment group. Median differences between treatment groups and 95% CIs were estimated using the Hodges-Lehman method. Additionally, shift tables were generated as appropriate.

[0302] As an additional exploratory analysis, the relationship between post-baseline biomarker values ​​and treatment effects on the primary and key secondary endpoints was assessed by adding biomarker values ​​(e.g., at 4 months or 1 year) as time-dependent covariates in Cox proportional hazards models. Diagnostic plots for the proportional hazards assumption were evaluated. Body weight was measured at the screening visit and all follow-up visits, including the end of the study. Waist circumference was measured at the randomization visit (Visit 2; Day 0), Visit 5 (Day 720), and the end of the study. Descriptive statistics were presented by visit and treatment group for baseline, post-treatment change from baseline, and percent change from baseline. Repeated measures analysis was used to compare percent change from baseline between treatments.

[0303] The pre-specified additional efficacy endpoints and analyses of this study are listed below. These endpoints and analyses were exploratory in nature and were not included in the original study scheme: • As done in the primary analysis, time-to-event analyses were conducted at the 1- and 2-year landmarks in the ITT population; • For recurrent CV event analysis based on the 5-component MACE (CV death, nonfatal MI, nonfatal stroke, unstable angina requiring hospitalization, or coronary revascularization), total CV events were performed using negative binomial model analysis; • An on-treatment sensitivity analysis was conducted, including primary events occurring up to day 0 and 30 after permanent discontinuation of study drug; • Time-to-event analysis at 1- and 2-year landmarks of key secondary endpoints in the ITT population, as performed in the primary analysis; Analysis of the following positively adjudicated clinical events as tertiary endpoints in the ITT population: o Composite of all-cause mortality or new CHF; o Composite of CV death or new CHF; o Sudden cardiac death; Peripheral artery disease (PAD); and  Atrial fibrillation or atrial flutter. Tertiary endpoint analyses of the ITT population included: The relationship between hsCRP and the primary and ranked secondary endpoints during treatment; and Relationship between serum EPA during treatment and primary and ranked secondary endpoints. • Subgroup analyses performed on the ITT population of patients grouped according to values ​​of (1) ≥2 mg / dL or (2) <2 mg / dL at baseline and 2 years to assess the relationship between hsCRP during treatment and the primary and key secondary endpoints; • To assess the relationship between on-treatment serum EPA and the primary and key secondary endpoints, Kaplan-Meier curves for AMR101 patients were grouped into tertiles based on values ​​at year 1 compared with placebo patients; The following subgroup analyses were added: ○ Baseline HbA1c level (<6.5%, ≥6.5%); Baseline PAD; and o Baseline TG ≥ 150 mg / dL with HDL-C ≤ 40 mg / dL for men and ≤ 50 mg / dL for women.

[0304] Listed below are additional pre-specified exploratory efficacy analyses of particular interest to the general clinical and scientific community that were also surveyed in this study. • Non-fatal myocardial infarction (MI) in the ITT population (including both clinical and asymptomatic MI classification); • Assessment of the impact of time-weighted (or area under the curve [AUC]) EPA data on the primary and key secondary composite endpoints in the ITT population; Sensitivity analysis for the primary and key secondary composite endpoints by excluding elective coronary revascularization if the event occurred <3 months after randomization, and also by excluding periprocedural MI in the ITT population; Two asymptomatic MI (SMI) sensitivity analyses for the primary and key secondary composite endpoints - ITT population: Count all potential SMIs identified by the CEC ECG reviewer, whether or not confirmed on the final ECG; and Only count potential SMIs with at least one confirmatory ECG showing sustained Q waves (even if not present on the final ECG). Non-alcoholic fatty liver disease (NAFLD) analysis using the NAFLD Fibrosis Score (NFS) evaluated the following in the intention-to-treat population: Impact on the primary and ranked secondary composite endpoints by baseline NFS classification; and Treatment effect on change from baseline in NFS at 1 and 5 years. • Attainment of individual and combined therapeutic goals of triglycerides (TG) ≤ 150 mg / dL and hsCRP ≤ 2 mg / L at 2 years, and study completion in the ITT population; Additional renal function (eGFR) analysis - ITT population: Baseline renal dysfunction [eGFR] ≥ 60 and < 90 mL / min / 1.73 m 2 the primary and ranked secondary composite endpoints for patients; and Treatment effect on change from baseline in renal function (eGFR) at 1 and 5 years. • Sensitivity analyses for the primary and key secondary composite endpoints by excluding patients with post-randomization LDL-C levels >100 mg / dL, and another sensitivity analysis >70 mg / dL in the ITT population; • Analysis of hospitalization data from the ITT population (combining aggressively adjudicated unstable angina requiring hospitalization, congestive heart failure [CHF] requiring hospitalization, and arrhythmias requiring hospitalization); time from randomization to first hospitalization; and Recurrent event analysis of hospitalizations. • Primary and ranked secondary composite endpoints; and potentially additional subgroup analyses for other endpoints in the ITT population (US vs. non-US); • Additional subgroup analyses of patients with very high-risk cardiovascular disease (CVD) (defined as recurrent cardiovascular [CV] events or CV events in two or more vascular beds, i.e., multivessel disease) for the primary and key secondary composite endpoints; and potentially for other endpoints in the ITT population; • A sensitivity analysis of apoB to assess whether subgroups whose apoB reduction from baseline exceeded certain thresholds had corresponding incremental reductions in clinical endpoint events; • Sensitivity analysis of myocardial infarction excluding perioperative MI (type 4a); ○ Additional analyses considering recency and number of previous MIs; • Sensitivity analysis of stroke considering patients with a history of stroke; • Sensitivity analysis of heart failure considering patients with a history of heart failure; • Sensitivity analysis of the endpoint consisting of coronary revascularization excluding early elective revascularization (e.g., within 30–90 days after randomization). Subgroup analyses of the primary (and potentially important secondary) endpoints within the following cohorts: o High-risk patients with "hypertriglyceridemic hips" (obese patients with high CV risk); High-risk subgroups defined by baseline hsTNT levels (and potentially by NT-proBNP from archived frozen samples); and High TG / low LDL-C phenotype; o High-risk patients as defined by atherothrombotic risk score. ●Treatment effects on: peripheral arterial events (e.g., major adverse limb events [MALE]); and o Hypertension using BP as a continuous variable. • Additional analyses of fatty acid levels (and ratios) using archived frozen serum biospecimens, including baseline and treatment effects on EPA, DHA, DPA, and AA (and related ratios), and the relationship between fatty acid levels and cardiovascular outcomes; ○ Relationship of fatty acid levels during treatment; Baseline fatty acid levels; and o Investigational drug compliance. Use of archived frozen biological samples (e.g., serum and whole blood) to analyze potential treatment effects on biomarkers and genetic markers and their association with outcomes, including but not limited to: o LDL-P; ○ RLP-C (measurement); o LDL-TG; ○Ox-LDL; o Galectin-3; Lp(a) at baseline as a predictor of CVD benefit; ○ LpPLA2; ○ HDL2, HDL3, apo AI, apo A-II, HDL-P, apo C-III (and apo C-III in apo B-containing proteins), apo AV, apo E subtypes (2, 3, 4), IL-6, lipoprotein lipase (LPL); and Analyses may include change (and percent change) from baseline, on-treatment comparisons between treatment arms by study as predictors of CV risk. Exploratory analysis of different treatment effects for potential benefits (from adverse event reporting) of: o Ophthalmological changes (e.g., development of age-related macular degeneration, progression of diabetic retinopathy); o Cognitive impairment; Erectile dysfunction, and o Ischemic cardiomyopathy (indicated by hospitalization for CHF, ICD placement, etc.). additional genetic bioassays, including genes that may be related to triglycerides, lipid metabolism, and CVD; and • Post-hoc identified effects of potential buffers on primary / important secondary outcome measures.

[0305] For this study, new-onset diabetes was defined as type 2 diabetes newly diagnosed during the treatment / follow-up period (i.e., patients with no history of diabetes at the time of randomization). For the purposes of this study, the diagnosis of diabetes was based on the following observations: HbA 1c ≥ 6.5%. Testing was performed in a laboratory certified by the National Glycohemoglobin Standardization Program (NGSP) and using standardized methods for the Diabetes Control and Complications Trial (DCCT) assay. In the absence of overt hyperglycemia, HbA 1c ≥6.5% confirmed by repeat testing; Fasting plasma glucose (FPG) ≥ 126 mg / dL (7.0 mmol / L). Fasting was defined as no caloric intake for at least 8 hours. In the absence of overt hyperglycemia, FPG ≥ 126 mg / dL (7.0 mmol / L) was confirmed by repeat testing. A 2-hour plasma glucose ≥ 200 mg / dL (11.1 mmol / L) during an oral glucose tolerance test (OGTT). This test was performed using a glucose load containing 75 g of anhydrous glucose dissolved in water as described by the World Health Organization. In the absence of overt hyperglycemia, a 2-hour plasma glucose ≥ 200 mg / dL (11.1 mmol / L) during an oral glucose tolerance test (OGTT) confirmed by repeat testing; and / or • In patients with typical symptoms of hyperglycemia or a hyperglycemic crisis, random plasma glucose ≥ 200 mg / dL (11.1 mmol / L).

[0306] In the absence of overt hyperglycemia, the first three criteria were confirmed by repeat testing.

[0307] Exploratory subgroup analyses were conducted to examine the impact of patients who did not take the study drug and discontinued the study on the primary endpoint. Subgroup analyses were conducted for the primary and key secondary endpoints as described for the primary endpoint. For each subgroup, Kaplan-Meier estimates, log-rank tests stratified by the stratification factors used at randomization (except when subgroup was a stratification factor), and HRs and CIs from the Cox proportional hazards model specified for the primary efficacy endpoint were summarized by treatment group. Demographic, disease, treatment, and baseline lipid and lipoprotein parameters were examined.

[0308] Demographic parameters included sex; age at baseline (<65 years and ≥65 years); race (white and non-white, or any other subset comprising at least 10% of the total number of patients); geographic region (Western, Eastern European, and Asia-Pacific countries); and baseline ezetimibe use (yes / no).

[0309] Disease parameters included CV risk classification; presence or absence of diabetes at baseline; and baseline renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL / min / 1.73 m 2 ) and uses the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation as follows: eGFR=141×Min(S cr / κ, 1) α ×Maximum(S cr / κ, 1) -1.209 ×0.993 年齢 × 1.018 [for women] × 1.159 [for black people] During the ceremony, S cr is serum creatinine in mg / dL, κ was 0.7 for women and 0.9 for men; Alpha was −0.329 for women and −0.411 for men; The minimum is S cr / κ is the minimum value or 1, The maximum is S cr / κ indicates the maximum value or 1.

[0310] Treatment parameters included baseline statin intensity (statin type and regimen); and statin intensity classification as defined by the ACC / AHA cholesterol guidelines (Stone 2013) and the patient's 10-year CV risk score (Goff 2013).

[0311] Baseline lipid and lipoprotein parameters were LDL-C (by tertiles); HDL-C (by tertiles and tertiles by sex); TG (by tertiles and tertiles by sex); RLP-C (by tertiles); TG ≥ 150 mg / dL and TG < 150 mg / dL; TG ≥ 200 mg / dL and TG < 200 mg / dL; TG ≥ median, TG < median; highest tertile of TG and lowest tertile of HDL-C combined; sex-specific highest tertile of TG and lowest tertile of HDL-C; HDL-C ≤ These included baseline TG levels ≥ 150 mg / dL, including TG ≥ 200 mg / dL, including 35 mg / dL; hsCRP (≤ 3 mg / L and > 3 mg / L) and by gender; hsCRP (≤ 2 mg / L and > 2 mg / L) and by gender; apoB (by tertiles); non-HDL-C (by tertiles); baseline hemoglobin A1c (Hb1c) levels (< 6.5%, ≥ 6.5%); baseline PAD; and high-density lipoprotein cholesterol (HDL-C) levels of ≤ 40 mg / dL for men and ≤ 50 mg / dL for women.

[0312] In addition to the Cox proportional hazards (PH) model described above, the data were fitted at each interval with baseline TG as a covariate. Diagnostic plots for the PH assumption were evaluated. The consistency of treatment effects in subgroups was assessed for the primary and key secondary efficacy endpoints. For each subgroup variable, a Cox PH model was performed for treatment, stratification factors (excluding subgroup variables related to stratification factors, i.e., CV risk classification), subgroup, and treatment-by-subgroup interactions. The main treatment effect was tested in this model. A P value for testing interaction terms <0.15 was considered significant. Results were presented in forest plots.

[0313] Subgroup analyses for the primary and key secondary endpoints were performed as described for the primary endpoint. For each subgroup, Kaplan-Meier estimates, log-rank tests stratified by the stratification factors used at randomization (except when subgroup was a stratification factor), and HRs and CIs from the Cox proportional hazards model specified for the primary efficacy endpoint were summarized by treatment group. All subgroup analyses were performed for the intention-to-treat, mITT, and pre-treatment populations.

[0314] Interim Efficacy Analyses: Two interim analyses were planned for the primary efficacy endpoint using adjudicated events at approximately 60% (967 events) and 80% (1290 events) of the total number of planned primary endpoint events (1612). The planned interim analyses were based on a group sequential design.

[0315] Interim results of the study were monitored by an independent Data Monitoring Committee (DMC). Analyses were performed by an independent statistical team unblinded to treatment allocation and reported only to the DMC. If the study was terminated immediately after an interim analysis, patients were notified immediately and brought to their final completion visit, and the final analyses of efficacy and safety included all data through the final visit. All suspected events were adjudicated in a blinded manner by the CEC. Time to event was calculated as the time from randomization to the date of onset of the event (as determined by the CEC). Patients who had not experienced any of the above events at the time of the interim data cutoff but were still on the study were considered censored at their last regular contact before the interim data cutoff.

[0316] The alpha levels for the pre-specified interim and final analyses of the two protocols were based on a group sequential design (GSD) with O'Brien-Fleming bounds generated using the Lan-DeMets alpha-splitting function. The one-sided alpha levels and bounds based on Z-tests, as well as the p-values ​​achieved for each of the two interim and final analyses, are shown in Table 10. [Table 11]

[0317] Safety Analyses: All safety analyses were performed on the safety population, defined as all randomized patients. Safety assessments were based on the frequency of adverse events, physical examinations, vital signs, and safety laboratory tests. New-onset AEs during the study from the start of study drug for each patient up to 30 days after the last dose of study drug were considered treatment-emergent (TEAEs). This included AEs that began before the start of study drug and increased in severity after treatment initiation.

[0318] Treatment-emergent adverse events were summarized by system organ class and preferred term and by treatment. This included overall incidence (regardless of severity and relationship to study drug) and incidence of moderate or severe adverse events. SAEs and adverse events leading to early discontinuation (≥30 days) were summarized in 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 parameter 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.

[0319] In addition to analyses of treatment-emergent adverse events, analyses of all AEs (serious and non-serious) and all serious AEs were performed.

[0320] All AEs included treatment-emergent adverse events (TEAEs) by high level group term (HLGT); TEAEs by high level term (HLT); and TEAEs by system organ class (SOC), HLGT, HLT, and preferred term (PT) (four-level tables).

[0321] All SAEs included SAEs occurring during treatment with HLGTs; SAEs occurring during treatment with HLTs; and SAEs occurring during treatment with SOCs, HLGTs, HLTs, and PTs (four-level tables).

[0322] Clinical laboratory evaluation Criteria for potentially clinically significant (PCS) laboratory values ​​are shown in Tables 11 and 12. A high PCS value occurring during treatment at any time was defined as a change from a value below the upper reference limit at baseline to a high PCS value at any post-baseline measurement. A low PCS value occurring during treatment at any time was defined as a change from a value above the lower upper reference limit at baseline to a low PCS value at any post-baseline measurement. The number (%) of patients with post-baseline PCS laboratory values ​​was summarized by treatment group. A listing of patients with PCS laboratory values ​​at any time, i.e., at baseline or at any post-baseline visit, was included. [Table 12] [Table 13]

[0323] Drug-induced liver injury (DILI) The case of DILI was investigated by the following analysis. A graph was created using a logarithmic scale to plot the distribution of peak alanine aminotransferase (ALT) values ​​versus peak total bilirubin (TBL) values ​​over the treatment period. For each patient, the product of peak TBL and peak ALT times the upper limit of normal (ULN) was plotted against the product of peak ALT times the ULN, where peak TBL and peak ALT may or may not have occurred on the same day of liver testing. The graph was divided into four quadrants, with the vertical line corresponding to 3 × ULN for ALT and the horizontal line corresponding to 2 × ULN for TBL. The upper right quadrant, referred to as the potential Hy's Law quadrant, includes potential DILI cases. A similar graph was plotted for aspartate aminotransferase (AST). Individual patient profiles of liver function tests (ALT, AST, alkaline phosphatase [ALP], and TBL) over time were provided with graphs of all patients with peak ALT >3 x ULN and peak TBL >2 x ULN during the treatment period. Number of patients (%) was provided for: ○ALT or AST >3 × ULN; ALT or AST >3 × ULN and TBL >2 × ULN; and o ALT or AST >3×ULN and TBL >2×ULN, and ALP <2×ULN.

[0324] research design This was a phase 3b, multicenter, multinational, prospective, randomized, double-blind, placebo-controlled, parallel-group study. It was also an event-driven trial comparing the effects of AMR101 versus placebo on the composite endpoint described above as the primary endpoint. The placebo contained mineral oil to mimic the color and consistency of icosapent ethyl in AMR101 and was administered in the same capsule fill volume and count as AMR101. The study yielded a total of 1,612 efficacy endpoint events at two planned interim analyses, when approximately 967 (60%) and 1,290 (80%) of the events were adjudicated. The study included patients aged ≥50 years with established CVD (CV risk category 1) and patients with diabetes and at least one additional risk factor for CVD but without established CVD (CV risk category 2). Randomization was stratified by cardiovascular risk strata, ezetimibe use or nonuse, and geographic region, including a secondary prevention cohort (i.e., CV risk category 1) or a primary prevention cohort (i.e., CV risk category 2), with the primary prevention cohort having an enrollment limit of 30%. Details of the study design are shown in Figure 1.

[0325] Sample size calculations were based on the assumption of constant hazards, asymmetric recruitment rates over time, and did not account for dropouts. We assumed a risk reduction corresponding to an HR of 0.85 (AMR101 vs. placebo). To detect this HR, approximately 90% power was required at a one-sided alpha level of 2.5%, and 1612 events with two interim analyses. The operating characteristics of this design were identical to those of the corresponding group-sequential sign at a two-sided alpha level of 0.05.

[0326] 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 final 0.2 years. The estimated maximum study duration was 6.5 years, unless the trial was terminated early due to efficacy or safety issues. A 1-year event rate of 5.2% (hazard = 0.053) in the control group was also assumed. Under these assumptions, the number of patients enrolled was N = 7990.

[0327] Because this was an event-driven trial, the "sample size" was the number of events, not the number of patients. The number of events that occurred depended primarily on three factors: the number of patients enrolled; the combined group event rate; and the length of patient follow-up. Because the combined event rate is difficult to predict, the sponsor monitored the event rate as the trial progressed. If the combined event rate was lower than expected, achieving a sample size of 1612 events would have required increasing the number of patients, extending the length of follow-up, or a balance of adjusting both factors.

[0328] At the completion of study enrollment, the actual number of patients randomized may have differed from the target number (original or revised) as a result of the inherent lag between the date the last patient began screening and the date the last patient was randomized.

[0329] Completing the research The end of the study was the patient's last visit at the end of the study follow-up period. The IRB and IEC were notified of the end of the study in accordance with country-specific regulatory requirements.

[0330] Standardized definitions of cardiovascular trial endpoint events The following definitions were used in the evaluation of patients in this clinical trial:

[0331] Definition of cardiovascular death: Cardiovascular death includes death resulting from 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 bleeding, and death due to other cardiovascular causes.

[0332] Death from acute myocardial infarction: This refers to death due to any mechanism (e.g., arrhythmia, CHF) within 30 days after MI that is related to the immediate consequences of MI, such as progressive CHF or refractory arrhythmia. Fatal events occurring after a "break" (e.g., a CHF- and arrhythmia-free period of at least 1 week) should be classified as CV or non-CV death. If classified as CV death, it should be attributed to a proximate cause, although the MI may have increased the risk of the event (e.g., the risk of arrhythmia-related death increases for several months after an acute MI). Acute MI should be verified, to the extent possible, by the diagnostic criteria outlined for acute MI (see definition of MI) or by autopsy findings indicating a recent MI or recent coronary thrombosis. Deaths resulting from procedures to treat MI (percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG)) or complications arising from MI should also be considered as deaths due to acute MI. Deaths resulting from elective coronary procedures to treat myocardial ischemia (i.e., chronic stable angina) or deaths due to MI occurring as a direct result of CV investigations / procedures / surgery should be considered CV procedural deaths.

[0333] Sudden cardiac death: refers to death occurring unexpectedly, not within 30 days of an acute MI, and includes the following: witnessed or immediate death without new or worsening symptoms; death witnessed within 60 minutes of the onset of new or worsening cardiac sy...

Claims

1. 1. A pharmaceutical composition containing eicosapentaenoic acid (EPA) for the treatment of a cardiovascular-related disease in a subject, said treatment comprising: determining whether the subject has a triglyceride level of at least 150 mg / dl and a history of atrial fibrillation and / or atrial flutter; obtaining or having obtained information indicating that the subject has a triglyceride level of at least 150 mg / dl and has previously had symptoms of atrial fibrillation and / or atrial flutter and / or has previously been diagnosed as suffering from atrial fibrillation and / or atrial flutter; and / or monitoring or having monitored the subject for said triglyceride level of at least 150 mg / dl and symptoms of atrial fibrillation and / or atrial flutter; Determining or determining by determining whether the reduction in risk of one or more cardiovascular events other than atrial fibrillation and / or atrial flutter when administered about 4 g of EPA per day to the subject is greater than the risk of the subject experiencing symptoms of atrial fibrillation and / or atrial flutter, if the subject has previously had symptoms of atrial fibrillation and / or atrial flutter, been previously diagnosed with atrial fibrillation and / or atrial flutter, and / or had symptoms of atrial fibrillation and / or atrial flutter during monitoring; and determining whether the risk of the one or more cardiovascular events is greater than the risk of the subject experiencing symptoms of atrial fibrillation and / or atrial flutter when the subject has a heart rate of 80 bpm to 100 bpm, no blood stasis in the atria, and established cardiovascular disease; and administering about 4 g of EPA per day to the subject if the subject has a reduced risk of one or more cardiovascular events other than atrial fibrillation and / or atrial flutter.

2. 2. The pharmaceutical composition of claim 1, wherein the subject, when administered approximately 4 g of EPA per day, is likely to experience both: (1) an increase in the frequency of atrial fibrillation and / or atrial flutter symptoms; and (2) a decrease in the frequency of cardiovascular events other than atrial fibrillation and / or atrial flutter.

3. The pharmaceutical composition of claim 1 , wherein the subject is being treated with a statin.

4. 1. A pharmaceutical composition containing eicosapentaenoic acid (EPA) for the treatment of a cardiovascular-related disease in a subject, said treatment comprising: determining whether the subject has a triglyceride level of at least 150 mg / dl and a history of atrial fibrillation and / or atrial flutter; (i) obtaining or having obtained information indicating that the subject has a triglyceride level of at least 150 mg / dl and previously had symptoms of atrial fibrillation and / or atrial flutter and / or was previously diagnosed as suffering from atrial fibrillation and / or atrial flutter; and / or (ii) determining, or having determined, by monitoring, the subject for said triglyceride level of at least 150 mg / dl and symptoms of atrial fibrillation and / or atrial flutter; and administering to the subject about 4 g of EPA per day to reduce the risk of cardiovascular events other than atrial fibrillation and / or atrial flutter, if the subject has no previous symptoms of atrial fibrillation and / or atrial flutter, has not been previously diagnosed as having atrial fibrillation and / or atrial flutter, and / or has not determined symptoms of atrial fibrillation and / or atrial flutter during said monitoring, and is receiving high-intensity statin therapy of about 40 mg to about 80 mg per day of atorvastatin or about 20 mg to about 40 mg per day of rosuvastatin, and has (i) established cardiovascular disease or (ii) diabetes and at least two additional risk factors for cardiovascular disease.

5. 5. The pharmaceutical composition of claim 4, wherein the subject in (a) is likely to experience both (1) an increase in the frequency of atrial fibrillation and / or atrial flutter symptoms and (2) a decrease in the frequency of cardiovascular events other than atrial fibrillation and / or atrial flutter when administered about 4 g of EPA per day.

6. The pharmaceutical composition of claim 4, wherein the subject is being treated with a statin.

7. 1. A pharmaceutical composition containing eicosapentaenoic acid (EPA) for the treatment of a cardiovascular-related disease in a subject, said treatment comprising: Identifying a subject with a measured triglyceride level greater than 150 mg / dl and who has previously experienced symptoms of atrial fibrillation or atrial flutter; determining that a reduction in the subject's frequency of cardiovascular events other than atrial fibrillation or atrial flutter is worth the risk of increasing the frequency of atrial fibrillation or atrial flutter in the subject, and therefore treating the subject with 4 g of EPA per day, wherein a reduction in the subject's frequency of cardiovascular events other than atrial fibrillation and / or atrial flutter is worth the risk of increasing the frequency of atrial fibrillation and / or atrial flutter when the subject does not have a heart rate of 80 bpm to 100 bpm and is receiving high-intensity statin therapy with about 40 mg to about 80 mg per day of atorvastatin or about 20 mg to about 40 mg per day of rosuvastatin, and has at least two additional risk factors for cardiovascular disease: (i) established cardiovascular disease or (ii) diabetes.

8. 1. A pharmaceutical composition containing eicosapentaenoic acid (EPA) for the treatment of a cardiovascular-related disease in a subject, said treatment comprising: Identifying subjects with measured triglyceride levels greater than 150 mg / dl, who are being treated with a statin, and who have a prior history of atrial fibrillation or atrial flutter; determining that individuals with triglyceride levels greater than 150 mg / dl, who are being treated with a statin, and who have a prior history of atrial fibrillation or atrial flutter, upon treatment with 4 g of EPA per day, are likely to experience both (1) an increase in the frequency of episodes of atrial fibrillation or atrial flutter, and (2) a predicted cardiovascular benefit from said EPA treatment; determining that the predicted cardiovascular benefit is worth the risk of increasing the frequency of atrial fibrillation or atrial flutter in the subject, and therefore treating the subject with 4 g of EPA per day, wherein the subject does not have a heart rate of 80 bpm to 100 bpm, and the subject is receiving high-intensity statin therapy with about 40 mg to about 80 mg per day of atorvastatin or about 20 mg to about 40 mg per day of rosuvastatin, and the subject has (i) established cardiovascular disease or (ii) diabetes, and at least two additional risk factors for cardiovascular disease, the predicted cardiovascular benefit is worth the risk of increasing the frequency of atrial fibrillation or atrial flutter.

9. A pharmaceutical composition containing eicosapentaenoic acid (EPA) for reducing the risk of cardiovascular events other than atrial fibrillation and / or atrial flutter in a subject having a triglyceride level of at least about 150 mg / dl, wherein the use comprises administering at least about 4 g of EPA per day to the subject for a period of time that is effective in reducing the cardiovascular events, and the subject develops atrial fibrillation and / or atrial flutter during the period of time that is effective in reducing the risk of the cardiovascular events.

10. 10. The pharmaceutical composition of claim 9, wherein the subject has no history of atrial fibrillation and / or flutter prior to administration of the 4 g of EPA.

11. 1. A pharmaceutical composition containing eicosapentaenoic acid (EPA) for reducing the risk of cardiovascular events other than atrial fibrillation and / or atrial flutter in a subject under the age of 65, having a triglyceride level of at least about 150 mg / dl, comprising administering to the subject at least about 4 g of eicosapentaenoic acid (EPA) per day for a period of time that is effective to reduce the cardiovascular event, wherein the subject is not experiencing increased symptoms of atrial fibrillation and / or atrial flutter, and the subject is receiving high-intensity statin therapy with about 40 mg to about 80 mg per day of atorvastatin or about 20 mg to about 40 mg per day of rosuvastatin, and has (i) established cardiovascular disease or (ii) diabetes and at least two additional risk factors for cardiovascular disease.

12. 9. The pharmaceutical composition of any one of claims 1 to 3, 7 and 8, wherein the established cardiovascular disease comprises previous coronary artery disease, previous cerebrovascular disease, previous carotid artery disease, previous peripheral artery disease, or a combination thereof.

13. The pharmaceutical composition of any one of claims 1 to 11, wherein the subject does not have established cardiovascular disease but has at least two risk factors for cardiovascular disease.

14. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the EPA is administered to the subject in dosage units 1 to 4 times per day.

15. 15. The pharmaceutical composition of any one of claims 1-14, wherein the subject has one or more of a baseline non-HDL-C level of about 200 mg / dL to about 300 mg / dL, a baseline total cholesterol level of about 250 mg / dL to about 300 mg / dL, a baseline VLDL-C level of about 140 mg / dL to about 200 mg / dL, a baseline HDL-C level of about 10 to about 30 mg / dL, and / or a baseline LDL-C level of about 40 to about 100 mg / dL.

16. 16. The pharmaceutical composition of any one of claims 1-15, wherein the subject is administered the EPA for at least about 4 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.

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