U.S. patent application number 16/672112 was filed with the patent office on 2020-02-27 for methods for the treatment of erectile dysfunction using fispemifene.
The applicant listed for this patent is Quatrx Pharmaceuticals. Invention is credited to Alexander Bridges, Stuart Dombey, Rochelle Hanley, Risto Lammintausta, Robert L. Zerbe.
Application Number | 20200060991 16/672112 |
Document ID | / |
Family ID | 40070738 |
Filed Date | 2020-02-27 |
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United States Patent
Application |
20200060991 |
Kind Code |
A1 |
Zerbe; Robert L. ; et
al. |
February 27, 2020 |
METHODS FOR THE TREATMENT OF ERECTILE DYSFUNCTION USING
FISPEMIFENE
Abstract
A method of treatment of erectile dysfunction (ED) comprises the
step of administering fispemifene to a subject in need thereof in
an amount effective to raise the subject's testosterone level.
Fispemifene may be used in combination with a PDE-5 inhibitor in
individuals who have failed to respond sufficiently to conventional
ED treatment. Methods are also disclosed of treating ED by
administering clomifene, enclomifene, ospemifene, toremifene and
mixtures thereof in combination with a PDE-5 inhibitor.
Inventors: |
Zerbe; Robert L.; (Ann
Arbor, MI) ; Bridges; Alexander; (Saline, MI)
; Lammintausta; Risto; (Turku, FI) ; Hanley;
Rochelle; (Ann Arbor, MI) ; Dombey; Stuart;
(Ann Arbor, MI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Quatrx Pharmaceuticals |
Ann Arbor |
MI |
US |
|
|
Family ID: |
40070738 |
Appl. No.: |
16/672112 |
Filed: |
November 1, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13848325 |
Mar 21, 2013 |
10500166 |
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16672112 |
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12795986 |
Jun 8, 2010 |
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13848325 |
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12138560 |
Jun 13, 2008 |
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12795986 |
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60943706 |
Jun 13, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 15/00 20180101;
A61K 31/4985 20130101; A61K 31/53 20130101; A61K 31/519 20130101;
A61K 9/00 20130101; A61P 15/10 20180101; A61K 31/075 20130101; A61K
31/135 20130101; A61K 31/085 20130101; A61K 31/496 20130101 |
International
Class: |
A61K 31/085 20060101
A61K031/085; A61K 31/4985 20060101 A61K031/4985; A61K 31/519
20060101 A61K031/519; A61K 31/53 20060101 A61K031/53; A61K 31/496
20060101 A61K031/496; A61K 9/00 20060101 A61K009/00; A61K 31/135
20060101 A61K031/135; A61K 31/075 20060101 A61K031/075 |
Claims
1. A method of raising testosterone, luteinizing hormone, and
follicle-stimulating hormone in a subject suffering from erectile
dysfunction and secondary hypogonadism comprising administering an
amount of fispemifene sufficient to raise levels of testosterone,
luteinizing hormone, and follicle-stimulating hormone.
2. The method of claim 1 wherein the amount of fispemifene is
effective to treat the erectile dysfunction.
3. The method of claim 1 further comprising administering a
therapeutically effective amount of a PDE-5 inhibitor to treat the
erectile dysfunction.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
application Ser. No. 13/848,325, filed Mar. 21, 2013, which is a
continuation of U.S. patent application Ser. No. 12/795,986, filed
Jun. 8, 2010, which is a continuation of U.S. patent application
Ser. No. 12/138,560, filed Jun. 13, 2008, which claims the benefit
of U.S. Provisional Application No. 60/943,706, filed Jun. 13,
2007. The disclosures of the priority applications are incorporated
by reference herein in their entirety.
FIELD OF THE INVENTION
[0002] The invention relates to a method for treatment of erectile
dysfunction ("ED") using fispemifene, including: the use of
fispemifene as a primary treatment for ED in individuals with low
testosterone; the use of fispemifene in combination with another ED
drug (such as type V phosphodiesterase ("PDE-5") inhibitors) as
combination therapy; and the use of fispemifene for the treatment
of ED in individuals who have failed treatment with a PDE-5
inhibitor. The invention also relates to the use of selective
estrogen receptor modulators (SERMs) including, but not limited to,
fispemifene, clomifene, enclomifene, ospemifene, toremifene,
afimoxifene, arzoxifene, bazedoxifene, lasofoxifene, ormeloxifene,
raloxifene, tamoxifen, droloxifene, levormeloxifene, and idoxifene
and mixtures thereof in combination with a PDE-5 inhibitor to treat
ED.
BACKGROUND OF THE INVENTION
[0003] Erectile dysfunction, defined as the persistent inability to
maintain an erection sufficient for satisfactory sexual
performance, affects millions of men worldwide. The conventional
treatment for ED is administration of a PDE-5 inhibitor, such as
sildenafil, vardenafil or tadalafil. However, a significant
percentage of subjects receiving PDE-5 inhibitors do not respond
adequately. Approximately 30% to 50% of men receiving sildenafil,
for example, do not adequately respond to therapy, such that other
therapeutic options for the treatment of ED are desirable.
[0004] The reasons that some subjects do not respond to treatment
with PDE-5 inhibitors are not completely known. Clearly,
testosterone plays a role in ED and may impact a subject's response
to conventional ED treatment. Studies conducted in which
testosterone is co-administered to ED subjects in combination with
a PDE-5 inhibitor suggest that raising the testosterone level in
certain individuals may improve their response to conventional ED
treatment. However, testosterone treatment is associated with
undesirable side effects, including prostate stimulation,
gynecomastia, and adverse effects on lipid metabolism.
[0005] Thus, it further would be desirable to provide a medicine
that can be coadministered with a PDE-5 inhibitor, having the
effect of raising testosterone levels and improving response to ED
treatment, with fewer of the deleterious side effects of exogenous
testosterone treatment.
[0006] Men with chronic obstructive pulmonary disorder (COPD),
HIV-infected men, and men with metabolic syndrome experience muscle
wasting and low testosterone. In one study, low testosterone was
observed in subjects with diabetes mellitus who failed conventional
ED treatment, and some improvement was noted when the subjects were
treated with testosterone together with VIAGRA.RTM. (sildenafil
citrate). Muscle wasting in RN-infected men having low testosterone
was ameliorated with a combined regimen of testosterone and
exercise. Thus, it further would be desirable to develop ED
treatments for these individuals, which at the same time would
address the concomitant problems of muscle wasting and ED.
[0007] As disclosed in U.S. Published Patent Application No.
2006/0293294, which is incorporated herein by reference, selective
estrogen receptor modulators (SERMs) have been suggested as a
treatment for androgen deficiency in males.
[0008] It is believed that fispemifene, which is a SERM that acts
as an estrogen antagonist, as a result of its unique properties and
mechanism of action, holds special attractiveness as a treatment
for ED, alone or in combination with other therapies. Fispemifene,
which is the generic name for
(Z)-2-{2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}
ethanol, is a selective estrogen receptor modulator having both
estrogen-like and antiestrogenic properties. Fispemifene has been
shown clinically to increase serum testosterone levels in males, as
described in the aforesaid U.S. Published Patent Application No.
2006/0293294, and is the most preferred agent for use in
combination with a PDE-5 inhibitor, as disclosed herein.
[0009] It is believed that fispemifene acts as an antiestrogen at
the level of the hypothalamic-pituitary axis, diminishing the
negative feedback of estrogen, which results in the enhanced
production of luteinizing hormone (LH) resulting in a subsequent
increase in testosterone levels.
[0010] Based on the foregoing, fispemifene is herein proposed as a
treatment for ED, alone or as adjuvant therapy with other
medications. Fispemifene may be especially useful in the treatment
of erectile dysfunction in men having low testosterone, as a result
of age or disease condition.
[0011] Ospemifene
(2-(4-((Z-4-chloro-1,2-diphenylbut-1-enyl)phenoxy) ethanol)) is a
SERM which may be administered in combination with conventional ED
treatment according to the present invention. Suitable forms and
dosage amounts of ospemifene are disclosed in U.S. Pat. No.
5,750,576, which is incorporated herein by reference.
[0012] Clomifene
(N-[2-[4-(2-chloro-1,2-diphenyl-ethenyl)phenoxy]ethyl]-Nethyl-ethanamine)
(mixture of cis- and trans-isomers) and enclomifene
(transclomifene, or a mixture in which trans-clomifene
predominates), have been proposed as agents for increasing
testosterone levels. U.S. Published Patent Application No.
2004/0097597, which is incorporated by reference, proposes a dosage
of trans-clomifene of about 1 to about 200 mg to increase serum
testosterone, and the connection between low testosterone level and
erectile dysfunction is noted, although treatment of ED per se,
alone or in combination with a PDE-5 inhibitor, is not disclosed in
that application.
[0013] Based on the foregoing, clomifene or enclomifene are also
proposed as a combination therapy with a PDE-5 inhibitor for
treatment of ED.
SUMMARY OF THE INVENTION
[0014] In one aspect, the invention is a method of treating
erectile dysfunction by administering an effective amount of
fispemifene to a subject in need thereof. Fispemifene is
administered to raise the testosterone level of these subjects to
improve erectile functioning.
[0015] In another aspect, the invention involves administering
fispemifene, toremifene, clomifene, enclomifene, ospemifene or a
mixture thereof, in an amount effective to increase serum
testosterone to an individual undergoing ED treatment who is
determined to have low testosterone. In certain embodiments, the
invention relates to administering one or more selective estrogen
receptor modulators (SERMs) including, but not limited to,
fispemifene, clomifene, enclomifene, ospemifene, toremifene,
afimoxifene, arzoxifene, bazedoxifene, lasofoxifene, ormeloxifene,
raloxifene, tamoxifen, droloxifene, levormeloxifene, and idoxifene
and mixtures thereof, in an amount effective to increase serum
testosterone to an individual undergoing ED treatment who is
determined to have low testosterone.
[0016] The individual may have low testosterone as a result of
advanced age or as a result of a disease condition, for example. In
another aspect, the invention is a method a treatment of ED
comprising administering fispemifene, toremifene, clomifene,
enclomifene, ospemifene or a mixture thereof, to an individual in
need thereof, in combination with a PDE-5 inhibitor. This may be an
individual who has been determined to be insufficiently responsive
to treatment with a PDE-5 inhibitor alone. In certain embodiments,
the invention also relates to methods for treating ED comprising
administering one or more selective estrogen receptor modulators
(SERMs) including, but not limited to, fispemifene, clomifene,
enclomifene, ospemifene, toremifene, afimoxifene, arzoxifene,
bazedoxifene, lasofoxifene, ormeloxifene, raloxifene, tamoxifen,
droloxifene, levormeloxifene, and idoxifene and mixtures thereof to
an individual in need thereof, in combination with a PDE-5
inhibitor.
[0017] In still another aspect, the invention is a method of
treating erectile dysfunction in an individual having low
testosterone and who is suffering from chronic obstructive
pulmonary disease, HIV infection, or metabolic syndrome, by
administering an effective amount of fispemifene, clomifene,
enclomifene, ospemifene or toremifene to said individual. In
certain embodiments, the invention relates to methods for treating
ED in an individual having low testosterone and who is suffering
from chronic obstructive pulmonary disease, HIV infection, or
metabolic syndrome, by administering an effective amount of one or
more selective estrogen receptor modulators (SERMs) including, but
not limited to, fispemifene, clomifene, enclomifene, ospemifene,
toremifene, afimoxifene, arzoxifene, bazedoxifene, lasofoxifene,
ormeloxifene, raloxifene, tamoxifen, droloxifene, levormeloxifene,
and idoxifene and mixtures thereof, to said individual.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 depicts a graph of the data of the study from Example
1 showing the serum total testosterone (ng/dL) over time for each
of the treatment groups (placebo or fispemifene 10 mg, 30 mg, 100
mg, or 300 mg/day). The bottom line on the graph is the 30 mg/day
dose denoted in triangular symbols, the top line on the graph is
the 300 mg/day dose denoted in square symbols, the curve second
from the top is the 10 mg/day dose denoted in circular symbols. The
symbol legend for each dose on the right hand margin of the graph
is across from the corresponding dose value on Day 28 on the
graph;
[0019] FIG. 1 depicts a graph of the data of the study from Example
1 showing the serum total testosterone (ng/dL) over time for each
of the treatment groups (placebo or fispemifene 10 mg, 30 mg, 100
mg, or 300 mg/day). The bottom line on the graph is the 30 mg/day
dose denoted in triangular symbols, the top line on the graph is
the 300 mg/day dose denoted in square symbols, the curve second
from the top is the 10 mg/day dose denoted in circular symbols. The
symbol legend for each dose on the right hand margin of the graph
is across from the corresponding dose value on Day 28 on the
graph;
[0020] FIG. 3 depicts a graph of the data of the study from Example
3 showing the calculated mean percent change in serum total
testosterone at 4 weeks for each of the treatment groups;
[0021] FIG. 4 depicts a graph of the data of the study from Example
3 showing the serum total testosterone versus time for each of the
treatment groups. The bars from left to right for each of the BL
(baseline), 2 week, 4 week, and 6 week timepoints (the 6 week
timepoint occurred 2 weeks after the discontinuation of study drug
at week 4) correspond to the placebo, 100 mg, 200 mg, and 300
mg/day doses, respectively;
[0022] FIG. 5 depicts a graph of the data of the study from Example
3 showing serum total testosterone (ng/dL) versus dose at BL and
after 4 weeks of dosing for each of the treatment groups. The bars
from left to right for each of placebo, 100 mg, 200 mg, and 300
mg/day doses are the BL (baseline) and 4 week time points,
respectively;
[0023] FIG. 6 depicts a graph of the data of the study from Example
3 showing serum free testosterone levels (ng/dL) measured by
equilibrium dialysis over time for each of the treatment groups.
The bars from left to right for each of the BL (baseline), 2 week,
4 week, and 6 week timepoints (the 6 week timepoint occurred 2
weeks after the discontinuation of study drug at week 4) correspond
to the placebo, 100 mg, 200 mg, and 300 mg/day doses,
respectively;
[0024] FIG. 7 depicts a graph of the data of the study from Example
3 showing the calculated serum free testosterone level (ng/dL) over
time for each of the treatment groups. The bars from left to right
for each of the BL (baseline), 2 week, 4 week, and 6 week
timepoints (the 6 week timepoint occurred 2 weeks after the
discontinuation of study drug at week 4) correspond to the placebo,
100 mg, 200 mg, and 300 mg/day doses, respectively;
[0025] FIG. 8 depicts a graph of the data of the study from Example
3 showing the serum DHT (dihydrotestosterone) (pg/mL) levels over
time for each of the treatment groups. The bars from left to right
for each of the BL (baseline), 2 week, 4 week, and 6 week
timepoints (the 6 week timepoint occurred 2 weeks after the
discontinuation of study drug at week 4) correspond to the placebo,
100 mg, 200 mg, and 300 mg/day doses, respectively.
[0026] FIG. 9 depicts a graph of the data of the study from Example
3 showing the serum LH (luteinizing hormone) level (IU/L) over time
for each of the treatment groups. The bars from left to right for
each of the BL (baseline), 2 week, 4 week, and 6 week timepoints
(the 6 week timepoint occurred 2 weeks after the discontinuation of
study drug at week 4) correspond to the placebo, 100 mg, 200 mg,
and 300 mg/day doses, respectively;
[0027] FIG. 10 depicts a graph of the data of the study from
Example 3 showing the serum FSH (follicle stimulating hormone)
level (IU/L) over time for each of the treatment groups. The bars
from left to right for each of the BL (baseline), 2 week, 4 week,
and 6 week timepoints (the 6 week timepoint occurred 2 weeks after
the discontinuation of study drug at week 4) correspond to the
placebo, 100 mg, 200 mg, and 300 mg/day doses, respectively;
[0028] FIG. 11 depicts a graph of the data of the study from
Example 3 showing the serum sex hormone-binding globulin level
(nmol/L) over time for each of the treatment groups. The bars from
left to right for each of the BL (baseline), 2 week, 4 week, and 6
week timepoints (the 6 week timepoint occurred 2 weeks after the
discontinuation of study drug at week 4) correspond to placebo, 100
mg, 200 mg, and 300 mg doses, respectively; and
[0029] FIG. 12 depicts a graph of the data of the study from
Example 3 showing the serum estradiol levels (pg/mL) over time for
each of the treatment groups. The bars from left to right for each
of the BL (baseline), 2 week, 4 week, and 6 week timepoints (the 6
week timepoint occurred 2 weeks after the discontinuation of study
drug at week 4) correspond to the placebo, 100 mg, 200 mg, and 300
mg/day doses, respectively.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The androgens, of which testosterone is the principal agent,
are male sex hormones, responsible for the development of the
masculine sex characteristics. Defects in cavernosal tissue arising
from testosterone deficiency can impair erectile capacity.
[0031] A shortage of testosterone (hypogonadism) may be classified
into two principal forms, which are designated primary and
secondary hypogonadism. Primary hypogonadism is the lack of
testosterone production or a decreased testosterone production
within the body originating from a malfunction of the testes, which
are the main synthetic location for testosterone. Primary
hypogonadism includes testicular failure due to congenital or
acquired anorchia, XYY Syndrome, XX males, Noonan Syndrome, gonadal
dysgenesis, Leydig cell tumors, maldescended testes, varicocele,
Sertoli-Cell-Only Syndrome, cryptorchidism, bilateral torsion,
vanishing testis syndrome, orchiectomy, Klinefelter Syndrome,
chemotherapy, toxic damage from alcohol or heavy metals, and
general disease (renal failure, liver cirrhosis, diabetes, myotonia
dystrophica). Patients with primary hypogonadism show an intact
feedback mechanism in that the low serum testosterone
concentrations are associated with high FSH (follicle-stimulating
hormone) and LH (luteinizing hormone) concentrations. However,
because of testicular or other failures, the high LH concentrations
are not effective at stimulating testosterone production.
[0032] Secondary (or hypogonadotrophic) hypogonadism arises where
the main reason for the low testosterone level is a malfunction of
the hypothalamus or the hypophysis. This involves an idiopathic
gonadotropin or LR-releasing hormone deficiency. This type
ofhypogonadism includes Kallman Syndrome, PraderLabhart-Willi
Syndrome, Laurence-Moon-Biedl Syndrome, pituitary
insufficiency/adenomas, Pasqualini Syndrome, hemochromatosis,
hyperprolactinemia, or pituitary-hypothalamic injury from tumors,
trauma, radiation, or obesity. Because patients with secondary
hypogonadism do not demonstrate an intact feedback pathway, the
lower testosterone concentrations are not associated with increased
LH or FSH levels. Thus, these men have low testosterone serum
levels but have gonadotropins in the normal to low range.
[0033] Men experience a slow but continuous decline in average
serum testosterone after approximately age 20 to 30 years
(age-related testosterone deficiency). Researchers estimate that
the decline is about 1-2% per year. Moreover, as men age, the
circadian rhythm of testosterone concentration is often muted,
dampened, or completely lost.
[0034] The normal ranges for testosterone concentration vary as
well as the definition of the limit value to diagnose hypogonadism.
For the purposes herein, unless otherwise stated: if serum total
testosterone levels are >400 ng/dL (i.e., 14 nmol/L), there is
no testosterone deficiency and this is referred to as a "normal
testosterone level;" if total serum testosterone level is <400
ng/dL, the subject may be considered to have a "low testosterone
level." An "effective amount" of an agent in connection with
raising testosterone, is the minimum amount required to achieve an
increase in testosterone level, whether or not testosterone is
raised to a normal level. In some instances, it may be preferable
to define low testosterone as <250 ng/dL or <300 ng/dL.
[0035] Erectile function is commonly evaluated by tabulating
responses provided to the International Index of Erectile Function
("IIEF"). The IIEF is a validated self-administered questionnaire
used to assess therapeutic efficacy of an ED treatment. The IIEF is
composed of five domains: erectile function, libido, orgasmic
function, sexual satisfaction and overall satisfaction. Other
questionnaires may be utilized, including the Sexual Health
Inventory for Men (SHIM), which is an abbreviated form of the IIEF;
and the Sexual Encounter Profile (SEP), which involves questions of
both the subject and the subject's partner. As used herein, a
directional improvement in any component of these criteria is
considered "treatment," and the minimum dosage required to obtain
such improvement is defined herein as an "effective amount." For
example, an important criterion of success of an ED therapy may be
determined to be the frequency of successful intercourse; and an
increase in that frequency, whether or not statistically
significant, may be deemed a successful treatment. Alternatively,
improvement may be measured by changes over various domains of the
IIEF, such as an increase in libido, or in overall satisfaction.
These improvements also constitute examples of "treatment," and the
minimum dosage required to achieve improvement on one or more of
these axes is an "effective amount." The administration of
fispemifene, enclomifene, ospemifene, clomifene or toremifene to
treat ED has particular relevance when administered in combination
with a PDE-5 inhibitor to a subject who continues to have symptoms
of ED despite treatment with a PDE-5 inhibitor. In certain
embodiments, the administration of selective estrogen receptor
modulators (SERMs) including, but not limited to, fispemifene,
clomifene, enclomifene, ospemifene, toremifene, afimoxifene,
arzoxifene, bazedoxifene, lasofoxifene, ormeloxifene, raloxifene,
tamoxifen, droloxifene, levormeloxifene, and idoxifene and mixtures
thereof to treat ED has particular relevance when administered in
combination with a PDE-5 inhibitor to a subject who continues to
have symptoms of ED despite treatment with a PDE-5 inhibitor.
[0036] Clinically, a subject is meaningfully suboptimally
responsive to treatment with a PDE-5 inhibitor when the subject
scores 21 or less (corresponding to a disease severity of
mild-to-moderate or worse) on the IIEF Erectile Function domain
despite PDE-5 inhibitor treatment. In general, a subject is
suboptimally Responsive to PDE-5 inhibitor treatment when the
subject attempts and fails to complete sexual intercourse over the
course of several weeks, notwithstanding treatment with a PDE-5
inhibitor. The administration of fispemifene, enclomifene,
ospemifene, clomifene or toremifene to treat ED has particular
relevance when administered in combination with a PDE-5 inhibitor
to a subject who is unresponsive to treatment with a PDE-5
inhibitor. Clinically, a subject is unresponsive to treatment with
a PDE-5 inhibitor when the subject receives a score of 2 or 3 on
questions 3 and 4 of the IIEF during a screening visit. In general,
a subject is not responsive to PDE-5 inhibitor treatment when the
subject attempts and fails to complete sexual intercourse over the
course of several weeks, notwithstanding treatment with a PDE-5
inhibitor.
[0037] Thus, a method of treating ED according to the invention may
comprise (1) a step of administering a PDE-5 inhibitor to a subject
in need thereof and observing a failure of the subject to respond;
and (2) a step of administering fispemifene, clomifene,
enclomifene, ospemifene, toremifene, or a mixture thereof, in
combination with a PDE-5 inhibitor. A method of the invention may
also comprise (1) a step of administering a PDE-5 inhibitor to a
subject in need thereof and observing a failure of the subject to
respond; and (2) a step of administering one or more selective
estrogen receptor modulators (SERMs) including, but not limited to,
fispemifene, clomifene, enclomifene, ospemifene, toremifene,
afimoxifene, arzoxifene, bazedoxifene, lasofoxifene, ormeloxifene,
raloxifene, tamoxifen, droloxifene, levormeloxifene, and idoxifene
and mixtures thereof in combination with a PDE-5 inhibitor
[0038] The above method of treating ED according to the invention
may further comprise a step of measuring the testosterone level of
the subject, as follows: (1) a step of administering a PDE-5
inhibitor to a subject in need thereof and observing a failure of a
subject to have an adequate response; (2) measuring the serum
testosterone level of the subject to determine that the level is
less than 400 ng/dL, or otherwise determining that the subject has
low androgen levels (such as by measuring free testosterone); and
(3) a step of administering fispemifene, clomifene, enclomifene,
ospemifene, toremifene, or a mixture thereof, in combination with a
PDE-5 inhibitor. These steps may also be performed in a different
order, such as: first diagnosing the subject with erectile
dysfunction and hypogonadism; and then treating with fispemifene,
clomifene, enclomifene, ospemifene, toremifene, or a mixture
thereof and observing that the subject has a suboptimal response;
and finally a step of administering fispemifene, clomifene,
enclomifene, ospemifene, toremifene, or a mixture thereof, in
combination with a PDE-5 inhibitor.
[0039] Fispemifene, enclomifene, ospemifene, clomifene and
toremifene may improve muscle wasting experienced by RN-infected
men experiencing weight loss and low testosterone. Accordingly,
these SERMs may be used in conjunction with other agents in ED
treatment of HIV-infected men.
[0040] Fispemifene, enclomifene, ospemifene, clomifene and
toremifene may be administered in combination with other ED agents
to raise the testosterone levels of subjects with metabolic
syndrome (and the like) and improve their symptoms of ED. In
addition, one or more selective estrogen receptor modulators
(SERMs) including, but not limited to, fispemifene, clomifene,
enclomifene, ospemifene, toremifene, afimoxifene, arzoxifene,
bazedoxifene, lasofoxifene, ormeloxifene, raloxifene, tamoxifen,
droloxifene, levormeloxifene, and idoxifene and mixtures thereof,
may be administered in combination with other ED agents to raise
the testosterone levels of subjects with metabolic syndrome (and
the like) and improve their symptoms of ED.
[0041] PDE-5 inhibitor as used herein includes any agent which
inhibits the type 5 cGMP-specific PDE5 enzyme, including without
limitation, sildenafil, vardenafil and tadalafil, which are
commercially recognized treatment agents for ED, all of which are
typically taken orally. Other PDE-5 inhibitors include those
disclosed in U.S. Pat. No. 6,512,002 B2, incorporated by
reference.
[0042] Fispemifene has been demonstrated to raise testosterone
levels and may be administered alone to treat ED in men. A suitable
dosage is expected to be in a range of about 5 mg/day to about 1500
mg/day. In a phase I repeated dose study, twenty-three healthy men
aged 50 to 70 years received daily 10 mg, 30 mg 100 mg and 300 mg
dosages of fispemifene for 28 days. Fispemifene was well tolerated
at all dose levels. The adverse events reported more than once
included upper respiratory tract infection, nausea and abdominal
pain. All other adverse events were single cases. Fispemifene at
the 100 and 300 mg/day dose levels increased serum total
testosterone levels 32% and 75% respectively. Thus, a preferred
dosage range of fispemifene to treat ED is expected to be 10 to
1000 mg/day.
[0043] As described above, fispemifene, clomifene, enclomifene,
ospemifene or toremifene (all of which are SERMs), or a mixture
thereof, may be administered in combination with a PDE-5 inhibitor
to men who are unresponsive to treatment with PDE-5 inhibitors
alone. In addition, selective estrogen receptor modulators (SERMs)
including, but not limited to, fispemifene, clomifene, enclomifene,
ospemifene, toremifene, afimoxifene, arzoxifene, bazedoxifene,
lasofoxifene, ormeloxifene, raloxifene, tamoxifen, droloxifene,
levormeloxifene, and idoxifene and mixtures thereof, may be
administered in combination with a PDE-5 inhibitor to men who are
unresponsive to treatment with PDE-5 inhibitors alone.
[0044] In this context "administered in combination" means: (1)
part of the same unitary dosage form; (2) administration
separately, but as part of the same therapeutic treatment program
or regimen, typically but not necessarily, on the same day. In a
preferred embodiment, the SERM and PDE-5 inhibitor are administered
in combination as a fixed daily dosage. The combination of
fispemifene (or other SERM) with a PDE-5 inhibitor as a unitary
dosage form is a novel composition according to the invention.
[0045] Alternatively, fispemifene, clomifene or toremifene may be
administered at a fixed daily dosage, and the PDE-5 inhibitors
taken on an as needed basis, in advance of expected sexual
activity, usually not more than once daily.
[0046] When fispemifene is administered as adjuvant therapy with a
PDE-5 inhibitor, a preferred daily dosage is about 10 mg to 1000
mg, more preferably 10 mg to 300 mg.
[0047] When enclomifene is administered as a combination therapy
with a PDE-5 inhibitor, a suitable daily dosage is about 1 to 200
mg. Clomifene is expected to be suitable at a daily dose of up to
100 mg in combination with a PDE-5 inhibitor.
[0048] A suitable daily oral dosage of PDE-5 inhibitor is believed
to be in range of 25 to 100 mg for sildenafil; 5 to 20 mg for
vardenafil; and 2.5 to 20 mg for tadalafil. However, the invention
is not limited to these dosage ranges, and the suitable dosage
amount for these well known and extensively studied compounds is
considered to be within the skill in the art.
[0049] The invention is not limited to particular administration
forms of the active agents described herein. For example, oral
formulations, parenteral injections, transdermal, buccal and rectal
formulations may be used. Oral formulations include, without
limitation, powders, tablets, caplets, and gelatin capsules. Oral
formulations of both the PDE-5 inhibitor (which are commercially
available) and the SERM are preferred. Suitable oral formulations
of fispemifene are described in U.S. Published Application No.
2007/0104743, which is incorporated by reference.
[0050] Reference to the active agents described herein includes
reference to their pharmaceutically acceptable salts. For example,
sildenafil is commercially available as sildenafil citrate.
Reference to any PDE-5 inhibitor herein refers also to salts of the
active agent, as disclosed in U.S. Pat. No. 6,512,002 (incorporated
by reference). Likewise, reference to SERMs includes reference to
their salts, as disclosed in U.S. Pat. Nos. 5,750,576 and
6,576,645, which are incorporated by reference.
[0051] The invention will be illustrated by the following
non-restrictive Experimental Section.
EXPERIMENTAL
Example 1
[0052] Fispemifene has been studied in two phase I studies in
humans--in a single dose and a repeated dose study. Effect of
fispemifene on hormone levels was one main focus of the repeated
dose study. The phase I repeated dose study (number 101-50202) was
a randomized, double-blind, placebo-controlled 28-day
dose-escalation study performed in 31 healthy, elderly men, aged
50-68 years. The main objective of the study was to investigate the
tolerability, safety and pharmacokinetics of fispemifene after
repeated oral doses, but the study focused also on the effects of
fispemifene on serum free and total testosterone, estradiol, and
other relevant hormones. The fispemifene doses 10, 30, 100 and 300
mg per day and placebo were administered once every morning as
capsules containing 10 mg or 100 mg of fispemifene, or placebo. The
dose was escalated to the next higher dose level, if the previous
dose had been safe and well tolerated evaluated by the laboratory
safety determinations and ultrasound of mammary glands.
[0053] The variables for safety and tolerability were adverse
events, vital signs, 12-lead ECG, clinical laboratory evaluations,
physical examination, ultrasound examinations (mammary glands) and
inhibin B. For pharmacokinetics, the concentrations of fispemifene
and its metabolite(s) were to be evaluated. For pharmacodynamics,
serum concentrations of FSH, LH, estradiol, testosterone, SHBG,
prolactin, aldosterone, cortisol and TSH before and during
treatment were measured and compared with the concentrations in the
placebo-group.
[0054] Results on the Effects of Fispemifene on Hormones
[0055] Fispemifene increased the serum concentrations of
testosterone, FSH, LH, and SHBG (Table 1) during the 28 days of
treatment. Testosterone was increased statistically significantly
with 100 mg and 300 mg fispemifene compared with placebo. With the
300 mg dose, the increase in the mean total testosterone was about
75% compared to the baseline concentration. Two out of six men
treated with the highest fispemifene dose had their serum
testosterone level above the upper limit of normal range (i.e., 33
nmol/L) during treatment. The other four had a significant increase
within the reference range. All the six men had normal testosterone
value at baseline. With the 100 mg dose, the increase of the mean
total testosterone was about 32%, and all the six men in the group
had their testosterone level increased within the reference range.
The increase in total testosterone levels in serum is illustrated
by group in FIG. 1. There were no safety concerns raised with any
dose suggesting that even a higher dose could be utilized if deemed
appropriate.
[0056] Serum total testosterone concentrations (mean and SD) and
the other hormones at baseline and during treatment in the
fispemifene study 101-50202 by dose.
TABLE-US-00001 TABLE 1 Serum total testosterone concentrations
(mean and SD) and the other hormones at baseline and during
treatment in the fispemifene study 101-50202 by dose. Fispemifene
Fispemifene Fispemifene Fispenifeme Placebo 10 mg 30 mg 100 mg 300
mg Mean SD Mean SD Mean SD Mean SD Mean SD Testosterone (nmol/L)
Baseline 17.25 4.2 19.33 4.7 15.00 3.5 14.27 4.0 15.67 3.6 Day 8
18.50 4.1 19.83 3.31 4.40 2.1 18.67 5.3 23.17 5.2 Day 15 18.43 4.4
20.50 4.9 15.00 2.7 19.00 6.0 27.00 6.5 Day 22 17.50 8.5 22.00 4.4
15.80 3.9 17.83 4.5 27.83 4.7 Day 28 15.43 3.2 17.40 7.2 14.80 5.3
18.83 4.8 27.50 10.3 FSH (U/L) Baseline 5.60 3.4 5.42 3.6 9.14 13.4
6.30 5.6 6.80 5.4 Day 8 5.65 2.9 5.87 4.2 9.78 14.2 7.68 7.8 8.80
7.6 Day 15 4.67 1.6 5.20 2.9 10.14 14.6 8.10 9.0 8.73 7.2 Day 22
4.47 1.6 6.60 4.1 10.18 15.1 8.20 9.0 8.85 8.1 Day 28 4.29 1.7 5.66
3.7 8.42 11.6 7.73 7.9 7.57 7.0 LH (U/L) Baseline 3.11 1.6 3.47 1.0
3.58 2.0 4.12 1.9 4.58 2.7 Day 8 3.29 0.8 3.12 1.5 4.26 2.2 5.52
4.2 6.80 3.5 Day 15 3.31 0.9 2.87 1.1 5.02 2.4 6.82 7.5 6.75 4.6
Day 22 2.80 0.8 3.56 1.2 4.32 2.3 7.18 8.3 7.77 6.6 Day 28 2.71 0.9
3.02 0.9 4.42 2.0 7.60 9.6 6.70 4.8 Estradiol (pmol/L) Baseline
100.6 31.2 106.2 20.9 97.8 17.9 84.3 22.6 102.5 30.0 Day 8 93.8
17.1 94.7 31.2 105.6 29.8 108.3 28.9 104.0 20.0 Day 15 85.0 31.6
81.7 25.4 102.4 22.2 111.5 48.2 97.8 26.9 Day 22 75.0 32.4 116.6
15.1 99.6 20.4 106.3 37.4 95.5 32.9 Day 28 73.6 32.6 75.0 20.1 87.0
22.2 94.5 48.4 89.7 30.9 SHBG (nmol/L) Baseline 49.1 18.6 47.7 19.9
34.2 12.8 41.7 29.4 50.7 15.1 Day 8 44.5 16.1 46.3 21.1 34.2 12.2
47.7 35.2 64.2 21.3 Day 15 46.0 19.1 48.2 22.8 37.4 20.8 52.0 39.5
66.2 21.1 Day 22 44.9 18.4 50.2 27.1 37.2 19.2 55.7 45.3 65.2 14.8
Day 28 45.0 18.5 45.2 24.3 36.6 19.1 50.8 42.8 58.3 12.3
[0057] Discussion and Conclusions
[0058] Fispemifene induced a clinically and statistically
significant and dose dependent increase in the serum testosterone
concentration in healthy older men within 28 days from the start of
the treatment. Also, within the 28-day treatment period, the
increase in testosterone serum concentration was seen in all the
subjects treated with 100 mg or 300 mg fispemifene. An increase of
75% from baseline can be considered clinically highly significant,
and thus clinical benefits in men with low testosterone can be
expected. The increases also in LH and FSH suggest that fispemifene
has an antiestrogenic effect on hypothalamus/hypophysis, and that
the increase in testosterone occurs due to the increase in the
hypophyseal hormones. The increase in testosterone is moderate and,
therefore, no harmful effects often associated with external
testosterone administration are expected. Furthermore, a SERM is
likely to provide protection against the possible safety problems
of testosterone like development of prostate cancer. Thus, a SERM
increasing testosterone provides an optimal treatment for
hypogonadism, balancing the efficacy and safety of the increased
testosterone.
Example 2
[0059] This is a prophetic example. Subjects would be selected from
men, all over twenty years of age, unresponsive to PDE-5 inhibitor
treatment as demonstrated by responses on the IIEF for a 28 day
lead-in period, having morning total testosterone level less than
or equal to 400 ng/dL. Half of the subjects would be assigned to
the fispemifene treatment group (fispemifene plus sildenafil) and
half will be assigned to the placebo control group (sildenafil
without fispemifene). Subjects would self administer fispemifene
once daily in the morning after breakfast for 8 weeks. Subjects
would take sildenafil 100 mg on an as needed basis when sexual
activity is anticipated.
[0060] The following observations would be expected: increases in
total testosterone levels from baseline to week 4 to week 8;
improvement in IIEF erectile function domain score from baseline to
week 4 to week 8; improvement in other IIEF domain scores from
baseline to week 4 to week 8.
Example 3
[0061] A randomized, double-blind, placebo controlled,
parallel-group study of once-daily doses of fispemifene (100, 200,
and 300 mg/day) given for 4 weeks was conducted in a population of
hypogonadal men. Subjects were required to meet all of the
following inclusion criteria at screening and prior to
randomization to be eligible for the study:
[0062] 1. The subject had signed a written informed consent to
participate in the study and had agreed to follow dosing
instructions and complete all required study visits;
[0063] 2. The subject was a male 2: 40 years of age at the time of
randomization.
[0064] 3. The subject had a screening total testosterone level and
a confirmatory baseline total testosterone level: S350 ng/dL.
Testosterone levels were determined from early morning (0700 h to
0900 h) specimens; and
[0065] 4. The subject had a serum LH level of 1.7-15.0 IU/L and an
FSH level of 1.5-15.0 IU/L at the screening visit.
[0066] Subjects were excluded from the study if they had an
elevated serum prolactin level, if they had evidence of benign
prostatic hypertrophy, or if they were taking medications that
affected the hypothalamic-pituitary-gonadal axis and had not
adequately washed off.
[0067] There were 77 subjects total. The number of subjects
randomized to the 100 mg fispemifene, 200 mg fispemifene, 300 mg
fispemifene, and placebo arms were 21, 21, 19, and 16,
respectively.
[0068] Subjects were randomly assigned to one of four treatment
groups in a 1:1:1:1 ratio: [0069] Treatment A (100 mg): fispemifene
100 mg+placebo+placebo; [0070] Treatment B (200 mg): fispemifene
100 mg+fispemifene 100 mg+placebo; [0071] Treatment C (300 mg):
fispemifene 100 mg+fispemifene 100 mg+fispemifene 100 mg; and
[0072] Treatment D (Placebo): placebo+placebo+placebo.
[0073] Subjects took one dose (three capsules) of study medication
once a day at home for 4 weeks. Capsules were to be taken in the
morning immediately after breakfast, with the exception of the
morning of the Week 4 visit. Capsules were not to be taken on the
morning of the Week 4 visit because trough plasma levels of
fispemifene were determined by a blood sample taken at this visit.
Each subject was randomly assigned to treatment with one of the 3
different dose regimens of fispemifene or placebo vehicle. Each
subject received a 4 week supply of study drug.
[0074] Blood samples were taken from the subjects within 1 week
prior to dosing with study drug to establish baseline values; after
2 and 4 weeks of randomization; and 2 weeks after the last dose of
study drug. Serum was prepared from those samples and used to
determine the mean % change from baseline in total testosterone,
free testosterone, SHBG (sex hormone-binding globulin), DHT
(dihydrotestosterone), E2 (estradiol), LH (luteinizing hormone),
FSH (follicle stimulating hormone), and inhibin B.
[0075] The primary efficacy endpoint was defined as percent change
from baseline in morning total testosterone levels at Week 4. The
intent-to-treat ("ITT") population was the primary population for
analysis. The secondary efficacy endpoints included:
[0076] 1. Percent change from baseline in free testosterone and
calculated free testosterone at Weeks 2, 4, and 6;
[0077] 2. Percent change from baseline in total testosterone levels
at Weeks 2 and 6; and
[0078] 3. Percent change from baseline in SHBG, DHT, E2, LH, FSH,
inhibin B, and testosterone/E2 ratio at Weeks 2, 4, and 6.
[0079] These values are graphed in FIGS. 3-12 and are also shown
below in table format in Tables 2-15 with the standard deviation
from the mean ("S.D.").
[0080] Essentially, fispemifene induced a clinically and
statistically significant and dose dependent increase to, but not
beyond, the normal range in the serum total testosterone
concentration within 14 days from the start of the treatment; and
this increase was maintained during the treatment period. Serum
FSH, LH, and estradiol levels were also increased, confirming the
observations in Example 1 and lending further support to the
proposed mechanism by which fispemifene raises serum testosterone
levels (i.e., that it has antiestrogenic effect on
hypothalamus/hypophysis, leading to an increase in the hypophyseal
hormones, and thus to an increase in testosterone).
[0081] It was also confirmed that the increase in testosterone is
moderate and, therefore, that the drug has a lesser likelihood of
safety problems or abuse than exogenously-administered
testosterone.
TABLE-US-00002 TABLE 2 Primary Efficacy Analysis: Morning Total
Testosterone Levels (ng/dL) for Intent-to-Treat Subjects
Fispemifene Pairwise Comparisons Statistics 100 mg 200 mg 300 mg
Placebo Overall 100 mg vs. 200 mg vs. 300 mg vs. Study Week N 21 21
19 16 P-value Placebo Placebo Placebo Actual Value Mean .+-. SD
248.6 .+-. 68.90 249.1 .+-. 60.90 234.2 .+-. 77.69 218.6 .+-. 79.13
0.531.sup.1 0.228.sup.1 0.258.sup.1 0.461.sup.1 at Baseline Median
266.0 253.0 246.0 227.5 (Visit 2) Min, Max 101.0, 347.0 133.0,
334.0 17.0, 348.0 58.0, 334.0 Actual Value Mean .+-. SD 371.6 .+-.
83.36 387.3 .+-. 107.39 430.7 .+-. 163.39 246.9 .+-. 95.26 NA NA NA
NA at Week 4 Median 353.0 372.0 479.0 265.5 Min, Max 246.0, 535.0
241.0, 626.0 8.0, 643.0 40.0, 397.0 % Change from Mean .+-. SD 0.60
.+-. 0.524 0.60 .+-. 0.390 0.78 .+-. 0.536 0.14 .+-. 0307
<0.001.sup.1 0.010.sup.1 0.002.sup.1 <0.001.sup.1 Baseline
Median 0.35 0.60 0.80 0.14 to Week 4 Min, Max 0.07, 1.98 -014, 127
-0.53, 1.81 -0.31, 0.74 % Change front Baseline is defined as (Week
4 minus Baseline) divided by Baseline. Missing values for ITT
subjects are replaced via LOCF approach. NA = Not Applicable (not
planned). .sup.1P-values for treatment comparisons from
non-parametric approach (Kruskal-Wallis test for overall
comparisons and Wilcoxon test for pairwise comparisons).
TABLE-US-00003 TABLE 3 Descriptive Summary: Free Testosterone
(ng/dL) by Visit for Intent-to-Treat Subjects Fispemifene 100 mg
200 mg 300 mg Placebo Study Week Statistics (N = 21) (N = 21) (N =
19) (N = 16) Baseline (Visit 2) N (%) Reported 21 (100.0%) 21
(100.0%) 19 (100.0%) 16 (100.0%) Mean .+-. SD 8.35 .+-. 2,536 8.48
.+-. 3,043 8.19 .+-. 2,966 7.83 .+-. 3,498 Median 8.40 8.50 8.20
8.35 Min, Max 3.20, 12.29 4.30, 15.90 0.30, 12.30 2.00, 13.20 Week
2 (Visit 4) N (%) Reported 19 (90.5%) 21 (100.0%) 19 (100.0%) 14
(87.5%) Mean .+-. SD 11.6 .+-. 3.93 10.6 .+-. 3.52 12.1 .+-. 4.96
9.86 .+-. 3,710 Median 10.3 10.0 12.9 9.90 Min, Max 5.7, 17.7 4.8,
16.4 0.2, 22.0 3.70, 18.20 Week 4 (Visit 5) N (%) Reported 21
(100.0%) 21 (100.0%) 19 (100.0%) 16 (100.0%) Mean .+-. SD 11.3 .+-.
3.40 11.8 .+-. 3.80 12.5 .+-. 5.00 8.64 .+-. 3,668 Median 10.8 12.2
14.0 8.35 Min, Max 6.4, 18.2 5.2, 19.4 0.1, 21.2 1.80, 14.70 Week 6
(Visit 6) N (%) Reported 21 (100.0%) 21 (100.0%) 19 (100.0%) 16
(100.0%) Mean .+-. SD 893 .+-. 2,300 9.10 .+-. 3,307 9.30 .+-.
3,567 9.36 .+-. 4,339 Median 9.80 8.06 9.80 3.55 Min, Max 4.90,
13.30 5.40, 16.80 0.30, 17.39 1.30, 18.36
TABLE-US-00004 TABLE 4 Secondary Efficacy Analysis: Free
Testosterone (ng/dL) for Intent-to-Treat Subjects Fispemifene 100
mg 200 mg 300 mg Placebo Category Study Week Statistics (N = 21) (N
= 21) 0 = 19) (N = 16) Descriptive Actual Value at Baseline N (%)
Reported 21 (100.0%) 21 (100.0.degree.%) 19 (100.0%) 16 (100.0%)
Summaries (Visit 2) Mean .+-. SD 8.35 .+-. 2.536 8.48 .+-. 3.043
8.19 .+-. 2.966 7.83 .+-. 3.490 Median 8.40 8.50 8.20 8.35 Min, Max
3.20, 12.20 4.30, 15.90 030, 12.30 2.00, 13.20 % Change from
Baseline N (%) Reported 19 (90.5%) 21 (100.0%) 19 (100.0%) 14
(87.5%) to Week 2 Mean .+-. SD 040 .+-. 0.387 0.30 .+-. 0.422 0.43
.+-. 0.340 0.26 .+-. 0.338 Median 0.30 019 0.43 0.12 Min, Max
-0.13, 1.22 -0.16, 1.83 -0.33, 1.00 -0.07, 1.19 % Change from
Baseline N (%) Reported 21 (100.0%) 21 (100.0%) 19 (100.0%) 16
(100.0%) to Week 4 Mean .+-. SD 0.44 .+-. 0.490 0.47 .+-. 0.483
0.48 .+-. 0.452 0.17 .+-. 0.385 Median 0.38 0.41 0.40 0.05 Min, Max
-0.17, 2.08 -0.17, 1.52 -0.67, 1.22 -0.31, 1.05 % Change from
Baseline N (%) Reported 21 (100.0%) 21 (100.0%) 19 (100.0%) 16
(100.0%) to Week 6 Mean = SD 0.18 .+-. 0.548 0.16 .+-. 0.479 0.16
.+-. 0.308 0.25 .+-. 0.406 Median -0.03 0.03 0.06 0.15 Min, Max
-0.38, 2.16 -0.60, 1.31 -0.37, 1.02 -0.31, 1.10 P-values.sup.1 for
All Arms 0.664 -- -- -- Comparing 100 mg vs. Placebo 0.304 -- -- --
Treatments 200 mg vs. Placebo 0.409 -- -- -- Over Time 300 mg vs.
Placebo 0.245 -- -- -- % Change from Baseline is defined as (Week
2, 4 or 6 minus Baseline) divided by Baseline. Missing values for
ITT subjects are replaced via LOCF approach. .sup.1P-values for
comparing treatment groups over time from a repeated-measures
analysis of variance model via PROC MIXED with % change as response
variable and terms of treatment, visit (study week), and treatment
by visit interactions.
TABLE-US-00005 TABLE 5 Descriptive Summary: Calculated Free
Testosterone (ng/dL) by Visit for Intent-to-Treat Subjects
Fispemifene 100 mg 200 mg 300 mg Placebo Study Week Statistics (N =
21) (N = 21) (N = 19) (N = 16) Baseline (Visit 2) N (%) Reported 21
(100.0%) 21 (100.0%) 18 (94.7%) 16 (100.0%) Mean .+-. SD 4.81 .+-.
1,368 4.80 .+-. 1,143 4.66 .+-. 1,509 4.41 .+-. 1,646 Median 4.95
4.70 4.94 4.36 Min, Max 2.19, 7.54 2.66, 7.29 0.23, 7.02 1.10, 6.94
Week 2 (Visit 4) N (%) Reported 19 (90.5%) 21 (100.0%) 19 (100.0%)
14 (87.5%) Mean .+-. SD 6.64 .+-. 1,732 6.37 .+-. 1,386 6.43 .+-.
2,152 5.46 .+-. 1,480 Median 6.46 6.21 7.25 5.68 Min, Max 4.32,
10.27 4.11, 8.98 0.14, 9.79 2.66, 7.90 Week 4 (Visit 5) N (%)
Reported 21 (100.0%) 21 (100.0%) 19 (100.0%) 16 (100.0%) Mean .+-.
SD 6.59 .+-. 1,396 6.64 .+-. 1,658 7.33 .+-. 2,589 5.01 .+-. 1,984
Median 6.63 6.39 8.40 4.99 Min, Max 4.15, 9.13 4.05, 9.83 0.10,
10.31 0.83, 7.93 Week 6 (Visit 6) N (%) Reported 21 (100.0%) 21
(100.0%) 19 (100.0%) 16 (100.0%) Mean .+-. SD 5.15 .+-. 1,057 5.153
.+-. 1,328 5.29 .+-. 1,791 5.01 .+-. 2,001 Median 5.10 4.88 5.44
4.87 Min, Max 2.57, 7.05 3.60, 7.81 0.22, 8.02 0.83, 8.09
TABLE-US-00006 TABLE 6 Secondary Efficacy Analysis: Calculated Free
Testosterone (ng/dL) for Intent-to-Treat Subjects Fispemifene 100
mg 200 mg 300 mg Placebo Category Study Week Statistics (N = 21) (N
= 21) (N = 19) (N = 16) Descriptive Actual Value at Baseline N (%)
Reported 21 (100.0%) 21 (100.0%) 18 (94.7%) 16 (100.0%) Summaries
(Visit 2) Mean .+-. SD 4.81 .+-. 1.368 4.80 .+-. 1.143 4.66 .+-.
1.509 4.41 .+-. 1.646 Median 4.95 4.70 4.94 4.36 Min, Max 2.19,
7.54 2.66, 7.29 0.23, 7.02 1.10, 6.94 % Change from Baseline N (%)
Reported 19 (90.5%) 21 (100.0%) 18 (94.7%) 14 (87.5%) to Week 2
Mean .+-. SD 0.42 .+-. 0.292 0.36 .+-. 0.321 0.38 .+-. 0.262 0.23
.+-. 0.327 Median 0.36 0.28 0.40 0.08 Min, Max 0.08, 1.00 0.01,
1.24 -0.37, 0.83 -0.05.0.99 % Change from Baseline N (%) Reported
21 (100.0%) 21 (100.0%) 18 (94.7%) 16 (100.0%) to Week 4 Mean .+-.
SD 0.46 .+-. 0.449 0.41 .+-. 0.324 0.56 .+-. 0.430 0.15 .+-. 0.305
Median 0.36 0.40 0.59 0.14 Min,. Max -0.00, 1.57 -0.15, 1.12 -0.58,
1.33 -0.30, 0.78 % Change from Baseline N (%) Reported 21 (100.0%)
21 (100.0%) 18 (94.7%) 16 (100.0%) to Week 6 Mean .+-. SD 0.14 .+-.
0.344 0.11 .+-. 0.314 0.17 .+-. 0.276 0.15 .+-. 0.357 Median 0.08
0.06 0.10 0.06 Min, Max -0.26, 1.15 -0.37, 0.75 -0.26, 0.65 -0.30,
1.08 P-values.sup.1 for All Arms 0.217 -- -- -- Comparing 100 mg
vs. Placebo 0.094 -- -- -- Treatments 200 mg vs. Placebo 0.184 --
-- -- Over Time 300 mg vs. Placebo 0.048 -- -- -- % Change from
Baseline is defined as (Week 2, 4 or 6 minus Baseline) divided by
Baseline. Missing values for ITT subjects are replaced via LOCF
approach. .sup.1P-values for comparing treatment groups over time
from a repeated-measures analysis of variance model via PROC MIXED
with % change as response variable and terms of treatment, visit
(study week), and treatment by visit interactions.
TABLE-US-00007 TABLE 7 Descriptive Summary: Total Testosterone
(ng/dL) by Visit for Intent-to-Treat Subjects Fispemifene 100 mg
200 mg 300 mg Placebo Study Week Statistics (N = 21) (N = 21) (N =
19) (N = 16) Baseline (Visit 2) N (%) Reported 21 (100.0%) 21
(100.0%) 19 (100.0%) 16 (100.0%) Mean .+-. SD 248.6 .+-. 68.90
249.1 .+-. 60.90 234.2 .+-. 77.69 218.6 .+-. 79.13 Median 266.0
253.0 246.0 227.5 Min, Max 101.0, 347.0 133.0, 334.0 17.0, 348.0
58.0, 334.0 Week 2 (Visit 4) N (%) Reported 19 (90.5%) 21 (100.0%)
19 (100.0%) 14 (87.5%) Mean .+-. SD 369.9 .+-. 88.23 370.0 .+-.
72.44 379.2 .+-. 122.04 270.1 .+-. 71.56 Median 350.0 354.0 427.0
288.0 Min, Max 235.0, 585.0 238.0, 497.0 13.0, 526.0 162.0, 388.0
Week 4 (Visit 5) N (%) Reported 21 (100.0%) 21 (100.0%) 19 (100.0%)
16 (100.0%) Mean .+-. SD 371.6 .+-. 83.36 387.3 .+-. 107.39 430.7
.+-. 163.39 246.9 .+-. 95.26 Median 353.0 372.0 479.0 265.5 Min,
Max 246.0, 535.0 241.0, 626.0 8.0, 643.0 40.0, 397.0 Week 6 (Visit
6) N (%) Reported 21 (100.0%) 21 (100.0%) 19 (100.0%) 16 (100.0%)
Mean .+-. SD 271.9 .+-. 69.21 276.2 .+-. 97.28 279.2 .+-. 102.84
247.6 .+-. 95.06 Median 265.0 240.0 293.0 246.5 Min, Max 121.9,
414.0 162.0, 539.0 16.0, 423.0 40.0, 397.0
TABLE-US-00008 TABLE 8 Secondary Efficacy Analysis: Total
Testosterone (ng/dL) for Intent-to-Treat Subjects Fispemifene 100
mg 200 mg 300 mg Placebo Category Study Week Statistics (N = 21) (N
= 21) (N = 19) (N = 16) Descriptive Actual Value at Baseline N (%)
Reported 21 (100.0%) 21 (100.0%) 19 (100.0%) 16 (100.0%) Summaries
(Visit 2) Mean .+-. SD 248.6 .+-. 68.90 249.1 .+-. 60.90 234.2 .+-.
77.69 218.6 .+-. 79.13 Median 266.0 253.0 246.0 227.5 Min, Max
101.0, 347.0 133.0, 334.0 17.0, 348.0 58.0, 334.0 % Change from
Baseline N (%) Reported 19 (90.5%) 21 (100.0%) 19 (100.0%) 14
(87.5%) to Week 2 Mean .+-. SD 0.55 .+-. 0.366 0.54 .+-. 0.337 0.60
.+-. 0.286 0.24 .+-. 0.354 Median 0.45 0.48 0.65 0.09 Min, Max
0.14, 1.33 0.17, 1.42 -0.24, 1.01 -0.13, 1.03 % Change from
Baseline N (%) Reported 21 (100.0%) 21 (100.0%) 19 (100.0%) 16
(100.0%) to Week 4 Mean .+-. SD 0.60 .+-. 0.524 0.60 .+-. 0.390
0.78 .+-. 0.536 0.14 .+-. 0.307 Median 0.35 0.60 0.80 0.14 Min, Max
0.07, 1.98 -0.14, 1.27 -0.53, 1.81 -0.31, 0.74 % Change from
Baseline N (%) Reported 21 (100.0%) 21 (100.0%) 19 (100.0%) 16
(100.0%) to Week 6 Mean .+-. SD 0.15 .+-. 0.341 0.13 .+-. 0.341 020
.+-. 0.310 0.16 .+-. 0.374 Median 0.11 0.11 0.14 0.10 Min, Max
-0.27, 1.19 -0.38, 0.79 -0.24, 0.77 -0.31, 1.10 P-values.sup.1 for
All Arms 0.017 -- -- -- Comparing 100 mg vs. Placebo 0.020 -- -- --
Treatments 200 mg vs. Placebo 0.023 -- -- -- Over Time 300 mg vs.
Placebo 0.002 -- -- -- % Change from Baseline is defined as (Week
2, 4 or 6 minus Baseline) divided by Baseline. Missing values for
ITT subjects are replaced via LOCF approach. .sup.1P-values for
comparing treatment groups over time from a repeated-measures
analysis of variance model via PROC MIXED with % change as response
variable and terms of treatment, visit (study week), and treatment
by visit interactions.
TABLE-US-00009 TABLE 9 Secondary Efficacy Analysis: Sex Hormone
Binding Globulin (nmol/L) for Intent to Treat Subjects Fispemifene
100 mg 200 mg 300 mg Placebo Category Study Week Statistics (N =
21) (N = 21) (N = 19) (N = 16) Descriptive Actual Value at Baseline
N (%) Reported 21 (100.0%) 21 (100.0%) 19 (100.0%) 16 (100.0%)
Summaries (Visit 2) Mean .+-. SD 18.4 .+-. 6.96 19.5 .+-. 11.12
20.0 .+-. 10.28 16.4 .+-. 6.10 Median 17.0 18.0 19.0 15.5 Min, Max
8.5, 35.0 3.7, 51.0 5.6, 48.0 9.0, 30.0 % Change from Baseline N
(%) Reported 19 (90.5%) 21 (100.0%) 19 (100.0%) 14 (87.5%) to Week
2 Mean .+-. SD 0.32 .+-. 0.211 0.46 .+-. 0.255 0.55 .+-. 0.253
0.017 .+-. 0.1299 Median 0.32 0.38 0.48 0.045 Min, Max 0.00, 0.85
0.09, 1.27 0.25, 1.11 -0.286, 0.222 % Change from Baseline N (%)
Reported 21 (100.0%) 21 (100.0%) 19 (100.0%) 16 (100.0%) to Week 4
Mean .+-. SD 0.35 .+-. 0.292 0.45 .+-. 0.338 0.47 .+-. 0.262 -0.013
.+-. 0.1403 Median 0.29 0.41 0.46 -0.028 Min, Max -0.11, 1.00 0.00,
1.27 0.05, 0.93 -0263, 0.280 % Change from Baseline N (%) Reported
21 (100.0%) 21 (100.0%) 19 (100.0%) 16 (100.0%) to Week 6 Mean .+-.
SD 0.055 .+-. 0.1469 0.065 .+-. 0.1886 0.037 .+-. 0.1447 0.010 .+-.
0.1164 Median 0.067 0.067 0.038 0.021 Min, Max -0.308, 0.294
-0.154, 0.546 -0.232, 0.296 -0.263, 0.188 P-values.sup.1 for All
Arms <0.001 -- -- -- Comparing 100 mg vs. Placebo <0.001 --
-- -- Treatments 200 mg vs. Placebo <0.001 -- -- -- Over Time
300 mg vs. Placebo <0.001 -- -- -- % Change from Baseline is
defined as (Week 2, 4 or 6 minus Baseline) divided by Baseline.
Missing values for ITT subjects are replaced via LOCF approach.
.sup.1P-values for comparing treatment groups over time from a
repeated-measures analysis of variance model via PROC MIXED with %
change as response variable and terms of treatment, visit (study
week), and treatment by visit interactions.
TABLE-US-00010 TABLE 10 Secondary Efficacy Analysis:
Dihydrotestosterone (pg/mL) for Intent to Treat Subjects
Fispemifene 100 mg 200 mg 300 mg Placebo Category Study Week
Statistics (N-21) (N-21) (N-19) (N-16) Descriptive Actual Value at
Baseline N (%) Reported 21 (100.0%) 19 (90.5%) 19 (100.0%) 16
(100.0%) Summaries (Visit 2) Mean .+-. SD 177.5 .+-. 88.58 185.2
.+-. 95.37 171.6 .+-. 76.42 156.5 .+-. 72.13 Median 180.0 168.0
179.0 149.0 Min, Max 50.0, 385.0 67.0, 398.0 50.0, 294.0 50.0,
313.0 % Change from Baseline N (%) Reported 19 (90.5%) 19 (90.5%)
19 (100.0%) 14 (87.5%) to Week 2 Mean .+-. SD 0.46 .+-. 0.342 0.50
.+-. 0.342 0.59 .+-. 0.387 0.028 .+-. 0.2336 Median 0.42 0.50 0.65
0.024 Min, Max 0.00, 1.09 -0.08, 1.28 0.00, 1.62 -0.355, 0.509 %
Change from Baseline N (%) Reported 21 (100.0%) 19 (90.5%) 19
(100.0%) 16 (100.0%) to Week 4 Mean .+-. SD 0.41 .+-. 0.351 0.68
.+-. 0.507 0.79 .+-. 0.504 -0.001 .+-. 0.2336 Median 0.33 0.61 0.73
-0.082 Min, Max -0.09, 0.98 -0.04, 1.62 0.00, 1.63 -0.305, 0.450 %
Change from Baseline N (%) Reported 21 (100.0%) 19 (90.5%) 19
(100.0%) 16 (100.0%) to Week 6 Mean .+-. SD 0.14 .+-. 0.306 0.16
.+-. 0.335 0.24 .+-. 0.366 0.064 .+-. 0.2698 Median 0.19 0.11 0.19
0.016 Min, Max -0.43, 0.64 -0.54, 0.78 -0.29, 0.98 -0.236, 0.650
P-values.sup.1 for All Arms <0.001 -- -- -- Comparing 100 mg vs.
Placebo 0.003 -- -- -- Treatments 200 mg vs. Placebo <0.001 --
-- -- Over Time 300 mg vs. Placebo <0.001 -- -- -- % Change from
Baseline is defined as (Week 2, 4 or 6 minus Baseline) divided by
Baseline. Missing values for ITT subjects are replaced via LOCF
approach. .sup.1P-values for comparing treatment groups over time
from a repeated-measures analysis of variance model via PROC MIXED
with % change as response variable and terms of treatment, visit
(study meek), and treatment by visit interactions.
TABLE-US-00011 TABLE 11 Secondary Efficacy Analysis: Estradiol
(pg/mL) for Intent to Treat Subjects Fispemifene 100 mg 200 mg 300
mg Placebo Category Study Week Statistics (N = 21) (N = 21) (N =
19) (N = 16) Descriptive Actual Value at Baseline N (%) Reported 21
(100.0%) 21 (100.0%) 19 (100.0%) 16 (100.0%) Summaries (Visit 2)
Mean .+-. SD 18.2 .+-. 6.54 19.2 .+-. 6.23 20.8 .+-. 7.15 19.7 .+-.
6.20 Median 18.0 17.0 22.0 19.0 Min, Max 10.0, 34.0 11.0, 33.0
10.0, 42.0 10.0, 33.0 % Change from Baseline N (%) Reported 19
(90.5%) 21 (100.0%) 19 (100.0%) 14 (87.5%) to Week 2 Mean .+-. SD
0.40 .+-. 0.453 0.36 .+-. 0.523 0.36 .+-. 0.343 0.091 .+-. 0.3155
Median 0.32 0.23 0.33 0.000 Min, Max -0.15, 1.31 -0.27, 1.71 -0.45,
1.08 -0.389, 0.765 % Change from Baseline N (%) Reported 21
(100.0%) 21 (100.0%) 19 (100.0%) 16 (100.0%) to Week 4 Mean .+-. SD
0.37 .+-. 0.323 0.48 .+-. 0.556 0.38 .+-. 0.366 0.082 .+-. 0.2924
Median 0.31 0.43 0.29 0.000 Min, Max -0.18, 1.10 -0.29, 1.50 -0.23,
1.00 -0.261, 0.750 % Change from Baseline N (%) Reported 21 (100.%)
21 (100.0%) 19 (100.0%) 16 (100.0%) to Week 6 Mean .+-. SD 0.16
.+-. 0.271 0.21 .+-. 0.488 0.10 .+-. 0.305 0.071 .+-. 0.3290 Median
0.13 0.23 0.00 0.000 Min, Max -0.17, 0.80 -0.33, 1.76 -0.32, 0.77
-0.444, 1.000 P-values.sup.1 for All Arms 0.093 -- -- -- Comparing
100 mg vs. Placebo 0.044 -- -- -- Treatments 200 mg vs. Placebo
0.017 -- -- -- Over Time 300 mg vs. Placebo 0.083 -- -- -- % Change
from Baseline is defined as (Week 2, 4 or 6 minus Baseline) divided
by Baseline. Missing values for ITT subjects are replaced via LOCF
approach. .sup.1P-values for comparing treatment groups over time
from a repeated-measures analysis of variance model via PROC MIXED
with % change as response variable and terms of treatment, visit
(study week), and treatment by visit interactions.
TABLE-US-00012 TABLE 12 Secondary Efficacy Analysis: LH (IU/L) for
Intent to Treat Subjects Fispemifene 100 mg 200 mg 300 mg Placebo
Category Study Week Statistics (N = 21) (N = 21) (N = 19) (N = 16)
Descriptive Actual Value at Baseline N (%) Reported 21 (100.0%) 21
(100.0%) 19 (100.0%) 16 (100.0%) Summaries (Visit 2) Mean .+-. SD
4.43 + 2.438 4.25 .+-. 2.028 3.62 .+-. 1.506 4.49 .+-. 1.699 Median
4.10 3.60 3.20 4.15 Min, Max 1.50, 13.50 1.00, 11.60 1.90, 8.00
150, 7.20 % Change from Baseline N (%) Reported 19 (90.5%) 21
(100.0%) 19 (100.0%) 14 (87.5%) to Week 2 Mean .+-. SD 039 .+-.
0.496 0.52 .+-. 0.364 0.57 .+-. 0.414 0.18 .+-. 0.356 Median 0.29
0.54 0.63 0.03 Min, Max -0.40, 1.41 -0.02, 1.23 -0.11, 1.34 -0.32,
0.80 % Change from Baseline N (%) Reported 21 (100.0%) 21 (100.0%)
19 (100.0%) 16 (100.0%) to Week 4 Mean .+-. SD 0.46 .+-. 0.600 0.55
.+-. 0.412 0.57 .+-. 0.577 0.17 .+-. 0.295 Median 0.49 0.52 0.42
0.07 Min, Max -0.32, 2.03 -0.22, 1.37 -0.19, 1.78 -0.21, 0.84 %
Change from Baseline N (%) Reported 21 (100.0%) 21 (100.0%) 19
(100.0%) 16 (100.0%) to Week 6 Mean .+-. SD 0.090 .+-. 0.3664 0.22
.+-. 0.397 0.16 .+-. 0.365 0.13 .+-. 0.362 Median 0.000 0.19 0.19
0.03 Min, Max -0.537, 1.000 -0.56, 0.80 -0.41, 0.84 -0.32, 1.28
P-values.sup.1 for All Arms 0.089 -- -- -- Comparing 100 mg vs.
Placebo 0.200 -- -- -- Treatments 200 mg vs. Placebo 0.027 -- -- --
Over Time 300 mg vs. Placebo 0.026 -- -- -- % Change from Baseline
is defined as (Week 2, 4 or 6 minus Baseline) divided by Baseline.
Missing values for ITT subjects are replaced via LOCF approach.
.sup.1P-values for comparing treatment groups over time from a
repeated-measures analysis of variance model via PROC MIXED with %
change as response variable and terms of treatment, visit (study
week), and treatment by visit interactions.
TABLE-US-00013 TABLE 13 Secondary Efficacy Analysis: FSH (IU/L) for
Intent to Treat Subjects Fispemifene 100 mg 200 mg 300 mg Placebo
Category Study Week Statistics (N = 21) (N = 21) (N = 19) (N = 16)
Descriptive Actual Value at Baseline N (%) Reported 21 (100.0%) 21
(100.0%) 19 (100.0%) 16 (100.0%) Summaries (Visit 2) Mean .+-. SD
649 .+-. 3.738 5.91 .+-. 3.054 5.08 .+-. 2.931 7.01 .+-. 3.399
Median 5.00 5.20 4.10 6.35 Min, Max 220, 14.90 2.40, 14.20 1.80,
12.30 2.60, 13.10 % Change from Baseline N (%) Reported 19 (90.5%)
21 (100.0%) 19 (100.0%) 14 (87.5%) to Week 2 Mean .+-. SD 0.29 .+-.
0.222 0.33 .+-. 0.147 0.36 .+-. 0.233 0.13 .+-. 0.171 Median 0.27
0.28 0.31 0.10 Min, Max -0.13, 0.76 0.03, 0.60 -0.21, 0.78 -0.10,
0.47 % Change from Baseline N (%) Reported 21 (100.0%) 21 (100.0%)
19 (100.0%) 16 (100.0%) to Week 4 Mean .+-. SD 0.28 .+-. 0.296 0.32
.+-. 0.157 0.29 .+-. 0.206 0.14 .+-. 0.181 Median 0.24 0.33 0.28
0.13 Min, Max -0.09, 1.12 0.02, 0.58 -0.24, 0.60 -0.20, 0.53 %
Change from Baseline N (%) Reported 21 (100.0%) 21 (100.0%) 19
(100.0%) 16 (100.0%) to Week 6 Mean .+-. SD 0.043 .+-. 0.2302 0.050
.+-. 0.1657 -0.010 .+-. 0.1786 0.084 .+-. 0.1797 Median 0.000 0.022
-0.043 0.056 Min, Max -0.345, 0.610 -0.167, 0.442 -0.255, 0.395
-0.205, 0.489 P-values.sup.1 for All Arms 0.198 -- -- -- Comparing
100 mg vs. Placebo 0.141 -- -- -- Treatments 200 mg vs. Placebo
0.042 -- -- -- Over Time 300 mg vs. Placebo 0.089 -- -- -- % Change
from Baseline is defined as (Week 2, 4 or 6 minus Baseline) divided
by Baseline. Missing values for ITT subjects are replaced via LOCF
approach. .sup.1P-values for comparing treatment groups over time
from a repeated-measures analysis of variance model via PROC MIXED
with % change as response variable and terms of treatment, visit
(study week), and treatment by visit interactions.
TABLE-US-00014 TABLE 14 Secondary Efficacy Analysis: Inhibin B
(pg/mL) for Intent to Treat Subjects Fispemifene 100 mg 200 mg 300
mg Placebo Category Study Week Statistics (N = 21) (N = 21) (N =
19) (N = 16) Descriptive Actual Value at Baseline N (%) Reported 21
(100.0%) 21 (100.0%) 19 (100.0%) 16 (100.0%) Summaries (Visit 2)
Mean .+-. SD 95.1 .+-. 46.32 105.6 .+-. 59.43 127.3 .+-. 75.76 95.4
.+-. 60.22 Median 89.0 95.0 128.0 88.5 Min, Max 22.0, 191.0 16.0,
220.0 16.0, 334.0 16.0, 250.0 % Change from Baseline N (%) Reported
19 (90.5%) 21 (100.0%) 18 (94.7%) 14 (87.5%) to Week 2 Mean .+-. SD
0.24 .+-. 0.493 039 .+-. 0.534 0.12 .+-. 0.400 0.13 .+-. 0.363
Median 0.17 0.21 0.05 0.02 Min, Max -0.44, 1.64 -0.22, 1.48 -0.42,
0.97 -0.34, 0.92 % Change from Baseline N (%) Reported 21 (100.0%)
21 (100.0%) 19 (100.0%) 15 (93.8%) to Week 4 Mean .+-. SD 0.30 .+-.
0.631 0.42 .+-. 0.862 0.016 .+-. 0.2904 0.12 .+-. 0.351 Median 0.09
0.12 -0.012 0.09 Min, Max -0.61, 1.86 -0.44, 3.40 -0.459, 0.878
-0.29, 1.07 % Change from Baseline N (%) Reported 21 (100.0%) 21
(100.0%) 19 (100.0%) 15 (93.8%) to Week 6 Mean .+-. SD 0.41 .+-.
0.572 0.40 .+-. 0.628 0.004 .+-. 0.3349 0.18 .+-. 0.583 Median 0.29
0.22 -0.057 0.00 Min, Max -0.41, 1.40 -0.34, 2.00 -0.493, 0.645
-0.63, 1.28 P-values.sup.1 for All Arms 0.097 -- -- -- Comparing
100 mg vs. Placebo 0.308 -- -- -- Treatments 200 mg vs. Placebo
0.106 -- -- -- Over Time 300 mg vs. Placebo 0.586 -- -- -- % Change
from Baseline is defined as (Week 2, 4 or 6 minus Baseline) divided
by Baseline. Missing values for ITT subjects are replaced via LOCF
approach. .sup.1P-values for comparing treatment groups over time
from a repeated-measures analysis of variance model via PROC MIXED
with % change as response variable and terms of treatment, visit
(study week), and treatment by visit interactions.
TABLE-US-00015 TABLE 15 Secondary Efficacy Analysis:
Testosterone/E2 Ratio for Intent to Treat Subjects Fispemifene 100
mg 200 mg 300 mg Placebo Category Study Week Statistics (N = 21) (N
= 21) (N = 19) (N = 16) Descriptive Actual Value at Baseline N (%)
Reported 21 (100.0%) 21 (100.0%) 18 (94.7%) 16 (100.0%) Summaries
(Visit 2) Mean .+-. SD 15.2 .+-. 6.39 14.2 .+-. 5.73 11.5 .+-. 4.87
11.7 .+-. 4.68 Median 14.7 14.9 10.6 11.9 Min, Max 5.2, 27.0 6.3,
30.2 1.7, 23.1 4.6, 19.4 % Change from Baseline N (%) Reported 19
(90.5%) 21 (100.0%) 18 (94.7%) 14 (87.5%) to Week 2 Mean .+-. SD
0.21 .+-. 0.457 0.25 .+-. 0.418 0.21 .+-. 0.372 0.23 .+-. 0.643
Median 0.18 0.19 0.15 0.14 Min, Max -0.39, 1.21 -0.29, 0.93 -0.24,
1.43 -0.27, 2.33 % Change from Baseline N (%) Reported 21 (100.0%)
21 (100.0%) 18 (94.7%) 16 (100.0%) to Week 4 Mean .+-. SD 0.22 .+-.
0.482 0.18 .+-. 0.387 0.33 .+-. 0.428 0.11 .+-. 0.403 Median 0.13
0.17 0.36 -0.01 Min, Max -0.29, 1.57 -0.34, 1.08 -0.53, 1.12 -0.31,
1.09 % Change from Baseline N (%) Reported 21 (100.0%) 21 (100.0%)
18 (94.7%) 16 (100.0%) to Week 6 Mean .+-. SD -0.002 .+-. 0.1993
0.019 .+-. 0.3760 0.12 .+-. 0.250 0.19 .+-. 0.633 Median 0.029
-0.030 0.11 -0.01 Min, Max -0.337, 0.411 -0.517, 0.937 -0.29, 0.65
-0.40, 2.06 P-values.sup.1 for All Arms 0.923 -- -- -- Comparing
100 mg vs. Placebo 0.878 -- -- -- Treatments 200 mg vs. Placebo
0.922 -- -- -- Over Time 300 mg vs. Placebo 0.661 -- -- -- % Change
from Baseline is defined as (Week 2, 4 or 6 minus Baseline) divided
by Baseline. Missing values for ITT subjects are replaced via LOCF
approach. .sup.1P-values for comparing treatment groups over time
from a repeated-measures analysis of variance model via PROC MIXED
with % change as response variable and terms of treatment, visit
(study week), and treatment by visit interactions.
* * * * *