U.S. patent application number 16/147153 was filed with the patent office on 2019-01-31 for methods of improving myocardial performance in fontan patients using udenafil compositions.
This patent application is currently assigned to Mezzion Pharma Co., Ltd.. The applicant listed for this patent is The Children's Hospital of Philadelphia, Mezzion Pharma Co., Ltd.. Invention is credited to David J. Goldberg, Stephen M. Paridon, James L. Yeager.
Application Number | 20190030038 16/147153 |
Document ID | / |
Family ID | 55301323 |
Filed Date | 2019-01-31 |
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United States Patent
Application |
20190030038 |
Kind Code |
A1 |
Yeager; James L. ; et
al. |
January 31, 2019 |
METHODS OF IMPROVING MYOCARDIAL PERFORMANCE IN FONTAN PATIENTS
USING UDENAFIL COMPOSITIONS
Abstract
The present invention relates generally to the field of using
udenafil or a pharmaceutically acceptable salt thereof in patients
who have undergone the Fontan operation.
Inventors: |
Yeager; James L.; (Lake
Forest, IL) ; Goldberg; David J.; (Philadelphia,
PA) ; Paridon; Stephen M.; (Strafford, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Mezzion Pharma Co., Ltd.
The Children's Hospital of Philadelphia |
Seoul
Philadelphia |
PA |
KR
US |
|
|
Assignee: |
Mezzion Pharma Co., Ltd.
Seoul
PA
The Children's Hospital of Philadelphia
Philadelphia
PA
The Children's Hospital of Philadelphia
Philadelphia
|
Family ID: |
55301323 |
Appl. No.: |
16/147153 |
Filed: |
September 28, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14788211 |
Jun 30, 2015 |
10137128 |
|
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16147153 |
|
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62036506 |
Aug 12, 2014 |
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62186132 |
Jun 29, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 9/00 20180101; A61K
31/519 20130101; A61K 31/522 20130101; A61K 31/00 20130101; C07D
487/04 20130101 |
International
Class: |
A61K 31/522 20060101
A61K031/522; A61K 31/00 20060101 A61K031/00 |
Claims
1-30. (canceled)
31. A pharmaceutical composition for administration to a subject,
said pharmaceutical composition comprising: udenafil, or a
pharmaceutically acceptable salt thereof, in an amount of about
87.5 mg; and a pharmaceutically acceptable excipient.
32. The pharmaceutical composition of claim 31, wherein said
pharmaceutical composition is an oral tablet.
33. The pharmaceutical composition of claim 31, wherein the
pharmaceutical composition is a solid or semi-solid oral
pharmaceutical composition.
34. The pharmaceutical composition of claim 33, wherein the solid
or semi-solid oral pharmaceutical composition is selected from a
group of solid or semi-solid oral pharmaceutical compositions
consisting of a tablet, a capsule, a gel, a liquid, a liquid
dispersion, a pill, a powder and a suspension.
35. The pharmaceutical composition of claim 31, wherein the subject
is a human, whose age ranges from about 12 to under about 18 years
old.
36. The pharmaceutical composition of claim 35, wherein said
pharmaceutical composition is an oral tablet.
37. The pharmaceutical composition of claim 31, wherein the subject
is a human, who is under about 18 years.
38. The pharmaceutical composition of claim 37, wherein said
pharmaceutical composition is an oral tablet.
39. A pharmaceutical composition for administration to a subject,
said pharmaceutical composition comprising: udenafil, or a
pharmaceutically acceptable salt thereof, in an amount of about 125
mg; and a pharmaceutically acceptable excipient.
40. The pharmaceutical composition of claim 39, wherein said
pharmaceutical composition is an oral tablet.
41. The pharmaceutical composition of claim 39, wherein the
pharmaceutical composition is a solid or semi-solid oral
pharmaceutical composition.
42. The pharmaceutical composition of claim 41, wherein the solid
or semi-solid oral pharmaceutical composition is selected from a
group of solid or semi-solid oral pharmaceutical compositions
consisting of a tablet, a capsule, a gel, a liquid, a liquid
dispersion, a pill, a powder and a suspension.
43. The pharmaceutical composition of claim 39, wherein the subject
is a human, whose age ranges from about 12 to under about 18 years
old.
44. The pharmaceutical composition of claim 43, wherein said
pharmaceutical composition is an oral tablet.
45. The pharmaceutical composition of claim 39, wherein the subject
is a human, who is under about 18 years.
46. The pharmaceutical composition of claim 45, wherein said
pharmaceutical composition is an oral tablet.
47. A pharmaceutical composition for oral administration to a
subject born with single ventricle heart disease who has undergone
Fontan surgery for improving, maintaining or reducing the rate of
decline in a clinically relevant measurement that is indicative of
the subject's health following the Fontan surgery or for increasing
the likelihood of improving, maintaining or reducing the rate of
decline in the clinically relevant measurement that is indicative
of the subject's health following the Fontan surgery, said
pharmaceutical composition comprising: udenafil, or a
pharmaceutically acceptable salt thereof, in an amount of at least
about 125 mg; and a pharmaceutically acceptable excipient; wherein,
the subject is a human, whose age ranges between about 12 years old
and under about 18 years old; and wherein, the clinically relevant
measurement is exercise capacity.
48. The pharmaceutical composition of claim 47, wherein the
udenafil, or a pharmaceutically acceptable salt thereof, is in an
amount of about 87.5 mg, to be administered twice daily.
49. The pharmaceutical composition of claim 47, wherein the
pharmaceutical composition is a solid or semi-solid oral
pharmaceutical composition.
50. The pharmaceutical composition of claim 49, wherein the solid
or semi-solid oral pharmaceutical composition is selected from a
group of solid or semi-solid oral pharmaceutical compositions
consisting of a tablet, a capsule, a gel, a liquid, a liquid
dispersion, a pill, a powder and a suspension.
51. The pharmaceutical composition of claim 47, wherein the
pharmaceutical composition is an oral tablet.
52. A pharmaceutical composition for oral administration to a
subject born with single ventricle heart disease who has undergone
Fontan surgery for improving, maintaining or reducing the rate of
decline in a clinically relevant measurement that is indicative of
the subject's health following the Fontan surgery or for increasing
the likelihood of improving, maintaining or reducing the rate of
decline in the clinically relevant measurement that is indicative
of the subject's health following the Fontan surgery, said
pharmaceutical composition comprising: udenafil, or a
pharmaceutically acceptable salt thereof, in an amount of at least
about 125 mg; and a pharmaceutically acceptable excipient; wherein,
the subject is a human, whose age ranges between about 12 years old
and under about 18 years old; and wherein, the clinically relevant
measurement is exercise capacity.
53. The pharmaceutical composition of claim 52, wherein the
udenafil, or a pharmaceutically acceptable salt thereof, is in an
amount of about 87.5 mg, to be administered twice daily.
54. The pharmaceutical composition of claim 52, wherein the
pharmaceutical composition is a solid or semi-solid oral
pharmaceutical composition.
55. The pharmaceutical composition of claim 54, wherein the solid
or semi-solid oral pharmaceutical composition is selected from a
group of solid or semi-solid oral pharmaceutical compositions
consisting of a tablet, a capsule, a gel, a pill, a suspension and
a powder.
56. The pharmaceutical composition of claim 52, wherein the
pharmaceutical composition is an oral tablet.
57. A pharmaceutical composition for oral administration to a
subject born with single ventricle heart disease who has undergone
Fontan surgery for improving, maintaining or reducing the rate of
decline in a clinically relevant measurement that is indicative of
the subject's health following the Fontan surgery or for increasing
the likelihood of improving, maintaining or reducing the rate of
decline in the clinically relevant measurement that is indicative
of the subject's health following the Fontan surgery, said
pharmaceutical composition comprising: udenafil, or a
pharmaceutically acceptable salt thereof, in a therapeutically
effective dose; and a pharmaceutically acceptable excipient, for
improving, maintaining or reducing the rate of decline in a
clinically relevant measurement that is indicative of the subject's
health following the Fontan surgery or for increasing the
likelihood of improving, maintaining or reducing the rate of
decline in the clinically relevant measurement that is indicative
of the subject's health following the Fontan surgery in the
subject; wherein, the subject is a human, whose age ranges from
about 12 to under about 18 years of age or older; wherein, the
therapeutically effective dose of udenafil, or a pharmaceutically
acceptable salt thereof, is at least about 125 mg; wherein, the
pharmaceutical composition is a solid or semi-solid oral
pharmaceutical composition; wherein, the solid or semi-solid oral
pharmaceutical composition is selected from a group of solid or
semi-solid oral pharmaceutical compositions consisting of a tablet,
a capsule, a gel, a pill, a suspension and a powder; and wherein,
the clinically relevant measurement is exercise capacity.
58. The pharmaceutical composition of claim 57, wherein, the
therapeutically effective dose of udenafil, or a pharmaceutically
acceptable salt thereof, is about 87.5 mg, to be administered twice
daily.
59. An oral pharmaceutical composition for oral administration to a
subject born with single ventricle heart disease who has undergone
Fontan surgery for improving the subject's exercise capacity or
increasing the likelihood of improving the subject's exercise
capacity, wherein the subject's exercise capacity is indicative of
the subject's health following the Fontan surgery, said oral
pharmaceutical composition comprising: a therapeutically effective
amount of udenafil, or a pharmaceutically acceptable salt thereof;
and a pharmaceutically acceptable excipient, for improving the
exercise capacity or increasing the likelihood of improving the
subject's exercise capacity; wherein, the therapeutically effective
amount of udenafil, or a pharmaceutically acceptable salt thereof,
is at least about 125 mg; and wherein, the subject is a human
subject.
60. The pharmaceutical composition of claim 59, wherein the
therapeutically effective amount of udenafil, or a pharmaceutically
acceptable salt thereof, is in an amount of about 87.5 mg, to be
administered twice daily.
61. The oral pharmaceutical composition of claim 59, wherein the
oral pharmaceutical composition is a tablet.
62. The oral pharmaceutical composition of claim 59, wherein the
oral pharmaceutical composition is a solid or semi-solid oral
pharmaceutical composition.
63. The oral pharmaceutical composition of claim 62, wherein the
solid or semi-solid oral pharmaceutical composition is selected
from a group of solid or semi-solid oral pharmaceutical
compositions consisting of a tablet, a capsule, a gel, a liquid, a
liquid dispersion, a pill, a powder and a suspension.
64. An oral pharmaceutical composition for oral administration to a
subject born with single ventricle heart disease who has undergone
Fontan surgery for improving the subject's s exercise capacity or
increasing the likelihood of improving the subject's exercise
capacity, wherein the subject's exercise capacity is indicative of
the subject's health following the Fontan surgery, said oral
pharmaceutical composition comprising: a therapeutically effective
amount of udenafil, or a pharmaceutically acceptable salt thereof;
and a pharmaceutically acceptable excipient, for improving the
exercise capacity or increasing the likelihood of improving the
subject's exercise capacity; wherein, the therapeutically effective
amount of udenafil, or a pharmaceutically acceptable salt thereof,
is at least about 125 mg; and wherein, the subject is a human
subject.
65. The pharmaceutical composition of claim 64, wherein the
therapeutically effective amount of udenafil, or a pharmaceutically
acceptable salt thereof, is in an amount of about 87.5 mg, to be
administered twice daily.
66. The oral pharmaceutical composition of claim 64, wherein the
oral pharmaceutical composition is a tablet.
67. The oral pharmaceutical composition of claim 64, wherein the
oral pharmaceutical composition is a solid or semi-solid oral
pharmaceutical composition.
68. The oral pharmaceutical composition of claim 67, wherein the
solid or semi-solid oral pharmaceutical composition is selected
from a group of solid or semi-solid oral pharmaceutical
compositions consisting of a tablet, a capsule, a gel, a pill, a
suspension and a powder.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present invention claims priority to U.S. Provisional
Patent Application No. 62/036,506, filed on Aug. 12, 2014, and U.S.
Provisional Patent Application No. 62/186,132, filed on Jun. 29,
2015, the disclosures of which are specifically incorporated herein
by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the field of
using phosphodiesterase E5 (PDE5) inhibitors in patients who have
undergone the Fontan operation. In particular, the PDE5 inhibitor
is udenafil or a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
1. Background Regarding the Fontan Procedure
[0003] The Fontan procedure, or Fontan/Kreutzer procedure, is a
palliative surgical procedure for children born with functional
single ventricle congenital heart disease. The Fontan operation was
designed to provide blood flow in series to the pulmonary and
systemic circulation without the requirement for a right
ventricular pumping chamber. The operation allows systemic venous
blood to flow directly into the pulmonary circulation on the basis
of a single ventricular impetus through the arteries, capillaries,
and systemic venous system. This arrangement has improved life
expectancy for patients with single-ventricle and pulmonary-outflow
obstruction compared with previous arterial shunts.
[0004] The operation, which creates a total cavopulmonary
connection, separates the systemic and pulmonary circuits and
eliminates both hypoxemia and ventricular volume overload. However,
following the Fontan operation there is no ventricular pump to
propel blood into the pulmonary arteries. Instead, blood returns to
the lungs via passive flow from the systemic veins. This results in
a circulation characterized by elevated central venous pressure,
abnormal pulmonary vascular resistance, and a chronically low
cardiac output. Over time, these inherent characteristics of Fontan
physiology result in a predictable, persistent deterioration of
cardiovascular efficiency, as marked by a progressive decline in
exercise performance that begins after puberty. This decline in
exercise capacity correlates with an increase in symptoms from
cardiovascular dysfunction and may result in the need for
hospitalization, escalation of heart failure management, or
transplant.
[0005] Those with the Fontan circulation do not have `normal` heart
physiology or functioning. Two major complications that might have
many "downstream" effects are the following effects on increasing
("hypertension") and decreasing ("hypotension") blood pressure
depending upon its location (veins or arteries). First, with Fontan
circulation, there is "systemic venous hypertension", which means
that the blood pressure in the veins (blood going back to the
heart) in the body is higher than in individuals with normal heart
function (not Fontan circulation). There are many negative
consequences that may be caused by systemic venous hypertension
(congestive heart failure, edema or swelling, dysfunction of the
liver, potentially protein-losing enteropathy) that are basically
related to the distribution of fluids in the body. A second
complication is "pulmonary arterial hypotension" where the blood
pressure in arteries going towards or in the lungs (hence
pulmonary) is lower than in individuals with normal heart function.
There are also a number of negative consequences associated with
pulmonary arterial hypotension such as cyanosis (blue lips) or lack
of exercise capacity. Many of the subsequent medical conditions and
deaths that follow the Fontan procedure (either in the short- or
long-term) are thought to originate from this change in systemic
and pulmonary blood pressure.
[0006] The long-term effects of marked single-ventricle preload and
inefficient oxygenation via an arterial shunt rarely allow survival
beyond the second or third decade of life. Uniformly lethal four
decades ago, the newborn with single ventricle type congenital
heart disease in 2010 is now not only likely--but expected--to
survive. However, as these children have grown into adolescence and
adulthood, it is clear that there are significant limitations to
this strategy. While lifesaving, the Fontan/Kreutzer operation
results in profound physiological disturbances with very serious
consequences. Pervasive abnormalities of multiple organ systems are
affected as time goes on. Realistically, it is unlikely that
patients will survive into their third or fourth decades of life
untouched by some potentially life-threatening complication. Thus,
there is a clear need to identify treatments that may ameliorate
the dysfunctional state of the Fontan operation. This is
particularly true given the increase in the prevalence of the
Fontan procedures: remarkably, the Fontan operation has become the
most common procedure performed for congenital heart disease after
the age of 2 years. W. M. Gersony, Circulation, 117: 13-15
(2008).
[0007] Multiple studies looking at the results of the Fontan
operation demonstrate a decrease in survival beyond 15 years after
surgery. An ongoing significant risk of death with continuous
attrition is present, regardless of surgical type of cavo-pulmonary
connection. In another study looking at morphologically single left
ventricle after Fontan surgery, results showed that odds are 1 out
4 that a child after Fontan will be dead by the time he or she
reaches their late 20s. J. Rychik, "Forty Years of the Fontan
Operation: A Failed Strategy," Pediatric Cardiac Surgery Annual,
96-100(2010).
[0008] Given the increased life span for Fontan patients,
researchers have sought out medical therapies to address the side
effects of the Fontan surgery. In particular, children and young
adults with single-ventricle physiology have abnormal exercise
capacity after the Fontan operation. Strategies targeted toward
improving cardiac output and reducing central venous pressure will
improve their overall well-being and mitigate against the impact of
this deleterious physiology.
[0009] In one study, the PDE5 inhibitor sildenafil was found to
significantly improve ventilatory efficiency during peak and
submaximal exercise. There was also a suggestion of improved oxygen
consumption at the anaerobic threshold in 2 subgroups. These
findings suggest that sildenafil may be an important agent for
improving exercise performance in children and young adults with
single-ventricle physiology after the Fontan operation. Goldberg et
al., Circulation, 123: 1185-1193 (2011).
[0010] Later studies verified that sildenafil increased ventricular
systolic elastance and improved ventriculo-arterial coupling in
patients palliated with Fontan circulation. Short-term sildenafil
was well tolerated in most of the patients with only minor side
effects. Shabanian et al., Pediatr. Cardiol., 34(1): 129-34 (2013).
The structure of sildenafil is shown below:
##STR00001##
[0011] In addition, a preliminary study assessed the short-term
effects of the PDE5 inhibitor tadalafil on the hemodynamic response
to exercise and exercise capacity in patients with Fontan
circulation. See
http://clinicaltrials.gov/ct2/show/record/NCT01291069. Short term
therapy with once daily dosing of tadalafil improved ventilatory
efficiency and oxygen saturation, but exercise capacity was
unchanged in young Fontan subjects, similar to published sildenafil
results. Menon et al., Circulation, 128: A16024 (2013). The
chemical structure of tadalafil is shown below:
##STR00002##
[0012] For optimal effectiveness, the PDE5 inhibitors sildenafil or
tadalafil would need to be given long term to Fontan patients to
delay or prevent the onset of failing Fontan circulation. Fontan
surgery produces chronic conditions; short term treatment is
unlikely to address mortality associated with children having a
Fontan surgery when they are an adolescent or adult. This is
particularly true as when Fontan failure sets in, there is an
inexorable hemodynamic and functional decline in the patients
leading to death or cardiac transplantation. The early experience
with transplantation in patients with Fontan circulation was of
high operative mortality and morbidity. The assumption that if a
patient survives with a Fontan circulation, then the PVR is low
enough for the right ventricle of the graft after cardiac
transplantation was found to be incorrect in the early experience
of Fontan transplants.
[0013] While both sildenafil and tadalafil are known to have
undesirable side effects, pulmonary arterial hypertension (PAH)
patients switched from sildenafil to tadalafil were found to show
significantly different oxygen saturation, significantly different
oxygen saturation after a 6-minute walk test, and significantly
different distances walked, thus showing that PDE5 inhibitors are
not interchangeable when used to treat heart or cardiovascular
conditions. Sabri et al., Pediatr Cardiol., 35(4):699-704
(2014).
II. Background Regarding PDE5 Inhibitors and Udenafil
[0014] PDE5 is a cyclic guanosine-3',5'-monophosphate
(cGMP)-specific phosphodiesterase belonging to a class of
phosphodiesterases which regulate various cell functions by
catalyzing the hydrolysis of the second messenger molecules (cGMP)
and cyclic adenosine-3',5'-monophosphate (cAMP). Boolell et al.,
Int'l J. Impot. Res., 8:47 (1996). Because PDE5 is present in the
arterial wall smooth muscle within the lungs, PDE5 inhibitors have
been explored for the treatment of pulmonary hypertension, a
disease in which blood vessels in the lungs become overloaded with
fluid, usually as a result of failure of the right ventricle of the
heart.
[0015] Udenafil is a drug used in urology to treat erectile
dysfunction. It belongs to a class of drugs called PDE5 inhibitors,
which also includes sildenafil, tadalafil, and vardenafil. Typical
doses are 100 and 200 mg. Udenafil is available in Korea, Russia,
and Philippines; in the United States, it is not approved for use
by the U.S. Food and Drug Administration.
[0016] The Fontan procedure is palliative, not curative. But in
many cases it can result in normal or near-normal growth,
development, exercise tolerance, and good quality of life. In
20/30% cases, patients will eventually require heart
transplantation.
[0017] Modifications in the Fontan operative model was one of the
early steps in improving outcome. Use of fenestration, staging of
Fontan completion and better perioperative management have led to a
significant drop in mortality rates in the current era. Despite
this, there is late attrition of patients with complications such
as arrhythmias, ventricular dysfunction, and unusual clinical
syndromes of protein-losing enteropathy (PLE) and plastic
bronchitis. Management of failing Fontan includes a detailed
hemodynamic and imaging assessment to treat any correctable lesions
such as obstruction within the Fontan circuit, early control of
arrhythmia and maintenance of sinus rhythm, symptomatic treatment
for PLE and plastic bronchitis, manipulation of systemic and
pulmonary vascular resistance, and Fontan conversion of less
favorable atriopulmonary connection to extra-cardiac total
cavopulmonary connection with arrythmia surgery. Cardiac
transplantation remains the only successful definitive palliation
in the failing Fontan patients. However, cardiac transplantation is
not a perfect solution because the Fontan circulation has already
wreaked havoc in the body such as negatively affecting hepatic or
kidney function, thus patients with Fontan circulation may still be
in poor shape even after a heart transplant.
[0018] There is a need in the art for improved therapies relating
to complications or side effects of the Fontan procedure with the
goal of increasing the life span of Fontan patients, and avoiding
or delaying the need for cardiac transplantation. There is also a
need in the art for improved therapies to delay the onset of
cardiac failure or to improve the quality of life for patients who
have had the Fontan procedure. The present invention satisfies this
need.
SUMMARY OF THE INVENTION
[0019] In one embodiment, the invention is directed to methods of
treating, preventing, or minimizing conditions, symptoms, or side
effects associated with a subject who has previously had a Fontan
procedure. In particular, the methods of the invention are directed
the use of udenafil or a pharmaceutically acceptable salt thereof
in single ventricle adolescent patients that have undergone the
Fontan procedure for the amelioration of associated acute symptoms
and chronic symptom development. The method comprises administering
a therapeutically effective amount of a PDE5 inhibitor to the
patient, where the PDE5 inhibitor is udenafil or a pharmaceutically
acceptable salt thereof.
[0020] In one embodiment, the invention is directed to a method of
improving cardiac output in a patient who has had a Fontan
procedure. The method comprises administering a therapeutically
effective amount of a PDE5 inhibitor to the patient, where the PDE5
inhibitor is udenafil or a pharmaceutically acceptable salt
thereof.
[0021] In another embodiment, the invention is directed to a method
of decreasing pulmonary vascular resistance in a patient who has
had a Fontan procedure. The method comprises administering a
therapeutically effective amount of a PDE5 inhibitor to the
patient, where the PDE5 inhibitor is udenafil or a pharmaceutically
acceptable salt thereof.
[0022] In yet another embodiment, the invention is directed to a
method of improving exercise capacity in a patient who has had a
Fontan procedure. The method comprises administering a
therapeutically effective amount of a PDE5 inhibitor to the
patient, where the PDE5 inhibitor is udenafil or a pharmaceutically
acceptable salt thereof.
[0023] In one embodiment, the invention is directed to a method of
improving myocardial performance in a patient who has had a Fontan
procedure. The method comprises administering a therapeutically
effective amount of a PDE5 inhibitor to the patient, where the PDE5
inhibitor is udenafil or a pharmaceutically acceptable salt
thereof.
[0024] In an exemplary embodiment, the methods of the invention
comprise administering a therapeutically effective dose of
udenafil, or a pharmaceutically acceptable salt thereof, once a day
to a patient.
[0025] In another embodiment, the methods of the invention comprise
administering a therapeutically effective dose of udenafil, or a
pharmaceutically acceptable salt thereof, twice a day to a
patient.
[0026] In another embodiment, the patient is a pediatric patient of
about 2 to about 18 years of age. Treatment of adult patients are
also encompassed by the methods of the invention.
[0027] In yet another embodiment, the invention is directed to
improved methods for treating a patient who has had a Fontan
procedure, wherein the methods show an improvement in patient
compliance with a dosing schedule of udenafil or a pharmaceutically
acceptable salt thereof, as compared to patients prescribed a
non-udenafil drug.
[0028] In one embodiment, the invention is directed to improved
methods for treating a patient who has had a Fontan procedure,
wherein the methods of the invention result in fewer or less severe
adverse events as compared to conventional, methods of treating
such patients. In another embodiment, the methods of the invention
result in few, if any, serious adverse events, moderate adverse
events, or mild adverse events.
[0029] In another embodiment, the methods of the invention result
in improved VO2 at the patient's maximal effort as compared to VO2
at maximal effort in the absence of the methods of the invention
(e.g., in the absence of udenafil administration). For example, the
improvement can be about 5, about 6, about 7, about 8, about 9,
about 10, about 11, about 12, about 13, about 14, about 15, about
16, about 17, about 18, about 19, about 20, about 21, about 22,
about 23, about 24, about 25, about 26, about 27, about 28, about
29, or about 30% or greater as compared to VO2 at maximal effort in
the absence of the methods of the invention (e.g., in the absence
of udenafil administration).
[0030] In another embodiment, the methods of the invention result
in improved VO2 at the patient's anaerobic threshold as compared to
VO2 at anaerobic threshold in the absence of the methods of the
invention (e.g., in the absence of udenafil administration). For
example, the improvement can be about 5, about 6, about 7, about 8,
about 9, about 10, about 11, about 12, about 13, about 14, about
15, about 16, about 17, about 18, about 19, about 20, about 21,
about 22, about 23, about 24, about 25, about 26, about 27, about
28, about 29, or about 30% or greater as compared to VO2 at maximal
effort in the absence of the methods of the invention (e.g., in the
absence of udenafil administration).
[0031] In another embodiment, the methods of the invention result
in the patient's blood pool MPI, or other disclosed measures of
ventricular performance, improving as compared to blood pool MPI,
or other disclosed measures of ventricular performance in the
absence of the methods of the invention (e.g., in the absence of
udenafil administration). For example, the improvement can be about
5, about 6, about 7, about 8, about 9, about 10, about 11, about
12, about 13, about 14, about 15, about 16, about 17, about 18,
about 19, about 20, about 21, about 22, about 23, about 24, about
25, about 26, about 27, about 28, about 29, or about 30% or greater
as compared to blood pool MPI, or other disclosed measures of
ventricular performance in the absence of the methods of the
invention (e.g., in the absence of udenafil administration).
[0032] In another embodiment, the methods of the invention result
in the patient's log of reactive hyperemia index, or another
disclosed measure of vascular function, improving as compared to
log of reactive hyperemia index, or another disclosed measure of
vascular function, in the absence of the methods of the invention
(e.g., in the absence of udenafil administration). For example, the
improvement can be about 5, about 6, about 7, about 8, about 9,
about 10, about 11, about 12, about 13, about 14, about 15, about
16, about 17, about 18, about 19, about 20, about 21, about 22,
about 23, about 24, about 25, about 26, about 27, about 28, about
29, or about 30% or greater as compared to log of reactive
hyperemia index, or another disclosed measure of vascular function,
in the absence of the methods of the invention (e.g., in the
absence of udenafil administration).
[0033] Finally, in yet another embodiment, the methods of the
invention may result in a characteristic pharmacokinetic profile.
The pharmacokinetic profile can comprises a C.sub.max between 300
and 700 ng/ml, or more specifically, about 500 ng/ml; a T.sub.max
between 1 and 1.6 hr, or more specifically, about 1.3 hr; an
AUC.sub..tau. between 2550 and 4150 nghr/ml, or more specifically,
about 3350 nghr/ml; and an AUC.sub.0-24 between 5110 and 8290
nghr/ml, or more specifically, about 6701 nghr/ml.
[0034] The foregoing general description and following detailed
description are exemplary and explanatory and are intended to
provide further explanation of the invention as claimed. Other
objects, advantages, and novel features will be readily apparent to
those skilled in the art from the following brief description of
the drawings and detailed description of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] FIG. 1 shows the percentage of subjects who reported at
least one, three, or five adverse events by treatment group.
[0036] FIG. 2 shows change in peak VO2 (ml/kg/min) at the maximum
effort from baseline (day 1) to the last visit (post-medication,
day 5) by treatment group, where a positive change indicates an
improvement.
[0037] FIG. 3 shows peak VO2 at the maximum effort at baseline (day
1) and at the last visit (post-medication, day 5) by treatment
group, where a positive change indicates an improvement.
[0038] FIG. 4 shows change in VO2 (ml/kg/min) at anaerobic
threshold from baseline (day 1) to the last visit (post-medication,
day 5) by treatment group, where a positive change indicates an
improvement.
[0039] FIG. 5 shows peak VO2 at anaerobic threshold at baseline
(day 1) and at the last visit (post-medication, day 5) by treatment
group, where a positive change indicates an improvement.
[0040] FIG. 6 shows change in natural log of Reactive Hyperemia
Index from baseline (day 1) to the last visit (post-medication, day
5) by treatment group. A positive change indicates an
improvement.
[0041] FIG. 7 shows natural log of Reactive Hyperemia Index (RHI)
at baseline (day 1) and at the last visit (post-medication, day 5)
by treatment group. A positive change indicates an improvement.
[0042] FIG. 8 shows change in blood pool MPI from baseline (day 1)
to the last visit (post-medication, day 5) by treatment group. A
negative change indicates an improvement.
[0043] FIG. 9 shows blood pool MPI at baseline (day 1) and at the
last visit (post-medication, day 5) by treatment group. A negative
change indicates an improvement.
[0044] FIG. 10 shows change in tissue Doppler MPI from baseline
(day 1) to the last visit (post-medication, day 5) by treatment
group. A negative change indicates an improvement.
[0045] FIG. 11 shows tissue Doppler MPI at baseline (day 1) and at
the last visit (post-medication, day 5) by treatment group. A
negative change indicates an improvement.
[0046] FIG. 12 shows change in average isovolumic contraction from
baseline (day 1) to the last visit (post-medication, day 5) by
treatment group. A negative change indicates an improvement.
[0047] FIG. 13 shows average isovolumic contraction at baseline
(day 1) and at the last visit (post-medication, day 5) by treatment
group. A negative change indicates an improvement.
[0048] FIG. 14 shows change in average isovolumic relaxation from
baseline (day 1) to the last visit (post-medication, day 5) by
treatment group. A negative change indicates an improvement.
[0049] FIG. 15 shows average isovolumic relaxation at baseline (day
1) and at the last visit (post-medication, day 5) by treatment
group. A negative change indicates an improvement.
[0050] FIG. 16 shows individual concentration time curves
stratified by dosing regimens of (A) 37.5 mg q24 h, (B) 37.5 mg q12
h, (C) 87.5 mg q24 h, (D) 87.5 mg q12 h, and (E) 125 mg q24 h.
[0051] FIG. 17 shows concentration time concentration profiles of
udenafil in study subjects. The solid line represents the observed
data, the dash line stands for the predicted data for the second
dose of the day for 12 hour regimens. Data are represented as
mean+/-standard deviation.
[0052] FIG. 18 shows a comparison of Cmax among various dosing
regimens. The box and whisker plot showed 10-90 percentile and
range of observations with middle line representing median value of
a dosing regimen. Significant difference: 37.5 mg q24 h vs 87.5 mg
q12 h, p<0.001; 37.5 mg q24 h vs 125 mg q24 h, p<0.001; 37.5
mg q12 h vs 87.5 mg q12 h, p<0.001; 37.5 mg q12 h vs 125 mg q24
h, p<0.01; 87.5 mg q24 h vs 87.5 mg q12 h, p<0.05.
[0053] FIG. 19 shows a comparison of (A) AUC.sub..tau. and (B)
AUC0-24 among various dosing regimens. The box and whisker plot
showed 10-90 percentile and range of observations with middle line
representing median value of a dosing regimen. Significant
difference: A) 37.5 mg q24 h vs 87.5 mg q12 h, p<0.001; 37.5 mg
q24 h vs 125 mg q24 h, p<0.001; 37.5 mg q12 h vs 87.5 mg q12 h,
p<0.01; 37.5 mg q12 h vs 125 mg q24 h, p<0.01; B) 37.5 mg q24
h vs 87.5 mg q12 h, p<0.001; 37.5 mg q24 h vs 125 mg q24 h,
p<0.01; 37.5 mg q12 h vs 87.5 mg q12 h, p<0.001; 87.5 mg q24
h vs 87.5 mg q12 h, p<0.001; 87.5 mg q12 h vs 125 mg q24 h,
p<0.001.
[0054] FIG. 20 shows a comparison of A) CL/F and B) V/F among
various dosing regimens. The box and whisker plot showed 10-90
percentile and range of observations with middle line representing
median value of a dosing regimen. Significant difference: A) 37.5
mg q24 h vs 87.5 mg q12 h, p<0.05; B) 37.5 mg q24 h vs 87.5 mg
q12 h, p<0.01.
[0055] FIG. 21 shows DV (observed concentrations) versus subject
ID.
[0056] FIG. 22 shows time (hours) versus subject ID.
[0057] FIG. 23 shows DV (observed concentrations) versus time after
dose (TAD).
[0058] FIG. 24 shows DV (observed concentrations) versus time
(hours).
[0059] FIG. 25 shows individual visual plots (SID 1-12) with
variation between observed concentration (DV) vs predicted
concentration (PRED) and individual predicted (IPRED) error vs time
(h).
[0060] FIG. 26 shows individual visual plots (SID 13-24) with
variation between observed concentration (DV) vs predicted
concentration (PRED) and individual predicted (IPRED) error vs time
(h).
[0061] FIG. 27 shows individual visual plots (SID 25-30) with
variation between observed concentration (DV) vs predicted
concentration (PRED) and individual predicted (IPRED) error vs time
(h).
[0062] FIG. 28 shows a summary of average plasma concentration per
time point from pharmacokinetic studies of udenafil in Fontan's
patients. Data are shown as mean+/-standard deviation.
[0063] FIG. 29 shows non-compartmental analysis of udenafil in
Fonatn's patients stratified by dosing regimens. Data are shown as
mean+/-standard deviation.
[0064] FIG. 30 shows a goodness of fit plot of observed data versus
predicted data (DV vs. PRED).
[0065] FIG. 31 shows a goodness of fit plot of observed data versus
individual predicted data (DV vs. IPRED).
[0066] FIG. 32 shows a goodness of fit plot of observed data versus
predicted data (DV vs. PRED) of the final model.
[0067] FIG. 33 shows a goodness of fit plot of observed data versus
individual predicted data (DV vs. IPRED) of the final model.
[0068] FIG. 34 shows characteristic Fontan physiology.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
I. Fontan Physiology
[0069] The Fontan physiology is the definitive palliation for those
classes of congenital heart defects that share the common feature
of a functional single ventricle. They include defects that result
in hypoplastic left or right ventricles. Usually through a series
of 2 or 3 operations, the systemic and pulmonary circulations are
separated to eliminate the mixing of oxygenated and un-oxygenated
blood. This is accomplished by directly attaching the superior and
inferior vena cavae to the pulmonary arteries. This results in a
physiology that works as follows: (1) the single systemic ventricle
pumps oxygenated blood out the aorta to the body's systemic
vascular bed. (2) Next, the systemic venous blood then returns by
the vena cavae and flows passively through the pulmonary vascular
bed without the aid of a sub-pulmonary ventricle. (3) Finally,
oxygenated blood returns to the common systemic atrium and the
cycle is repeated. This anatomy is illustrated in FIG. 34.
[0070] The Fontan operation, which creates a total cavopulmonary
connection, separates the systemic and pulmonary circuits and
eliminates both hypoxemia and ventricular volume overload. However,
following the Fontan operation there is no ventricular pump to
propel blood into the pulmonary arteries. Instead blood returns to
the lungs via passive flow from the systemic veins. Thus, the major
physiologic consequence of this type of palliation is that
pulmonary blood flow is completely dependent upon the pressure
gradient from the systemic venous bed to the atrium. The normal
circulation flow through the pulmonary bed is augmented by the
increased pressure generated by the right ventricle. In a healthy
adolescent, this results in an increase of about 20 to 25 mm Hg in
the pressure present in the pulmonary arteries at rest, which may
double with exercise. With the Fontan physiology, there is no
sub-pulmonary ventricle and thus no augmentation of pressure as the
blood enters the pulmonary arteries. At rest, the pressure gradient
across the pulmonary vascular bed is significantly less. The
ability to increase this pressure gradient with exercise is
extremely limited by the body's ability to tolerate increasingly
elevated central venous pressures.
[0071] As a unique consequence of being entirely dependent upon the
passive drop in venous pressure to drive pulmonary blood flow, the
Fontan physiology is exquisitely sensitive to changes in pulmonary
vascular resistance. Even increases that are well within the normal
range for pulmonary resistance in normal physiology will have
detrimental effects on the Fontan physiology. Likewise any decrease
in resistance, even if this value is already normal, has the
potential to augment pulmonary blood flow. For this reason, the use
of udenafil offers a potential therapy that is unique to this class
of palliated congenital heart defects. Unlike other uses for PDE-5
inhibitors, this therapy would be to lower resistance in a
population without elevated pulmonary resistances or pressures.
This is a distinctly different use of this class of agents as
compared to patients with either structurally normal hearts and
pulmonary vascular disease or the very rare patient with congenital
heart disease palliated with a two ventricle repair (and thus
having a sub-pulmonary ventricle) and associated pulmonary vascular
disease.
II. Clinical Measurements Relevant to Fontan Patients
[0072] For children born with functional single ventricle
congenital heart disease, the Fontan procedure is the current
standard of care. The Fontan procedure is palliative, rather than
curative, and while it has greatly increased the survival of
pediatric subjects with functional single ventricle congenital
heart disease, the procedure also results in a series of side
effects and complications that can lead to late attrition of
patients, with complications such as arrhythmias, ventricular
dysfunction, and unusual clinical syndromes of protein-losing
enteropathy (PLE) and plastic bronchitis, as well as hepatic and
kidney complications.
[0073] In certain embodiments, the disclosed invention relates to
improving or preventing the decline of specific clinically relevant
measurements that are indicative of a patient's health following a
Fontan procedure. Such measurements include, but are not limited
to, exercise testing, vascular function testing, and
echocardiographic assessment of ventricular performance.
Exercise Testing
[0074] Exercise testing can include assessment of VO2 values during
maximal effort or at anaerobic threshold. VO2 max, or maximal
oxygen consumption, refers to the maximum amount of oxygen that an
individual can utilize during intense exercise. This measurement is
generally considered a reliable indicator of cardiovascular fitness
and aerobic endurance. Theoretically, the more oxygen a person can
use during high level exercise, the more energy that person can
produce. This test is the gold standard for cardiorespiratory
fitness because muscles need oxygen for prolonged (aerobic)
exercise; blood carries oxygen to the muscles and the heart must
pump adequate amounts of blood to meet the demands of aerobic
exercise.
[0075] VO2 is often measured by putting a mask on a subject, and
measuring the volume and gas concentrations of inhaled and expired
air. This measurement is often used in both clinical settings and
research and is considered the most accurate. Testing commonly
involves either exercising on a treadmill or riding a bike at
increasing intensity until exhaustion, and is designed to provide
readings at a maximal effort of the subject and/or at the subject's
anaerobic threshold.
[0076] Patients that have previously undergone a Fontan procedure
will generally see a decline in VO2 measurements over time.
Treating a patient with a method according to the invention such
that the patient's VO2 measurement are either maintained at a
similar level, demonstrating that there has been no further decline
in VO2 function, or improve with therapy indicates that the
treatment is clinically beneficial and may improve or prevent
decline in cardiovascular function.
[0077] In one embodiment, the invention is directed to a method of
improving or maintaining VO2 measurements of a subject who has
previously had a Fontan procedure. The method comprises
administering a therapeutically effective amount of a PDE5
inhibitor to the patient, where the PDE5 inhibitor is udenafil or a
pharmaceutically acceptable salt thereof. In some embodiments, VO2
is measured at maximal effort, while in other embodiments, VO2 is
measured at the subject's anaerobic threshold.
[0078] In some embodiments, the disclosed methods and compositions
are administered to a Fontan patient and result in no decrease, or
a minimal decrease, in exercise capacity over time. More
specifically, the disclosed methods and compositions may result in
a decrease in exercise capacity of less than about 40, less than
about 35, less than about 30, less than about 35, less than about
20, less than about 15, less than about 10, or less than about 5%
over time. The time period between a first and second measurement
used to calculate the decrease in exercise capacity can be, for
example, about 1, about 2, about 3, about 4, about 5, about 6,
about 7, about 8, about 9, about 10, about 11, or about 12 months;
about 1, about 2, about 3, about 4, about 5, about 6, about 7,
about 8, about 9, about 10, about 11, about 12, about 13, about 14,
or about 15 years, or any combination thereof, e.g., 1 year, 3
months; 4 years, 7 months, etc.
[0079] In some embodiments, the disclosed methods and compositions
may be administered to a Fontan patient and result in an
improvement of exercise capacity. More specifically, the disclosed
methods and compositions may result in a 1, 2, 5, 10, 15, 20, 25,
30, 35, 40, 45, or 50% or more improvement in VO2 at maximal
effort. Alternatively, the disclosed methods and compositions may
result in a 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% or more
improvement in VO2 at the patient's anaerobic threshold.
Vascular Function Testing
[0080] Vascular endothelial dysfunction is an important outcome for
assessing vascular health in intervention studies. It is now well
established that vascular endothelial dysfunction is positively
associated with traditional cardiovascular disease (CVD) risk
factors, and independently predicts cardiovascular events over
intervals of 1 to 6 years.
[0081] Pulse amplitude tonometry (PAT), a FDA-approved method for
assessing vascular function, is increasingly being used as an
alternative measure of endothelium-dependent dilation in response
to reactive hyperemia and flow-mediated dilation (FMD). The PAT
device records digital pulse wave amplitude (PWA) using fingertip
plethysmography. PWA can be measured continuously during three
phases: a quiet baseline period, 5-min forearm occlusion, and
reactive hyperemia following cuff release. Unlike FM D, PAT testing
is not dependent upon a highly skilled technician and post-test
analysis is largely automated. Most importantly, at least one
longitudinal study has shown that PAT measures of endothelial
function predict CVD events over a 6-year follow-up period. These
significant advantages may make PAT testing suitable for clinical
practice if prognostic significance and reliability can be
verified.
[0082] Patients that have previously undergone a Fontan procedure
will generally see a decline in vascular function over time.
Treating a patient such that the patient's vascular function
increases or preventing further decline in vascular function would
indicate that the treatment is clinically beneficial and may
improve patient quality of life or prevent decline in
cardiovascular function.
[0083] In one embodiment, the invention is directed to a method of
improving or maintaining vascular function of a subject who has
previously had a Fontan procedure. The method comprises
administering a therapeutically effective amount of a PDE5
inhibitor to the patient, where the PDE5 inhibitor is udenafil or a
pharmaceutically acceptable salt thereof. In some embodiments,
vascular function is measured using a PAT index.
[0084] In some embodiments, the disclosed methods and compositions
are administered to a Fontan patient and result in no decrease, or
a minimal decrease, in vascular function over time. Vascular
function can be measured using any conventional known technique,
including but not limited to pulse amplitude tonometry
measurements, the natural log of reactive hyperemia index, Reactive
Hyperemia Index, Framingham RHI, area under the curve to
max-occlusion/control, average up to max-occlusion/control, and
other known EndoPAT indices. In some embodiments, vascular function
is measured using a PAT index. More specifically, the disclosed
methods and compositions may result in a decrease in vascular
function of less than about 40, less than about 35, less than about
30, less than about 35, less than about 20, less than about 15,
less than about 10, or less than about 5% over time. The time
period between a first and second measurement used to calculate the
decrease in vascular function can be, for example, about 1, about
2, about 3, about 4, about 5, about 6, about 7, about 8, about 9,
about 10, about 11, or about 12 months; about 1, about 2, about 3,
about 4, about 5, about 6, about 7, about 8, about 9, about 10,
about 11, about 12, about 13, about 14, or about 15 years, or any
combination thereof, e.g., 1 year, 3 months; 4 years, 7 months,
etc.
[0085] In some embodiments, the disclosed methods and compositions
may be administered to a Fontan patient and result in an
improvement of vascular function. Vascular function can be measured
using any conventional known technique, including but not limited
to pulse amplitude tonometry measurements, the natural log of
reactive hyperemia index, Reactive Hyperemia Index, Framingham RHI,
area under the curve to max-occlusion/control, average up to
max-occlusion/control, and other known EndoPAT indices. In some
embodiments, vascular function is measured using a PAT index. More
specifically, the disclosed methods and compositions may result in
about a 1, about 2, about 5, about 10, about 15, about 20, about
25, about 30, about 35, about 40, about 45, or about 50% or more
improvement in one or more measurements of vascular function,
including but not limited to pulse amplitude tonometry measurement,
the natural log of reactive hyperemia index, Reactive Hyperemia
Index, Framingham RHI, area under the curve to
max-occlusion/control, average up to max-occlusion/control, and
other known EndoPAT indices.
Echocardiographic Assessment of Ventricular Performance
[0086] Ventricular performance and cardiac contractility are
important measurements that can reveal impairment of cardiovascular
health before overt heart failure is present. Ventricular
performance can be assessed using echocardiographic methods and
quantified via a myocardial performance index or MPI. MPI is an
index that combines systolic and diastolic function. Specifically,
MPI is defined as the sum of isovolumic contraction time and
isovolumic relaxation time divided by the ejection time.
[0087] Various versions of MPI are known in the art, and each
version of MPI may be used to assess ventricular performance. For
instance, MPI indices may include but are not limited to blood pool
MPI, tissue doppler MPI, average isovolumetric contraction, and
average isovolumetric relaxation.
[0088] Patients that have previously undergone a Fontan procedure
will generally see a decline in ventricular performance over time.
Treating a patient such that the patient's ventricular performance
is maintained, exhibits minimal decrease over time, or increases
indicates that the treatment is clinically beneficial and may
improve patient quality of life or prevent decline in
cardiovascular function.
[0089] In one embodiment, the invention is directed to a method of
maintaining, producing a minimal decrease in, or increasing
ventricular performance of a subject who has previously had a
Fontan procedure. The method comprises administering a
therapeutically effective amount of a PDE5 inhibitor to the
patient, where the PDE5 inhibitor is udenafil or a pharmaceutically
acceptable salt thereof. In some embodiments, ventricular
performance is measured using a myocardial performance index (MPI).
In some embodiments, the MPI may be a blood pool MPI, while in
other embodiments the MPI may be a tissue doppler MPI.
[0090] In some embodiments, the disclosed methods and compositions
may be administered to a Fontan patient and result in minimal or no
decrease in ventricular performance over time. Ventricular
performance can be measured using any conventional known technique,
including but not limited to myocardial performance index (MPI),
blood pool MPI, tissue doppler MPI, average isovolumetric
contraction and relaxation, and other known ventricular performance
indices. More specifically, the disclosed methods and compositions
may result in a decrease in ventricular performance of less than
about 40, less than about 35, less than about 30, less than about
35, less than about 20, less than about 15, less than about 10, or
less than about 5% over time. The time period between a first and
second measurement used to calculate the decrease in ventricular
performance can be, for example, about 1, about 2, about 3, about
4, about 5, about 6, about 7, about 8, about 9, about 10, about 11,
or about 12 months; about 1, about 2, about 3, about 4, about 5,
about 6, about 7, about 8, about 9, about 10, about 11, about 12,
about 13, about 14, or about 15 years, or any combination thereof,
e.g., 1 year, 3 months; 4 years, 7 months, etc.
[0091] In some embodiments, the disclosed methods and compositions
may be administered to a Fontan patient and result in an
improvement of ventricular performance over time. Ventricular
performance can be measured using any conventional known technique,
including but not limited to myocardial performance index (MPI),
blood pool MPI, tissue doppler MPI, average isovolumetric
contraction and relaxation, and other known ventricular performance
indices. For example, the disclosed methods and compositions may
result in about a 1, about 2, about 5, about 10, about 15, about
20, about 25, about 30, about 35, about 40, about 45, or about 50%
or more improvement in ventricular performance, as measured by any
known technique, including but not limited to myocardial
performance index (MPI), blood pool MPI, tissue doppler MPI,
average isovolumetric contraction and relaxation, and other known
ventricular performance indices.
III. Methods According to the Invention
[0092] In one embodiment, the invention is directed to methods of
treating, preventing, or minimizing conditions, symptoms, or side
effects associated with a subject who has previously had a Fontan
procedure. The method comprises administering a therapeutically
effective amount of a PDE5 inhibitor to the patient, where the PDE5
inhibitor is udenafil or a pharmaceutically acceptable salt
thereof.
[0093] In the Fontan circulation, pulmonary blood flow is passive,
driven by the pressure difference between the systemic venous
circulation and the ventricular end-diastolic pressure. A
medication capable of allowing for more efficient transit of blood
through the pulmonary vascular bed can allow for improvement in
cardiac preload, and therefore improve cardiac output.
[0094] PDE5 inhibitors are a class of medications that reduce
pulmonary vascular resistance and improve ventricular performance
in patients with pulmonary hypertension and myocardial
dysfunction.
[0095] Some studies have evaluated the single-use or longer-term
use of sildenafil in children and young adults who have had the
Fontan procedure. However, sildenafil has a short half-life, and is
typically administered three to four times per day. Such an
administration schedule is not convenient and is likely to reduce
patient compliance. In addition, the administration of a short
half-life drug results in greater fluctuations of therapeutic
levels of drug, increasing the risk that the blood level of the
PDE5 inhibitor will drop below the therapeutically effective level
for parts of the day. The present inventors hypothesize that
administration of a PDE5 inhibitor having a longer half-life to
patients who have had the Fontan procedure will prevent or
ameliorate the decline in aerobic exercise performance in patients
following the Fontan procedure.
[0096] Patient compliance is critical for optimal therapeutic
efficacy, particularly for a drug that is to be taken daily for an
extended period of time, such as for several years or more. This is
particularly true for Fontan patients. In particular, individuals
that had the Fontan procedure most often die from heart failure,
stroke (thrombosis), or some unexplained sudden death. Of note is
the fact that the risk of death from heart failure is quite low
within 10 years of the Fontan procedure but increases with time
after 10 years post-Fontan.
http://bendantzer.wordpress.com/2013/03/13/fontan-circulation-success-or--
failure/.
[0097] Not surprisingly, as time passes from the date of the Fontan
procedure, the risk of death or need from a heart transplant
increases. This could be from some sudden death or heart failure,
but it could also be from a gradual decline in heart function. As
the years tick by after the Fontan procedure, heart function gets
worse, which is reflected in the decline in the ability to do
aerobic exercise. For example, for patients that had the Fontan
early in life, they may have exercise capacity that is highly
reduced (44%) compared to normal patients and this capacity to do
exercise tends to decline in a linear fashion each year (declines
2.6% each year). At thirty years of age, patients with Fontan
circulation have much reduced exercise capacity (55% less than
normal) and the number of health problems and hospitalization rates
increase dramatically. This is probably not surprising since,
again, one ventricle is doing the work of two. Thus, methods
according to the invention which can diminish or significantly
decrease decline in heart function over time, are highly desirable
for Fontan patients. Key to the success of such methods is patient
compliance with a preferred dosing schedule.
[0098] Patient compliance, or lack thereof, to a prescribed dosing
schedule is known to be a critical factor in the success of any
therapy. In particular, quality healthcare outcomes depend upon
patients' adherence to recommended treatment regimens. Patient
nonadherence can be a pervasive threat to health and wellbeing and
carry an appreciable economic burden as well. In some disease
conditions, more than 40% of patients sustain significant risks by
misunderstanding, forgetting, or ignoring healthcare advice.
Moreover, when preventive or treatment regimens are very complex
and/or require lifestyle changes and the modification of existing
habits, nonadherence can be as high as 70%. Martin et al., Ther.
Clin. Risk Manag., 1(3): 189-199 (2005) ("A significant barrier to
effective medical treatment, however, is the patient's failure to
follow the recommendations of his or her physician or other
healthcare provider."). Thus, a therapy that can produce the
desired results (e.g., improved cardiac output, decreased pulmonary
vascular resistance, improved exercise capacity, improved
myocardial performance, preventing or ameliorating the decline in
aerobic exercise performance), with a preferred once or twice a day
dosage, as compared to multiple daily dosages--e.g., 3 to 6.times.
daily--required to be taken at least 4 to 6 hours apart, such as
with sildenafil, is highly desirable. Such a more simplistic dosing
regimen is likely to lead to a significant increase in patient
compliance, and concomitant improved therapeutic results.
[0099] In one embodiment, the invention is directed to a method of
improving cardiac output in a patient who has had the Fontan
procedure, the method comprising administering a therapeutically
effective amount of the PDE5 inhibitor udenafil, or a
pharmaceutically acceptable salt thereof, to the patient. For
example, the method of the invention can result in an improvement
in cardiac output, as compared to a subject who is not administered
udenafil, of about 5%, about 8%, about 10%, about 15%, about 20%,
about 25%, about 30%, about 35%, about 40%, about 45%, or about
50%.
[0100] In another embodiment, the invention is directed to a method
of decreasing pulmonary vascular resistance in a patient who has
had the Fontan procedure, the method comprising administering a
therapeutically effective amount of the PDE5 inhibitor udenafil, or
a pharmaceutically acceptable salt thereof, to the patient. For
example, the method of the invention can result in an decreased
pulmonary vascular resistance, as compared to a subject who is not
administered udenafil, of about 5%, about 8%, about 10%, about 15%,
about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,
or about 50%.
[0101] In yet another embodiment, the invention is directed to a
method of improving exercise capacity in a patient who has had the
Fontan procedure, the method comprising administering a
therapeutically effective amount of the PDE5 inhibitor udenafil, or
a pharmaceutically acceptable salt thereof, to the patient. For
example, the method of the invention can result in an increase in
exercise capacity measured by maximal VO2, as compared to a subject
who is not administered udenafil, of about 5%, about 8%, about 10%,
about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,
about 45%, or about 50%.
[0102] In one embodiment, the invention is directed to a method of
improving myocardial performance in a patient who has had the
Fontan procedure, the method comprising administering a
therapeutically effective amount of a PDE5 inhibitor to the
patient. For example, the method of the invention can result in an
improvement in myocardial performance, as compared to a subject who
is not administered udenafil, of about 5%, about 8%, about 10%,
about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,
about 45%, or about 50%.
[0103] In one embodiment, the invention is directed to a method of
preventing or ameliorating the decline in aerobic exercise
performance in a patient who has had the Fontan procedure, the
method comprising administering a therapeutically effective amount
of the PDE5 inhibitor udenafil, or a pharmaceutically acceptable
salt thereof, to the patient. For example, the method of the
invention can result in an amelioration of the decline in aerobic
exercise performance measured by maximal VO2, as compared to a
subject who is not administered udenafil, of about 5%, about 8%,
about 10%, about 15%, about 20%, about 25%, about 30%, about 35%,
about 40%, about 45%, or about 50%.
[0104] In yet another embodiment, the invention is directed to
improved methods for treating a patient who has had a Fontan
procedure, wherein the methods show an improvement in patient
compliance with a dosing schedule of udenafil or a pharmaceutically
acceptable salt thereof, as compared to patients prescribed a
non-udenafil drug.
[0105] Udenafil has a half-life of 7.3-12.1 hours, and is believed
to possibly have a much better safety profile as compared to
sildenafil or tadalafil. Udenafil has unique properties, with a
T.sub.max of 1.0-1.5 h and a T.sub.1/2 of 11-13 h (a relatively
rapid onset and a long duration of action). Therefore, both
on-demand and once-daily use of udenafil have been reported.
Udenafil's efficacy and tolerability have been evaluated in several
studies, and recent and continuing studies have demonstrated
udenafil's promise in both dosing regimens. Presently, tadalafil is
the only FDA-approved drug for daily dosing, but udenafil can be
used as a once-daily dose for erectile dysfunction patients who
cannot tolerate tadalafil due to phosphodiesterase subtype
selectivity. Gu Kang et al., Ther. Adv. Urol., 5(2): 101-110
(2013). Once-daily dosing of udenafil was evaluated for the
treatment of erectile dysfunction (ED), and the results showed that
udenafil significantly improved erectile function among ED patients
when administered in doses of 50 mg or 75 mg once daily for 12 wk.
Zhao et al., Eur. J. of Urology, 60: 380-387 (2011). While these
reports suggest that udenafil may be useful as a once a day therapy
for various conditions, other reports show that PDE5 inhibitors
show varying efficacy in treating symptoms associated with the
Fontan operation. Sabri et al., Pediatr. Cardiol., 35(4):699-704
(2014).
[0106] Thus, it was surprising that the present invention, directed
to methods of treating, minimizing, and/or preventing symptoms
associated with the Fontan operation comprising administering
udenafil or a pharmaceutically acceptable salt thereof, shows
desirable results, preferably with a once or twice a day dosage.
"Desirable results" include, but are not limited to, improved
cardiac output, decreased pulmonary vascular resistance, improved
exercise capacity, improved myocardial performance, preventing or
ameliorating the decline in aerobic exercise performance, and/or an
improvement in patient compliance.
[0107] In one embodiment of the invention, once a day
administration of a therapeutically effective dosage of uldenafil,
or a pharmaceutically acceptable salt thereof, results in
therapeutic levels of uldenafil, present in the patient's blood
stream, for up to about 8 hours. In other embodiments of the
invention, once a day administration of a therapeutically effective
dosage of uldenafil, or a pharmaceutically acceptable salt thereof,
results in therapeutic levels of uldenafil, present in the
patient's blood stream, for up to about 10, about 11, about 12,
about 13, about 14, about 15, about 16, about 17, about 18, about
19, about 20, about 21, about 22, about 23, or about 24 hours.
[0108] In one embodiment of the invention, twice a day
administration of a therapeutically effective dosage of udenafil,
or a pharmaceutically acceptable salt thereof, results in
therapeutic levels of udenafil for at least about 16 hours in a 24
hour dosing period. In other embodiments, twice a day
administration of a therapeutically effective dosage of udenafil,
or a pharmaceutically acceptable salt thereof, results in
therapeutic levels of udenafil for at least about 9 hours, about 10
hours, about 11 hours, about 12 hours, about 13 hours, about 14
hours, about 15 hours, about 16 hours, about 17 hours, about 18
hours, about 19 hours, about 20 hours, about 21 hours, about 22
hours, about 23 hours, or about 24 hours, in a 24 hour dosing
period.
[0109] In another embodiment, it was surprising that that the
methods of the invention show improved results as compared to prior
art treatments using a non-udenafil PDE5 inhibitor, such as
sildenafil or tadalafil. In yet another embodiment, it was
surprising that the methods of the invention show fewer side
effects, and/or less severe side effects, as compared to prior art
treatments using a non-udenafil PDE5 inhibitor, such as sildenafil
or tadalafil.
[0110] In one embodiment, it is surprising that the administration
of twice a day udenafil or a pharmaceutically acceptable salt
thereof results in fewer side effects than the administration of
once a day udenafil or a pharmaceutically acceptable salt thereof.
In another embodiment, it is surprising that twice a day
administration of udenafil or a pharmaceutically acceptable salt
thereof can achieve therapeutically effective levels of udenafil at
a lower total daily dosage than a once a day administration.
[0111] In one embodiment, the patient who has had the Fontan
procedure is a human patient. In one embodiment, the patient is an
adult human patient over about 18 years of age. In another
embodiment, the patient is a pediatric patient of about 2 to about
18 years of age. In another embodiment, the patient is a pediatric
patient of about 12 to about 18 years of age, or from about 12 to
about 16 years of age.
IV. Pediatric Patients
[0112] Treatment of pediatric patients presents particular
challenges, as pediatric physiology is not just a miniature version
of an adult. Physical size is just one of the many differences.
Children's body surface area, organ and system maturity and
function, as well as cognitive and emotional development can result
in differences in response to illness, diagnosis, treatment, and
medications. Even illnesses that are seen in adults can act
differently in children because of their unique anatomy and
physiology. Moreover, pediatric patients process drugs differently
than adults, and therefore the effects as well as the dosages of
drugs may vary widely from those observed with adults. Since
children differ from adults in many ways beyond size, simply
adjusting the dose of a drug for a smaller size person will not
necessarily produce the same response and can lead to adverse drug
reactions. Thus, the effectiveness of a drug used in treating an
adult condition does not with certainty predict success of treating
a pediatric patient with the same drug.
[0113] Thus, the invention is also directed to the surprising
discovery that pediatric Fontan patients can be successfully
treated with the methods of the invention. The methods comprise
administering a therapeutically effective amount of a PDE5
inhibitor to the pediatric patient, where the PDE5 inhibitor is
udenafil or a pharmaceutically acceptable salt thereof.
[0114] The structure of udenafil is shown below:
##STR00003##
V. Doses and Dosage Forms
[0115] In one embodiment, the udenafil or a pharmaceutically
acceptable salt thereof is administered at total daily dosage
amounts of about 0.01 to about 150 mg/kg. In another embodiment,
the udenafil or a pharmaceutically acceptable salt thereof is
administered at total daily doses of about 0.01 mg/kg up to about
30 mg/kg. In another embodiment, the udenafil or a pharmaceutically
acceptable salt thereof is administered at total daily doses of
about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,
about 27.5 mg, about 30 mg, about 32.5, about 35 mg, about 37.5 mg,
about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, about 50
mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75
mg, about 80 mg, about 85 mg, about 87.5 mg, about 90 mg, about 95
mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about
200 mg, about 225 mg, about 250 mg, or about 275 mg. In one
embodiment, the udenafil or a pharmaceutically acceptable salt
thereof is administered in total daily doses of about 25 mg, about
37.5 mg, about 50 mg, about 75 mg, about 87.5 mg, 125 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, or about 700 mg. In another particular
embodiment, udenafil or a pharmaceutically acceptable salt thereof
is administered at a total daily dose of about 37.5 mg, about 75
mg, about 87.5 mg, 125 mg, or about 175 mg.
[0116] In one embodiment, the udenafil or a pharmaceutically
acceptable salt thereof is administered once a day.
[0117] In another embodiment, the udenafil or a pharmaceutically
acceptable salt thereof is administered twice a day. In one
embodiment, the udenafil or a pharmaceutically acceptable salt
thereof is administered twice a day such that therapeutically
effective blood levels are maintained for at least about 18, about
19, about 20, about 21, about 22, about 23 or about 24 hours of a
24 hour dosing period. In some embodiments, the total daily dosage
amount of udenafil or a pharmaceutically acceptable salt
administered twice a day is less than the total daily dosage amount
of udenafil or a pharmaceutically acceptable salt thereof
administered once a day. In some embodiments, the total daily
dosage amount of udenafil or a pharmaceutically acceptable salt
thereof administered twice a day, maintains therapeutically
effective blood levels for the same number of hours in a 24 hour
period as a higher dosage of udenafil or a pharmaceutically
acceptable salt thereof when administered once a day. In other
embodiments, the total daily dosage amount of udenafil or a
pharmaceutically acceptable salt thereof administered twice a day,
maintains therapeutically effective blood levels for a higher
number of hours in a 24 hour period as the same dosage of udenafil
or a pharmaceutically acceptable salt thereof when administered
once a day.
[0118] In some embodiments, the udenafil or a pharmaceutically
acceptable salt thereof administered twice a day produces a greater
reduction in the conditions, symptoms, or side effects associated
with a subject who has previously had a Fontan procedure, when
compared to udenafil or a pharmaceutically acceptable salt thereof
administered once a day.
[0119] In some embodiments, the pharmaceutically acceptable salt of
udenafil is an acid addition salt. In one embodiment, the acid
addition salt of udenafil is an inorganic acid addition salt such
as, hydrochloric, hydrobromic, sulfuric, or phosphoric acid
addition salt. In another embodiment, the acid addition salt is an
organic acid addition salt such as citrate, tartarate, acetate,
lactate, maleate, fumarate, gluconate, methanesulfonate (mesylate),
glycolate, succinate, p-toluenesulfonate (tosylate), galacturonate,
embonate, glutamate, aspartate, oxalate, benzensulfonate,
camphorsulfonate, cinnamate, adipate, or cyclamate. In a particular
embodiment, the pharmaceutically acceptable salt of udenafil is an
oxalate, benzensulfonate, camphorsulfonate, cinnamate, adipate, or
cyclamate salt.
[0120] In one embodiment the udenafil or a pharmaceutically
acceptable salt thereof is administered as a pharmaceutical
composition. In one embodiment, the pharmaceutical composition
comprising udenafil or a pharmaceutically acceptable salt thereof
can be formulated in a wide variety of oral or parenteral dosage
forms on clinical application. Each of the dosage forms can contain
various disintegrating agents, surfactants, fillers, thickeners,
binders, diluents such as wetting agents or other pharmaceutically
acceptable excipients.
[0121] The udenafil composition can be administered using any
pharmaceutically acceptable method, such as intranasal, buccal,
sublingual, oral, rectal, ocular, parenteral (intravenously,
intradermally, intramuscularly, subcutaneously, intracisternally,
intraperitoneally), pulmonary, intravaginal, locally administered,
topically administered, topically administered after scarification,
mucosally administered, via an aerosol, or via a buccal or nasal
spray formulation.
[0122] Further, the udenafil composition can be formulated into any
pharmaceutically acceptable dosage form, such as a solid dosage
form, tablet, pill, lozenge, capsule, liquid dispersion, gel,
aerosol, pulmonary aerosol, nasal aerosol, ointment, cream,
semi-solid dosage form, and a suspension. Further, the composition
may be a controlled release formulation, sustained release
formulation, immediate release formulation, or any combination
thereof. Further, the composition may be a transdermal delivery
system.
[0123] In another embodiment, the pharmaceutical composition
comprising udenafil or a pharmaceutically acceptable salt thereof
can be formulated in a solid dosage form for oral administration,
and the solid dosage form can be powders, granules, capsules,
tablets or pills. In yet another embodiment, the solid dosage form
can include one or more excipients such as calcium carbonate,
starch, sucrose, lactose, microcrystalline cellulose or gelatin. In
addition, the solid dosage form can include, in addition to the
excipients, a lubricant such as talc or magnesium stearate. In some
embodiments, the oral dosage form can be immediate release, or a
modified release form. Modified release dosage forms include
controlled or extended release, enteric release, and the like. The
excipients used in the modified release dosage forms are commonly
known to a person of ordinary skill in the art.
[0124] In a further embodiment, the pharmaceutical composition
comprising udenafil or a pharmaceutically acceptable salt thereof
can be formulated as a sublingual or buccal dosage form. Such
dosage forms comprise sublingual tablets or solution compositions
that are administered under the tongue and buccal tablets that are
placed between the cheek and gum.
[0125] In yet a further embodiment, the pharmaceutical composition
comprising udenafil or a pharmaceutically acceptable salt thereof
can be formulated as a nasal dosage form. Such dosage forms of the
present invention comprise solution, suspension, and gel
compositions for nasal delivery.
[0126] In one embodiment, the pharmaceutical composition can be
formulated in a liquid dosage form for oral administration, such as
suspensions, emulsions or syrups. In other embodiments, the liquid
dosage form can include, in addition to commonly used simple
diluents such as water and liquid paraffin, various excipients such
as humectants, sweeteners, aromatics or preservatives. In
particular embodiments, the composition comprising udenafil or a
pharmaceutically acceptable salt thereof can be formulated to be
suitable for administration to a pediatric patient.
[0127] In one embodiment, the pharmaceutical composition can be
formulated in a dosage form for parenteral administration, such as
sterile aqueous solutions, suspensions, emulsions, non-aqueous
solutions or suppositories. In other embodiments, the non-aqueous
solutions or suspensions can include propyleneglycol,
polyethyleneglycol, vegetable oils such as olive oil or injectable
esters such as ethyl oleate. As a base for suppositories, witepsol,
macrogol, tween 61, cacao oil, laurin oil or glycerinated gelatin
can be used.
[0128] The dosage of the pharmaceutical composition can vary
depending on the patient's weight, age, gender, administration time
and mode, excretion rate, and the severity of disease.
VI. Adverse Events
[0129] Adverse events are an important consideration, particularly
when treating a susceptible population such as pediatric patients
with Fontan physiology. PDE-5 inhibitors may produce adverse events
including eye and/or hearing issues. Therefore, developing methods
in which PDE-5 inhibitors such as udenafil or a pharmaceutically
acceptable salt thereof can safely be administered to pediatric
patients is one aspect of the invention.
[0130] In some embodiments, a pediatric patient with Fontan
physiology may be administered a PDE-5 inhibitor to treat,
minimize, and/or prevent the deleterious effects of Fontan
physiology.
[0131] In some embodiments, administering the PDE-5 inhibitor,
specifically udenafil or a pharmaceutically acceptable salt
thereof, results in minimal if any serious adverse events. In other
embodiments, administering the PDE-5 inhibitor, specifically
udenafil or a pharmaceutically acceptable salt thereof, results in
minimal if any unexpected adverse events.
[0132] In some embodiments, a pediatric patient with Fontan
physiology being administered udenafil or a pharmaceutically
acceptable salt thereof may experience only mild adverse events
related to the medication, and in other embodiments, the patient
may experience only moderate adverse events related to the
medication. In some embodiments, a pediatric patient with Fontan
physiology being administered udenafil or a pharmaceutically
acceptable salt thereof may experience fewer, less frequent, or
less severe adverse events compared to a Fontan patient receiving
another PDE-5 inhibitor.
VII. Pharmacokinetic Parameters
[0133] Pharmacokinetics refers to the absorption, distribution,
metabolism, and excretion of a drug once it has been administered
to a subject. The kinetics of a drug have an impact on the drug's
efficacy and toxicity. A given drug's kinetic profile can depend
not only on the compound itself, but also on the size of the dose
and the dosing regimen as well as how the drug is formulated and
administered. Pharmacokinetic parameters that may be useful in
determining clinical utility include but are not limited to plasma
concentration, plasma concentration over time, maximum plasma
concentration (C.sub.max), time to reach maximum concentration
(T.sub.max), area under concentration time curve within the dosing
interval (AUC.sub..tau.), daily area under concentration time curve
at steady state (AUC.sub.0-24); CL/F, apparent clearance; V/F,
apparent volume of distribution; ke, elimination rate constant;
T1/2, terminal half-life.
[0134] In some embodiments, the disclosed invention is directed to
methods of administering udenafil or a pharmaceutically acceptable
salt thereof to a patient with Fontan physiology, wherein the
administration results in a unique pharmacokinetic profile. For
instance, in some embodiments the disclosed methods can produce
plasma concentrations of udenafil ranging from about 10 to about
700 ng/ml, about 50 to about 650 ng/ml, about 100 to about 600
ng/ml, about 150 to about 550 ng/ml, or about 200 to about 500
ng/ml. In other words, dosing regimens of the disclosed methods may
result in sustained plasma concentrations of udenafil above 25, 50,
75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375,
400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, or 700
ng/ml. In some embodiments, the plasma concentration is maintained
above about 140 ng/ml.
[0135] In some embodiments, the disclosed methods include a
characteristic pharmacokinetic profile in which the C.sub.max is
about 25, about 50, about 75, about 100, about 125, about 150,
about 175, about 200, about 225, about 250, about 275, about 300,
about 325, about 350, about 375, about 400, about 425, about 450,
about 475, about 500, about 525, about 550, about 575, about 600,
about 625, about 650, about 675, or about 700 ng/ml. In some
embodiments, the C.sub.m, is about 506.
[0136] In some embodiments, the disclosed methods include a
characteristic pharmacokinetic profile in which the T.sub.m, is
about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2,
1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,
2.6, 2.7, 2.8, 2.9, or 3.0 hours (hr). In some embodiments, the
T.sub.max is about 1.3 hr.
[0137] In some embodiments, the disclosed methods include a
characteristic pharmacokinetic profile in which the area under the
curve (AUC) is unique to a therapeutically effective dose of
udenafil in a Fontan's patient. For instance AUC.tau. is between
750 and 4500 nghr/ml, 800-4000 nghr/ml, or 850-3500 nghr/ml. More
specifically AUC.tau. is about 750, about 800, about 850, about
900, about 950, about 1000, about 1050, about 1100, about 1150,
about 1200, about 1250, about 1300, about 1400, about 1500, about
1600, about 1700, about 1800, about 1900, about 2000, about 2100,
about 2200, about 2300, about 2400, about 2500, about 2600, about
2700, about 2800, about 2900, about 3000, about 3100, about 3200,
about 3300, about 3400, about 3500, about 3600, about 3700, about
3800, about 3900, about 4000, about 4100, about 4200, about 4300,
about 4400, or about 4500 nghr/ml. In some embodiments, the
AUC.sub..tau. is about 3350.
[0138] In some embodiments, AUC.sub.0-24 is between 750 and 8500
nghr/ml, 800-8000 nghr/ml, or 850-7500 nghr/ml. More specifically
AUC.sub.0-24 is about 750, about 800, about 850, about 900, about
950, about 1000, about 1050, about 1100, about 1150, about 1200,
about 1250, about 1300, about 1400, about 1500, about 1600, about
1700, about 1800, about 1900, about 2000, about 2100, about 2200,
about 2300, about 2400, about 2500, about 2600, about 2700, about
2800, about 2900, about 3000, about 3100, about 3200, about 3300,
about 3400, about 3500, about 3600, about 3700, about 3800, about
3900, about 4000, about 4100, about 4200, about 4300, about 4400,
about 4500, about 4600, about 4700, about 4800, about 4900, about
5000, about 5100, about 5200, about 5300, about 5400, about 5500,
about 5600, about 5700, about 5800, about 5900, about 6000, about
6100, about 6200, about 6300, about 6400, about 6500, about 6600,
about 6700, about 6800, about 6900, about 7000, about 7100, about
7200, about 7300, about 7400, about 7500, about 7600, about 7700,
about 7800, about 7900, about 8000, about 8100, about 8200, about
8300, about 8400, or about 8500 nghr/ml. In some embodiments, the
AUC.sub.0-24 is about 6700.
[0139] In some embodiments, the pharmacodynamics results of
administering udenafil to a patient with Fontan's physiology can be
attributed to the characteristic pharmacokinetic profile of the
drug administration or regimen.
VIII. Definitions
[0140] As used herein, the term "about" will be understood by
persons of ordinary skill in the art and will vary to some extent
depending upon the context in which it is used. If there are uses
of the term which are not clear to persons of ordinary skill in the
art given the context in which it is used, "about" will mean up to
plus or minus 10% of the particular term.
[0141] "A treatment" is intended to target the disease state and
combat it, i.e., ameliorate or prevent the disease state. The
particular treatment thus will depend on the disease state to be
targeted and the current or future state of medicinal therapies and
therapeutic approaches. A treatment may have associated
toxicities.
[0142] The terms "administration of" or "administering" an active
agent should be understood to mean providing an active agent of the
invention to the subject in need of treatment in a form that can be
introduced into that individual's body in a therapeutically useful
form and therapeutically effective amount.
[0143] The term "therapeutically effective amount" refers to a
sufficient quantity of the active agents of the present invention,
in a suitable composition, and in a suitable dosage form to treat
or prevent the symptoms, progression, or onset of the complications
seen in patients who have had the Fontan procedure. The
therapeutically effective amount will vary depending on the state
of the patient's condition or its severity, and the age, weight,
etc., of the subject to be treated. A therapeutically effective
amount can vary, depending on any of a number of factors,
including, e.g., the route of administration, the condition of the
subject, as well as other factors understood by those in the
art.
[0144] The term "treatment" or "treating" generally refers to an
intervention in an attempt to alter the natural course of the
subject being treated, and can be performed either for prophylaxis
or during the course of clinical pathology. Desirable effects
include, but are not limited to, preventing occurrence or
recurrence of disease, alleviating symptoms, suppressing,
diminishing or inhibiting any direct or indirect pathological
consequences of the disease, ameliorating or palliating the disease
state, and causing remission or improved prognosis.
[0145] The terms "individual," "host." "subject," and "patient" are
used interchangeably herein.
[0146] As used herein, "improving cardiac output" means an increase
in the volume of blood pumped by the heart. The cardiac output is
commonly measured as a function of the oxygen consumption.
[0147] As used herein, the term "exercise capacity" refers to the
maximum amount of physical exertion that a patient can sustain.
Exercise capacity can be measured by a number of different clinical
methods, including by interview or by direct measurement. The
present methods include different methods of measuring exercise
capacity, including but not limited to, riding a cycle ergometer or
walking on a treadmill. Thus, the term "improving exercise
capacity" means increasing the ability of the patient to perform
any level of physical exertion or exercise.
[0148] As used herein, the term "decreasing pulmonary vascular
resistance" refers to decreasing or reducing the resistance offered
by lung vasculature to blood flow.
[0149] As used herein, "improving myocardial performance" refers to
an increase or decrease, as the case can be, in specific heart
function measurements, including but not limited to, specific
electrocardiographic readings, echocardiographic readings, cardiac
output measures, heart rate, systolic or diastolic pressure, forced
vital capacity, oxygen saturation, and respiratory rate.
[0150] As used herein, "aerobic exercise performance" refers to the
ability of a patient to perform a specified aerobic exercise.
[0151] As used herein, "pediatric" refers to a population of
subjects ranging between a newborn and about 18 years of age. A
pediatric subject can include a subject that begins a course of
treatment with the disclosed compositions or according to the
disclosed methods prior to turning about 18 years of age, even if
the subject continues treatment beyond 18 years of age. More
specifically, within the population of "pediatric" subjects,
neonates may be defined as 1 week to 1 month in age, infants may be
1 to less than 2 years of age, toddlers may be 2 to less than 6
years of age, and school age may refer to subjects 6-18 years of
age.
[0152] The following examples are given to illustrate the present
invention. It should be understood, however, that the invention is
not to be limited to the specific conditions or details described
in these examples. All printed publications referenced herein are
specifically incorporated by reference.
EXAMPLES
Example 1--Phase I/II Pharmacokinetic and Pharmacodynamic Study
[0153] A Phase I/II dose escalation trial of Udenafil in
adolescents with single ventricle physiology after Fontan
palliation was conducted.
[0154] The trial was conducted over a 5 month period, with an
additional 3 month follow-up period for adverse events (AE). The 36
subjects enrolled in the trial were comprised of 6 cohorts, as
described in Table 1.
TABLE-US-00001 TABLE 1 Dose escalation design Cohort 1 Cohort 2
Cohort 3 Cohort 4 Cohort 5 Cohort 6 Dose 37.5 mg 37.5 mg 87.5 mg
87.5 mg 125 mg Control daily twice daily daily twice daily daily
(no drug) N 6 6 6 6 6 6
[0155] The goals for this trial were to assess the safety of
udenafil at multiple dose levels over a five-day period, the
pharmacokinetic profile of udenafil in adolescents with Fontan
physiology, and the short-term effect of udenafil on
pharmacodynamic measures of exercise capacity, ventricular
performance, and vascular function.
[0156] Multiple doses of udenafil or a pharmaceutically acceptable
salt thereof were administered to male and female Fontan patients
who are 14-18 years of age.
[0157] Inclusion Criteria for the trial were: [0158] Males and
females with Fontan physiology who are 14-18 years of age. [0159]
Willingness to return to center to complete blood draws and
exercise tests as described in the study protocol. [0160] Patients
must agree to abstain from alcohol, caffeinated beverages, and
grapefruit juice for the duration of the trial. [0161] Informed
assent from subject and informed consent from parent/legal guardian
as appropriate.
[0162] Exclusion Criteria for the study include: [0163] Non-cardiac
medical, psychiatric, and/or social disorder that would prevent
successful completion of planned study testing or would invalidate
its results. [0164] Height <132 cm (minimum height requirement
for exercise stress testing). [0165] Known Fontan baffle
obstruction, branch pulmonary artery stenosis, or pulmonary vein
stenosis resulting in a mean gradient of >4 mmHg between the
regions proximal and distal to the obstruction. [0166] Single lung
physiology. [0167] Severe ventricular dysfunction or valvular
regurgitation (systemic atrioventricular or semilunar valve)
determined from review of the echocardiogram performed in closest
proximity to study enrollment. [0168] Significant renal (serum
creatinine >2.0), hepatic (serum AST and/or ALT >3 times
upper limit of normal), gastrointestinal or biliary disorders that
could impair absorption, metabolism or excretion of orally
administered medications, based on laboratory assessment at the
time of screening visit. [0169] Hospitalization for acute
decompensated heart failure within the 12 months preceding study
screening. [0170] A diagnosis of active protein-losing enteropathy
or plastic bronchitis. [0171] Active evaluation or listing for
heart transplant. [0172] History of use of a PDE5 inhibitor within
three months of study screening. [0173] Concurrent illness that, in
the opinion of the investigator, precludes participation. [0174]
Current therapy with alpha-blockers or nitrates. [0175] Pregnancy
at the time of enrollment. [0176] Latex allergy.
[0177] Table 2 presents baseline characteristics of 36 enrolled
subjects--in aggregate (2nd column) and for each of the 6
individual cohorts. Median age of enrolled subjects is 16 years
(with the range from 14 to 18 years), 58% were male, 78% were white
and 6% were Hispanic. There were no significant differences in
baseline characteristics among the cohorts (right column).
TABLE-US-00002 TABLE 2 Baseline Characteristics for Enrolled
Subjects Exercise 37.5 mg 87.5 mg 87.5 mg 125 mg testing P- Overall
37.5 mg twice daily daily twice daily daily only value
Characteristic (N = 36) daily (N = 6) (N = 6) (N = 6) (N = 6) (N =
6) (N = 6) * Age, year 15.8 .+-. 1.3 15.5 .+-. 1.0 16.2 .+-. 0.8
15.0 .+-. 0.9 15.5 .+-. 1.8 16.5 .+-. 1.5 16.2 .+-. 1.2 0.319
Median 16 (15, 17) 16 (15, 16) 16 (16, 17) 15 (14, 16) 15 (14, 17)
17 (16, 18) 16 (15, 17) 0.309 (Interquartile Range) Range, Min-
14-18 14-17 15-17 14-16 14-18 14-18 15-18 Max Male 21 (58.3%) 4
(66.7%) 3 (50.0%) 3 (50.0%) 3 (50.0%) 4 (66.7%) 4 (66.7%) 1.000
Hispanic or 2 (5.7%) 1 (16.7%) 1 (16.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
0 (0.0%) 1.000 Latino/Latina Race 0.453 White/Caucasian 28 (77.8%)
3 (50.0%) 4 (66.7%) 6 (100.0%) 6 (100.0%) 4 (66.7%) 5 (83.3%)
Black/African 3 (8.3%) 2 (33.3%) 1 (16.7%) 0 (0.0%) 0 (0.0%) 0
(0.0%) 0 (0.0%) American Other/Unknown 4 (11.1%) 1 (16.7%) 1
(16.7%) 0 (0.0%) 0 (0.0%) 1 (16.7%) 1 (16.7%) Weight, cm 165.7 .+-.
10.1 161.0 .+-. 12.9 164.9 .+-. 10.9 168.6 .+-. 7.8 164.7 .+-. 14.2
171.3 .+-. 7.8 163.6 .+-. 5.6 0.585 Weight, kg 62.4 .+-. 15.9 72.5
.+-. 27.1 56.3 .+-. 7.7 66.8 .+-. 11.0 62.0 .+-. 15.5 61.9 .+-. 9.0
54.9 .+-. 16.8 0.425 Body mass 22.6 .+-. 5.0 27.2 .+-. 8.1 20.8
.+-. 3.2 23.4 .+-. 3.2 22.6 .+-. 4.8 21.0 .+-. 2.0 20.3 .+-. 4.8
0.157 index, kg/m.sup.2 *P-values for continuous variables were
calculated by ANOVA for parametric analysis or Kruskal-Wallis test
for non-parametric analysis. P-values for categorical variables
were calculated by Fisher's exact test.
Example 2--Safety and Adverse Events
[0178] The purpose of this example was to describe and evaluate the
safety of the udenafil compositions administered in the study
described in Example 1.
[0179] Tables 3-6 present numbers of subjects reporting at least
one AE; data are presented by treatment group. The counts are
presented by AE category (Table 3) and by preferred term (Table 6).
Tables 3-6 report all AEs by category (Table 3), serious AEs (Table
4), non-serious AEs (Table 5), and all AEs by preferred term (Table
6). No serious AEs were reported.
TABLE-US-00003 TABLE 3 Adverse Events by Category Exercise 37.5 mg
37.5 mg 87.5 mg 87.5 mg 125 mg testing daily twice daily daily
twice daily daily only AE Category (N = 6) (N = 6) (N = 6) (N = 6)
(N = 6) (N = 6) Subjects Reporting at Least One 5 (83%) 6 (100%) 6
(100%) 5 (83%) 6 (100%) 1 (17%) Adverse Event Allergy/Immunology 1
(17%) 0 (0%) 1 (17%) 0 (0%) 0 (0%) 0 (0%) Auditory/ocula 0 (0%) 0
(0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Cardiovascular 0 (0%) 0 (0%) 0
(0%) 0 (0%) 0 (0%) 1 (17%) Endocrine/metabolic 0 (0%) 0 (0%) 0 (0%)
0 (0%) 1 (17%) 0 (0%) Gastrointestinal 2 (33%) 1 (17%) 1 (17%) 1
(17%) 3 (50%) 0 (0%) Hematological 0 (0%) 1 (17%) 0 (0%) 0 (0%) 1
(17%) 0 (0%) Hepatobiliary/pancreas 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0
(0%) 0 (0%) Infection 0 (0%) 0 (0%) 0 (0%) 1 (17%) 0 (0%) 0 (0%)
Musculoskeletal/skin 1 (17%) 1 (17%) 1 (17%) 2 (33%) 2 (33%) 0 (0%)
Neurological/psychiatric 3 (50%) 3 (50%) 5 (83%) 2 (33%) 5 (83%) 0
(0%) Pulmonary/upper respiratory 2 (33%) 3 (50%) 1 (17%) 1 (17%) 1
(17%) 0 (0%) Renal/genitourinary 0 (0%) 2 (33%) 1 (17%) 0 (0%) 0
(0%) 0 (0%) Sexual/reproductive function 0 (0%) 0 (0%) 0 (0%) 2
(33%) 2 (33%) 0 (0%) Vascular 1 (17%) 2 (33%) 4 (67%) 1 (17%) 1
(17%) 0 (0%) Other 0 (0%) 2 (33%) 4 (67%) 3 (50%) 2 (33%) 0 (0%) At
each level of summation, subjects reporting more than one adverse
event are counted only once. N = number of subjects in each cohort.
n (%) = number and percentage of subjects in category and cohort
(n/N .times. 100)
TABLE-US-00004 TABLE 4 Serious Adverse Events 37.5 mg 37.5 mg 87.5
mg 87.5 mg 125 mg Exercise daily twice daily daily twice daily
daily testing only AE Category (N = 6) (N = 6) (N = 6) (N = 6) (N =
6) (N = 6) Subjects Reporting at Least One 0 (0%) 0 (0%) 0 (0%) 0
(0%) 0 (0%) 0 (0%) Adverse Event Serious adverse events were not
reported for this trial. At each level of summation, subjects
reporting more than one adverse event are counted only once. N =
number of subjects in each cohort. n(%) = number and percentage of
subjects in category and cohort (n/N .times. 100)
TABLE-US-00005 TABLE 5 Non-Serious Adverse Events 37.5 mg 37.5 mg
87.5 mg 87.5 mg 125 mg Exercise daily twice daily daily twice daily
daily testing only AE Category (N = 6) (N = 6) (N = 6) (N = 6) (N =
6) (N = 6) Subjects Reporting at Least One 5 (83%) 6 (100%) 6
(100%) 5 (83%) 6 (100%) 1 (17%) Adverse Event At each level of
summation, subjects reporting more than one adverse event are
counted only once. N = number of subjects in each cohort. n(%) =
number and percentage of subjects in category and cohort (n/N
.times. 100)
TABLE-US-00006 TABLE 6 Adverse Events by Preferred Term 37.5 mg
87.5 mg Exercise 37.5 mg twice 87.5 mg twice 125 mg testing daily
daily daily daily daily only Preferred Term (N = 6) (N = 6) (N = 6)
(N = 6) (N = 6) (N = 6) Subjects Reporting, at Least 5 (83%) 6
(100%) 6 (100%) 5 (83%) 6 (100%) 1 (17%) One Adverse Event
Abdominal discomfort 1 (17%) 0 (0%) 0 (0%) 1 (17%) 1 (17%) 0 (0%)
Abdominal pain upper 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (17%) 0 (0%)
Back pain 0 (0%) 0 (0%) 0 (0%) 1 (17%) 0 (0%) 0 (0%) Chest pain 0
(0%) 0 (0%) 0 (0%) 0 (0%) 1 (17%) 0 (0%) Diarrhoea 0 (0%) 0 (0%) 0
(0%) 0 (0%) 1 (17%) 0 (0%) Dizziness 0 (0%) 0 (0%) 0 (0%) 1 (17%) 1
(17%) 0 (0%) Dry mouth 0 (0%) 0 (0%) 1 (17%) 0 (0%) 0 (0%) 0 (0%)
Dysmenorrhoea 0 (0%) 1 (17%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Dyspnoea 1
(17%) 1 (17%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Epistaxis 0 (0%) 1 (17%)
0 (0%) 0 (0%) 2 (33%) 0 (0%) Face oedema 0 (0%) 0 (0%) 0 (0%) 0
(0%) 1 (17%) 0 (0%) Fatigue 0 (0%) 1 (17%) 0 (0%) 1 (17%) 0 (0%) 0
(0%) Flushing 1 (17%) 2 (33%) 4 (67%) 2 (33%) 1 (17%) 0 (0%) Head
injury 0 (0%) 0 (0%) 1 (17%) 0 (0%) 0 (0%) 0 (0%) Headache 3 (50%)
4 (67%) 4 (67%) 4 (67%) 5 (83%) 0 (0%) Injection site pain 1 (17%)
0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Lacrimation increased 0 (0%) 0
(0%) 1 (17%) 0 (0%) 0 (0%) 0 (0%) Migraine 0 (0%) 0 (0%) 0 (0%) 0
(0%) 1 (17%) 0 (0%) Motion sickness 0 (0%) 0 (0%) 1 (17%) 0 (0%) 0
(0%) 0 (0%) Myalgia 0 (0%) 1 (17%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Nasal congestion 3 (50%) 2 (33%) 2 (33%) 1 (17%) 1 (17%) 0 (0%)
Nasopharyngitis 0 (0%) 1 (17%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) At each
level of summation, subjects reporting more than one adverse event
are counted only once. N = number of subjects in each cohort. n(%)
= number and percentage of subjects in category and cohort (n/N
.times. 100)
[0180] Table 7 presents narratives for all adverse events (limited
to non-serious at the moment of writing) classified by cohort,
subject, AE term, and preferred term.
TABLE-US-00007 TABLE 7 Related Subject Adverse Event Term// Onset
Resolution to Study Cohort ID* Preferred Term Date Date Severity
Drug Outcome Med..sup.1 Disc..sup.2 37.5 mg T12 Nausea//Nausea Aug.
5, 2014 Aug. 5, 2014 Moderate Possibly Resolved without sequelae No
No daily Nausea//Nausea Mild None Resolved without sequelae No NA
Headache//Headache Aug. 2, 2014 Aug. 2, 2014 Mild Possibly Resolved
without sequelae No No Headache//Headache Aug. 5, 2014 Aug. 5, 2014
Moderate Possibly Resolved without sequelae No No
headache//Headache Aug. 6, 2014 Aug. 7, 2014 Moderate Possibly
Resolved without sequelae No NA Headache//Headache Aug. 4, 2014
Aug. 4, 2014 Moderate Possibly Resolved without sequelae No No
headache//Headache Aug. 7, 2014 Aug. 7, 2014 Moderate Possibly
Resolved without sequelae No NA Stuffy nose//Nasal congestion Aug.
22, 2014 Aug. 29, 2014 Mild None Resolved without sequelae No NA
T13 Stomach discomfort//Abdominal Aug. 1, 2014 Aug. 1, 2014
Moderate None Resolved without sequelae No No discomfort
Headache//Headache Aug. 2, 2014 Aug. 5, 2014 Moderate Possibly
Resolved without sequelae No No Headache//Headache Aug. 7, 2014
Moderate Possibly Resolved without sequelae No No
Headache//Headache Mild Possibly Ongoing Yes NA Shortness of
breath//Dyspnoea Aug. 1, 2014 Aug. 1, 2014 Severe None Resolved
without sequelae No No Congestion (Nose)//Nasal Aug. 5, 2014
Moderate Possibly Resolved without sequelae No No congestion T14
Flushing//Flushing Aug. 1, 2014 Aug. 1, 2014 Mild Probably Resolved
without sequelae No No Flushing//Flushing Aug. 2, 2014 Aug. 3, 2014
Mild Probably Resolved without sequelae No No Headache//Headache
Aug. 1, 2014 Aug. 1, 2014 Moderate Possibly Resolved without
sequelae Yes No T15 Pain/other//Injection site pain Aug. 5, 2014
Aug. 8, 2014 Moderate None Resolved without sequelae Yes No T16
nasal congestion//Nasal Aug. 4, 2014 Aug. 5, 2014 Mild None
Resolved without sequelae No No congestion 37.5 mg T21 Nose
bleed//Epistaxis Moderate None Resolved without sequelae Yes NA
twice daily 37.5 mg T22 Shortness of breath//Dyspnoea Nov. 5, 2014
Nov. 5, 2014 Moderate None Resolved without sequelae Yes NA twice
daily upper respiratory infection// Nov. 2, 2014 Mild None Resolved
without sequelae No NA Upper respiratory tract infection Facial
flushing//Flushing Aug. 9, 2014 Aug. 9, 2014 Mild Possibly Resolved
without sequelae No No T23 Headache//Headache Aug. 8, 2014 Aug. 9,
2014 Mild Possibly Resolved without sequelae No No congestion
(stuffy nose)//Nasal Aug. 8, 2014 Aug. 8, 2014 Mild Possibly
Resolved without sequelae No No congestion cold/congestion// Sep.
14, 2014 Sep. 19, 2014 Mild None Resolved without sequelae No NA
Nasopharyngitis Menstrual Cramps// Aug. 11, 2014 Aug. 16, 2014 Mild
None Resolved without sequelae Yes No Dysmenorrhoea Facial
flushing//Flushing Aug. 10, 2014 Aug. 10, 2014 Mild Possibly
Resolved without sequelae No No T24 Nausea//Nausea Aug. 10, 2014
Aug. 10, 2014 Mild Possibly Resolved without sequelae No No
Nausea//Nausea Aug. 11, 2014 Aug. 11, 2014 Mild Possibly Resolved
without sequelae No No Soreness in chest and arms// Aug. 10, 2014
Aug. 11, 2014 Mild Possibly Resolved without sequelae No No Myalgia
Headache//Headache Aug. 8, 2014 Aug. 8, 2014 Mild Possibly Resolved
without sequelae No No Headache//Headache Mild Possibly Resolved
without sequelae Yes NA Congestion (stuffy nose)//Nasal Aug. 10,
2014 Aug. 10, 2014 Mild Possibly Resolved without sequelae No No
congestion Sponatenous penile erection// Aug. 11, 2014 Aug. 11,
2014 Mild Possibly Resolved without sequelae No No Sponatenous
penile erection Sponatenous penile erection// Aug. 14, 2014 Aug.
14, 2014 Mild Possibly Resolved without sequelae No NA Sponatenous
penile erection T25 Headache//Headache Aug. 8, 2014 Aug. 8, 2014
Mild Possibly Resolved without sequelae No No T26
Headache//Headache Aug. 9, 2014 Aug. 9, 2014 Mild Possibly Resolved
without sequelae Yes No Sinus pain//Sinus headache Aug. 9, 2014
Nov. 18, 2014 Mild Probably Resolved without sequelae No No
Headache//Headache Aug. 10, 2014 Sep. 22, 2014 Moderate Probably
Resolved without sequelae Yes No Fatigue//Fatigue Aug. 9, 2014 Aug.
10, 2014 Mild Possibly Resolved without sequelae No No 87.5 mg T31
headache//Headache Aug. 15, 2014 Aug. 15, 2014 Mild Probably
Resolved without sequelae No No daily headache//Headache Aug. 17,
2014 Aug. 17, 2014 Mild Probably Resolved without sequelae No No
headache//Headache Aug. 18, 2014 Aug. 18, 2014 Moderate Probably
Resolved without sequelae No No congestion (stuffy nose)//Sinus
Aug. 15, 2014 Aug. 21, 2014 Mild Probably Resolved without sequelae
No No congestion Facial flushing//Flushing Aug. 18, 2014 Aug. 18,
2014 Mild Probably Resolved without sequelae No No spotty
vision//Vision blurred Aug. 15, 2014 Aug. 15, 2014 Mild None
Resolved without sequelae No No T32 motion sickness//Motion Aug.
15, 2014 Aug. 15, 2014 Mild Possibly Resolved without sequelae No
No sickness headache//Headache Aug. 15, 2014 Aug. 15, 2014 Mild
Probably Resolved without sequelae Yes No headache//Headache Aug.
16, 2014 Aug. 16, 2014 Mild Probably Resolved without sequelae No
No headache//Headache Aug. 17, 2014 Aug. 17, 2014 Mild Probably
Resolved without sequelae No No dry mouth//Dry mouth Aug. 16, 2014
Aug. 16, 2014 Mild Possibly Resolved without sequelae No No T33
Head Injury//Head injury Aug. 21, 2014 Aug. 22, 2014 Mild None
Resolved without sequelae Yes NA facial flushing//Flushing Aug. 16,
2014 Aug. 22, 2014 Mild Probably Resolved without sequelae No No
tearing//Lacrimation increased Aug. 16, 2014 Aug. 22, 2014 Mild
None Resolved without sequelae No No T34 Sleepiness//Somnolence
Aug. 16, 2014 Aug. 25, 2014 Mild Possibly Resolved without sequelae
No No Sponatenous penile erection// Aug. 20, 2014 Aug. 20, 2014
Mild Possibly Resolved without sequelae No No Sponatenous penile
erection Facial flushing//Flushing Aug. 16, 2014 Aug. 21, 2014 Mild
Possibly Resolved with sequelae No No T35 headache//Headache Aug.
15, 2014 Aug. 15, 2014 Mild Probably Resolved without sequelae No
No 87.5 mg headache//Headache Aug. 16, 2014 Aug. 16, 2014 Mild
Probably Resolved without sequelae No No daily stuffy nose//Nasal
congestion Sep. 20, 2014 Sep. 23, 2014 Moderate None Resolved
without sequelae No NA T36 Nasal congestion//Nasal Aug. 19, 2014
Aug. 21, 2014 Mild Possibly Resolved without sequelae Yes No
congestion Flushing//Flushing Aug. 15, 2014 Aug. 15, 2014 Mild
Probably Resolved without sequelae No No Headache//Headache Aug.
15, 2014 Aug. 15, 2014 Mild Possibly Resolved without sequelae No
No 87.5 mg T42 Nausea/vomiting//Nausea Aug. 26, 2014 Aug. 26, 2014
Mild Possibly Resolved without sequelae No No twice daily Stomach
discomfort//Abdominal Aug. 22, 2014 Aug. 22, 2014 Mild Possibly
Resolved with sequelae No No discomfort Facial flushing//Flushing
Aug. 26, 2014 Aug. 26, 2014 Mild Probably Resolved without sequelae
No No Headache//Headache Aug. 23, 2014 Aug. 23, 2014 Mild Probably
Resolved without sequelae No No Headache//Headache Aug. 25, 2014
Aug. 25, 2014 Mild Probably Resolved without sequelae No No
Headache//Headache Aug. 24, 2014 Aug. 24, 2014 Mild Probably
Resolved without sequelae No No Headache//Headache Aug. 26, 2014
Aug. 26, 2014 Mild Probably Resolved without sequelae No No T43
headache//Headache Aug. 22, 2014 Aug. 22, 2014 Moderate Possibly
Resolved without sequelae No No headache//Headache Aug. 23, 2014
Aug. 23, 2014 Mild Possibly Resolved without sequelae No No
headache//Headache Aug. 24, 2014 Aug. 24, 2014 Mild Possibly
Resolved without sequelae No No T44 Stuffy nose//Nasal congestion
Aug. 22, 2014 Aug. 22, 2014 Mild Possibly Resolved without sequelae
No No Stuffy nose//Nasal congestion Aug. 25, 2014 Aug. 25, 2014
Mild Possibly Resolved without sequelae No No Stuffy nose//Nasal
congestion Aug. 25, 2014 Aug. 25, 2014 Mild Possibly Resolved
without sequelae No No sponatenous penile erection// Aug. 21, 2014
Aug. 21, 2014 Mild Possibly Resolved without sequelae No No
Sponatenous penile erection 87.5 mg Sponatenous penile erection//
Aug. 21, 2014 Aug. 21, 2014 Mild Possibly Resolved without sequelae
No No twice Sponatenous penile erection daily Sponatenous penile
erection// Aug. 22, 2014 Aug. 22, 2014 Mild Possibly Resolved
without sequelae No No Sponatenous penile erection sponatenous
penile erection// Aug. 25, 2014 Aug. 25, 2014 Mild Possibly
Resolved without sequelae No No Sponatenous penile erection
Sponatenous penile erection// Aug. 26, 2014 Aug. 26, 2014 Mild
Possibly Resolved without sequelae No No Sponatenous penile
erection Headache//Headache Aug. 21, 2014 Aug. 21, 2014 Mild
Possibly Resolved without sequelae No No Headache//Headache Aug.
22, 2014 Aug. 22, 2014 Mild Possibly Resolved without sequelae No
No headache//Headache Aug. 23, 2014 Aug. 23, 2014 Mild Possibly
Resolved without sequelae No No headache//Headache Aug. 24, 2014
Aug. 24, 2014 Mild Possibly Resolved without sequelae No No T45
sponatenous penile erection// Aug. 31, 2014 Aug. 31, 2014 Mild
Possibly Resolved without sequelae No No Sponatenous penile
erection T46 sinusitis//Sinusitis Aug. 26, 2014 Moderate None
Ongoing No No back pain//Back pain Aug. 31, 2014 Sep. 5, 2014 Mild
Possibly Resolved without sequelae No No flushing//Flushing Aug.
30, 2014 Aug. 31, 2014 Mild Possibly Resolved without sequelae No
No flushing//Flushing Sep. 1, 2014 Sep. 1, 2014 Mild Possibly
Resolved without sequelae No No flushing//Flushing Sep. 2, 2014
Sep. 2, 2014 Mild Possibly Resolved without sequelae No No
flushing//Flushing Sep. 2, 2014 Sep. 3, 2014 Mild Possibly Resolved
without sequelae No No Headache//Headache Aug. 29, 2014 Sep. 5,
2014 Mild Possibly Resolved without sequelae Yes No
Dizziness//Dizziness Aug. 30, 2014 Aug. 30, 2014 Mild Possibly
Resolved with sequelae No No flushing//Flushing Aug. 31, 2014 Aug.
31, 2014 Mild Possibly Resolved without sequelae No No 87.5 mg
Fatigue//Fatigue Aug. 30, 2014 Sep. 1, 2014 Mild Possibly Resolved
without sequelae No No twice daily edema//Oedema Sep. 2, 2014 Mild
Possibly Ongoing No No 125 mg T51 headache//Headache Feb. 9, 2015
Mild None Resolved without sequelae Yes NA daily T52 Increased
frequency of Nov. 7, 2014 Nov. 8, 2014 Mild Possibly Resolved
without sequelae No No sponatenous penile erections// Sponatenous
penile erection T53 Diarrhea//Diarrhoea Dec. 6, 2014 Dec. 6, 2014
Mild Possibly Resolved without sequelae No No Epistaxis//Epistaxis
Dec. 7, 2014 Dec. 7, 2014 Mild None Resolved without sequelae No No
Headache//Headache Dec. 3, 2014 Dec. 3, 2014 Mild Possibly Resolved
without sequelae No No Sponatenous penile erection// Dec. 4, 2014
Dec. 4, 2014 Mild Possibly Resolved without sequelae No No
Sponatenous penile erection Flushing//Flushing Dec. 4, 2014 Dec. 8,
2014 Mild Probably Resolved without sequelae No No
T54 Headache//Headache Oct. 10, 2014 Oct. 10, 2014 Moderate
Possibly Resolved without sequelae No No headache//Headache Oct.
12, 2014 Oct. 13, 2014 Mild Possibly Resolved without sequelae Yes
No headaches//Headache Oct. 13, 2014 Moderate Possibly Ongoing Yes
No Dizziness//Dizziness Oct. 13, 2014 Oct. 13, 2014 Moderate
Possibly Resolved without sequelae Yes No Stuffy nose
(congestion)//Nasal Oct. 11, 2014 Mild Possibly Ongoing No No
congestion Nose bleed//Epitaxis Oct. 13, 2014 Oct. 13, 2014 Mild
Possibly Resolved without sequelae No No itchy throat//Throat
irritation Oct. 30, 2014 Oct. 30, 2014 Moderate None Resolved
without sequelae Yes NA T55 Nausea//Nausea Jan. 13, 2015 Jan. 14,
2015 Moderate None Resolved without sequelae Yes NA Swollen/puffy
cheeks//Face Nov. 29, 2014 Nov. 29, 2014 Mild None Resolved without
sequelae No No oedema headaches//Headache Nov. 25, 2014 Nov. 25,
2014 Mild Possibly Resolved without sequelae No No 125 mg
Headache//Headache Nov. 27, 2014 Nov. 27, 2014 Mild Possibly
Resolved without sequelae No No daily Headache//Headache Nov. 28,
2014 Nov. 28, 2014 Mild Possibly Resolved without sequelae No No
Headache//Headache Nov. 30, 2014 Nov. 30, 2014 Mild Possibly
Resolved without sequelae No NA Migraine Headache//Migraine Jan.
12, 2015 Jan, 14, 2015 Moderate None Resolved without sequelae Yes
NA T56 Stomach discomfort//Abdominal Sep. 8, 2014 Sep. 8, 2014 Mild
Possibly Resolved without sequelae No No discomfort Stomach
discomfort//Abdominal Sep. 6, 2014 Sep. 10, 2014 Mild Possibly
Resolved with sequelae No No discomfort Stomach
discomfort//Abdominal Sep. 7, 2014 Sep. 7, 2014 Mild Possibly
Resolved without sequelae No No discomfort Stomach
discomfort//Abdominal Sep. 9, 2014 Sep. 9, 2014 Mild Possibly
Resolved without sequelae No No discomfort Chest pain//Chest pain
Sep. 6, 2014 Sep. 7, 2014 Mild Possibly Resolved with sequelae No
No Rash//Rash Sep. 7, 2014 Sep. 10, 2014 Mild Possibly Resolved
without sequelae No No Chest pain//Chest pain Sep. 6, 2014 Sep. 6,
2014 Mild None Resolved without sequelae No No Rash//Rash Sep. 8,
2014 Sep. 8, 2014 Mild None Resolved without sequelae No No
Rash//Rash Sep. 9, 2014 Sep. 9, 2014 Mild None Resolved without
sequelae No No Rash//Rash Sep. 11, 2014 Sep. 11, 2014 Mild None
Resolved without sequelae No No Rash//Rash Sep. 12, 2014 Sep. 12,
2014 Mild None Resolved without sequelae No No Headache//Headache
Sep. 6, 2014 Sep. 6, 2014 Mild Probably Resolved with sequelae Yes
No Headache//Headache Sep. 7, 2014 Sep. 7, 2014 Mild Possibly
Resolved without sequelae Yes No Headache//Headache Sep. 8, 2014
Sep. 8, 2014 Mild Possibly Resolved without sequelae No No
Headache//Headache Sep. 9, 2014 Sep. 9, 2014 Mild Probably Resolved
without sequelae Yes No Headache//Headache Sep. 10, 2014 Sep. 10,
2014 Mild Probably Resolved without sequelae Yes No Exercise C2
Ventricular arrhythmia// Dec. 11, 2014 Dec. 11, 2014 Mild None
Resolved without sequelae No NA testing Ventricular arrhythmia//
only Ventricular Tachycardia// Dec. 15, 2014 Dec. 15, 2014 Mild
None Resolved without sequelae No NA Ventricular tachycardia//
[0181] Table 8 presents numbers of subjects with number of
AEs.gtoreq.n, where n=1, 2, . . . , 6, by treatment group.
TABLE-US-00008 TABLE 8 Adverse Events by Treatment Group N (%) of
Subjects 37.5 mg 87.5 mg 87.5 mg Exercise Reporting 37.5 mg daily
twice daily daily twice daily 125 mg daily testing only at Least:
(N = 6) (N = 6) (N = 6) (N = 6) (N = 6) (N = 6) 1 event 5 (83%) 6
(100%) 6 (100%) 5 (83%) 6 (100%) 1 (17%) 2 events 3 (50%) 4 (67%) 6
(100%) 4 (67%) 4 (67%) 1 (17%) 3 events 3 (50%) 4 (67%) 6 (100%) 4
(67%) 4 (67%) 0 (0%) 4 events 2 (33%) 3 (50%) 2 (33%) 3 (50%) 4
(67%) 0 (0%) 5 events 2 (33%) 2 (33%) 2 (33%) 3 (50%) 4 (67%) 0
(0%) 6 events 2 (33%) 1 (17%) 1 (17%) 3 (50%) 3 (50%) 0 (0%)
[0182] Tables 9-12 present AEs by preferred term (similar to Table
6), but additionally report the number of subjects with an AE and
the number of AEs (Table 9), the number of AE events/subjects
grouped by treatment group and by related (including possibly or
probably) vs. not related to the study drug (Table 10), mild vs.
moderate/severe (Table 11), and expected vs. unexpected AEs (Table
12).
TABLE-US-00009 TABLE 9 Adverse Events by Preferred Term Preferred
37.5 37.5 mg 87.5 87.5 mg 125 Exercise Term mg twice mg twice mg
testing #Events daily daily daily daily daily only (#Subjects) (N =
6) (N = 6) (N = 6) (N = 6) (N = 6) (N = 6) Abdominal 1 (1) 0 (0) 0
(0) 1 (1) 3 (1) 0 (0) discomfort Abdominal 0 (0) 0 (0) 0 (0) 0 (0)
1 (1) 0 (0) pain upper Back pain 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) Chest pain 0 (0) 0 (0) 0 (0) 0 (0) 2 (1) 0 (0) Diarrhoea 0 (0)
0 (0) 0 (0) 0 (0) 1 (1) 0 (0) Dizziness 0 (0) 0 (0) 0 (0) 1 (1) 1
(1) 0 (0) Dry mouth 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0)
Dysmenorrhoea 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) Dyspnoea 1 (1) 1
(1) 0 (0) 0 (0) 0 (0) 0 (0) Epistaxis 0 (0) 1 (1) 0 (0) 0 (0) 2 (2)
0 (0) Face oedema 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) Fatigue 0 (0)
1 (1) 0 (0) 1 (1) 0 (0) 0 (0) Flushing 2 (1) 2 (2) 4 (4) 6 (2) 1
(1) 0 (0) Head injury 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) Headache
9 (3) 6 (4) 9 (4) 12 (4) 14 (5) 0 (0) Injection site 1 (1) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) pain Lacrimation 0 (0) 0 (0) 1 (1) 0 (0) 0
(0) 0 (0) increased Migraine 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0)
Motion sickness 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) Myalgia 0 (0) 1
(1) 0 (0) 0 (0) 0 (0) 0 (0) Nasal 3 (3) 2 (2) 2 (2) 3 (1) 1 (1) 0
(0) congestion Nasopharyngitis 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0)
Nausea 2 (1) 2 (1) 0 (0) 1 (1) 1 (1) 0 (0) Oedema 0 (0) 0 (0) 0 (0)
1 (1) 0 (0) 0 (0) Rash 0 (0) 0 (0) 0 (0) 0 (0) 5 (1) 0 (0) Sinus 0
(0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) congestion Sinus headache 0 (0) 1
(1) 0 (0) 0 (0) 0 (0) 0 (0) Sinusitis 0 (0) 0 (0) 0 (0) 1 (1) 0 (0)
0 (0) Somnolence 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) Spontaneous 0
(0) 2 (1) 1 (1) 6 (2) 2 (2) 0 (0) penile erection Throat irritation
0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) Upper 0 (0) 1 (1) 0 (0) 0 (0) 0
(0) 0 (0) respiratory tract infection Ventricular 0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 1 (1) arrhythmia Ventricular 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 1 (1) tachycardia Vision blurred 0 (0) 0 (0) 1 (1) 0 (0) 0 (0)
0 (0)
TABLE-US-00010 TABLE 10 Related and Unrelated AEs 37.5 mg twice
87.5 mg twice Preferred 37.5 mg daily daily 87.5 mg daily daily 125
mg daily Exercise only Term, (N = 6) (N = 6) (N = 6) (N = 6) (N =
6) (N = 6) #Events Drug Not Drug Not Drug Not Drug Not Drug Not
Drug Not (#Subjects) related* related related* related related*
related related* related related* related related* related
Abdominal 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 3 (1) 0
(0) 0 (0) 0 (0) discomfort Abdominal 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) pain upper Back pain 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) Chest pain 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1
(1) 1 (1) 0 (0) 0 (0) Diarrhoea 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) Dizziness 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 1 (1) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) Dry mouth 0 (0)
0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Dys- 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) menorrhoea Dyspnoea 0 (0) 1 (1) 0 (0) 1 (1) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Epistaxis 0 (0) 0 (0) 0 (0) 1 (1)
0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 1 (1) 0 (0) 0 (0) Face oedema 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0)
Fatigue 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0)
0 (0) 0 (0) Flushing 2 (1) 0 (0) 2 (2) 0 (0) 4 (4) 0 (0) 6 (2) 0
(0) 1 (1) 0 (0) 0 (0) 0 (0) Head injury 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Headache 9 (3) 0 (0)
6 (4) 0 (0) 9 (4) 0 (0) 12 (4) 0 (0) 13 (4) 1 (1) 0 (0) 0 (0)
Injection site 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) pain Lacrimation 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) increased Migraine 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0
(0) Motion 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) sickness Myalgia 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Nasal 1 (1) 2 (2) 2 (2) 0
(0) 1 (1) 1 (1) 3 (1) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) congestion
Naso- 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) pharyngitis Nausea 1 (1) 1 (1) 2 (1) 0 (0) 0 (0) 0 (0) 1
(1) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) Oedema 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Rash 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 4 (1) 0 (0) 0 (0) Sinus 0
(0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) congestion Sinus 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) headache Sinusitis 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) Somnolence 0
(0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) Spontaneous 0 (0) 0 (0) 2 (1) 0 (0) 1 (1) 0 (0) 6 (2) 0 (0) 2
(2) 0 (0) 0 (0) 0 (0) penile erection Throat 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) irritation
Upper 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) respiratory tract infection Ventricular 0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) arrhythmia
Ventricular 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 1 (1) tachycardia Vision 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1
(1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) blurred Total 13 (3) 6 (4)
17 (5) 5 (3) 19 (6) 4 (3) 33 (5) 1 (1) 26 (5) 11 (5) 0 (0) 2 (1)
*Drug related = possibly related, probably related or related to
study drug Out of all 36 study subjects, none had adverse events
related to the study drug, and 11, 21 and 17 subjects had adverse
events that were probably related, possibly related and unrelated
to the study drug, respectively.
TABLE-US-00011 TABLE 11 AEs by Severity 37.5 mg twice 87.5 mg twice
Preferred 37.5 mg daily daily 87.5 mg daily daily 125 mg daily
Exercise only Term, (N = 6) (N = 6) (N = 6) (N = 6) (N = 6) (N = 6)
#Events Moderate/ Moderate/ Moderate/ Moderate/ Moderate/ Moderate/
(#Subjects) Mild severe Mild severe Mild severe Mild severe Mild
severe Mild severe Abdominal 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 1
(1) 0 (0) 3(1) 0 (0) 0 (0) 0 (0) discomfort Abdominal 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) pain
upper Back pain 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) Chest pain 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 2 (1) 0 (0) 0 (0) 0 (0) Diarrhoea 0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) Dizziness 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 1 (1) 0 (0) 0
(0) Dry mouth 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0) Dys- 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) menorrhoea Dyspnoea 0 (0) 1 (1) 0 (0) 1
(1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Epistaxis 0 (0)
0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 2 (2) 0 (0) 0 (0) 0 (0)
Face oedema 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0
(0) 0 (0) 0 (0) Fatigue 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 1 (1) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) Flushing 2 (1) 0 (0) 2 (2) 0 (0) 4 (4)
0 (0) 6 (2) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) Head injury 0 (0) 0 (0) 0
(0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Headache
2 (2) 7 (3) 5 (4) 1 (1) 8 (4) 1 (1) 11 (4) 1 (1) 12 (5) 2 (1) 0 (0)
0 (0) Injection site 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) pain Lacrimation 0 (0) 0 (0) 0 (0) 0
(0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) increased
Migraine 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1
(1) 0 (0) 0 (0) Motion 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) sickness Myalgia 0 (0) 0 (0) 1 (1) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Nasal 2 (2) 1
(1) 2 (2) 0 (0) 1 (1) 1 (1) 3 (1) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0)
congestion Naso- 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) pharyngitis Nausea 1 (1) 1 (1) 2 (1) 0 (0) 0
(0) 0 (0) 1 (1) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) Oedema 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Rash 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 5 (1) 0 (0) 0 (0) 0
(0) Sinus 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) congestion Sinus 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) headache Sinusitis 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0)
Somnolence 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) Spontaneous 0 (0) 0 (0) 2 (1) 0 (0) 1 (I) 0 (0) 6
(2) 0 (0) 2 (2) 0 (0) 0 (0) 0 (0) penile erection Throat 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0)
irritation Upper 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) respiratory tract infection Ventricular 0 (0)
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0)
arrhythmia Ventricular 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 1 (1) 0 (0) tachycardia Vision 0 (0) 0 (0) 0 (0) 0
(0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) blurred Total 7
(4) 12 (4) 19 (5) 3 (3) 21 (6) 2 (2) 32 (5) 2 (2) 31 (6) 6 (2) 2
(1) 0 (0) Out of all 36 study subjects, 27 had mild adverse events,
13 had moderate and 1 subject had a severe adverse event.
TABLE-US-00012 TABLE 12 AEs by Expectedness 37.5 mg twice 87.5 mg
twice 37.5 mg daily daily 87.5 mg daily daily 125 mg daily Exercise
only Preferred (N = 6) (N = 6) (N = 6) (N = 6) (N = 6) (N = 6)
Term, Not Not Not Not Not Not #Events Ex- Ex- Ex- Ex- Ex- Ex- Ex-
Ex- Ex- Ex- Ex- Ex- (#Subjects) pected pected pected pected pected
pected pected pected pected pected pected pected Abdominal 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 3 (1) 0 (0) 0 (0) 0 (0)
discomfort Abdominal 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1
(1) 0 (0) 0 (0) 0 (0) 0 (0) pain upper Back pain 0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (1) 0 (0) 0 (0) Chest pain 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0
(0) Diarrhoea 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
1 (1) 0 (0) 0 (0) Dizziness 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) Dry mouth 0 (0) 0 (0) 0 (0) 0 (0)
0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Dys- 0 (0) 0 (0) 0
(0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
menorrhoea Dyspnoea 0 (0) 1 (1) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0) 0 (0) Epistaxis 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 2 (2) 0 (0) 0 (0) Face oedema 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) Fatigue 0
(0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0
(0) Flushing 2 (1) 0 (0) 2 (2) 0 (0) 4 (4) 0 (0) 5 (2) 1 (1) 1 (1)
0 (0) 0 (0) 0 (0) Head injury 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Headache 8 (3) 1 (1) 5 (4) 1 (1)
9 (4) 0 (0) 11 (3) 1 (1) 13 (5) 1 (1) 0 (0) 0 (0) Injection site 0
(0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) pain Lacrimation 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) increased Migraine 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) Motion 0 (0) 0
(0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
sickness Myalgia 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) Nasal 2 (2) 1 (1) 2 (2) 0 (0) 2 (2) 0 (0) 3
(1) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) congestion Naso- 0 (0) 0 (0) 1
(1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
pharyngitis Nausea 2 (1) 0 (0) 2 (1) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1)
0 (0) 1 (1) 0 (0) 0 (0) Oedema 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
1 (1) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) Rash 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 5 (1) 0 (0) 0 (0) Sinus 0 (0) 0 (0) 0
(0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
congestion Sinus 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) headache Sinusitis 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) Somnolence 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Spontaneous 0 (0) 0 (0) 2 (1) 0 (0) 1 (1) 0 (0) 6 (2) 0 (0) 2 (2) 0
(0) 0 (0) 0 (0) penile erection Throat 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) irritation Upper 0
(0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) respiratory tract infection Ventricular 0 (0) 0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) arrhythmia
Ventricular 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0
(0) 1 (1) 0 (0) tachycardia Vision 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1
(1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) blurred Total 14 (4) 5 (3)
15 (5) 7 (5) 18 (6) 5 (4) 26 (5) 8 (2) 22 (6) 15 (4) 2 (1) 0 (0)
Out of all 36 study subjects, 27 subjects had expected and 18 had
unexpected adverse events
[0183] Table 13 focuses on a subset of Table 7 limited to preferred
terms for which AEs happened more than once (either >2 AEs for
one subject, or >2 subjects with at least one AE) in at least
one cohort.
TABLE-US-00013 TABLE 13 Events That Occurred More Than Once in One
Subject or in More Than One Subject 37.5 mg 37.5 mg 87.5 mg 87.5 mg
125 mg Exercise Preferred Term, daily twice daily daily twice daily
daily testing only #Events (#Subjects) (N = 6) (N = 6) (N = 6) (N =
6) (N = 6) (N = 6) Abdominal discomfort 1 (1) 0 (0) 0 (0) 1 (1) 3
(1) 0 (0) Chest pain 0 (0) 0 (0) 0 (0) 0 (0) 2 (1) 0 (0) Epistaxis
0 (0) 1 (1) 0 (0) 0 (0) 2 (2) 0 (0) Flushing 2 (1) 2 (2) 4 (4) 6
(2) 1 (1) 0 (0) Headache 9 (3) 6 (4) 9 (4) 12 (4) 14 (5) 0 (0)
Nasal congestion 3 (3) 2 (2) 2 (2) 3 (1) 1 (1) 0 (0) Nausea 2 (1) 2
(1) 0 (0) 1 (1) 1 (1) 0 (0) Rash 0 (0) 0 (0) 0 (0) 0 (0) 5 (1) 0
(0) Spontaneous penile 0 (0) 2 (1) 1 (1) 6 (2) 2 (2) 0 (0)
erection
[0184] FIG. 1 displays the percent of subjects reporting at least
one, three or five adverse events by treatment group (the numbers
are taken from Table 6). The cohorts at horizontal axis are sorted
from the lowest daily dose at the left (exercise only group; zero
dose, though not a placebo) to the highest one-time dose (125 mg)
at the right. The percentages vary from 100% to 0% (exercise only
group). As expected, the exercise only group features the lowest
percentage. The plot doesn't suggest a clear association between
the dose and percent of subjects reporting AEs.
Example 3--Exercise Testing
[0185] The purpose of this example was to evaluate the efficacy of
the treatment protocol described in Example 1 using various
exercise testing parameters.
[0186] The primary outcome of this arm of the study was maximal VO2
as determined by exercise testing. Table 14 summarizes results for
the key outcome from the exercise testing--peak VO2 (limited to the
subjects who achieved maximum effort) by treatment group. Out of
the 36 subjects enrolled in the trial, 33 reached max effort in the
exercise testing at each of the time points, and 31 subjects at
both time points. The first two lines present data for baseline and
follow-up measurements, while the third line presents differences
between the two measurements (change scores, the outcome for this
aim). Analysis of variances suggests lack of differences between
the change scores (p=0.85).
TABLE-US-00014 TABLE 14 Peak VO2 at Maximum Effort, ml/kg/min 87.5
37.5 37.5 mg 87.5 mg All mg twice mg twice 125 mg Exercise P- N
subjects N daily N daily N daily N daily N daily N only value
Baseline 34 28.5 .+-. 5.8 6 24.6 .+-. 6.9 6 30.4 .+-. 6.2 6 28.4
.+-. 6.2 5 28.0 .+-. 5.2 5 28.6 .+-. 3.0 6 30.6 .+-. 6.2 0.542
measurement Follow-up 33 28.2 .+-. 5.8 5 24.7 .+-. 6.7 6 28.8 .+-.
8.1 6 27.1 .+-. 5.0 5 28.2 .+-. 6.0 6 28.6 .+-. 3.8 5 31.8 .+-. 5.0
0.570 measurement Difference, 32 -0.6 .+-. 3.3 5 -0.8 .+-. 1.7 6
-1.6 .+-. 5.1 6 -1.4 .+-. 2.5 5 0.2 .+-. 5.0 5 0.9 .+-. 2.6 5 -0.3
.+-. 1.8 0.851 FU - BL P-values were calculated by ANOVA. The
maximum effort was achieved when the respiratory quotient at peak
.gtoreq. 1.1.
[0187] FIGS. 2 and 3 present the findings for change scores in a
visual way (with a positive change indicating an improvement). FIG.
2 displays individual change score for each subject with paired
measurements (circles) and two lines with mean and median values.
The plots don't suggest that change scores increase with the dose.
FIG. 3 displays maximal VO2 values before and after the treatment
for each subject and in each cohort.
[0188] As expected, baseline and follow-up measurements are
strongly correlated, with the correlation coefficient >0.8.
[0189] An additional outcome, VO2 at anaerobic threshold, was also
measured. Similar analyses were performed for this outcome. Results
are presented in Table 15 and FIGS. 4 and 5. Overall results are
similar to those for maximal VO2.
TABLE-US-00015 TABLE 15 Peak VO2 at Anaerobic Threshold, ml/kg/min
37.5 37.5 mg 87.5 87.5 mg All mg twice mg twice 125 mg Exercise P-
N subjects N daily N daily N daily N daily N daily N only value
Baseline 36 18.6 .+-. 6 17.2 .+-. 6 18.0 .+-. 6 17.6 .+-. 6 18.3
.+-. 6 18.8 .+-. 6 21.7 .+-. 0.570 measurement 4.5 5.0 3.0 5.3 4.6
1.8 6.2 Follow-up 34 18.2 .+-. 5 16.3 .+-. 6 18.1 .+-. 6 16.5 .+-.
6 16.5 .+-. 6 20.0 .+-. 5 22.4 .+-. 0.135 measurement 4.4 2.0 3.0
4.8 5.2 3.2 5.5 Difference 34 -0.3 .+-. 5 -0.5 .+-. 6 0.1 .+-. 6
-1.1 .+-. 6 -1.7 .+-. 6 1.2 .+-. 5 0.1 .+-. 0.469 FU - BL 2.6 4.1
1.0 1.9 2.1 1.9 3.8 P-values were calculated by ANOVA.
[0190] Of note, both exercise outcomes (peak VO2 and VO2 at
anaerobic threshold) are highly correlated (with the correlation
coefficient at each visit above 0.7), which may explain
similarities in the trend lines in FIGS. 2 and 4.
Example 4--Vascular Function Testing
[0191] The primary outcome of vascular function was determined
according to an endothelial pulse amplitude tonometry (PAT) index
as determined by the EndoPAT.RTM. device (Itamar Medical, Caesarea,
Israel).
[0192] Table 16 summarizes the results for the key outcome from the
vascular function testing--natural log of Reactive Hyperemia Index
(InRHI) by treatment group. Out of the 30 subjects enrolled in the
treatment arms of the trial, 27 subjects had paired measurements
with an acceptable quality (with QC score equal to 3 (the best) or
2). The structure of the table is similar to the one for exercise
variables.
TABLE-US-00016 TABLE 16 Natural Log of Reactive Hyperemia Index
37.5 37.5 mg 87.5 87.5 mg All mg twice mg twice 125 mg N subjects N
daily N daily N daily N daily N daily P-value Baseline 28 0.52 .+-.
6 0.48 .+-. 6 0.60 .+-. 6 0.41 .+-. 4 0.49 .+-. 6 0.63 .+-. 0.704
measurement 0.28 0.31 0.30 0.25 0.12 0.37 Follow-up 28 0.49 .+-. 6
0.51 .+-. 6 0.53 .+-. 5 0.45 .+-. 5 0.40 .+-. 6 0.52 .+-. 0.945
measurement 0.28 0.26 0.29 0.31 0.29 0.34 Difference, 27 -0.02 .+-.
6 0.03 .+-. 6 -0.07 .+-. 5 0.07 .+-. 4 -0.03 .+-. 6 -0.10 .+-.
0.902 FU - BL 0.30 0.47 0.17 0.22 0.20 0.38
[0193] FIGS. 6 and 7 present the findings for change scores in a
visual way (with a positive change indicating an improvement). FIG.
6 displays the individual change score for each subject with paired
measurements (circles) and two lines with mean and median values.
The plots do not suggest that change scores increase with the dose.
FIG. 7 displays InRHI values before and after the treatment for
each subject and in each cohort.
[0194] Baseline and follow-up measurements are moderately
correlated, with an overall correlation coefficient of 0.4.
[0195] Of note, both mean baseline and follow-up measurements are
close to the cut-off value of 0.51 suggested by the EndoPAT
documentation as a threshold between the normal (defined as
InRHI>0.51) and abnormal (InRHI <0.51) values. Analysis of
the data indicates that some patients showed as much as a 9.75%
improvement in this measure.
[0196] Table 17 reports change scores only for secondary EndoPAT
outcomes (RHI, Framingham RHI etc; top panel) and other EndoPAT
indices. In all cases a positive change suggests a possible
improvement.
TABLE-US-00017 TABLE 17 Secondary and Other EndoPAT Outcomes, FU -
BL 37.5 mg 87.5 mg All 37.5 mg twice 87.5 mg twice 125 mg P- N
subjects N daily N daily N daily N daily N daily value Secondary
EndoPAT outcomes Reactive 27 -0.04 .+-. 6 0.03 .+-. 6 -0.12 .+-. 5
0.12 .+-. 4 0.01 .+-. 6 -0.21 .+-. 0.895 Hyperemia 0.56 0.84 0.30
0.34 0.38 0.78 Index Framingham 27 -0.06 .+-. 6 -0.00 .+-. 6 -0.17
.+-. 5 0.04 .+-. 4 0.00 .+-. 6 -0.13 .+-. 0.901 RHI 0.39 0.58 0.19
0.36 0.20 0.51 AUC2max_oc: 27 0.51 .+-. 6 -0.93 .+-. 6 -1.19 .+-. 5
3.03 .+-. 4 0.16 .+-. 6 1.80 .+-. 0.058 Area under the 2.91 4.37
1.84 2.49 1.08 1.18 curve to Max- Occlusion/ Control Avg2Max_oc: 27
-0.16 .+-. 6 -0.35 .+-. 6 -0.33 .+-. 5 0.17 .+-. 4 0.24 .+-. 6
-0.32 .+-. 0.626 average up to 0.79 1.01 0.26 0.43 0.73 1.28 max-
Occlusion, Control Other EndoPAT indices AUC2max_o: 27 -0.26 .+-. 6
-0.23 .+-. 6 0.09 .+-. 5 -1.26 .+-. 4 -0.51 .+-. 6 0.37 .+-. 0.910
Area under the 2.75 2.74 1.45 4.89 1.64 2.71 curve to Max-
Occlusion (ratio to baseline) AUCall_o: 27 0.18 .+-. 6 -0.01 .+-. 6
-0.69 .+-. 5 1.66 .+-. 4 0.60 .+-. 6 -0.28 .+-. 0.864 Area under
the 3.54 2.73 2.17 5.96 2.95 3.98 curve all- Occlusion (ratio to
baseline) AUCall_oc: 27 -0.60 .+-. 6 -1.34 .+-. 6 -1.19 .+-. 5 1.88
.+-. 4 0.17 .+-. 6 -1.84 .+-. 0.772 Area under the 4.93 6.42 2.00
3.25 4.30 7.21 curve all- Occlusion/ Control Avg2Max-o: 27 0.04
.+-. 6 -0.12 .+-. 6 0.15 .+-. 5 0.10 .+-. 4 0.03 .+-. 6 0.07 .+-.
0.930 average upto 0.51 0.28 0.19 0.69 0.36 0.86 max- Occlusion**
Avgall_o: 27 0.02 .+-. 6 0.02 .+-. 6 -0.08 .+-. 5 0.14 .+-. 4 0.09
.+-. 6 -0.03 .+-. 0.927 average all- 0.40 0.27 0.24 0.67 0.33 0.49
Occlusion** Avgall_oc: 27 -0.06 .+-. 6 -0.10 .+-. 6 -0.13 .+-. 5
0.16 .+-. 4 0.05 .+-. 6 -0.20 .+-. 0.848 average all- 0.54 0.66
0.22 0.36 0.45 0.84 Occlusion/ Control P-values were calculated by
ANOVA. **ratio to baseline
Example 5--Echocardiographic Assessment of Ventricular
Performance
[0197] The primary outcome of ventricular performance with assessed
using echocardiographic methods and measured according to a
myocardial performance Index (MPI). The MPI is a ventricular
geometry-independent measure of combined systolic and diastolic
ventricular performance (Charles S. Kleinman et al, 2008--Health
and Fitness). It is obtained by indexing the sum of isovolumetric
contraction and relaxation time to ejection time.
[0198] Table 18 summarizes results for the key outcome from the
Echocardiographic Assessment of Ventricular Performance--Blood Pool
MPI. Out of the 30 subjects enrolled in the treatment arms of the
trial, 27 subjects had paired measurements. The structure of the
table is similar to the one for exercise variables. Analysis of the
data indicates that some patients showed as much as a 21.5%
improvement in this measure.
TABLE-US-00018 TABLE 18 Blood Pool MPI All 37.5 mg 37.5 mg 87.5 mg
87.5 mg 125 mg P- N subjects N daily N twice daily N daily N twice
daily N daily value Baseline 29 0.581 .+-. 6 0.537 .+-. 6 0.496
.+-. 6 0.588 .+-. 5 0.548 .+-. 6 0.728 .+-. 0.305 measurement 0.197
0.304 0.150 0.158 0.136 0.155 Follow-up 28 0.517 .+-. 5 0.504 .+-.
6 0.494 .+-. 6 0.512 .+-. 6 0.410 .+-. 5 0.696 .+-. 0.058
measurement 0.165 0.187 0.087 0.163 0.078 0.202 Difference, 27
-0.059 .+-. 5 -0.052 .+-. 6 -0.003 .+-. 6 -0.076 .+-. 5 -0.118 .+-.
5 -0.054 .+-. 0.744 FU - BL 0.134 0.166 0.102 0.144 0.090 0.180
[0199] FIGS. 8 and 9 present the findings for change scores in a
visual way (with a negative change indicating an improvement). FIG.
8 displays individual change score for each subject with paired
measurements (circles) and two lines with mean and median values.
The plots don't suggest that change scores increase with the dose.
FIG. 9 displays blood pool MPI index values before and after the
treatment for each subject and in each cohort.
[0200] Baseline and follow-up measurements are strongly correlated,
with the overall correlation coefficient of 0.7 (last 2 lines). Of
note, both mean baseline and follow-up measurements are in the
elevated area (>0.4).
[0201] Tables 19-21 and FIGS. 9-15 report similar results for three
other versions of MPI: Tissue Doppler MPI, and Average
Isovolumetric Contraction and Relaxation.
TABLE-US-00019 TABLE 19 Tissue Doppler MPI All 37.5 mg 37.5 mg 87.5
mg 87.5 mg 125 mg P- N subjects N daily N twice daily N daily N
twice daily N daily value Baseline 28 0.760 .+-. 6 0.701 .+-. 6
0.818 .+-. 6 0.804 .+-. 4 0.540 .+-. 6 0.861 .+-. 0.517 measurement
0.299 0.417 0.361 0.118 0.019 0.323 Follow-up 28 0.707 .+-. 5 0.637
.+-. 6 0.729 .+-. 6 0.716 .+-. 6 0.638 .+-. 5 0.822 .+-. 0.579
measureulent 0.201 0.206 0.230 0.142 0.168 0.271 Difference, 26
-0.056 .+-. 5 -0.052 .+-. 6 -0.089 .+-. 6 -0.089 .+-. 4 0.060 .+-.
5 -0.074 .+-. 0.813 FL - BL 0.198 0.398 0.142 0.131 0.068 0.141
TABLE-US-00020 TABLE 20 Average Isovolumic Contraction All 37.5 mg
37.5 mg 87.5 mg 87.5 mg 125 mg P- N subjects N daily N twice daily
N daily N twice daily N daily value Baseline 28 115.6 .+-. 6 99.2
.+-. 6 109.4 .+-. 6 122.4 .+-. 4 84.1 .+-. 6 152.4 .+-. 0.236
measurement 50.5 50.7 51.1 36.7 20.3 64.4 Follow-up 28 107.1 .+-. 5
86.4 .+-. 6 103.6 .+-. 6 115.0 .+-. 6 83.8 .+-. 5 150.5 .+-. 0.047
measurement 41.3 22.7 32.4 32.9 26.4 60.5 Difference, 26 -4.6 .+-.
5 -3.5 .+-. 6 -5.8 .+-. 6 -7.4 .+-. 4 4.1 .+-. 5 -8.0 .+-. 0.977 FU
- BL 28.3 50.0 25.7 26.5 12.1 24.6
TABLE-US-00021 TABLE 21 Average Isovolumetrie Relaxation 87.5 mg
125 All 37.5 mg 37.5 mg 87.5 mg twice mg P- N subjects N daily N
twice daily N daily N daily N daily value Baseline 28 91.2 .+-. 6
83.8 .+-. 6 100.8 .+-. 6 93.4 .+-. 4 72.3 .+-. 6 99.5 .+-. 0.236
measurement 22.2 16.1 32.3 11.0 10.5 25.0 Follow-up 28 92.0 .+-. 5
94.0 .+-. 6 101.6 .+-. 6 86.4 .+-. 6 82.4 .+-. 5 96.8 .+-. 0.674
measurement 23.8 26.7 40.0 15.3 11.4 17.4 Difference, 26 0.1 .+-. 5
9.0 .+-. 6 0.8 .+-. 6 -6.9 .+-. 4 5.2 .+-. 5 -5.4 .+-. 0.354 FU -
BL 14.4 11.5 21.2 10.1 12.6 11.1
[0202] For these three additional versions of MPI, a negative
change also suggests a possible improvement and the overall
conclusions are similar to those for Blood Pool MPI.
[0203] Additionally, because positive outcomes were seen during the
short duration of the studies described in Examples 1-5,
administering udenafil or a pharmaceutically acceptable salt
thereof to a Fontan patient for a longer period of time could
produce even more beneficial pharmacodynamic outcomes.
Example 6--Pharmacokinetic Testing
[0204] NONMEM version 7.2, R, PDxPOP.RTM. 5, Xpose, and Phoenix
WinNonlin was used for the pharmacokinetic analysis.
[0205] Pharmacokinetic analysis was performed on Fontan patients
receiving udenafil. FIG. 16 show the results of data evaluation for
individual subjects by dosing cohort, and FIG. 17 shows the
concentration profiles of udenafil in the study subjects. Plasma
concentrations were determined at various time points and
non-compartmental analysis was performed in patients and stratified
by dosing regimens.
[0206] FIGS. 18-20 demonstrate various comparisons among the dosing
cohorts. Based on the non-compartment analysis, C.sub.max was
significantly increased in 87.5 mg q12 h cohort and 125 mg q24 h
cohort compared to the 37.5 mg q12 h or q24 h cohorts (FIG.
18).
[0207] The 87.5 mg q12 h cohort exhibited increased C.sub.max
compared to its q24 h counterpart (FIG. 18). AUC.sub..tau. was
significantly increased in 87.5 mg q12 h cohort and 125 mg q24 h
cohort compared to the 37.5 mg q12 h or q24 h cohorts (FIG. 19).
AUC.sub.0-24 was significantly increased in 125 mg q24 h cohort
compared to the 37.5 mg q24 h cohorts. The 87.5 mg q12 h cohort
showed increased highest AUC.sub.0-24 among all the regimens tested
(FIG. 19). No significant difference was observed in CL/F or V/F
among dosing regimens, expect the significant differences between
37.5 mg q24 h and 87.5 mg q12 h (FIG. 20). There was no
statistically significant difference in k.sub.e, T.sub.1/2, or
T.sub.max among all 5 tested dosing regimens.
[0208] Population PK Model Development
[0209] The population PK analysis was performed using a non-linear
mixed effects modeling approach. This approach estimates the
typical value of parameters and their variances. It was assumed
subjects were at steady state (SS): at a time (t) after dose (D)
given at time tD after repeated administration of dose D given at
interval .tau. (t.gtoreq.t.sub.D) as PK samples/udenafil
concentrations were taken on study day 6.
[0210] As only the drug administration at Day 6 was supplied, it is
expected that the subjects have taken the drug at regular intervals
at home; due to this a steady state flag will be tested to account
for the doses which are not available. As stated, it is assumed
steady state has been reached by Day 6, as previous studies of
udenafil have stated that during multiple dosing, steady state is
reached in 5 days, with apparently little additional accumulation
occurring after dosing for 7 days. If there were missed doses
during the study period prior to the PK sampling, this can affect
the ability to determine whether steady state could be assumed or
not for the PK profile. If two or more additional drug
administration dates and times were available prior to the visit
where the PK samples were taken, then a much better dosing profile
could be used for analysis.
[0211] Structural Model
[0212] One- and two-compartment models were explored (based on
literature and available data). The equation for the Input model
for the drug described oral absorption. For the one-compartment
model, the following equation may apply to the model:
dA dt = Input - ( k 10 * A ) ##EQU00001##
[0213] And considering that CL=k10*V, the following equation may
also apply:
dC dt = Input - ( CL * C ) V ##EQU00002##
[0214] The two-compartment model can be described by the following
differential equation:
dX 1 dt = ka Xg + k 21 X 2 - ( k 12 + kel ) X 1 ##EQU00003##
[0215] Drug Amount in the body after oral administration may be
described by the following differential equation:
Cp=Ae.sup.-.alpha.t+Be.sup.-.beta.t+Ce.sup.-k.alpha.t
[0216] The robustness of the final model was assessed in
PDxPOP.RTM. 5 by bootstrap re-sampling (n=1000). Values obtained
with the bootstrap (based on all runs with successful minimization)
were compared to the parameter estimates from the final model. To
evaluate the accuracy of the model predictions, normalized
prediction distribution errors (NPDE) was performed.
[0217] Certain a priori information was used in guiding the
development of the models.
[0218] One- and two-compartment models with oral absorption input
were evaluated using initial estimates obtained from the literature
as described above, and were explored to determine the potential
structure of the model. The models were evaluated during the model
building process by using objective function value, level of
statistical significance, goodness of fit plots, and standard
error.
[0219] The only covariate available for analysis was current body
weight. Weight was tested as a fixed effect on typical values for
clearance and volume of distribution (e.g., weight has a "fixed
effect" on clearance). Median weight in the dataset was 65.3
kg.
[0220] The "typical value" for clearance is predicted per 70 kg
patient using weight (WT) in the data set. The estimated THETA(1)
and THETA(2) for subjects of known WT can be directly compared with
CL and V values in subjects of "standard" weight, e.g. WTs=70
kg.
[0221] Concern is sometimes expressed that scaling parameter values
estimated in children in terms of an adult size standard of 70 kg
may bias the estimates, or affect the precision of estimation.
There is no basis for this concern. This can be seen by inspection
of the allometric scaled covariate model which may be re-arranged
and is simply a constant that is determined by whatever weight is
chosen for standardization. The precision of a parameter estimate
will not be changed by multiplying the parameter value by an ad hoc
constant. The criteria for covariate equation selection for weight
in the model was statistical significance.
[0222] FIGS. 21-29 show the results of the pharmacokinetic data
analysis.
[0223] During the model building process, a number of residual
error models were evaluated. Proportional and exponential error
models were unable to run, these terminated every time. Additive
error models were able to run, but the GOF plots showed a poor fit
for one-compartment models with a better fit in the two compartment
model. The choice was made to use a combined error model for the
base model, despite the high CV % in the residual variability, as
this model gave good estimates for other parameters, 95% CIs and
showed a good fit on visual inspection of GOF plots (FIGS. 30-31).
It may be possible to control for the high CV % if all of the doses
from days 1-5 were included from each subject in the dataset before
the day 6 dose, around which the sampling occurred. It is not be
necessary to do this as the model fit is good as presently
described, but this may further reduce the % CVs.
[0224] After comparing observed data and predicted data, a final
model was produced. GOF plots for the final model are found in
FIGS. 32 and 33.
[0225] Bootstrap re-sampling was undertaken to compare the
parameter estimates from the final model with those determined
following 1000 bootstrap runs. In addition: visual predictive
checks (plot comparing 95% prediction interval with observed data)
and normalized prediction distribution errors (NPDE) techniques
were applied for final model evaluation. Additionally a visual
predictive check was performed.
[0226] Udenafil pharmacokinctics were well described by a
two-compartment model with combined additive and proportional
error. Apparent clearance (CL/F) were scaled using current body
weight standardized to adult weight, 70 kg. Absorption rate
constant was estimated as 0.28 h-1 (95% CI 0.16-0.39), apparent
clearance (CL/F/70 kg) 36 L/h (95% CI 28.5-43.1), central volume of
distribution (V2/F) 74 L (95% CI 36.2-112), inter-compartmental
clearance (Q/F) 21.1 L (95% CI 10.4-31.8) and peripheral volume of
distribution (V3/F) 181 L (95% CI 141-221). The final model was
evaluated by bootstrap re-sampling, normalized prediction
distribution errors, and visual predictive check techniques. These
techniques demonstrated a good fit of the final covariate model to
the data.
[0227] A two-compartment model with absorption rate constant
successfully described the pharmacokinetics of udenafil in
adolescents with single ventricle physiology after Fontan
palliation. There was a statistically significantly influence on
apparent clearance (CL/F) when subject body weight was standardized
to adult weight, 70 kg included in the final model, CL/F L/hr/70
kg.
Example 7--Phase III Study of Udenafil in Fontan Patients
[0228] A Phase III study of udenafil in Fontan patients will
determine the safety of udenafil (87.5 mg, twice daily) in an
adolescent population with single ventrile congenital heart disease
palliated with the Fontan procedure. The study will also evaluate
the pharmacodynamics profile of udenafil over a period of time
ranging from at least six months and up to one year.
Pharmacodynamic outcomes will include exercise capacity,
echocardiographic measures of ventricular function, endothelial
function, and serum biomarkers, as well as measures of functional
health status/quality of life. It is expected that udenafil (87.5
mg, twice daily) will be safe, and effective for improving exercise
capacity and other endpoints of cardiovascular health, as well as
improving quality of life.
[0229] Methodology--Randomized, double-blind, placebo-controlled
clinical trial of a six month to one-year treatment with an 87.5
mg/twice a day dose in 300 subjects between 12 and 19 years of age
who have had the Fontan surgery before 5 years of age.
[0230] Inclusion Criteria for the study include: [0231] Males or
females age 12-19. [0232] Fontan surgery before 5 years of age.
[0233] Exclusion Criteria for the study include: [0234] Height
<132 cm. [0235] Hospitalization for acute decompensated heart
failure within the last 12 months. [0236] Current intravenous
inotropic drugs. [0237] Undergoing evaluation for heart
transplantation or listed for transplantation. [0238] Diagnosis of
protein losing enteropathy, plastic bronchitis, liver cirrhosis.
[0239] Known Fontan baffle obstruction, branch pulmonary artery
stenosis, or pulmonary vein stenosis resulting in a mean gradient
of >4 mm Hg between the regions proximal and distal to the
obstruction as measured by either catheterization or
echocardiography. [0240] Single lung physiology. [0241] Severe
ventricular dysfunction assessed qualitatively by clinical
echocardiography within 6 months prior to enrollment. [0242] Severe
valvar regurgitation, ventricular outflow obstruction, or aortic
arch obstruction assessed by clinical echocardiography within 6
months prior to enrollment. [0243] Significant renal, hepatic,
gastrointestinal or biliary disorders that could impair absorption,
metabolism or excretion of orally administered medications. [0244]
Inability to complete exercise testing at baseline screening.
[0245] History of PDE-5 inhibitor use within 3 months before study
onset. [0246] Use of any other drug to treat pulmonary hypertension
within 3 months before study onset. [0247] Known intolerance to
oral udenafil. [0248] Frequent use of medications or other
substances that inhibit or induce CYP3A4. [0249] Current use of
alpha-blockers or nitrates. [0250] Ongoing or planned participation
in another research protocol that would either prevent successful
completion of planned study testing or invalidate its results.
[0251] Noncardiac medical, psychiatric, and/or social disorder that
would prevent successful completion of planned study testing or
would invalidate its results. [0252] Cardiac care, ongoing or
planned, at a non-study center that would impede study completion.
[0253] For females: Pregnancy at the time of screening, pregnancy
planned before study completion, or refusal to use an acceptable
method of contraception for study duration. [0254] Unable to
abstain or limit intake of grapefruit juice during the duration of
the trial. [0255] Refusal to provide written informed
consent/assent. [0256] In the opinion of the primary care
physician, the subject is likely to be non-compliant with the study
protocol.
[0257] The study will include baseline measures of the proposed
pharmacodynamics (PD) endpoints as well as quality of life surveys.
For example, EndoPAT vascular assessment will be completed as the
first PD test following consent. This must be performed in a
fasting (from midnight until after the test), non-caffeinated
state. After the vascular assessment, subjects will have a targeted
echocardiogram to assess ventricular function. A short break will
be given, either after the vascular assessment or after the
echocardiogram, and a light snack will be provided. Safety labs
will be performed following the vascular assessment,
echocardiogram, and break. These will include collection of blood
to evaluate serum creatinine and liver enzyme (aspartate
transaminase and alanine transaminase) levels for all participants,
and a urine pregnancy test for female participants. If the
pregnancy test is positive all further testing will be stopped, the
patient will not be enrolled into the trial and the result will be
conveyed to the subject and/or guardians by the site-principal
investigator in accordance with local IRB procedures. After the
safety labs, an exercise test will be administered using a braked
cycle ergometer following a ramp protocol previously published in
the PHN Fontan Cross-Sectional Study. After exercise testing,
subjects will have completed the baseline testing. Additionally,
The Peds QL, cardiac specific Peds QL, and PCQLI will be
administered during the baseline testing visit.
[0258] A study coordinator will call each subject weekly for four
weeks and then monthly thereafter to collect adverse events and
answer questions related to the study.
[0259] At the end of the study, subjects will arrive in a fasting,
non-caffeinated state, and first undergo vascular function
assessment including repeating the baseline tests as well as the
quality of life surveys. Follow up with subjects may occur at 30
and 90 days following end-of-study testing to record any additional
adverse events possibly or probably related to the study drug that
may have occurred in the 90 days following completion of the study
protocol.
[0260] It is expected that udenafil (87.5 mg bid) in adolescents
with Fontan physiology over a 6-12 month period will be safe and
well tolerated, with few, if any, serious adverse events related to
udenafil. The severity of adverse events is determined according to
the Common Terminology Criteria for Adverse Events (CTCAE) Version
4.0 MedDRA 12.1 (http://ctep.cancer.gov). Likewise, the effect of
udenafil on pharmacodynamic outcomes including exercise capacity,
echocardiographic measures of ventricular function, endothelial
function, and biomarkers associated with heart failure is expected
to improve over the course of treatment. The outcomes to be
measured to determine the efficacy of udenafil in this patient
population will include: [0261] Exercise: Change in maximal oxygen
consumption from baseline to end-of-study testing measured using a
standardized exercise test; [0262] Echo: Change in myocardial
performance index as measured by pulse wave Doppler
echocardiography from baseline to end-of-study testing; [0263]
Endothelial Function: Change in log-transformed Reactive Hyperemia
Index derived from the EndoPAT.RTM. device; and [0264] Biomarkers:
Change in serum BNP level from baseline to end-of-study.
[0265] As well as: [0266] Exercise: Submaximal measures of exercise
capacity will be collected and evaluated. [0267] Echo: Measure of
systolic and diastolic function will be collected from a targeted
echocardiogram.
[0268] The study may also look at outcomes related to ventricular
cavity size, eccentricity, and mass; systolic function as estimated
using mean dP/dt during isovolumetric contraction (dP/dtic) and
peak systolic annular velocity (S') on tissue Doppler; tissue
Doppler based estimates of diastolic function and MPI; and
qualitative and quantitative estimate of AV valve
insufficiency.
[0269] It is also expected that functional health status will
improve following administration of udenafil. The change in
functional health status from baseline to the end of the study may
be measured by the full scale Peds QL, Peds QL physical functioning
score, Peds QL psychosocial functioning score, Peds QL
cardiac-specific module quality of life score, and/or the pediatric
cardiac quality of life inventory (PCQLI) score.
[0270] Furthermore, genetic material may be collected during the
study to identify genetic determinants of response to udenafil
after the Fontan procedure in persons with single-ventricle
lesions. This will provide an indication of whether specific
sub-populations of patients will have a more positive response to
udenafil than others. For instance, the response to udenafil may be
influenced by variants related to the vascular response to
udenafil. Variants in the endothelial nitric oxide synthase gene
have been reported to influence the response to sildenafil in
patients with erectile dysfunction, although this has not been
studied for udenafil. Variation in genes that regulate the
vascular, inotropic and chronotropic response to exercise may
influence the exercise capacity of patients after the Fontan
procedure as well as the response to udenafil. DNA will be stored
to perform future genotyping studies to analyze the genetic
contribution to the response to udenafil.
[0271] Additional covariate measures will include, but may not be
limited to, age, gender, race/ethnicity, height/weight, ventricular
morphology, resting oxygen saturation, baseline pharmacodynamics
test results, and current medication use. Observance of these
variables will allow for the identification of associations between
a variety of clinical factors and both safety and PD outcomes.
[0272] Data collection will include recording demographic
information including age, gender, race, ethnicity, cardiac
anatomy, date of Fontan procedure, presence of a fenestration,
degree of atrioventricular valve regurgitation, grade of
ventricular function, concomitant medications, and significant
co-morbidities. Safety data will reviewed with each subject at each
study visit and during telephone encounters. These events will be
recorded and graded by severity and relationship to the study drug
based upon established criteria. Two additional telephone
encounters will take place 30 days and 90 days following
end-of-study testing to assess for any adverse events possibly or
probably related to the study drug in the period following the
completion of study procedures.
[0273] Other data collection will include: [0274] Exercise stress
test--Data from the braked cycle ergometry exercise stress tests
will be collected according to protocol established in the PHN
Fontan Cross-Sectional Study3. [0275] Assessment of ventricular
performance--Each study echocardiogram will be stored in a
de-identified manner and sent to a core laboratory, which will
perform the data analysis and submit the measurements to the PHN
Data Coordinating Center (DCC). [0276] Vascular function
testing--De-identified data from EndoPAT.RTM. testing will be
collected according to a standardized protocol. These data will be
sent to a vascular core lab, which will perform the analysis and
submit the measurements to the PHN DCC. [0277] Biomarkers--Serum
for measurement of BNP level will be sent to a core clinical lab.
Results will be sent directly to the PHN DCC. [0278] Quality of
life survey--Results of the Quality of life surveys will be
submitted to the PHN DCC. [0279] Samples for the
biorepository--Samples collected for the biorepository will be
shipped directly to the biorepository for future analysis.
[0280] Subjects will be treated with other medications at the
discretion of their physicians. At the study visits, current
medications will be recorded on the study forms. If a subject
begins open-label use of any other PDE-5 inhibitor at any time
during the study, withdrawal from the study drug is required.
[0281] When an individual subject completes the study, the
subject's primary cardiologist will be notified, and the study drug
will be stopped; there is no need to wean subjects off of the study
drugs. The decision of whether to continue the use of an off label
PDE-5 inhibitor for individual subjects will be decided by the
subjects and their primary cardiologist.
[0282] While certain of the preferred embodiments of the present
invention have been described and specifically exemplified above,
it is not intended that the invention be limited to such
embodiments. Various modifications may be made thereto without
departing from the scope and spirit of the present invention.
* * * * *
References