U.S. patent application number 17/077773 was filed with the patent office on 2021-05-20 for methods of treating or preventing prostate cancer.
The applicant listed for this patent is Amarin Pharmaceuticals Ireland Limited. Invention is credited to Joseph S. Zakrzewski.
Application Number | 20210145786 17/077773 |
Document ID | / |
Family ID | 1000005360716 |
Filed Date | 2021-05-20 |
United States Patent
Application |
20210145786 |
Kind Code |
A1 |
Zakrzewski; Joseph S. |
May 20, 2021 |
METHODS OF TREATING OR PREVENTING PROSTATE CANCER
Abstract
In various embodiments, the present invention provides methods
of treating and/or preventing prostate cancer and, in particular,
the method comprising administering to a subject in need thereof a
pharmaceutical composition comprising eicosapentaenoic acid or a
derivative thereof.
Inventors: |
Zakrzewski; Joseph S.;
(Bedminster, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Amarin Pharmaceuticals Ireland Limited |
Dublin |
|
IE |
|
|
Family ID: |
1000005360716 |
Appl. No.: |
17/077773 |
Filed: |
October 22, 2020 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15703782 |
Sep 13, 2017 |
10888539 |
|
|
17077773 |
|
|
|
|
14477034 |
Sep 4, 2014 |
|
|
|
15703782 |
|
|
|
|
61873596 |
Sep 4, 2013 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/202 20130101;
A61K 31/232 20130101; A61K 45/06 20130101 |
International
Class: |
A61K 31/232 20060101
A61K031/232; A61K 31/202 20060101 A61K031/202; A61K 45/06 20060101
A61K045/06 |
Claims
1. A method of treating or preventing prostate cancer in a subject
having an elevated PSA level of at least about 2.5 ng/mL and a
fasting baseline triglyceride level of at least about 500 mg/dL,
the method comprising administering to the subject a pharmaceutical
composition comprising about 1 g to about 4 g of ethyl
eicosapentaenoate daily.
2. The method of claim 1, wherein triglycerides are reduced in the
subject with no increase in an LDL-C level in the subject.
3. The method of claim 2, wherein the reduction in triglycerides
and the no increase in LDL-C level is in comparison to baseline, or
in comparison to a second subject or subject group that has
received a prostate cancer therapy but not the ethyl
eicosapentaenoate.
4. The method of claim 1, wherein ethyl eicosapentaenoate
represents at least about 96%, by weight of all fatty acids (and/or
derivatives thereof) present in the pharmaceutical composition.
5. The method of claim 1, wherein docosahexaenoic acid and its
esters represent no more than about 4%, by weight of all fatty
acids (and/or derivatives thereof) present in the pharmaceutical
composition.
6. The method of claim 1, wherein the subject has a risk factor
associated with prostate cancer.
7. The method of claim 6, wherein the risk factor is selected from
the group consisting of: a genetic risk factor, a family history
risk factor, a dietary risk factor, a viral risk factor, a
sexual-related risk factor, a risk factor associated with exposure
to medication, and a risk factor associated with a medical
procedure.
8. The method of claim 7, wherein the genetic risk factor comprises
a mutation in BRCA1, a mutation in BRCA2, a mutation in HPC1, a
mutation in the androgen receptor, a mutation in the vitamin D
receptor, overexpression of one or more ETS transcription factors,
a mutation in or loss of one or more copies of PTEN, a mutation in
or loss of one or more copies of KAI1, a mutation in or loss of one
or more copies of E-cadherin, a mutation in or loss of one or more
copies of CD44, a TT allele pair at SNP rs10993994, a mutation in
the promoter region of the MSMB gene, or a combination thereof.
9. The method of claim 1, wherein the subject is identified as
having prostate cancer before administration of the pharmaceutical
composition to the subject.
10. The method of claim 9, wherein the method further comprises
providing the subject with a prostate cancer therapy selected from
the group consisting of: surveillance, surgery, radiation,
ultrasound, chemotherapy, cryotherapy, primary hormone therapy, and
combinations thereof.
11. The method of claim 10, the method further comprising reducing
or discontinuing the prostate cancer therapy after administration
of the pharmaceutical composition.
12. The method of claim 11, wherein the prostate cancer therapy is
reduced or discontinued after administration of the pharmaceutical
composition for a period of time effective to reduce a prostate
cancer diagnostic result associated with the subject.
13. The method of claim 12, wherein the prostate cancer diagnostic
result is one or more of: a PSA score, a prostate ultrasound image,
a prostate MRI image, a biopsy sample, a Gleason score, and a
prostate tumor grade.
14. The method of claim 12, wherein the period of time is less than
about 6 months.
15. The method of claim 14, wherein the period of time is about 12
weeks.
16. (canceled)
17. The method of claim 1, the method further comprises determining
a second, lower PSA level associated with the subject after
administration of the pharmaceutical composition.
18. The method of claim 17, wherein the pharmaceutical composition
is administered to the subject for a period of time effective to
reduce the PSA level by at least about 50%.
19-20. (Canceled)
Description
PRIORITY
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/703,782 filed Sep. 13, 2017, which is a
continuation of U.S. patent application Ser. No. 14/477,034 filed
Sep. 4, 2014, which claims priority to U.S. Provisional Patent
Application serial no. 61/873,596, filed Sep. 4, 2013, the entire
contents of which are incorporated herein by reference.
BACKGROUND
[0002] As the sixth-leading cause of cancer-related death globally,
prostate cancer represents a significant risk for men. While the
causes of prostate cancer are not fully understood, primary risk
factors appear to include obesity, age and family history.
Cardiovascular factors, diet, and sexual history may also play
roles. Common treatments include surveillance, surgery, radiation,
ultrasound, chemotherapy, and combinations thereof. However, many
of the common treatments carry significant risks of complication.
Studies probing links between diet and prevention of prostate
cancer are tenuous and offer conflicting conclusions, although one
recent study by T. M. Brasky, et al., has correlated high blood
levels of EPA, DHA and DPA with an increased risk of prostate
cancer. A need exists for improved treatments and preventatives for
prostate cancer.
SUMMARY
[0003] In one embodiment, the present disclosure provides a method
of treating or preventing prostate cancer in a subject, the method
comprising administering to the subject a pharmaceutical
composition comprising at least about 80%, by weight of all fatty
acids (and/or derivatives thereof) present, ethyl
eicosapentaenoate.
[0004] In another embodiment, the present disclosure provides a
method of treating or preventing prostate cancer in a subject, the
method comprising administering to the subject about 1 to about 4
capsules per day, each capsule comprising about 1 g of ethyl
eicosapentaenoate.
[0005] In some embodiments, the subject has a risk factor
associated with prostate cancer. In other embodiments, the subject
is identified as having prostate cancer before administration of
the pharmaceutical composition to the subject.
[0006] In another embodiment, the invention provides a method of
treating moderate to severe hypertriglyceridemia comprising
administering a composition as described herein to a subject in
need thereof one to about four times per day.
[0007] In some embodiments, a method of reducing triglycerides in a
subject having prostate cancer or at risk of developing prostate
cancer according to the present invention comprises administering
to the subject a composition comprising at least about 80%, by
weight of all fatty acids (and/or derivatives thereof) present,
ethyl eicosapentaenoate.
[0008] These and other embodiments of the present invention will be
disclosed in further detail herein below.
DETAILED DESCRIPTION
[0009] While the present invention is capable of being embodied in
various forms, the description below of several embodiments is made
with the understanding that the present disclosure is to be
considered as an exemplification of the invention, and is not
intended to limit the invention to the specific embodiments
illustrated. Headings are provided for convenience only and are not
to be construed to limit the invention in any manner. Embodiments
illustrated under any heading may be combined with embodiments
illustrated under any other heading.
[0010] The use of numerical values in the various quantitative
values specified in this application, unless expressly indicated
otherwise, are stated as approximations as though the minimum and
maximum values within the stated ranges were both preceded by the
word "about." Also, the disclosure of ranges is intended as a
continuous range including every value between the minimum and
maximum values recited as well as any ranges that can be formed by
such values. Also disclosed herein are any and all ratios (and
ranges of any such ratios) that can be formed by dividing a
disclosed numeric value into any other disclosed numeric value.
Accordingly, the skilled person will appreciate that many such
ratios, ranges, and ranges of ratios can be unambiguously derived
from the numerical values presented herein and in all instances
such ratios, ranges, and ranges of ratios represent various
embodiments of the present invention.
[0011] In one embodiment, the invention provides a method for
treatment and/or prevention of a cardiovascular-related disease.
The term "cardiovascular-related disease" herein refers to any
disease or disorder of the heart or blood vessels (i.e. arteries
and veins) or any symptom thereof. Non-limiting examples of
cardiovascular-related disease and disorders include
hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia,
coronary heart disease, vascular disease, stroke, atherosclerosis,
arrhythmia, hypertension, myocardial infarction, and other
cardiovascular events.
[0012] The term "treatment" in relation a given disease or
disorder, includes, but is not limited to, inhibiting the disease
or disorder, for example, arresting the development of the disease
or disorder; relieving the disease or disorder, for example,
causing regression of the disease or disorder; or relieving a
condition caused by or resulting from the disease or disorder, for
example, relieving, preventing or treating symptoms of the disease
or disorder. The term "prevention" in relation to a given disease
or disorder means: preventing the onset of disease development if
none had occurred, preventing the disease or disorder from
occurring in a subject that may be predisposed to the disorder or
disease but has not yet been diagnosed as having the disorder or
disease, and/or preventing further disease/disorder development if
already present.
[0013] As used herein, the term "prostate cancer" refers to any one
of or the combination of: high-grade prostate cancer and low-grade
prostate cancer. "High-grade prostate cancer" is sometimes referred
to as high-grade prostatic intraepithelial neoplasia, HGPIN,
prostatic intraepithelial neoplasia, or PIN. "Low-grade prostate
cancer" is sometimes referred to as low-grade PIN.
[0014] In one embodiment, the present invention provides a method
of blood lipid therapy comprising administering to a subject or
subject group in need thereof a pharmaceutical composition as
described herein. In another embodiment, the subject or subject
group has one or more of: hypercholesterolemia, familial
hypercholesterolemia, high LDL-C serum levels, high total
cholesterol levels, and/or low HDL-C serum levels. In some
embodiments, the subject and/or the subject group has prostate
cancer or is at risk of developing prostate cancer (e.g., has one
or more risk factors associated with prostate cancer).
[0015] In another embodiment, the subject or subject group being
treated has a baseline triglyceride level (or median baseline
triglyceride level in the case of a subject group), fed or fasting,
of at least about 300 mg/dl, at least about 400 mg/dl, at least
about 500 mg/dl, at least about 600 mg/dl, at least about 700
mg/dl, at least about 800 mg/dl, at least about 900 mg/dl, at least
about 1000 mg/dl, at least about 1100 mg/dl, at least about 1200
mg/dl, at least about 1300 mg/dl, at least about 1400 mg/dl, or at
least about 1500 mg/dl, for example about 400 mg/dl to about 2500
mg/dl, about 450 mg/dl to about 2000 mg/dl or about 500 mg/dl to
about 1500 mg/dl.
[0016] In one embodiment, the subject or subject group being
treated in accordance with methods of the invention has previously
been treated with Lovaza.RTM. and has experienced an increase in,
or no decrease in, LDL-C levels and/or non-HDL-C levels. In one
such embodiment, Lovaza.RTM. therapy is discontinued and replaced
by a method of the present invention.
[0017] In another embodiment, the subject or subject group being
treated in accordance with methods of the invention exhibits a
fasting baseline absolute plasma level of free EPA (or mean thereof
in the case of a subject group) not greater than about 0.70
nmol/ml, not greater than about 0.65 nmol/ml, not greater than
about 0.60 nmol/ml, not greater than about 0.55 nmol/ml, not
greater than about 0.50 nmol/ml, not greater than about 0.45
nmol/ml, or not greater than about 0.40 nmol/ml. In another
embodiment, the subject or subject group being treated in
accordance with methods of the invention exhibits a baseline
fasting plasma level (or mean thereof) of free EPA, expressed as a
percentage of total free fatty acid, of not more than about 3%, not
more than about 2.5%, not more than about 2%, not more than about
1.5%, not more than about 1%, not more than about 0.75%, not more
than about 0.5%, not more than about 0.25%, not more than about
0.2% or not more than about 0.15%. In one such embodiment, free
plasma EPA and/or total fatty acid levels are determined prior to
initiating therapy.
[0018] In another embodiment, the subject or subject group being
treated in accordance with methods of the invention exhibits a
fasting baseline absolute plasma level of total fatty acid (or mean
thereof) not greater than about 250 nmol/ml, not greater than about
200 nmol/ml, not greater than about 150 nmol/ml, not greater than
about 100 nmol/ml, or not greater than about 50 nmol/ml.
[0019] In another embodiment, the subject or subject group being
treated in accordance with methods of the invention exhibits a
fasting baseline plasma, serum or red blood cell membrane EPA level
not greater than about 70 .mu.g/ml, not greater than about 60
.mu.g/ml, not greater than about 50 .mu.g/ml, not greater than
about 40 .mu.g/ml, not greater than about 30 .mu.g/ml, or not
greater than about 25 .mu.g/ml.
[0020] In another embodiment, methods of the present invention
comprise a step of measuring the subject's (or subject group's
mean) baseline lipid profile prior to initiating therapy. In
another embodiment, methods of the invention comprise the step of
identifying a subject or subject group having one or more of the
following: baseline non-HDL-C value of about 200 mg/dl to about 400
mg/dl, for example at least about 210 mg/dl, at least about 220
mg/dl, at least about 230 mg/dl, at least about 240 mg/dl, at least
about 250 mg/dl, at least about 260 mg/dl, at least about 270
mg/dl, at least about 280 mg/dl, at least about 290 mg/dl, or at
least about 300 mg/dl; baseline total cholesterol value of about
250 mg/dl to about 400 mg/dl, for example at least about 260 mg/dl,
at least about 270 mg/dl, at least about 280 mg/dl or at least
about 290 mg/dl; baseline vLDL-C value of about 140 mg/dl to about
200 mg/dl, for example at least about 150 mg/dl, at least about 160
mg/dl, at least about 170 mg/dl, at least about 180 mg/dl or at
least about 190 mg/dl; baseline HDL-C value of about 10 to about 60
mg/dl, for example not more than about 40 mg/ dl, not more than
about 35 mg/dl, not more than about 30 mg/dl, not more than about
25 mg/dl, not more than about 20 mg/dl, or not more than about 15
mg/dl; and/or baseline LDL-C value of about 50 to about 300 mg/dl,
for example not less than about 100 mg/dl, not less than about 90
mg/dl, not less than about 80 mg/dl, not less than about 70 mg/dl,
not less than about 60 mg/dl or not less than about 50 mg/dl.
[0021] In a related embodiment, upon treatment in accordance with
the present invention, for example over a period of about 1 to
about 200 weeks, about 1 to about 100 weeks, about 1 to about 80
weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about
1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12
weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1
to about 2 weeks or about 1 week, the subject or subject group
exhibits one or more of the following outcomes:
[0022] (a) reduced triglyceride levels compared to baseline or
control;
[0023] (b) reduced Apo B levels compared to baseline or
control;
[0024] (c) increased HDL-C levels compared to baseline or
control;
[0025] (d) no increase in LDL-C levels compared to baseline or
control;
[0026] (e) a reduction in LDL-C levels compared to baseline or
control;
[0027] (f) a reduction in non-HDL-C levels compared to baseline or
control;
[0028] (g) a reduction in vLDL levels compared to baseline or
control;
[0029] (h) an increase in apo A-I levels compared to baseline or
control;
[0030] (i) an increase in apo A-I/apo B ratio compared to baseline
or control;
[0031] (j) a reduction in lipoprotein A levels compared to baseline
or control;
[0032] (k) a reduction in LDL particle number compared to baseline
or control;
[0033] (l) an increase in LDL size compared to baseline or
control;
[0034] (m) a reduction in remnant-like particle cholesterol
compared to baseline or control;
[0035] (n) a reduction in oxidized LDL compared to baseline or
control;
[0036] (o) no change or a reduction in fasting plasma glucose (FPG)
compared to baseline or control;
[0037] (p) a reduction in hemoglobin A1c (HbA1c) compared to
baseline or control;
[0038] (q) a reduction in homeostasis model insulin resistance
compared to baseline or control;
[0039] (r) a reduction in lipoprotein associated phospholipase A2
compared to baseline or control;
[0040] (s) a reduction in intracellular adhesion molecule-1
compared to baseline or control;
[0041] (t) a reduction in interleukin-6 compared to baseline or
control;
[0042] (u) a reduction in plasminogen activator inhibitor-1
compared to baseline or control;
[0043] (v) a reduction in high sensitivity C-reactive protein
(hsCRP) compared to baseline or control;
[0044] (w) an increase in serum or plasma EPA compared to baseline
or control;
[0045] (x) an increase in red blood cell (RBC) membrane EPA
compared to baseline or control;
[0046] (y) a reduction or increase in one or more of serum
phospholipid and/or red blood cell content of docosahexaenoic acid
(DHA), docosapentaenoic acid (DPA), arachidonic acid (AA), palmitic
acid (PA), staeridonic acid (SA) or oleic acid (OA) compared to
baseline or control;
[0047] (z) a reduction in or prevention of membrane cholesterol
domain formation compared to baseline or control;
[0048] (aa) a reduction in or prevention of oxidative modification
of membrane polyunsaturated fatty acids compared to baseline or
control;
[0049] (bb) a reduction in prostate-specific antigen (PSA) compared
to baseline or control;
[0050] (cc) an improvement in a prostate ultrasound diagnostic
compared to baseline or control;
[0051] (dd) an improvement in a prostate MRI diagnostic compared to
baseline or control;
[0052] (ee) an improvement in biopsy diagnostic compared to
baseline or control;
[0053] (ff) a reduction in Gleason score compared to baseline or
control; and/or
[0054] (gg) a reduction in prostate tumor grade compared to
baseline or control.
[0055] In one embodiment, upon administering a composition of the
invention to a subject, the subject exhibits a decrease in
triglyceride levels, an increase in the concentrations of EPA and
DPA (n-3) in red blood cells, and an increase of the ratio of
EPA:arachidonic acid in red blood cells. In a related embodiment
the subject exhibits substantially no or no increase in RBC
DHA.
[0056] In one embodiment, methods of the present invention comprise
measuring baseline levels of one or more markers set forth in
(a)-(gg) above prior to dosing the subject or subject group. In
another embodiment, the methods comprise administering a
composition as disclosed herein to the subject after baseline
levels of one or more markers set forth in (a)-(gg) are determined,
and subsequently taking an additional measurement of said one or
more markers.
[0057] In another embodiment, upon treatment with a composition of
the present invention, for example over a period of about 1 to
about 200 weeks, about 1 to about 100 weeks, about 1 to about 80
weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about
1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12
weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1
to about 2 weeks or about 1 week, the subject or subject group
exhibits any 2 or more of, any 3 or more of, any 4 or more of, any
5 or more of, any 6 or more of, any 7 or more of, any 8 or more of,
any 9 or more of, any 10 or more of, any 11 or more of, any 12 or
more of, any 13 or more of, any 14 or more of, any 15 or more of,
any 16 or more of, any 17 or more of, any 18 or more of, any 19 or
more of, any 20 or more of, any 21 or more of, any 22 or more of,
any 23 or more, any 24 or more, any 25 or more, any 26 or more, any
27 or more of, any 28 or more of, any 29 or more of, any 30 or more
of, any 31 or more of, any 32 or more of, or all 33 of outcomes
(a)-(gg) described immediately above.
[0058] In another embodiment, upon treatment with a composition of
the present invention, the subject or subject group exhibits one or
more of the following outcomes:
[0059] (a) a reduction in triglyceride level 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% (actual % change or median % change) as
compared to baseline;
[0060] (b) a less than 30% increase, less than 20% increase, less
than 10% increase, less than 5% increase or no increase in
non-HDL-C levels or a reduction in non-HDL-C levels 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%, at least about 50%, at least about 55% or at least about
75% (actual % change or median % change) as compared to
baseline;
[0061] (c) substantially no change in HDL-C levels, no change in
HDL-C levels, or 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% (actual % change or median % change) as
compared to baseline;
[0062] (d) a less than 60% increase, a less than 50% increase, a
less than 40% increase, a less than 30% increase, less than 20%
increase, less than 10% increase, less than 5% increase or no
increase in LDL-C levels or 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%, at least
about 55%, at least about 55% or at least about 75% (actual %
change or median % change) as compared to baseline;
[0063] (e) a decrease in Apo B 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% (actual % change or median % change) as compared
to baseline;
[0064] (f) a reduction in vLDL levels of at least about 5%, at
least about 10%, at least about 15%, at least about 20%, at least
about 25%, at least about 30%, at least about 35%, at least about
40%, at least about 45%, at least about 50%, or at least about 100%
(actual % change or median % change) compared to baseline;
[0065] (g) an increase in apo A-I levels of at least about 5%, at
least about 10%, at least about 15%, at least about 20%, at least
about 25%, at least about 30%, at least about 35%, at least about
40%, at least about 45%, at least about 50%, or at least about 100%
(actual % change or median % change) compared to baseline;
[0066] (h) an increase in apo A-I/apo B ratio 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% (actual % change or median % change) compared to
baseline;
[0067] (i) a reduction in lipoprotein (a) levels of at least about
5%, at least about 10%, at least about 15%, at least about 20%, at
least about 25%, at least about 30%, at least about 35%, at least
about 40%, at least about 45%, at least about 50%, or at least
about 100% (actual % change or median % change) compared to
baseline;
[0068] (j) a reduction in mean LDL particle number 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% (actual % change or median % change) compared to
baseline;
[0069] (k) an increase in mean LDL particle size 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% (actual % change or median % change) compared to
baseline;
[0070] (l) a reduction in remnant-like particle cholesterol 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% (actual % change or median % change) compared
to baseline;
[0071] (m) a reduction in oxidized LDL 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%
(actual % change or median % change) compared to baseline;
[0072] (n) substantially no change, no significant change, or a
reduction (e.g. in the case of a diabetic subject) in fasting
plasma glucose (FPG) 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% (actual % change or
median % change) compared to baseline;
[0073] (o) substantially no change, no significant change or a
reduction in hemoglobin A1c (HbA1c) 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%, or at least about 50% (actual % change or median %
change) compared to baseline;
[0074] (p) a reduction in homeostasis model index insulin
resistance 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% (actual % change or median %
change) compared to baseline;
[0075] (q) a reduction in lipoprotein associated phospholipase A2
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% (actual % change or median % change)
compared to baseline;
[0076] (r) a reduction in intracellular adhesion molecule-1 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% (actual % change or median % change) compared
to baseline;
[0077] (s) a reduction in interleukin-6 of at least about 5%, at
least about 10.degree. A, 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% (actual % change or median % change) compared to
baseline;
[0078] (t) a reduction in plasminogen activator inhibitor-1 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% (actual % change or median % change) compared
to baseline;
[0079] (u) a reduction in high sensitivity C-reactive protein
(hsCRP) 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% (actual % change or median %
change) compared to baseline;
[0080] (v) an increase in serum, plasma and/or RBC EPA 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 100%, at least about 200% or at least about 400% (actual %
change or median % change) compared to baseline;
[0081] (w) an increase in serum phospholipid and/or red blood cell
membrane EPA 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 100%, at least about 200%, or at
least about 400% (actual % change or median % change) compared to
baseline;
[0082] (x) a reduction or increase in one or more of serum
phospholipid and/or red blood cell DHA, DPA, AA, PA and/or OA 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% (actual % change or median %
change) compared to baseline;
[0083] (y) a reduction in total cholesterol 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% (actual % change or median % change)
compared to baseline;
[0084] (z) a reduction in membrane cholesterol domain formation of
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 60%, at least about 65%, at least about 70%, at
least about 75%, at least about 80%, at least about 85%, at least
about 90%, at least about 95%, at least about 98%, at least about
99%, or about 100% (actual % change or median % change) compared to
baseline or control;
[0085] (aa) a reduction in oxidative modification of membrane
polyunsaturated fatty acids of 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 60%, at least about
65%, at least about 70%, at least about 75%, at least about 80%, at
least about 85%, at least about 90%, at least about 95%, at least
about 98%, at least about 99%, or about 100% (actual % change or
median % change) compared to baseline or control;
[0086] (bb) a reduction in prostate-specific antigen (PSA) 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 60%, at least about 65%, at least
about 70%, or at least about 75% (actual % change or median %
change) compared to baseline or to a control arm;
[0087] (cc) an improvement in a prostate ultrasound diagnostic 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 60%, at least about 65%, at least
about 70%, or at least about 75% (actual % change or median %
change) compared to baseline or to a control arm;
[0088] (dd) an improvement in a prostate MRI diagnostic 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 60%, at least about 65%, at least about
70%, or at least about 75% (actual % change or median % change)
compared to baseline or to a control arm;
[0089] (ee) an improvement in biopsy diagnostic 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 60%, at least about 65%, at least about 70%, or
at least about 75% (actual % change or median % change) compared to
baseline or to a control arm;
[0090] (ff) a reduction in Gleason score 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 60%, at least about 65%, at least about 70%, or at
least about 75% (actual % change or median % change) compared to
baseline or to a control arm; and/or
[0091] (gg) a reduction in prostate tumor grade 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 60%, at least about 65%, at least about 70%, or
at least about 75% (actual % change or median % change) compared to
baseline or to a control arm.
[0092] In one embodiment, methods of the present invention comprise
measuring baseline levels of one or more markers set forth in
(a)-(gg) prior to dosing the subject or subject group. In another
embodiment, the methods comprise administering a composition as
disclosed herein to the subject after baseline levels of one or
more markers set forth in (a)-(gg) are determined, and subsequently
taking a second measurement of the one or more markers as measured
at baseline for comparison thereto.
[0093] In another embodiment, upon treatment with a composition of
the present invention, for example over a period of about 1 to
about 200 weeks, about 1 to about 100 weeks, about 1 to about 80
weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about
1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12
weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1
to about 2 weeks or about 1 week, the subject or subject group
exhibits any 2 or more of, any 3 or more of, any 4 or more of, any
5 or more of, any 6 or more of, any 7 or more of, any 8 or more of,
any 9 or more of, any 10 or more of, any 11 or more of, any 12 or
more of, any 13 or more of, any 14 or more of, any 15 or more of,
any 16 or more of, any 17 or more of, any 18 or more of, any 19 or
more of, any 20 or more of, any 21 or more of, any 22 or more of,
any 23 or more of, any 24 or more of, any 25 or more of, any 26 or
more of, any 27 or more of, any 28 or more of, any 29 or more of,
any 30 or more of, any 31 or more of, any 32 or more of, or all 33
of outcomes (a)-(gg) described immediately above.
[0094] Parameters (a)-(gg) can be measured in accordance with any
clinically acceptable methodology. For example, triglycerides,
total cholesterol, HDL-C and fasting blood sugar can be sample from
serum and analyzed using standard photometry techniques. VLDL-TG,
LDL-C and VLDL-C can be calculated or determined using serum
lipoprotein fractionation by preparative ultracentrifugation and
subsequent quantitative analysis by refractometry or by analytic
ultracentrifugal methodology. Apo A1, Apo B and hsCRP can be
determined from serum using standard nephelometry techniques.
Lipoprotein (a) can be determined from serum using standard
turbidimetric immunoassay techniques. LDL particle number and
particle size can be determined using nuclear magnetic resonance
(NMR) spectrometry. Remnants lipoproteins and LDL-phospholipase A2
can be determined from EDTA plasma or serum and serum,
respectively, using enzymatic immunoseparation techniques. Oxidized
LDL, intercellular adhesion molecule-1 and interleukin-6 levels can
be determined from serum using standard enzyme immunoassay
techniques. These techniques are described in detail in standard
textbooks, for example Tietz Fundamentals of Clinical Chemistry,
6th Ed. (Burtis, Ashwood and Borter Eds.), WB Saunders Company.
[0095] In one embodiment, subjects fast for up to 12 hours prior to
blood sample collection, for example about 10 hours.
[0096] In another embodiment, the present invention provides a
method of treating or preventing primary hypercholesterolemia
and/or mixed dyslipidemia (Fredrickson Types IIa and IIb) in a
patient in need thereof, comprising administering to the patient
one or more compositions as disclosed herein. In a related
embodiment, the present invention provides a method of reducing
triglyceride levels in a subject or subjects when treatment with a
statin or niacin extended-release monotherapy is considered
inadequate (Frederickson type IV hyperlipidemia). In some
embodiments, the patient has prostate cancer or is at risk of
developing prostate cancer (e.g., has one or more risk factors
associated with prostate cancer).
[0097] In another embodiment, the present invention provides a
method of treating or preventing risk of recurrent nonfatal
myocardial infarction in a patient with a history of myocardial
infarction, comprising administering to the patient one or more
compositions as disclosed herein.
[0098] In another embodiment, the present invention provides a
method of slowing progression of or promoting regression of
atherosclerotic disease in a patient in need thereof, comprising
administering to a subject in need thereof one or more compositions
as disclosed herein. In some embodiments, the subject has prostate
cancer or is at risk of developing prostate cancer (e.g., has one
or more risk factors associated with prostate cancer).
[0099] In another embodiment, the present invention provides a
method of treating or preventing very high serum triglyceride
levels (e.g. Types IV and V hyperlipidemia) in a patient in need
thereof, comprising administering to the patient one or more
compositions as disclosed herein. In some embodiments, the patient
has prostate cancer or is at risk of developing prostate cancer
(e.g., has one or more risk factors associated with prostate
cancer).
[0100] In another embodiment, the present invention provides a
method of treating subjects having very high serum triglyceride
levels (e.g. greater than 1000 mg/dl or greater than 2000 mg/dl)
and that are at risk of developing pancreatitis, comprising
administering to the patient one or more compositions as disclosed
herein. In some embodiments, the subjects have prostate cancer or
is at risk of developing prostate cancer (e.g., has one or more
risk factors associated with prostate cancer).
[0101] In one embodiment, a composition of the invention is
administered to a subject in an amount sufficient to provide a
daily dose of eicosapentaenoic acid of about 1 mg to about 10,000
mg, 25 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 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, 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 3100 mg, about 3125 mg, about 3150 mg, about 3175
mg, about 3200 mg, about 3225 mg, about 3250 mg, about 3275 mg,
about 3300 mg, about 3325 mg, about 3350 mg, about 3375 mg, about
3400 mg, about 3425 mg, about 3450 mg, about 3475 mg, about 3500
mg, about 3525 mg, about 3550 mg, about 3575 mg, about 3600 mg,
about 3625 mg, about 3650 mg, about 3675 mg, about 3700 mg, about
3725 mg, about 3750 mg, about 3775 mg, about 3800 mg, about 3825
mg, about 3850 mg, about 3875 mg, about 3900 mg, about 3925 mg,
about 3950 mg, about 3975 mg, about 4000 mg, about 4025 mg, about
4050 mg, about 4075 mg, about 4100 mg, about 4125 mg, about 4150
mg, about 4175 mg, about 4200 mg, about 4225 mg, about 4250 mg,
about 4275 mg, about 4300 mg, about 4325 mg, about 4350 mg, about
4375 mg, about 4400 mg, about 4425 mg, about 4450 mg, about 4475
mg, about 4500 mg, about 4525 mg, about 4550 mg, about 4575 mg,
about 4600 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, about 5000 mg, about
5025 mg, about 5050 mg, about 5075 mg, about 5100 mg, about 5125
mg, about 5150 mg, about 5175 mg, about 5200 mg, about 5225 mg,
about 5250 mg, about 5275 mg, about 5300 mg, about 5325 mg, about
5350 mg, about 5375 mg, about 5400 mg, about 5425 mg, about 5450
mg, about 5475 mg, about 5500 mg, about 5525 mg, about 5550 mg,
about 5575 mg, about 5600 mg, about 5625 mg, about 5650 mg, about
5675 mg, about 5700 mg, about 5725 mg, about 5750 mg, about 5775
mg, about 5800 mg, about 5825 mg, about 5850 mg, about 5875 mg,
about 5900 mg, about 5925 mg, about 5950 mg, about 5975 mg, about
6000 mg, about 6025 mg, about 6050 mg, about 6075 mg, about 6100
mg, about 6125 mg, about 6150 mg, about 6175 mg, about 6200 mg,
about 6225 mg, about 6250 mg, about 6275 mg, about 6300 mg, about
6325 mg, about 6350 mg, about 6375 mg, about 6400 mg, about 6425
mg, about 6450 mg, about 6475 mg, about 6500 mg, about 6525 mg,
about 6550 mg, about 6575 mg, about 6600 mg, about 6625 mg, about
6650 mg, about 6675 mg, about 6700 mg, about 6725 mg, about 6750
mg, about 6775 mg, about 6800 mg, about 6825 mg, about 6850 mg,
about 6875 mg, about 6900 mg, about 6925 mg, about 6950 mg, about
6975 mg, about 7000 mg, about 7025 mg, about 7050 mg, about 7075
mg, about 7100 mg, about 7125 mg, about 7150 mg, about 7175 mg,
about 7200 mg, about 7225 mg, about 7250 mg, about 7275 mg, about
7300 mg, about 7325 mg, about 7350 mg, about 7375 mg, about 7400
mg, about 7425 mg, about 7450 mg, about 7475 mg, about 7500 mg,
about 7525 mg, about 7550 mg, about 7575 mg, about 7600 mg, about
7625 mg, about 7650 mg, about 7675 mg, about 7700 mg, about 7725
mg, about 7750 mg, about 7775 mg, about 7800 mg, about 7825 mg,
about 7850 mg, about 7875 mg, about 7900 mg, about 7925 mg, about
7950 mg, about 7975 mg, about 8000 mg, about 8025 mg, about 8050
mg, about 8075 mg, about 8100 mg, about 8125 mg, about 8150 mg,
about 8175 mg, about 8200 mg, about 8225 mg, about 8250 mg, about
8275 mg, about 8300 mg, about 8325 mg, about 8350 mg, about 8375
mg, about 8400 mg, about 8425 mg, about 8450 mg, about 8475 mg,
about 8500 mg, about 8525 mg, about 8550 mg, about 8575 mg, about
8600 mg, about 8625 mg, about 8650 mg, about 8675 mg, about 8700
mg, about 8725 mg, about 8750 mg, about 8775 mg, about 8800 mg,
about 8825 mg, about 8850 mg, about 8875 mg, about 8900 mg, about
8925 mg, about 8950 mg, about 8975 mg, about 9000 mg, about 9025
mg, about 9050 mg, about 9075 mg, about 9100 mg, about 9125 mg,
about 9150 mg, about 9175 mg, about 9200 mg, about 9225 mg, about
9250 mg, 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.
[0102] In another embodiment, any of the methods disclosed herein
are used in treatment or prevention of a subject or subjects that
consume a traditional Western diet. In one embodiment, the methods
of the invention include a step of identifying a subject as a
Western diet consumer or prudent diet consumer and then treating
the subject if the subject is deemed a Western diet consumer. The
term "Western diet" herein refers generally to a typical diet
consisting of, by percentage of total calories, about 45% to about
50% carbohydrate, about 35% to about 40% fat, and about 10% to
about 15% protein. A Western diet may alternately or additionally
be characterized by relatively high intakes of red and processed
meats, sweets, refined grains, and desserts, for example more than
50%, more than 60% or more or 70% of total calories come from these
sources.
[0103] In one embodiment, a composition for use in methods of the
invention comprises eicosapentaenoic acid, or a pharmaceutically
acceptable ester, derivative, conjugate or salt thereof, or
mixtures of any of the foregoing, collectively referred to herein
as "EPA." The term "pharmaceutically acceptable" in the present
context means that the substance in question does not produce
unacceptable toxicity to the subject or interaction with other
components of the composition.
[0104] In one embodiment, the EPA comprises all-cis
eicosa-5,8,11,14,17-pentaenoic acid. 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, eicosapentaenoic acid methyl ester, eicosapentaenoic acid
propyl ester, or eicosapentaenoic acid butyl ester. In another
embodiment, the EPA comprises In one embodiment, the EPA comprises
all-cis eicosa-5,8,11,14,17-pentaenoic acid ethyl ester.
[0105] In another embodiment, the EPA is in the form of ethyl-EPA,
lithium EPA, mono-, di- or triglyceride EPA or any other ester or
salt of EPA, or the free acid form of EPA. The EPA may also be in
the form of a 2-substituted derivative or other derivative which
slows down its rate of oxidation but does not otherwise change its
biological action to any substantial degree.
[0106] In another embodiment, EPA is present in a composition
useful in accordance with methods of the invention in an amount of
about 50 mg to about 5000 mg, about 75 mg to about 2500 mg, or
about 100 mg to about 1000 mg, for example about 75 mg, about 100
mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about
225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg,
about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450
mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about
575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg,
about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800
mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about
925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg,
about 1050 mg, about 1075 mg, about 1100 mg, 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
3100 mg, about 3125 mg, about 3150 mg, about 3175 mg, about 3200
mg, about 3225 mg, about 3250 mg, about 3275 mg, about 3300 mg,
about 3325 mg, about 3350 mg, about 3375 mg, about 3400 mg, about
3425 mg, about 3450 mg, about 3475 mg, about 3500 mg, about 3525
mg, about 3550 mg, about 3575 mg, about 3600 mg, about 3625 mg,
about 3650 mg, about 3675 mg, about 3700 mg, about 3725 mg, about
3750 mg, about 3775 mg, about 3800 mg, about 3825 mg, about 3850
mg, about 3875 mg, about 3900 mg, about 3925 mg, about 3950 mg,
about 3975 mg, about 4000 mg, about 4025 mg, about 4050 mg, about
4075 mg, about 4100 mg, about 4125 mg, about 4150 mg, about 4175
mg, about 4200 mg, about 4225 mg, about 4250 mg, about 4275 mg,
about 4300 mg, about 4325 mg, about 4350 mg, about 4375 mg, about
4400 mg, about 4425 mg, about 4450 mg, about 4475 mg, about 4500
mg, about 4525 mg, about 4550 mg, about 4575 mg, about 4600 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.
[0107] In another embodiment, a composition useful in accordance
with the invention contains not more than about 10%, not more than
about 9%, not more than about 8%, not more than about 7%, not more
than about 6%, not more than about 5%, not more than about 4%, not
more than about 3%, not more than about 2%, not more than about 1%,
or not more than about 0.5%, by weight of all fatty acids (and/or
derivatives thereof) present, docosahexaenoic acid (DHA), if any.
In another embodiment, a composition of the invention contains
substantially no docosahexaenoic acid. In still another embodiment,
a composition useful in the present invention contains no
docosahexaenoic acid and/or derivative thereof.
[0108] In another embodiment, EPA comprises at least 70%, at least
80%, at least 90%, at least 95%, at least 96%, at least 97%, at
least 98%, at least 99%, or 100%, by weight of all fatty acids
(and/or derivatives thereof) present, in a composition that is
useful in methods of the present invention.
[0109] In one embodiment, a composition of the invention comprises
ultra-pure EPA. The term "ultra-pure" as used herein with respect
to EPA refers to a composition comprising at least 95%, by weight
of all fatty acids (and/or derivatives thereof) present, EPA (as
the term "EPA" is defined and exemplified herein). Ultra-pure EPA
comprises at least 96%, by weight of all fatty acids (and/or
derivatives thereof) present, EPA, at least 97%, by weight of all
fatty acids (and/or derivatives thereof) present, EPA, or at least
98%, by weight of all fatty acids (and/or derivatives thereof)
present, EPA, wherein the EPA is any form of EPA as set forth
herein.
[0110] In another embodiment, a composition useful in accordance
with methods of the invention contains less than 10%, less than 9%,
less than 8%, less than 7%, less than 6%, less than 5%, less than
4%, less than 3%, less than 2%, less than 1%, less than 0.5% or
less than 0.25%, by weight of all fatty acids (and/or derivatives
thereof) present, of any fatty acid other than EPA. Illustrative
examples of a "fatty acid 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, a composition useful in accordance with methods of the
invention contains about 0.1% to about 4%, about 0.5% to about 3%,
or about 1% to about 2%, by weight of all fatty acids (and/or
derivatives thereof) present, other than EPA and/or DHA.
[0111] In another embodiment, a composition useful in accordance
with the invention has one or more of the following features: (a)
eicosapentaenoic acid ethyl ester represents at least about 96%, at
least about 97%, or at least about 98%, by weight of all fatty
acids (and/or derivatives thereof) present, in the composition; (b)
the composition contains not more than about 4%, not more than
about 3%, or not more than about 2%, by weight of all fatty acids
(and/or derivatives thereof) present, other than eicosapentaenoic
acid ethyl ester; (c) the composition contains not more than about
0.6%, not more than about 0.5%, or not more than about 0.4%, by
weight of all fatty acids (and/or derivatives thereof) present, of
any individual fatty acid other than eicosapentaenoic acid ethyl
ester; (d) the composition has a refractive index (20.degree. 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.degree. 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 not more than about 20
ppm, not more than about 15 ppm or not more than about 10 ppm heavy
metals, (f) the composition contains not more than about 5 ppm, not
more than about 4 ppm, not more than about 3 ppm, or not more than
about 2 ppm arsenic, and/or (g) the composition has a peroxide
value of not more than about 5 meq/kg, not more than about 4
meq/kg, not more than about 3 meq/kg, or not more than about 2
meq/kg.
[0112] In another embodiment, a composition useful in accordance
with the invention comprises, consists of or consists essentially
of at least 95%, by weight of all fatty acids (and/or derivatives
thereof) present, ethyl eicosapentaenoate (EPA-E), about 0.2% to
about 0.5%, by weight of all fatty acids (and/or derivatives
thereof) present, ethyl octadecatetraenoate (ODTA-E), about 0.05%
to about 0.25%, by weight of all fatty acids (and/or derivatives
thereof) present, ethyl nonadecapentaenoate (NDPA-E), about 0.2% to
about 0.45%, by weight of all fatty acids (and/or derivatives
thereof) present, ethyl arachidonate (AA-E), about 0.3% to about
0.5%, by weight of all fatty acids (and/or derivatives thereof)
present, ethyl eicosatetraenoate (ETA-E), and about 0.05% to about
0.32%, by weight of all fatty acids (and/or derivatives thereof)
present, ethyl heneicosapentaenoate (HPA-E). In another embodiment,
the composition is present in a capsule shell.
[0113] In another embodiment, compositions useful in accordance
with the invention comprise, consist essential of, or consist of at
least 95%, 96% or 97%, by weight of all fatty acids (and/or
derivatives thereof) present, ethyl eicosapentaenoate, about 0.2%
to about 0.5% by weight ethyl octadecatetraenoate, about 0.05% to
about 0.25%, by weight of all fatty acids (and/or derivatives
thereof) present, ethyl nonadecapentaenoate, about 0.2% to about
0.45%, by weight of all fatty acids (and/or derivatives thereof)
present, ethyl arachidonate, about 0.3% to about 0.5%, by weight of
all fatty acids (and/or derivatives thereof) present, ethyl
eicosatetraenoate, and about 0.05% to about 0.32%, by weight of all
fatty acids (and/or derivatives thereof) present, ethyl
heneicosapentaenoate. Optionally, the composition contains not more
than about 0.06%, about 0.05%, or about 0.04%, by weight of all
fatty acids (and/or derivatives thereof) present, DHA or derivative
thereof such as ethyl-DHA. In one embodiment the composition
contains substantially no or no amount of DHA or derivative thereof
such as ethyl-DHA. The composition further optionally comprises one
or more antioxidants (e.g. tocopherol) or other impurities in an
amount of not more than about 0.5% or not more than 0.05%. In
another embodiment, the composition comprises about 0.05% to about
0.4%, for example about 0.2% by weight tocopherol. In another
embodiment, about 500 mg to about 1 g of the composition is
provided in a capsule shell.
[0114] In another embodiment, compositions useful in accordance
with the invention comprise, consist essential of, or consist of at
least 96%, by weight of all fatty acids (and/or derivatives
thereof) present, ethyl eicosapentaenoate, about 0.22% to about
0.4%, by weight of all fatty acids (and/or derivatives thereof)
present, ethyl octadecatetraenoate, about 0.075% to about 0.20%, by
weight of all fatty acids (and/or derivatives thereof) present,
ethyl nonadecapentaenoate, about 0.25% to about 0.40%, by weight of
all fatty acids (and/or derivatives thereof) present, ethyl
arachidonate, about 0.3% to about 0.4%, by weight of all fatty
acids (and/or derivatives thereof) present, ethyl eicosatetraenoate
and about 0.075% to about 0.25%, by weight of all fatty acids
(and/or derivatives thereof) present, ethyl heneicosapentaenoate.
Optionally, the composition contains not more than about 0.06%,
about 0.05%, or about 0.04%, by weight of all fatty acids (and/or
derivatives thereof) present, DHA or derivative thereof such as
ethyl-DHA. In one embodiment the composition contains substantially
no or no amount of DHA or derivative thereof such as ethyl-DHA. The
composition further optionally comprises one or more antioxidants
(e.g. tocopherol) or other impurities in an amount of not more than
about 0.5% or not more than 0.05%. In another embodiment, the
composition comprises about 0.05% to about 0.4%, for example about
0.2% by weight tocopherol. In another embodiment, the invention
provides a dosage form comprising about 500 mg to about 1 g of the
foregoing composition in a capsule shell. In one embodiment, the
dosage form is a gel or liquid capsule and is packaged in blister
packages of about 1 to about 20 capsules per sheet.
[0115] In another embodiment, compositions useful in accordance
with the invention comprise, consist essential of, or consist of at
least 96%, 97% or 98%, by weight of all fatty acids (and/or
derivatives thereof) present, ethyl eicosapentaenoate, about 0.25%
to about 0.38%, by weight of all fatty acids (and/or derivatives
thereof) present, ethyl octadecatetraenoate, about 0.10% to about
0.15%, by weight of all fatty acids (and/or derivatives thereof)
present, ethyl nonadecapentaenoate, about 0.25% to about 0.35%, by
weight of all fatty acids (and/or derivatives thereof) present,
ethyl arachidonate, about 0.31% to about 0.38%, by weight of all
fatty acids (and/or derivatives thereof) present, ethyl
eicosatetraenoate, and about 0.08% to about 0.20%, by weight of all
fatty acids (and/or derivatives thereof) present, ethyl
heneicosapentaenoate. Optionally, the composition contains not more
than about 0.06%, about 0.05%, or about 0.04%, by weight of all
fatty acids (and/or derivatives thereof) present, DHA or derivative
thereof such as ethyl-DHA. In one embodiment the composition
contains substantially no or no amount of DHA or derivative thereof
such as ethyl-DHA. The composition further optionally comprises one
or more antioxidants (e.g. tocopherol) or other impurities in an
amount of not more than about 0.5% or not more than 0.05%. In
another embodiment, the composition comprises about 0.05% to about
0.4%, for example about 0.2% by weight tocopherol. In another
embodiment, the invention provides a dosage form comprising about
500 mg to about 1 g of the foregoing composition in a capsule
shell.
[0116] In another embodiment, a composition as described herein is
administered to a subject once or twice per day. In another
embodiment, 1, 2, 3 or 4 capsules, each containing about 1 g of a
composition as described herein, are administered to a subject
daily. In another embodiment, 1 or 2 capsules, each containing
about 1 g of a composition as described herein, are administered to
the subject in the morning, for example between about 5 am and
about 11 am, and 1 or 2 capsules, each containing about 1 g of a
composition as described herein, are administered to the subject in
the evening, for example between about 5 pm and about 11 pm.
[0117] In one embodiment, a subject being treated in accordance
with methods of the invention is not otherwise on lipid-altering
therapy, for example statin, fibrate, niacin and/or ezetimibe
therapy. In another embodiment, a subject being treated in
accordance with methods of the invention is not otherwise on
prostate cancer prevention or treatment therapy.
[0118] In another embodiment, compositions useful in accordance
with methods of the invention are orally deliverable. The terms
"orally deliverable" or "oral administration" herein include any
form of delivery of a therapeutic agent or a composition thereof to
a subject wherein the agent or composition is placed in the mouth
of the subject, whether or not the agent or composition is
swallowed. Thus "oral administration" includes buccal and
sublingual as well as esophageal administration. In one embodiment,
the composition is present in a capsule, for example a soft gelatin
capsule.
[0119] In one embodiment, administration of eicosapentaenoic acid
(or a derivative thereof) effects a reduction in or elimination of
the prevalence and/or severity (e.g., frequency of occurrence
and/or intensity) of one or more side effects commonly associated
with prostate cancer therapy. In one embodiment, administration of
eicosapentaenoic acid (or a derivative thereof to a subject or a
subject group effects a reduction in or elimination of one or more
of: urinary dysfunction, bowel dysfunction, erectile dysfunction,
loss of fertility, pain, fatigue, loss of energy, numbness and/or
weakness in toes or fingers (e.g., neuropathy), bleeding, anemia,
reduced heart function, hair loss, diarrhea, nail changes, loss of
appetite, shortness of breath, fluid retention, headache, abdominal
pain, low blood pressure, skin irritation, enlarged pores,
darkening of the skin, increased skin sensitivity, decrease skin
sensitivity, thickening of skin tissue, incontinence, nausea,
vomiting, frequent urination, and/or proctitis. In some
embodiments, the reduction or elimination of the one or more side
effect is statistically significant compared to a subject or a
subject group receiving the glucosamine but not the
eicosapentaenoic acid (or derivative thereof).
[0120] In some embodiments, a method of treating and/or preventing
prostate cancer in a subject according to the present invention
comprises administering to the subject a composition comprising at
least about 80%, by weight of all fatty acids (and/or derivatives
thereof) present, ethyl eicosapentaenoate. In other embodiments, a
method of reducing triglycerides in a subject on glucosamine
therapy according to the present invention comprises administering
to the subject about 1 to about 4 capsules per day, each capsule
comprising about 1 g of ethyl eicosapentaenoate. In some
embodiments, the capsules comprise at least about 80%, by weight of
all fatty acids (and/or derivatives thereof) present, ethyl
eicosapentaenoate.
[0121] In some embodiments, the subject has a fasting baseline
triglyceride level of about 200 mg/dl to 499 mg/dl. In some
embodiments, the second subject or second subject group has a
fasting baseline triglyceride level or a mean or median fasting
baseline triglyceride level of about 200 mg/dl to 499 mg/dl. In
some embodiments, the subject has a fasting baseline triglyceride
level of at least 500 mg/dl. In some embodiments, the second
subject or second subject group has a fasting baseline triglyceride
level or a mean or median fasting baseline triglyceride level of at
least 500 mg/dl. In some embodiments, triglycerides are reduced in
the subject with no increase in an LDL-C level in the subject. In
some embodiments, the reduction in triglycerides and the no
increase in LDL-C level is in comparison to baseline or to a second
subject or subject group that has received glucosamine but not the
ethyl eicosapentaenoate.
[0122] A composition for use in accordance with the invention can
be formulated as one or more dosage units. The terms "dose unit"
and "dosage unit" herein refer to a portion of a pharmaceutical
composition that contains an amount of a therapeutic agent suitable
for a single administration to provide a therapeutic effect. Such
dosage units may be administered one to a plurality (i.e. 1 to
about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of times per day, or as
many times as needed to elicit a therapeutic response.
[0123] In another embodiment, the invention provides use of any
composition described herein for treating moderate to severe
hypertriglyceridemia and/or for treating or preventing prostate
cancer in a subject in need thereof, comprising: providing a
subject having a fasting baseline triglyceride level of 500 mg/dl
to about 1500 mg/dl and administering to the subject a
pharmaceutical composition as described herein. In one embodiment,
the composition comprises about 1 g to about 4 g of
eicosapentaenoic acid ethyl ester, wherein the composition contains
substantially no docosahexaenoic acid. In some embodiments,
cholesterol domain formation in membranes of the subject is reduced
or prevented. In some embodiments, the subject experiences no
substantial increase, or no increase, or a reduction, in LDL-C
levels.
[0124] In another embodiment, the invention provides use of any
composition described herein for treating moderate to severe
hypertriglyceridemia and/or for treating or preventing prostate
cancer in a subject in need thereof, comprising: providing a
subject on statin therapy and having a fasting baseline
triglyceride level of about 200 mg/dl to 499 mg/dl and
administering to the subject a pharmaceutical composition as
described herein. In one embodiment, the composition comprises
about 1 g to about 4 g of eicosapentaenoic acid ethyl ester,
wherein the composition contains substantially no docosahexaenoic
acid. In some embodiments, cholesterol domain formation in
membranes of the subject is reduced or prevented. In some
embodiments, the subject experiences no substantial increase, or no
increase, or a reduction, in LDL-C levels.
[0125] In one embodiment, compositions of the invention, upon
storage in a closed container maintained at room temperature,
refrigerated (e.g. about 5 to about 5-10.degree. C.) temperature,
or frozen for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
or 12 months, exhibit at least about 90%, at least about 95%, at
least about 97.5%, or at least about 99% of the active
ingredient(s) originally present therein.
[0126] In one embodiment, the invention provides use of a
composition as described herein in manufacture of a medicament for
treatment of any of a cardiovascular-related disease and/or for
treating or preventing prostate cancer. In another embodiment, the
subject is diabetic.
[0127] In one embodiment, a composition as set forth herein is
packaged together with instructions for using the composition to
treat a cardiovascular disorder and/or for treating or preventing
prostate cancer.
[0128] In one embodiment, a method of treating or preventing
prostate cancer in a subject is provided, the method comprising
administering to the subject a pharmaceutical composition
comprising at least about 80%, at least about 90%, at least about
95%, or at least about 96%, by weight of all fatty acids (and/or
derivatives thereof) present, ethyl eicosapentaenoate. In some
embodiments, triglycerides are reduced in the subject with no
increase in an LDL-C level in the subject In some embodiments, the
reduction in triglycerides and the no increase in LDL-C level is in
comparison to baseline, or in comparison to a second subject or
subject group that has received a prostate cancer therapy but not
the ethyl eicosapentaenoate. In some embodiments, the subject has a
fasting baseline triglyceride level of about 200 mg/dl to 499
mg/dl. In some embodiments, the second subject or second subject
group has a fasting baseline triglyceride level or a mean or median
fasting baseline triglyceride level of about 200 mg/dl to 499
mg/dl. In some embodiments, the subject has a fasting baseline
triglyceride level of at least 500 mg/dl. In some embodiments, the
second subject or second subject group has a fasting baseline
triglyceride level or a mean or median fasting baseline
triglyceride level of at least 500 mg/dl In some embodiments,
docosahexaenoic acid and its esters represent no more than about
20%, no more than about 10%, no more than about 5%, or no more than
about 3%, by weight of all fatty acids (and/or derivatives thereof)
present in the pharmaceutical composition.
[0129] In another embodiment, a method of treating or preventing
prostate cancer in a subject is provided, the method comprising
administering to the subject about 1 to about 4 capsules per day,
each capsule comprising about 1 g of ethyl eicosapentaenoate. In
some embodiments, the capsules comprise at least about 80%, at
least about 90%, at least about 95%, or at least about 96%, by
weight of all fatty acids (and/or derivatives thereof) present,
ethyl eicosapentaenoate. In some embodiments, triglycerides are
reduced in the subject with no increase in an LDL-C level in the
subject In some embodiments, the reduction in triglycerides and the
no increase in LDL-C level is in comparison to baseline, or in
comparison to a second subject or subject group that has received a
prostate cancer therapy but not the ethyl eicosapentaenoate. In
some embodiments, the subject has a fasting baseline triglyceride
level of about 200 mg/dl to 499 mg/dl. In some embodiments, the
second subject or second subject group has a fasting baseline
triglyceride level or a mean or median fasting baseline
triglyceride level of about 200 mg/dl to 499 mg/dl. In some
embodiments, the subject has a fasting baseline triglyceride level
of at least 500mg/dl. In some embodiments, the second subject or
second subject group has a fasting baseline triglyceride level or a
mean or median fasting baseline triglyceride level of at least 500
mg/dl In some embodiments, docosahexaenoic acid and its esters
represent no more than about 20%, no more than about 10%, no more
than about 5%, or no more than about 3%, by weight of all fatty
acids (and/or derivatives thereof) present in the capsules.
[0130] In any method disclosed herein, the subject may have a risk
factor associated with prostate cancer. In some embodiments, the
risk factor is selected from the group consisting of: a genetic
risk factor, a family history risk factor, a dietary risk factor, a
viral risk factor, a sexual-related risk factor, a risk factor
associated with exposure to medication, and a risk factor
associated with a medical procedure. In some embodiments, the risk
factor is a genetic risk factor comprising a mutation in BRCA1, a
mutation in BRCA2, a mutation in HPC1, a mutation in the androgen
receptor, a mutation in the vitamin D receptor, overexpression of
one or more ETS transcription factors, a mutation in or loss of one
or more copies of PTEN, a mutation in or loss of one or more copies
of KAI1, a mutation in or loss of one or more copies of E-cadherin,
a mutation in or loss of one or more copies of CD44, a TT allele
pair at SNP rs10993994, a mutation in the promoter region of the
MSMB gene, or a combination thereof. In some embodiments, the risk
factor is a family history risk factor comprising diagnosis of
prostate cancer in a close relative of the subject. In some
embodiments, the relative is a first-degree relative. In some
embodiments, the risk factor is a dietary risk factor comprising
high consumption of meat, low consumption of vitamin D, high
consumption of fish and/or seafood, or a combination thereof. In
some embodiments, the fish and/or seafood is high in omega-3 fatty
acids. In some embodiments, the risk factor is a viral risk factor
comprising exposure to a retrovirus associated with human prostate
tumors. In some embodiments, the retrovirus is Xenotropic
MuLV-related virus (XMRV). In some embodiments, the risk factor is
a sexual-related risk factor comprising a high number of sexual
partners, early onset of sexual activity, presence or diagnosis of
a sexually-transmissible infection (STI), or a combination thereof.
In some embodiments, the STI is HPV-16, HPV-18, HSV-2, chlamydia,
gonorrhea, and/or syphilis. In some embodiments, the risk factor is
a risk factor associated with exposure to medication comprising use
or discontinuance of use of a statin, an elevated level of
testosterone, exposure to Agent Orange, or a combination thereof.
In some embodiments, the risk factor is a risk factor associated
with a medical procedure comprises vasectomy.
[0131] In some embodiments, the risk factor associated with
prostate cancer is identified before administration of the
pharmaceutical composition to the subject. In some embodiments, the
subject is identified as having prostate cancer before
administration of the pharmaceutical composition to the
subject.
[0132] In some embodiments, a method of the present disclosure
further comprises providing the subject with a prostate cancer
therapy selected from the group consisting of: surveillance,
surgery, radiation, ultrasound, chemotherapy, cryotherapy, primary
hormone therapy, and combinations thereof. In some embodiments, the
radiation comprises brachytherapy, proton therapy and/or external
beam radiation therapy. In some embodiments, the chemotherapy
comprises administering to the subject temozolomide, docetaxel,
cabazitaxel, ketoconazole, abiraterone, bevacizumab, thalidomide,
prednisone, sipuleucel-T, enzalutamide, ZD5054 (Zibotensan),
atrasentan (Xinlay), OGX-11, finasteride, dutasteride, or a
combination thereof. In some embodiments, the chemotherapy
comprises administering to the subject a combination of
bevacizumab, docetaxel, thalidomide and prednisone. In some
embodiments, the chemotherapy comprises administering to the
subject a combination of abiraterone and prednisone, optionally
wherein the subject has previously been treated with docetaxel.
[0133] In some embodiments, a method according to the present
disclosure comprises co-administering to a subject in need thereof
a prostate cancer drug(s) and ethyl eicosapentaenoate.
Co-administration of a prostate cancer drug and eicosapentaenoic
acid (or a derivative thereof) can be accomplished by any suitable
means. For example, and without limitation, the prostate cancer
drug can be admixed, encapsulated, conjugated or otherwise
associated with the eicosapentaenoic acid (or derivative thereof).
In some embodiments, the prostate cancer drug and the
eicosapentaenoic acid (or derivative thereof) are co-administered
in an oral dosage form, such as by oral capsule (e.g., a gelatin
capsule). Alternatively, the prostate cancer drug may be
co-administered with the eicosapentaenoic acid (or derivative
thereof) in separate dosage forms. For example, in one such
embodiment the eicosapentaenoic acid (or derivative thereof) is
orally administered (e.g., in oral capsule or gelatin capsule
form), while the prostate cancer drug is administered topically
(e.g., to ophthalmic or mucous membranes), pulmonarily (e.g., by
inhalation or insufflation of powders or aerosols), or parenterally
(e.g., intravenously, intraarterially, subcutaneously, by
intraperitoneal or intramuscular injection or infusion, or
intracranially).
[0134] In some embodiments, the method further comprises reducing
or discontinuing the prostate cancer therapy after administration
of the pharmaceutical composition. In some embodiments, the
prostate cancer therapy is reduced or discontinued after
administration of the pharmaceutical composition for a period of
time effective to reduce a prostate cancer diagnostic result
associated with the subject. In some embodiments, the prostate
cancer diagnostic result is one or more of: a PSA score, a prostate
ultrasound image, a prostate MRI image, a biopsy sample, a Gleason
score, and a prostate tumor grade. In some embodiments, the period
of time is less than about 6 months, for example about 6 months,
about 5 months, about 4 months, about 3 months, about 2 months, or
about 1 month. In some embodiments, the period of time is about 1
week to about 100 weeks, for example about 1 week, about 2 weeks,
about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7
weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11
weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15
weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19
weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23
weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27
weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31
weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35
weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39
weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43
weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47
weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51
weeks, about 52 weeks, about 53 weeks, about 54 weeks, about 55
weeks, about 56 weeks, about 57 weeks, about 58 weeks, about 59
weeks, about 60 weeks, about 61 weeks, about 62 weeks, about 63
weeks, about 64 weeks, about 65 weeks, about 66 weeks, about 67
weeks, about 68 weeks, about 69 weeks, about 70 weeks, about 71
weeks, about 72 weeks, about 73 weeks, about 74 weeks, about 75
weeks, about 76 weeks, about 77 weeks, about 78 weeks, about 79
weeks, about 80 weeks, about 81 weeks, about 82 weeks, about 83
weeks, about 84 weeks, about 85 weeks, about 86 weeks, about 87
weeks, about 88 weeks, about 89 weeks, about 90 weeks, about 91
weeks, about 92 weeks, about 93 weeks, about 94 weeks, about 95
weeks, about 96 weeks, about 97 weeks, about 98 weeks, about 99
weeks, or about 100 weeks.
[0135] In some embodiments, the subject has an elevated PSA level
before administration of the pharmaceutical composition. In some
embodiments, the elevated PSA level is a baseline PSA level of at
least about 2.5 ng/mL, at least about 3 ng/ml, or at least about 4
ng/ml in a blood sample associated with the subject. In some
embodiments, the method further comprises determining a second,
lower PSA level associated with the subject after administration of
the pharmaceutical composition. In some embodiments, the
pharmaceutical composition is administered to the subject for a
period of time effective to reduce the PSA level 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 60%, at least about 65%, at least about 70%, at
least about 75%, at least about 80%, at least about 85%, at least
about 90%, or at least about 95% compared to the baseline PSA
level. In some embodiments, the period of time is less than about 6
months, for example about 6 months, about 5 months, about 4 months,
about 3 months, about 2 months, or about 1 month. In some
embodiments, the period of time is about 1 week to about 100 weeks,
for example about 1 week, about 2 weeks, about 3 weeks, about 4
weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks,
about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks,
about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks,
about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks,
about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks,
about 25 weeks, about 26weeks, about 27 weeks, about 28 weeks,
about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks,
about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks,
about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks,
about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks,
about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks,
about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks,
about 53 weeks, about 54 weeks, about 55 weeks, about 56 weeks,
about 57 weeks, about 58 weeks, about 59 weeks, about 60 weeks,
about 61 weeks, about 62 weeks, about 63 weeks, about 64 weeks,
about 65 weeks, about 66 weeks, about 67 weeks, about 68 weeks,
about 69 weeks, about 70 weeks, about 71 weeks, about 72 weeks,
about 73 weeks, about 74 weeks, about 75 weeks, about 76 weeks,
about 77 weeks, about 78 weeks, about 79 weeks, about 80 weeks,
about 81 weeks, about 82 weeks, about 83 weeks, about 84 weeks,
about 85 weeks, about 86 weeks, about 87 weeks, about 88 weeks,
about 89 weeks, about 90 weeks, about 91 weeks, about 92 weeks,
about 93 weeks, about 94 weeks, about 95 weeks, about 96 weeks,
about 97 weeks, about 98 weeks, about 99 weeks, or about 100
weeks.
EXAMPLES
Example 1
[0136] A multi-center, placebo-controlled randomized, double-blind,
12-week study with an open-label extension was performed to
evaluate the efficacy and safety of AMR101 in patients with fasting
triglyceride levels .gtoreq.500 mg/dL. The primary objective of the
study was to determine the efficacy of AMR101 2 g daily and 4 g
daily, compared to placebo, in lowering fasting TG levels in
patients with fasting TG levels .gtoreq.500 mg/dL and .ltoreq.1500
mg/dL (.gtoreq.5.65 mmol/L and .ltoreq.16.94 mmol/L).
[0137] The secondary objectives of this study were the following:
[0138] To determine the safety and tolerability of AMR101 2 g daily
and 4 g daily; [0139] To determine the effect of AMR101 on lipid
and apolipoprotein profiles; [0140] To determine the effect of
AMR101 on low-density lipoprotein (LDL) particle number and size;
[0141] To determine the effect of AMR101 on oxidized LDL; [0142] To
determine the effect of AMR101 on fasting plasma glucose (FPG) and
hemoglobin A1c (HbA1c); [0143] To determine the effect of AMR101 on
insulin resistance; [0144] To determine the effect of AMR101 on
high-sensitivity C-reactive protein (hsCRP); [0145] To determine
the effects of AMR101 2 g daily and 4 g daily on the incorporation
of fatty acids into red blood cell membranes and into plasma
phospholipids; [0146] To explore the relationship between baseline
fasting TG levels and the reduction in fasting TG levels; and
[0147] To explore the relationship between an increase in red blood
cell membrane eicosapentaenoic acid (EPA) concentrations and the
reduction in fasting TG levels.
[0148] The population for this study was men and women (women of
childbearing potential needed to be on contraception or practice
abstinence) >18 years of age with a body mass index .ltoreq.45
kg/m.sup.2 who were not on lipid altering therapy or were not
currently on lipid altering therapy. Patients currently on statin
therapy (with or without ezetimibe) were evaluated by the
investigator as to whether this therapy could be safely
discontinued at screening, or if it should have been continued. If
statin therapy (with or without ezetimibe) was to be continued,
dose(s) must have been stable for .gtoreq.4 weeks prior to
randomization. Patients taking non-statin, lipid-altering
medications (niacin >200 mg/day, fibrates, fish oil, other
products containing omega 3 fatty acids, or other herbal products
or dietary supplements with potential lipid altering effects),
either alone or in combination with statin therapy (with or without
ezetimibe), must have been able to safely discontinue non-statin,
lipid altering therapy at screening.
[0149] Approximately 240 patients were randomized at approximately
50 centers in North America, South America, Central America,
Europe, India, and South Africa. The study was a 58- to 60-week,
Phase 3, multi-center study consisting of 3 study periods: (1) a 6-
to 8-week screening period that included a diet and lifestyle
stabilization and washout period and a TG qualifying period; (2) a
12-week, double-blind, randomized, placebo controlled treatment
period; and (3) a 40-week, open-label, extension period.
[0150] During the screening period and double-blind treatment
period, all visits were within .+-.3 days of the scheduled time.
During the open-label extension period, all visits were within
.+-.7 days of the scheduled time. The screening period included a
4- or 6-week diet and lifestyle stabilization period and washout
period followed by a 2-week TG qualifying period.
[0151] The screening visit (Visit 1) occurred for all patients at
either 6 weeks (for patients not on lipid-altering therapy at
screening or for patients who did not need to discontinue their
current lipid-altering therapy) or 8 weeks (for patients who
required washout of their current lipid altering therapy at
screening) before randomization, as follows:
[0152] Patients who did not require a washout: The screening visit
will occur at Visit 1 (Week -6). Eligible patients entered a 4 week
diet and lifestyle stabilization period. At the screening visit,
all patients received counseling regarding the importance of the
National Cholesterol Education Program (NCEP) Therapeutic Lifestyle
Changes (TLC) diet and received instructions on how to follow this
diet. Patients who required a washout: The screening visit occurred
at Visit 1 (Week -8). Eligible patients began a 6 week washout
period at the screening visit. Patients received counseling
regarding the NCEP TLC diet and received instructions on how to
follow this diet. Site personnel contacted patients who did not
qualify for participation based on screening laboratory test
results to instruct them to resume their prior lipid altering
medications.
[0153] At the end of the 4-week diet and lifestyle stabilization
period or the 6-week diet and stabilization and washout period,
eligible patients entered the 2-week TG qualifying period and had
their fasting TG level measured at Visit 2 (Week -2) and Visit 3
(Week -1). Eligible patients must have had an average fasting TG
level .gtoreq.500 mg/dL and .ltoreq.1500 mg/dL (.gtoreq.5.65 mmol/L
and .ltoreq.16.94 mmol/L) to enter the 12 week double blind
treatment period. The TG level for qualification was based on the
average (arithmetic mean) of the Visit 2 (Week -2) and Visit 3
(Week -1) values. If a patient's average TG level from Visit 2 and
Visit 3 fell outside the required range for entry into the study,
an additional sample for fasting TG measurement was collected 1
week later at Visit 3.1. If a third sample was collected at Visit
3.1, entry into the study was based on the average (arithmetic
mean) of the values from Visit 3 and Visit 3.1.
[0154] After confirmation of qualifying fasting TG values, eligible
patients entered a 12-week, randomized, double-blind treatment
period. At Visit 4 (Week 0), patients were randomly assigned to one
of the following treatment groups: [0155] AMR101 2 g daily, [0156]
AMR101 4 g daily, or [0157] Placebo.
[0158] During the double-blind treatment period, patients returned
to the site at Visit 5 (Week 4), Visit 6 (Week 11), and Visit 7
(Week 12) for efficacy and safety evaluations.
[0159] Patients who completed the 12-week double-blind treatment
period were eligible to enter a 40 week, open label, extension
period at Visit 7 (Week 12). All patients received open label
AMR101 4 g daily. From Visit 8 (Week 16) until the end of the
study, changes to the lipid-altering regimen were permitted (e.g.,
initiating or raising the dose of statin or adding non-statin,
lipid-altering medications to the regimen), as guided by standard
practice and prescribing information. After Visit 8 (Week 16),
patients returned to the site every 12 weeks until the last visit
at Visit 11 (Week 52).
[0160] Eligible patients were randomly assigned at Visit 4 (Week 0)
to orally receive AMR101 2 g daily, AMR101 4 g daily, or placebo
for the 12-week double-blind treatment period. AMR101 was provided
in 1 g liquid-filled, oblong, gelatin capsules. The matching
placebo capsule was filled with light liquid paraffin and contained
0 g of AMR101. During the double-blind treatment period, patients
took 2 capsules (AMR101 or matching placebo) in the morning and 2
in the evening for a total of 4 capsules per day. Patients in the
AMR101 2 g/day treatment group received 1 AMR101 1 g capsule and 1
matching placebo capsule in the morning and in the evening.
Patients in the AMR101 4 g/day treatment group received 2 AMR101 1
g capsules in the morning and evening.
[0161] Patients in the placebo group received 2 matching placebo
capsules in the morning and evening. During the extension period,
patients received open-label AMR101 4 g daily. Patients took 2
AMR101 1 g capsules in the morning and 2 in the evening.
[0162] The primary efficacy variable for the double-blind treatment
period was percent change in TG from baseline to Week 12 endpoint.
The secondary efficacy variables for the double-blind treatment
period included the following: [0163] Percent changes in total
cholesterol (TC), high-density lipoprotein cholesterol (HDL-C),
calculated low density lipoprotein cholesterol (LDL-C), calculated
non-high-density lipoprotein cholesterol (non-HDL-C), and very
low-density lipoprotein cholesterol (VLDL-C) from baseline to Week
12 endpoint; [0164] Percent change in very low-density lipoprotein
TG from baseline to Week 12; [0165] Percent changes in
apolipoprotein A-I (apo A-I), apolipoprotein B (apo B), and apo A
I/apo B ratio from baseline to Week 12; [0166] Percent changes in
lipoprotein(a) from baseline to Week 12 (selected sites only);
[0167] Percent changes in LDL particle number and size, measured by
nuclear magnetic resonance, from baseline to Week 12 (selected
sites only); [0168] Percent change in remnant-like particle
cholesterol from baseline to Week 12 (selected sites only); [0169]
Percent change in oxidized LDL from baseline to Week 12 (selected
sites only); [0170] Changes in FPG and HbA1c from baseline to Week
12; [0171] Change in insulin resistance, as assessed by the
homeostasis model index insulin resistance, from baseline to Week
12; [0172] Percent change in lipoprotein associated phospholipase
A2 from baseline to Week 12 (selected sites only); [0173] Change in
intracellular adhesion molecule-1 from baseline to Week 12
(selected sites only); [0174] Change in interleukin-6 from baseline
to Week 12 (selected sites only); [0175] Change in plasminogen
activator inhibitor-1 from baseline to Week 12 (selected sites
only); [0176] Change in hsCRP from baseline to Week 12 (selected
sites only); [0177] Change in serum phospholipid EPA content from
baseline to Week 12; [0178] Change in red blood cell membrane EPA
content from baseline to Week 12; and [0179] Change in serum
phospholipid and red blood cell membrane content in the following
fatty acids from baseline to Week 12: docosapentaenoic acid,
docosahexaenoic acid, arachidonic acid, palmitic acid, stearic
acid, and oleic acid.
[0180] The efficacy variable for the open-label extension period
was percent change in fasting TG from extension baseline to end of
treatment. Safety assessments included adverse events, clinical
laboratory measurements (chemistry, hematology, and urinalysis),
12-lead electrocardiograms (ECGs), vital signs, and physical
examinations
[0181] For TG, TC, HDL-C, calculated LDL-C, calculated non-HDL-C,
and VLDL-C, baseline was defined as the average of Visit 4 (Week 0)
and the preceding lipid qualifying visit (either Visit 3 [Week -1]
or if it occurs, Visit 3.1) measurements. Baseline for all other
efficacy parameters was the Visit 4 (Week 0) measurement.
[0182] For TC, HDL-C, calculated LDL-C, calculated non-HDL-C, and
VLDL-C, Week 12 endpoint was defined as the average of Visit 6
(Week 11) and Visit 7 (Week 12) measurements. Week 12 endpoint for
all other efficacy parameters was the Visit 7 (Week 12)
measurement.
[0183] The primary efficacy analysis was performed using a 2-way
analysis of covariance (ANCOVA) model with treatment as a factor
and baseline TG value as a covariate. The least squares mean,
standard error, and 2-tailed 95% confidence interval for each
treatment group and for each comparison was estimated. The same
2-way ANCOVA model was used for the analysis of secondary efficacy
variables.
[0184] The primary analysis was repeated for the per-protocol
population to confirm the robustness of the results for the
intent-to-treat population.
[0185] The primary efficacy variable was the percent change in
fasting TG levels from baseline to Week 12. A sample size of 69
completed patients per treatment group was expected to provide
.gtoreq.90% power to detect a difference of 30% between AMR101 and
placebo in percent change from baseline in fasting TG levels,
assuming a standard deviation of 45% in TG measurements and a
significance level of p<0.01. To accommodate a 15% drop-out rate
from randomization to completion of the double-blind treatment
period, a total of 240 randomized patients was planned (80 patients
per treatment group).
Example 2
[0186] A multi-center, placebo-controlled, randomized,
double-blind, 12-week study was performed to evaluate the efficacy
and safety of >96% E-EPA in patients with fasting triglyceride
levels .gtoreq.200 mg/dl and <500 mg/dl despite statin therapy
(the mean of two qualifying entry values needed to be .gtoreq.185
mg/dl and at least one of the values needed to be .gtoreq.200
mg/dl). The primary objective of the study was to determine the
efficacy of >96% E-EPA 2 g daily and 4 g daily, compared to
placebo, in lowering fasting TG levels in patients with high risk
for cardiovascular disease and with fasting TG levels
.quadrature.200 mg/dl and <500 mg/dl, despite treatment to LDL-C
goal on statin therapy.
[0187] The secondary objectives of this study were the following:
[0188] To determine the safety and tolerability of >96% E-EPA 2
g daily and 4 g daily; [0189] To determine the effect of >96%
E-EPA on lipid and apolipoprotein profiles including total
cholesterol (TC), non-high-density lipoprotein cholesterol
(non-HDL-C), low density lipoprotein cholesterol (LDL-C), high
density lipoprotein cholesterol (HDL-C), and very high density
lipoprotein cholesterol (VHDL-C); [0190] To determine the effect of
>96% E-EPA on lipoprotein associated phospholipase A2 (Lp-PLA2)
from baseline to week 12; [0191] To determine the effect of >96%
E-EPA on low-density lipoprotein (LDL) particle number and size;
[0192] To determine the effect of >96% E-EPA on oxidized LDL;
[0193] To determine the effect of >96% E-EPA on fasting plasma
glucose (FPG) and hemoglobin A1c (HbA1c); [0194] To determine the
effect of >96% E-EPA on insulin resistance; [0195] To determine
the effect of >96% E-EPA on high-sensitivity C-reactive protein
(hsCRP); [0196] To determine the effects of >96% E-EPA 2 g daily
and 4 g daily on the incorporation of fatty acids into red blood
cell membranes and into plasma phospholipids; [0197] To explore the
relationship between baseline fasting TG levels and the reduction
in fasting TG levels; and [0198] To explore the relationship
between changes of fatty acid concentrations in plasma and red
blood cell membranes, and the reduction in fasting TG levels.
[0199] The population for this study was men and women >18 years
of age with a body mass index .ltoreq.45 kg/m2 with fasting TG
levels greater than or equal to 200 mg/dl and less than 500 mg/dl
and on a stable does of statin therapy (with or without ezetimibe).
The statin was atorvostatin, rosuvastatin or simvastatin. The dose
of statin must have been stable for weeks prior to the LDL-C/TG
baseline qualifying measurement for randomization. The statin dose
was optimized such that the patients are at their LDL-C goal at the
LDL-C/TG baseline qualifying measurements. The same statin at the
same dose was continued until the study ended.
[0200] Patients taking any additional non-statin, lipid-altering
medications (niacin >200 mg/day, fibrates, fish oil, other
products containing omega 3 fatty acids, or other herbal products
or dietary supplements with potential lipid altering effects),
either alone or in combination with statin therapy (with or without
ezetimibe), must have been able to safely discontinue non-statin,
lipid altering therapy at screening.
[0201] Patients at high risk for CVD, i.e., patients with clinical
coronary heart disease (CHD) or clinical CHD risk equivalents
(10-year risk >20%) as defined in the National Cholesterol
Education Program (NCEP) Adult Treatment Panel III (ATP III)
Guidelines were eligible to participate in this study. Those
included patients with any of the following criteria: (1) Known
CVD, either clinical coronary heart disease (CHD), symptomatic
carotid artery disease (CAD), peripheral artery disease (PAD) or
abdominal aortic aneurism; or (2) Diabetes Mellitus (Type 1 or
2).
[0202] Approximately 702 patients were randomized at approximately
80 centers in the U.S. The study was a 18- to 20-week, Phase 3,
multi-center study consisting of 2 study periods: (1) A 6- to
8-week screening period that included a diet and lifestyle
stabilization, a non-statin lipid-altering treatment washout, and
an LDL-C and TG qualifying period and (2) A 12-week, double-blind,
randomized, placebo controlled treatment period.
[0203] During the screening period and double-blind treatment
period, all visits were within .+-.3 days of the scheduled time.
All patients continued to take the statin product (with or without
ezetimibe) at the same dose they were taking at screening
throughout their participation in the study.
[0204] The 6- to 8-week screening period included a diet and
lifestyle stabilization, a non-statin lipid-altering treatment
washout, and an LDL-C and TG qualifying period. The screening visit
(Visit 1) occurred for all patients at either 6 weeks (for patients
on stable statin therapy [with or without ezetimibe] at screening)
or 8 weeks (for patients who will require washout of their current
non-statin lipid altering therapy at screening) before
randomization, as follows: [0205] Patients who did not require a
washout: The screening visit occurred at Visit 1 (Week -6).
Eligible patients entered a 4 week diet and lifestyle stabilization
period. At the screening visit, all patients received counseling
regarding the importance of the National Cholesterol Education
Program (NCEP) Therapeutic Lifestyle Changes (TLC) diet and
received basic instructions on how to follow this diet. [0206]
Patients who required a washout: The screening visit occurred at
Visit 1 (Week -8). Eligible patients began a 6 week washout period
at the screening visit (i.e. 6 weeks washout before the first
LDL-C/TG qualifying visit). Patients received counseling regarding
the NCEP TLC diet and received basic instructions on how to follow
this diet. Site personnel contacted patients who did not qualify
for participation based on screening laboratory test results to
instruct them to resume their prior lipid altering medications.
[0207] At the end of the 4-week diet and lifestyle stabilization
period or the 6-week diet and stabilization and washout period,
eligible patients entered the 2-week LDL-C and TG qualifying period
and had their fasting LDL-C and TG levels measured at Visit 2 (Week
-2) and Visit 3 (Week -1). Eligible patients must have had an
average fasting LDL-C level .gtoreq.40 mg/dL and <100 mg/dL and
an average fasting TG level .gtoreq.200 mg/dL and <500 mg/dL to
enter the 12 week double blind treatment period. The LDL-C and TG
levels for qualification were based on the average (arithmetic
mean) of the Visit 2 (Week -2) and Visit 3 (Week -1) values. If a
patient's average LDL-C and/or TG levels from Visit 2 and Visit 3
fell outside the required range for entry into the study, an
additional fasting lipid profile was collected 1 week later at
Visit 3.1. If a third sample was collected at Visit 3.1, entry into
the study was based on the average (arithmetic mean) of the values
from Visit 3 and Visit 3.1.
[0208] After confirmation of qualifying fasting LDL-C and TG
values, eligible patients entered a 12-week, randomized,
double-blind treatment period. At Visit 4 (Week 0), patients were
randomly assigned to 1 of the following treatment groups: [0209]
>96% E-EPA 2 g daily, [0210] >96% E-EPA 4 g daily, or [0211]
Placebo.
[0212] 226 to 234 patients per treatment group were randomized in
this study. Stratification was by type of statin (atorvastatin,
rosuvastatin or simvastatin), the presence of diabetes, and
gender.
[0213] During the double-blind treatment period, patients returned
to the site at Visit 5 (Week 4), Visit 6 (Week 11), and Visit 7
(Week 12) for efficacy and safety evaluations.
[0214] Eligible patients were randomly assigned at Visit 4 (Week 0)
to receive orally >96% E-EPA 2 g daily, >96% E-EPA 4 g daily,
or placebo.
[0215] >96% E-EPA was provided in 1 g liquid-filled, oblong,
gelatin capsules. The matching placebo capsule was filled with
light liquid paraffin and contained 0 g of >96% E-EPA. >96%
E-EPA capsules were to be taken with food (i.e. with or at the end
of a meal).
[0216] During the double-blind treatment period, patients were to
take 2 capsules (>96% E-EPA or matching placebo) in the morning
and 2 capsules in the evening for a total of 4 capsules per day.
[0217] Patients in the >96% E-EPA 2 g/day treatment group
received 1 >96% E-EPA 1 g capsule and 1 matching placebo capsule
in the morning and in the evening. [0218] Patients in the >96%
E-EPA 4 g/day treatment group received 2 >96% E-EPA 1 g capsules
in the morning and evening. [0219] Patients in the placebo group
received 2 matching placebo capsules in the morning and
evening.
[0220] The primary efficacy variable for the double-blind treatment
period was percent change in TG from baseline to Week 12 endpoint.
The secondary efficacy variables for the double-blind treatment
period included the following: [0221] Percent changes in total
cholesterol (TC), high-density lipoprotein cholesterol (HDL-C),
LDL-C, calculated non-HDL-C, and very low-density lipoprotein
cholesterol (VLDL-C) from baseline to Week 12 endpoint; [0222]
Percent change in very low-density lipoprotein TG from baseline to
Week 12; [0223] Percent changes in apolipoprotein A-I (apo A-I),
apolipoprotein B (apo B), and apo A I/apo B ratio from baseline to
Week 12; [0224] Percent changes in lipoprotein(a) from baseline to
Week 12; [0225] Percent changes in LDL particle number and size,
measured by nuclear magnetic resonance, from baseline to Week 12;
[0226] Percent change in remnant-like particle cholesterol from
baseline to Week 12; [0227] Percent change in oxidized LDL from
baseline to Week 12; [0228] Changes in FPG and HbA1c from baseline
to Week 12; [0229] Change in insulin resistance, as assessed by the
homeostasis model index insulin resistance, from baseline to Week
12; [0230] Percent change in lipoprotein associated phospholipase
A2 (Lp-PLA2) from baseline to Week 12; [0231] Change in
intracellular adhesion molecule-1 from baseline to Week 12; [0232]
Change in interleukin-2 from baseline to Week 12; [0233] Change in
plasminogen activator inhibitor-1 from baseline to Week 12. Note:
this parameter will only be collected at sites with proper storage
conditions; [0234] Change in hsCRP from baseline to Week 12; and
[0235] Change in plasma concentration and red blood cell membrane
content of fatty acid from baseline to Week 12 including EPA,
docosapentaenoic acid (DPA), docosahexaenoic acid (DHA),
arachidonic acid (AA), dihomo-.gamma.-linolenic acid (DGLA), the
ratio of EPA/AA, ratio of oleic acid/stearic acid (OA/SA), and the
ratio of total omega-3 acids over total omega-6 acids.
[0236] Safety assessments included adverse events, clinical
laboratory measurements (chemistry, hematology, and urinalysis),
12-lead electrocardiograms (ECGs), vital signs, and physical
examinations.
[0237] For TG, TC, HDL-C, LDL-C, calculated non-HDL-C, and VLDL-C,
baseline was defined as the average of Visit 4 (Week 0) and the
preceding lipid qualifying visit (either Visit 3 [Week -1] or if it
occurs, Visit 3.1) measurements. Baseline for all other efficacy
parameters was the Visit 4 (Week 0) measurement.
[0238] For TG, TC, HDL-C, LDL-C, calculated non-HDL-C, and VLDL-C,
Week 12 endpoint was defined as the average of Visit 6 (Week 11)
and Visit 7 (Week 12) measurements.
[0239] Week 12 endpoint for all other efficacy parameters were the
Visit 7 (Week 12) measurement.
[0240] The primary efficacy analysis was performed using a 2-way
analysis of covariance (ANCOVA) model with treatment as a factor
and baseline TG value as a covariate. The least squares mean,
standard error, and 2-tailed 95% confidence interval for each
treatment group and for each comparison were estimated. The same
2-way ANCOVA model was used for the analysis of secondary efficacy
variables.
[0241] The primary analysis was repeated for the per-protocol
population to confirm the robustness of the results for the
intent-to-treat population.
[0242] Non-inferiority tests for percent change from baseline in
LDL-C were performed between >96% E-EPA doses and placebo using
a non-inferiority margin of 6% and a significant level at 0.05.
[0243] For the following key secondary efficacy parameters,
treatment groups were compared using Dunnett's test to control the
Type 1 error rate: TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, Lp-PLA2,
and apo B. For the remaining secondary efficacy parameters,
Dunnett's test was be used and the ANCOVA output were considered
descriptive.
[0244] The evaluation of safety was based primarily on the
frequency of adverse events, clinical laboratory assessments, vital
signs, and 12-lead ECGs. The primary efficacy variable is the
percent change in fasting TG levels from baseline to Week 12. A
sample size of 194 completed patients per treatment group provided
90.6% power to detect a difference of 15% between >96% E-EPA and
placebo in percent change from baseline in fasting TG levels,
assuming a standard deviation of 45% in TG measurements and a
significance level of p<0.05.
[0245] Previous data on fasting LDL-C show a difference in percent
change from baseline of 2.2%, with a standard deviation of 15%,
between study drug and placebo. A sample size of 194 completed
patients per treatment group provided 80% power to demonstrate non
inferiority (p<0.05, one-sided) of the LDL-C response between
>96% E-EPA 4 g daily and placebo, within a 6% margin. To
accommodate a 10% drop-out rate from randomization to completion of
the double-blind treatment period, a total of 648 randomized
patients was planned (216 patients per treatment group); 702
subjects were randomized, as further described below.
RESULTS
[0246] Of the 702 randomized subjects, 687 were in the
intent-to-treat ("ITT") population as follows: [0247] Ultra-pure
EPA, 4 g/day: 226 subjects [0248] Ultra-pure EPA, 2 g/day: 234
subjects [0249] Placebo: 227 subjects
[0250] Lipids were extracted from plasma and red blood cell ("RBC")
suspensions and converted into fatty acid methyl esters for
analysis using a standard validated gas chromatography/flame
ionization detection method. Fatty acid parameters were compared
between EPA treatment groups and placebo using an ANCOVA model with
treatment, gender, type of statin therapy, and presence of diabetes
as factors, and the baseline parameter value as a covariate. LSMs,
SEs, and 2-tailed 95% confidence intervals for each treatment group
and for each comparison were determined.
[0251] Baseline characteristics of the three ITT groups were
comparable, with 61.4% of the ITT subjects being male, 96.3% being
white, having a mean age of 61.4 years, a weight of 95.7 kg and a
BMI of 32.9 kg/m.sup.2. ITT subjects with incomplete fatty acid
data at baseline and/or at 12 weeks were excluded from the analyses
described below.
[0252] From the foregoing, it will be appreciated that specific
embodiments of the invention have been described herein for
purposes of illustration, but that various modifications may be
made without deviating from the scope of the invention.
Accordingly, the invention is not limited except as by the appended
claims.
* * * * *