U.S. patent application number 14/482704 was filed with the patent office on 2014-12-25 for methods of distributing a pharmaceutical product comprising nitric oxide gas for inhalation.
This patent application is currently assigned to INO THERAPEUTICS LLC. The applicant listed for this patent is INO Therapeutics LLC. Invention is credited to James S. Baldassarre.
Application Number | 20140377378 14/482704 |
Document ID | / |
Family ID | 42062590 |
Filed Date | 2014-12-25 |
United States Patent
Application |
20140377378 |
Kind Code |
A1 |
Baldassarre; James S. |
December 25, 2014 |
METHODS OF DISTRIBUTING A PHARMACEUTICAL PRODUCT COMPRISING NITRIC
OXIDE GAS FOR INHALATION
Abstract
Disclosed are methods of distributing a pharmaceutical product
comprising nitric oxide gas for inhalation. The methods include,
for example, obtaining a cylinder containing nitric oxide gas and
supplying the cylinder to a medical provider along with
instructions regarding how to administer the gas safely to
pediatric patients, the instructions including information that
patients who have pre-existing left ventricular dysfunction and are
administered inhaled nitric oxide may experience pulmonary
edema.
Inventors: |
Baldassarre; James S.;
(Doylestown, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INO Therapeutics LLC |
Hampton |
NJ |
US |
|
|
Assignee: |
INO THERAPEUTICS LLC
Hampton
NJ
|
Family ID: |
42062590 |
Appl. No.: |
14/482704 |
Filed: |
September 10, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13683236 |
Nov 21, 2012 |
8846112 |
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14482704 |
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12820866 |
Jun 22, 2010 |
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13683236 |
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12494598 |
Jun 30, 2009 |
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12820866 |
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12821041 |
Jun 22, 2010 |
8293284 |
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13651660 |
Oct 15, 2012 |
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12494598 |
Jun 30, 2009 |
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12821041 |
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13683444 |
Nov 21, 2012 |
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12494598 |
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12820866 |
Jun 22, 2010 |
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13683444 |
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12494598 |
Jun 30, 2009 |
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12820866 |
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12821041 |
Jun 22, 2010 |
8293284 |
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13651660 |
Oct 15, 2012 |
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12494598 |
Jun 30, 2009 |
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12821041 |
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Current U.S.
Class: |
424/718 ;
514/742; 600/18; 600/481 |
Current CPC
Class: |
A61K 33/00 20130101;
A61B 5/02007 20130101; A61P 9/10 20180101; F17C 2221/03 20130101;
A61P 9/08 20180101; A61K 31/04 20130101; A61P 9/00 20180101; A61K
31/21 20130101; F17C 2223/036 20130101; A61K 33/00 20130101; A61K
2300/00 20130101; F17C 2221/014 20130101; A61K 31/21 20130101; A61B
5/0205 20130101; A61P 11/00 20180101; A61M 16/12 20130101; F17C
2203/0646 20130101; A61B 5/08 20130101; G16H 20/10 20180101; A61B
8/0883 20130101; A61M 16/104 20130101; F17C 2223/0123 20130101;
F17C 2201/058 20130101; A61B 5/7278 20130101; A61M 16/0057
20130101; A61B 8/48 20130101; F17C 2270/025 20130101; A61B 5/7275
20130101; A61P 9/12 20180101; A61B 5/4839 20130101; A61K 45/06
20130101; A61M 1/1072 20130101; G06Q 99/00 20130101; A61K 31/21
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/718 ;
514/742; 600/481; 600/18 |
International
Class: |
A61K 33/00 20060101
A61K033/00; A61B 5/02 20060101 A61B005/02; A61M 1/10 20060101
A61M001/10; A61K 31/04 20060101 A61K031/04 |
Claims
1-30. (canceled)
31. A method of providing pharmaceutically acceptable nitric oxide
gas to a medical provider, the method comprising: obtaining a
cylinder containing compressed, pharmaceutically acceptable nitric
oxide gas in the form of a gaseous blend of nitric oxide and
nitrogen; supplying the cylinder containing compressed nitric oxide
gas to a medical provider responsible for treating pediatric
patients who have pulmonary hypertension, including some who do not
have left ventricular dysfunction; providing to the medical
provider instructions regarding how to administer the nitric oxide
gas safely to pediatric patients, the instructions including
information that patients who have pre-existing left ventricular
dysfunction and are administered inhaled nitric oxide may
experience pulmonary edema.
32. The method of claim 31, wherein the instructions appear in
prescribing information supplied to the medical provider with the
cylinder containing compressed nitric oxide gas.
33. The method of claim 31, wherein the instructions include
instructions regarding how to administer nitric oxide gas to
neonates.
34. The method of claim 33, wherein the neonates include neonates
with hypoxic respiratory failure.
35. The method of claim 31, wherein the instructions include
information that patients who have pre-existing left ventricular
dysfunction and are administered inhaled nitric oxide gas may
experience increased pulmonary capillary wedge pressure (PCWP),
leading to pulmonary edema.
36. The method of claim 35, wherein the instructions appear in
prescribing information supplied to the medical provider with the
cylinder containing compressed nitric oxide gas.
37. The method of claim 31, wherein the instructions include
information regarding possible adverse events that a patient who
has pre-existing left ventricular dysfunction may experience upon
administration of inhaled nitric oxide, the adverse events
including increased PCWP, pulmonary edema, systemic hypotension,
bradycardia, and cardiac arrest.
38. The method of claim 37, wherein the instructions appear in
prescribing information supplied to the medical provider with the
cylinder containing compressed nitric oxide gas.
39. The method of claim 31, wherein the information that, in
patients with pre-existing left ventricular dysfunction, inhaling
nitric oxide may cause pulmonary edema is sufficient to cause a
medical provider considering inhaled nitric oxide administration
for a plurality of pediatric patients who have pulmonary
hypertension and pre-existing left ventricular dysfunction to elect
to avoid administering inhaled nitric oxide to one or more of the
plurality of patients, in order to avoid putting the one or more
patients at increased risk of pulmonary edema.
40. The method of claim 31, further comprising: performing at least
one diagnostic process to identify a first pediatric patient who
has pulmonary hypertension and is a candidate for inhaled nitric
oxide administration; determining that the first patient has
pre-existing left ventricular dysfunction; evaluating the potential
benefit of administering inhaled nitric oxide to the first patient
vs. the potential risk that inhaled nitric oxide can induce
pulmonary edema in patients who have pre-existing left ventricular
dysfunction, in order to arrive at a decision of whether or not to
administer inhaled nitric oxide to the first patient; identifying a
second pediatric patient as having pulmonary hypertension and not
having left ventricular dysfunction; and administering inhaled
nitric oxide from the cylinder to the second patient, in accordance
with the instructions.
41. The method of claim 31, further comprising: performing at least
one diagnostic process to identify a plurality of pediatric
patients who have pulmonary hypertension and so are candidates for
inhaled nitric oxide administration; determining prior to
administration of inhaled nitric oxide whether or not each patient
of the plurality has pre-existing left ventricular dysfunction;
determining that a first patient of the plurality does not have
pre-existing left ventricular dysfunction; administering inhaled
nitric oxide from the cylinder to the first patient in accordance
with the instructions; determining that other patients of the
plurality do have pre-existing left ventricular dysfunction; for
each patient of the plurality determined to have pre-existing left
ventricular dysfunction, evaluating on a case-by-case basis the
potential benefit of administering inhaled nitric oxide vs. the
potential risk that inhaled nitric oxide could induce pulmonary
edema; for at least one patient of the plurality determined to have
pre-existing left ventricular dysfunction, determining that the
potential benefit of administering inhaled nitric oxide outweighs
the potential risk of pulmonary edema; administering inhaled nitric
oxide to the at least one patient; for a second patient of the
plurality determined to have pre-existing left ventricular
dysfunction, determining that the potential risk of pulmonary edema
outweighs the potential benefit of administering inhaled nitric
oxide; and excluding the second patient from administration of
inhaled nitric oxide.
42. A method of providing pharmaceutically acceptable nitric oxide
gas to a medical provider, the method comprising: obtaining a
cylinder containing compressed nitric oxide gas in the form of a
gaseous blend of nitric oxide and nitrogen; supplying the cylinder
containing compressed nitric oxide gas to a medical provider
responsible for treating pediatric patients who have pulmonary
hypertension, including some who do not have pre-existing left
ventricular dysfunction; and providing to the medical provider (i)
instructions regarding how to administer the nitric oxide safely to
pediatric patients, the instructions including information that
patients who have pre-existing left ventricular dysfunction and are
administered inhaled nitric oxide may experience pulmonary edema,
and (ii) a recommendation that, if pulmonary edema occurs in a
patient who has pre-existing left ventricular dysfunction and is
administered inhaled nitric oxide, the inhaled nitric oxide
administration should be discontinued.
43. The method of claim 42, wherein the instructions and the
recommendation appear in prescribing information supplied to the
medical provider with the cylinder containing compressed nitric
oxide gas.
44. The method of claim 42, wherein the instructions include
instructions regarding administration of inhaled nitric oxide to
neonates.
45. The method of claim 44, wherein the neonates include neonates
with hypoxic respiratory failure.
46. The method of claim 42, wherein the instructions include
information that patients who have pre-existing left ventricular
dysfunction and are administered inhaled nitric oxide may
experience increased PCWP, leading to pulmonary edema.
47. The method of claim 42, wherein the instructions include
information regarding of possible adverse events that a patient who
has pre-existing left ventricular dysfunction may experience upon
administration of inhaled nitric oxide, the adverse events
including increased PCWP, pulmonary edema, systemic hypotension,
bradycardia, and cardiac arrest.
48. The method of claim 42, wherein the recommendation is
sufficient to cause a medical provider to discontinue
administration of inhaled nitric oxide to a pediatric patient who
has pre-existing left ventricular dysfunction and develops
pulmonary edema upon administration of inhaled nitric oxide.
49. A method comprising: obtaining a source of nitric oxide gas
comprising (a) a cylinder of compressed gas and/or (b) a device
that delivers nitric oxide gas into an inspiratory limb of a
breathing circuit, for inhalation by a patient; supplying the
source of nitric oxide gas to a medical provider responsible for
treating pediatric patients who have pulmonary hypertension,
including some who do not have left ventricular dysfunction; and
providing to the medical provider instructions regarding how to
administer the nitric oxide gas safely to pediatric patients, the
instructions including information that patients who have
pre-existing left ventricular dysfunction and are administered
inhaled nitric oxide may experience pulmonary edema.
50. The method of claim 49, wherein the instructions appear in
prescribing information supplied to the medical provider with the
source of nitric oxide gas.
51. The method of claim 49, wherein the instructions include
instructions regarding how to administer the nitric oxide gas to
neonates.
52. The method of claim 49, wherein the instructions include
information that patients who have pre-existing left ventricular
dysfunction and are administered inhaled nitric oxide may
experience increased PCWP, leading to pulmonary edema.
53. The method of claim 49, wherein the instructions include
information regarding possible adverse events that a patient who
has pre-existing left ventricular dysfunction may experience upon
administration of inhaled nitric oxide, the adverse events
including increased PCWP, pulmonary edema, systemic hypotension,
bradycardia, and cardiac arrest.
54. The method of claim 49, wherein the information that, in
patients with pre-existing left ventricular dysfunction, inhaled
nitric oxide may cause pulmonary edema is sufficient to cause a
medical provider considering inhaled nitric oxide administration
for a plurality of pediatric patients who have pulmonary
hypertension and pre-existing left ventricular dysfunction to elect
to avoid administering inhaled nitric oxide to one or more of the
plurality of patients in order to avoid putting the one or more
patients at risk of pulmonary edema.
55. A method comprising: obtaining a device that delivers nitric
oxide gas into an inspiratory limb of a breathing circuit, for
inhalation by a patient; supplying the device to a medical provider
responsible for treating pediatric patients who have pulmonary
hypertension, including some who do not have pre-existing left
ventricular dysfunction; providing to the medical provider
instructions regarding how to administer the nitric oxide gas
safely to pediatric patients, the instructions including
information that patients who have pre-existing left ventricular
dysfunction and are administered inhaled nitric oxide may
experience pulmonary edema.
56. The method of claim 55, wherein the instructions appear in
prescribing information supplied to the medical provider with the
device.
57. The method of claim 55, wherein the instructions include
instructions regarding how to administer nitric oxide gas safely to
neonates.
58. The method of claim 55, wherein the instructions include
information that patients who have pre-existing left ventricular
dysfunction and are administered inhaled nitric oxide may
experience increased PCWP, leading to pulmonary edema.
59. The method of claim 55, wherein the instructions include
information regarding possible adverse events that a patient who
has pre-existing left ventricular dysfunction may experience upon
administration of inhaled nitric oxide, the adverse events
including increased PCWP, pulmonary edema, systemic hypotension,
bradycardia, and cardiac arrest.
60. The method of claim 55, further comprising: identifying a first
pediatric patient who has pulmonary hypertension and is a candidate
for inhaled nitric oxide administration; determining that the first
patient has pre-existing left ventricular dysfunction; based on the
information that patients who have pre-existing left ventricular
dysfunction and are administered inhaled nitric oxide may
experience pulmonary edema, evaluating the potential benefit of
administering inhaled nitric oxide to the first patient vs. the
potential risk of pulmonary edema described in the information;
using the device to administer inhaled nitric oxide to the first
patient while monitoring the first patient for increased PCWP
and/or pulmonary edema; identifying a second pediatric patient as
having pulmonary hypertension and not having pre-existing left
ventricular dysfunction; and using the device to administer inhaled
nitric oxide to the second patient.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/683,236, filed Nov. 21, 2012, which is a divisional of U.S.
application Ser. No. 12/820,866, filed Jun. 22, 2010, and now
abandoned, which is a continuation of U.S. application Ser. No.
12/494,598, filed Jun. 30, 2009, and now abandoned. U.S.
application Ser. No. 13/683,236 is also a divisional of U.S.
application Ser. No. 13/651,660 (now U.S. Pat. No. 8,431,163),
filed Oct. 15, 2012, which is a continuation of U.S. application
Ser. No. 12/821,041 (now U.S. Pat. No. 8,293,284), filed Jun. 22,
2010, which is a continuation of U.S. application Ser. No.
12/494,598, filed Jun. 30, 2009, and now abandoned. This
application is also a division of U.S. application Ser. No.
13/683,444, filed Nov. 21, 2012, which is a division of U.S.
application Ser. No. 12/820,866, filed Jun. 22, 2010, and now
abandoned, which is a continuation of U.S. application Ser. No.
12/494,598, filed Jun. 30, 2009, and now abandoned. U.S.
application Ser. No. 13/683,444 is also a division of U.S.
application Ser. No. 13/651,660 (now U.S. Pat. No. 8,431,163),
filed Oct. 15, 2012, which is a continuation of U.S. application
Ser. No. 12/821,041 (now U.S. Pat. No. 8,293,284), filed Jun. 22,
2010, which is a continuation of U.S. application Ser. No.
12/494,598, filed Jun. 30, 2009, and now abandoned. The contents of
the foregoing applications are incorporated by reference in the
present application.
STATEMENT CONCERNING GOVERNMENT INTEREST
[0002] Not applicable.
BACKGROUND OF THE INVENTION
[0003] INOmax.RTM., (nitric oxide) for inhalation is an approved
drug product for the treatment of term and near-term (>34 weeks
gestation) neonates having hypoxic respiratory failure associated
with clinical or echocardiographic evidence of pulmonary
hypertension.
[0004] The use of inhaled NO (iNO) has been studied and reported in
the literature. (Kieler-Jensen M et al., 1994, Inhaled Nitric Oxide
in the Evaluation of Heart Transplant Candidates with Elevated
Pulmonary Vascular Resistance, J Heart Lung Transplantation
13:366-375; Pearl R G et al., 1983, Acute Hemodynamic Effects of
Nitroglycerin in Pulmonary Hypertension, American College of
Physicians 99:9-13; Ajami G H et al., 2007, Comparison of the
Effectiveness of Oral Sildenafil Versus Oxygen Administration as a
Test for Feasibility of Operation for Patients with Secondary
Pulmonary Arterial Hypertension, Pediatr Cardiol; Schulze-Neick I
et al., 2003, Intravenous Sildenafil Is a Potent Pulmonary
Vasodilator in Children With Congenital Heart Disease, Circulation
108(Suppl II):II-167-II-173; Lepore J J et al., 2002, Effect of
Sildenafil on the Acute Pulmonary Vasodilator Response to Inhaled
Nitric Oxide in Adults with Primary Pulmonary Hypertension, The
American Journal of Cardiology 90:677-680; and Ziegler J W et al.,
1998, Effects of Dipyridamole and Inhaled Nitric Oxide in Pediatric
Patients with Pulmonary Hypertension, American Journal of
Respiratory and Critical Care Medicine 158:1388-95).
SUMMARY OF THE INVENTION
[0005] One aspect of the invention relates to a pre-screening
methodology or protocol having exclusionary criteria to be
evaluated by a medical provider prior to treatment of a patient
with iNO. One objective of the invention is to evaluate and
possibly exclude from treatment patients eligible for treatment
with iNO, who have pre-existing left ventricular dysfunction (LVD).
Patients who have pre-existing LVD may experience, and are at risk
of, an increased rate of adverse events or serious adverse events
(e.g., pulmonary edema) when treated with iNO. Such patients may be
characterized as having a pulmonary capillary wedge pressure (PCWP)
greater than 20 mm Hg, and should be evaluated on a case-by-case
basis with respect to the benefit versus risk of using iNO as a
treatment option.
[0006] Accordingly, one aspect of the invention includes a method
of reducing the risk or preventing the occurrence, in a human
patient, of an adverse event (AE) or a serious adverse event (SAE)
associated with a medical treatment comprising inhalation of nitric
oxide, said method comprising the steps or acts of (a) providing
pharmaceutically acceptable nitric oxide gas to a medical provider;
and (b) informing the medical provider that excluding human
patients who have pre-existing left ventricular dysfunction from
said treatment reduces the risk or prevents the occurrence of the
adverse event or the serious adverse event associated with said
medical treatment.
[0007] Further provided herein is a method of reducing the risk or
preventing the occurrence, in a human patient, of an adverse event
or a serious adverse event associated with a medical treatment
comprising inhalation of nitric oxide, said method comprising the
steps or acts of (a) providing pharmaceutically acceptable nitric
oxide gas to a medical provider; and (b) informing the medical
provider that human patients having pre-existing left ventricular
dysfunction experience an increased risk of serious adverse events
associated with said medical treatment.
[0008] Another aspect of the invention is a method of reducing one
or more of an AE or a SAE in an intended patient population in need
of being treated with iNO comprising the steps or acts of (a)
identifying a patient eligible for iNO treatment; (b) evaluating
and screening the patient to identify if the patient has
pre-existing LVD, and (c) excluding from iNO treatment a patient
identified as having pre-existing LVD.
[0009] Another aspect of the invention is a method of reducing the
risk or preventing the occurrence, in a patient, of one or more of
an AE or a SAE associated with a medical treatment comprising iNO,
the method comprising the steps or acts of (a) identifying a
patient in need of receiving iNO treatment; (b) evaluating and
screening the patient to identify if the patient has pre-existing
LVD; and (c) administering iNO if the patient does not have
pre-existing LVD, thereby reducing the risk or preventing the
occurrence of the AE or the SAE associated with the iNO treatment.
Alternatively, step (c) may comprise further evaluating the risk
versus benefit of utilizing iNO in a patient where the patient has
clinically significant LVD before administering iNO to the
patient.
[0010] In an exemplary embodiment of the method, the method further
comprises informing the medical provider that there is a risk
associated with using inhaled nitric oxide in human patients who
have preexisting or clinically significant left ventricular
dysfunction and that such risk should be evaluated on a case by
case basis.
[0011] In another exemplary embodiment of the method, the method
further comprises informing the medical provider that there is a
risk associated with using inhaled nitric oxide in human patients
who have left ventricular dysfunction.
[0012] In an exemplary embodiment of the methods described herein,
a patient having pre-existing LVD is characterized as having PCWP
greater than 20 mm Hg.
[0013] In an exemplary embodiment of the method, the patients
having pre-existing LVD demonstrate a PCWP.gtoreq.20 mm Hg.
[0014] In another exemplary embodiment of the method, the iNO
treatment further comprises inhalation of oxygen (O.sub.2) or
concurrent ventilation.
[0015] In another exemplary embodiment of the method, the patients
having pre-existing LVD have one or more of diastolic dysfunction,
hypertensive cardiomyopathy, systolic dysfunction, ischemic
cardiomyopathy, viral cardiomyopathy, idiopathic cardiomyopathy,
autoimmune disease related cardiomyopathy, drug-related
cardiomyopathy, toxin-related cardiomyopathy, structural heart
disease, valvular heart disease, congenital heart disease, or
associations thereof.
[0016] In another exemplary embodiment of the method, the patient
population comprises children.
[0017] In another exemplary embodiment of the method, the patient
population comprises adults.
[0018] In another exemplary embodiment of the method, the patients
who have pre-existing LVD are at risk of experiencing an increased
rate of one or more AEs or SAEs selected from pulmonary edema,
hypotension, cardiac arrest, electrocardiogram changes, hypoxemia,
hypoxia, bradycardia or associations thereof.
[0019] In another exemplary embodiment of the method, the intended
patient population in need of being treated with inhalation of
nitric oxide has one or more of idiopathic pulmonary arterial
hypertension characterized by a mean pulmonary artery pressure
(PAPm)>25 mm Hg at rest, PCWP.ltoreq.15 mm Hg, and a pulmonary
vascular resistance index (PVRI)>3 um.sup.2; congenital heart
disease with pulmonary hypertension repaired and unrepaired
characterized by PAPm>25 mm Hg at rest and PVRI>3 um.sup.2;
cardiomyopathy characterized by PAPm>25 mm Hg at rest and
PVRI>3 um.sup.2; or the patient is scheduled to undergo right
heart catheterization to assess pulmonary vasoreactivity by acute
pulmonary vasodilatation testing.
[0020] In another exemplary embodiment of any of the above methods,
the method further comprises reducing left ventricular afterload to
minimize or reduce the risk of the occurrence of an adverse event
or serious adverse event being pulmonary edema in the patient. The
left ventricular afterload may be minimized or reduced by
administering a pharmaceutical dosage form comprising nitroglycerin
or calcium channel blocker to the patient. The left ventricular
afterload may also be minimized or reduced using an intra-aortic
balloon pump.
DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS
[0021] INOmax.RTM. (nitric oxide) for inhalation was approved for
sale in the United States by the U.S. Food and Drug Administration
("FDA") in 1999. Nitric oxide, the active substance in INOmax.RTM.,
is a selective pulmonary vasodilator that increases the partial
pressure of arterial oxygen (PaO.sub.2) by dilating pulmonary
vessels in better ventilated areas of the lung, redistributing
pulmonary blood flow away from the lung regions with low
ventilation/perfusion (V/Q) ratios toward regions with normal
ratios. INOmax.RTM. significantly improves oxygenation, reduces the
need for extracorporeal oxygenation and is indicated to be used in
conjunction with ventilatory support and other appropriate agents.
The FDA-approved prescribing information for INOmax.RTM. in effect
on the filing date of U.S. application Ser. No. 12/494,598 (Jun.
30, 2009) is incorporated herein by reference in its entirety. The
DOSAGE section of the prescribing information for INOmax.RTM.
states that the recommended dose of INOmax.RTM. is 20 ppm, and that
treatment should be maintained up to 14 days or until the
underlying oxygen desaturation has resolved and the neonate is
ready to be weaned from INOmax.RTM. therapy. The ADMINISTRATION
section of the prescribing information says that the safety and
effectiveness of inhaled nitric oxide have been established in a
population receiving other therapies for hypoxic respiratory
failure, including vasodilators, intravenous fluids, bicarbonate
therapy, and mechanical ventilation. The CONTRAINDICATIONS section
of the prescribing information states that INOmax.RTM. should not
be used in the treatment of neonates known to be dependent on
right-to-left shunting of blood.
[0022] INOmax.RTM. is a gaseous blend of NO and nitrogen (0.08% and
99.92% respectively for 800 ppm; and 0.01% and 99.99% respectively
for 100 ppm) and is supplied in aluminium cylinders as a compressed
gas under high pressure. In general, INOmax.RTM. is administered to
a patient in conjunction with ventilatory support and O.sub.2.
Delivery devices suitable for the safe and effective delivery of
gaseous NO for inhalation include the INOvent.RTM., INOmax DS.RTM.,
INOpulse.RTM., INOblender.RTM., or other suitable drug delivery and
regulation devices or components incorporated therein, or other
related processes, which are described in various patent documents
including U.S. Pat. Nos. 5,558,083; 5,732,693; 5,752,504;
5,732,694; 6,089,229; 6,109,260; 6,125,846; 6,164,276; 6,581,592;
5,918,596; 5,839,433; 7,114,510; 5,417,950; 5,670,125; 5,670,127;
5,692,495; 5,514,204; 7,523,752; 5,699,790; 5,885,621; U.S. patent
application Ser. No. 11/355,670 (US 2007/0190184); Ser. No.
10/520,270 (US 2006/0093681); Ser. No. 11/401,722 (US
2007/0202083); Ser. No. 10/053,535 (US 2002/0155166); Ser. No.
10/367,277 (US 2003/0219496); Ser. No. 10/439,632 (US
2004/0052866); Ser. No. 10/371,666 (US 2003/0219497); Ser. No.
10/413,817 (US 2004/0005367); Ser. No. 12/050,826 (US
2008/0167609); and PCT/US2009/045266, all of which are incorporated
herein by reference in their entirety.
[0023] Such devices deliver INOmax.RTM. into the inspiratory limb
of the patient breathing circuit in a way that provides a constant
concentration of NO to the patient throughout the inspired breath.
Importantly, suitable delivery devices provide continuous
integrated monitoring of inspired O.sub.2, NO.sub.2 and NO, a
comprehensive alarm system, a suitable power source for
uninterrupted NO delivery, and a backup NO delivery capability.
[0024] As used herein, the term "children" (and variations thereof)
includes those being around 4 weeks to 18 years of age.
[0025] As used herein, the term "adult" (and variations thereof)
includes those being over 18 years of age.
[0026] As used herein, the terms "adverse event" and "AE" (and
variations thereof) mean any untoward occurrence in a subject or
clinical investigation subject administered a pharmaceutical
product (such as nitric oxide) and which does not necessarily have
a causal relationship with such treatment. An adverse event can
therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease temporarily
associated with the use of a medicinal/investigational product,
whether or not related to the investigational product. A
relationship to the investigational product is not necessarily
proven or implied. However, abnormal values are not reported as
adverse events unless considered clinically significant by the
investigator.
[0027] As used herein, the terms "adverse drug reaction" and "ADR"
(and variations thereof) mean any noxious and unintended response
to a medicinal product related to any dose.
[0028] As used herein, the terms "serious adverse event" and "SAE"
(or "serious adverse drug reaction" and "serious ADR") (and
variations thereof) mean a significant hazard or side effect,
regardless of the investigator's opinion on the relationship to the
investigational product. A serious adverse event or reaction is any
untoward medical occurrence that at any dose: results in death; is
life-threatening (which refers to an event/reaction where the
patient was at risk of death at the time of the event/reaction,
however this does not refer to an event/reaction that
hypothetically may have caused death if it were more severe);
requires inpatient hospitalization or results in prolongation of
existing hospitalization; results in persistent or significant
disability/incapacity; is a congenital anomaly/birth defect; or is
a medically important event or reaction. Medical and scientific
judgment is exercised in deciding whether reporting is appropriate
in other situations, such as important medical events that may not
be immediately life threatening or result in death or
hospitalization but may jeopardize the subject or may require
medical or surgical intervention to prevent one of the other
outcomes listed above--these are also considered serious. Examples
of such medical events include cancer, allergic bronchospasm
requiring intensive treatment in an emergency room or at home,
blood dyscrasias or convulsions that do not result in
hospitalizations, or the development of drug dependency or drug
abuse. Serious clinical laboratory abnormalities directly
associated with relevant clinical signs or symptoms are also
reported.
[0029] Left Ventricular Dysfunction. Patients having pre-existing
LVD may be described in general as those with elevated pulmonary
capillary wedge pressure, including those with diastolic
dysfunction (including hypertensive cardiomyopathy), those with
systolic dysfunction, including those with cardiomyopathies
(including ischemic or viral cardiomyopathy, or idiopathic
cardiomyopathy, or autoimmune disease related cardiomyopathy, and
side effects due to drug related or toxic-related cardiomyopathy),
or structural heart disease, valvular heart disease, congenital
heart disease, idiopathic pulmonary arterial hypertension,
pulmonary hypertension and cardiomyopathy, or associations thereof.
Identifying patients with pre-existing LVD is known to those
skilled in the medicinal arts, and such techniques for example may
include assessment of clinical signs and symptoms of heart failure,
or echocardiography diagnostic screening.
[0030] Pulmonary Capillary Wedge Pressure. Pulmonary capillary
wedge pressure, or "PCWP", provides an estimate of left atrial
pressure. Identifying patients with pre-existing PCWP is known to
those skilled in the medicinal arts, and such techniques for
example may include measuring by inserting balloon-tipped,
multi-lumen catheter (also known as a Swan-Ganz catheter).
Measurement of PCWP may be used as a means to diagnose the severity
of LVD (sometimes also referred to as left ventricular failure).
PCWP is also a desired measure when evaluating pulmonary
hypertension. Pulmonary hypertension is often caused by an increase
in pulmonary vascular resistance (PVR), but may also arise from
increases in pulmonary venous pressure and pulmonary blood volume
secondary to left ventricular failure or mitral or aortic valve
disease.
[0031] In cardiac physiology, the term "afterload" is used to mean
the tension produced by a chamber of the heart in order to
contract. If the chamber is not mentioned, it is usually assumed to
be the left ventricle. However, the strict definition of the term
relates to the properties of a single cardiac myocyte. It is
therefore of direct relevance only in the laboratory; in the
clinic, the term end-systolic pressure is usually more appropriate,
although not equivalent.
[0032] The term "left ventricular afterload" (and variations
thereof) refers to the pressure that the chamber of the heart has
to generate in order to eject blood out of the chamber. Thus, it is
a consequence of the aortic pressure, since the pressure in the
ventricle must be greater than the systemic pressure in order to
open the aortic valve. Everything else held equal, as afterload
increases, cardiac output decreases. Disease processes that
increase the left ventricular afterload include increased blood
pressure and aortic valve disease. Hypertension (increased blood
pressure) increases the left ventricular afterload because the left
ventricle has to work harder to eject blood into the aorta. This is
because the aortic valve won't open until the pressure generated in
the left ventricle is higher than the elevated blood pressure.
Aortic stenosis increases the afterload because the left ventricle
has to overcome the pressure gradient caused by the stenotic aortic
valve in addition to the blood pressure in order to eject blood
into the aorta. For instance, if the blood pressure is 120/80, and
the aortic valve stenosis creates a trans-valvular gradient of 30
mmHg, the left ventricle has to generate a pressure of 110 mmHg in
order to open the aortic valve and eject blood into the aorta.
Aortic insufficiency increases afterload because a percentage of
the blood that is ejected forward regurgitates back through the
diseased aortic valve. This leads to elevated systolic blood
pressure. The diastolic blood pressure would fall, due to
regurgitation. This would result in an increased pulse pressure.
Mitral regurgitation decreases the afterload. During ventricular
systole, the blood can regurgitate through the diseased mitral
valve as well as be ejected through the aortic valve. This means
that the left ventricle has to work less to eject blood, causing a
decreased afterload. Afterload is largely dependent upon aortic
pressure.
[0033] An intra-aortic balloon pump (IABP) is a mechanical device
that is used to decrease myocardial oxygen demand while at the same
time increasing cardiac output. By increasing cardiac output it
also increases coronary blood flow and therefore myocardial oxygen
delivery. It consists of a cylindrical balloon that sits in the
aorta and counterpulsates. That is, it actively deflates in
systole, increasing forward blood flow by reducing afterload, and
actively inflates in diastole, increasing blood flow to the
coronary arteries. These actions have the combined result of
decreasing myocardial oxygen demand and increasing myocardial
oxygen supply. The balloon is inflated during diastole by a
computer controlled mechanism, usually linked to either an ECG or a
pressure transducer at the distal tip of the catheter; some IABPs,
such as the Datascope System 98XT, allow for asynchronous
counterpulsation at a set rate, though this setting is rarely used.
The computer controls the flow of helium from a cylinder into and
out of the balloon. Helium is used because its low viscosity allows
it to travel quickly through the long connecting tubes, and it has
a lower risk of causing a harmful embolism should the balloon
rupture while in use. Intraaortic balloon counterpulsation is used
in situations when the heart's own cardiac output is insufficient
to meet the oxygenation demands of the body. These situations could
include cardiogenic shock, severe septic shock, post cardiac
surgery and numerous other situations.
[0034] Patients eligible for treatment with iNO. In general,
patients approved for treatment of iNO are term and near-term
(>34 weeks gestation) neonates having hypoxic respiratory
failure associated with clinical or echocardiographic evidence of
pulmonary hypertension, a condition also known as persistent
pulmonary hypertension in the newborn (PPHN). Due to the selective,
non-systemic nature of iNO to reduce pulmonary hypertension,
physicians skilled in the art further employ INOmax.RTM. to treat
or prevent pulmonary hypertension and improve blood O.sub.2 levels
in a variety of other clinical settings, including in both
pediatric and adult patients suffering from acute respiratory
distress syndrome (ARDS), pediatric and adult patients undergoing
cardiac or transplant surgeries, pediatric and adult patients for
testing to diagnose reversible pulmonary hypertension, and in
pediatric patients with congenital diaphragmatic hernia. In most,
if not all, of these applications, INOmax.RTM. acts by preventing
or treating reversible pulmonary vasoconstriction, reducing
pulmonary arterial pressure and improving pulmonary gas
exchange.
[0035] A small proportion of INOmax.RTM. sales stem from its use by
clinicians in a premature infant population. In these patients,
INOmax.RTM. is generally utilized by physicians as a rescue therapy
primarily to vasodilate the lungs and improve pulmonary gas
exchange. Some physicians speculate that INOmax.RTM. therapy may
promote lung development and/or reduce or prevent the future
development of lung disease in a subset of these patients. Although
the precise mechanism(s) responsible for the benefits of
INOmax.RTM. therapy in these patients is not completely understood,
it appears that the benefits achieved in at least a majority of
these patients are due to the ability of INOmax.RTM. to treat or
prevent reversible pulmonary vasoconstriction.
[0036] In clinical practice, the use of INOmax.RTM. has reduced or
eliminated the use of high risk systemic vasodilators for the
treatment of PPHN. INOmax.RTM., in contrast to systemic
vasodilators, specifically dilates the pulmonary vasculature
without dilating systemic blood vessels. Further, iNO
preferentially vasodilates vessels of aveoli that are aerated, thus
improving V/Q matching. In contrast, systemic vasodilators may
increase blood flow to atelectatic (deflated or collapsed) alveoli,
thereby increasing V/Q mismatch and worsening arterial oxygenation.
(See Rubin L J, Kerr K M, Pulmonary Hypertension, in Critical Care
Medicine: Principles of Diagnosis and Management in the Adult, 2d
Ed., Parillo J E, Dellinger R P (eds.), Mosby, Inc. 2001, pp.
900-09 at 906; Kinsella J P, Abman S H, The Role of Inhaled Nitric
Oxide in Persistent Pulmonary Hypertension of the Newborn, in Acute
Respiratory Care of the Neonate: A Self-Study Course, 2d Ed., Askin
D F (ed.), NICU Ink Book Publishers, 1997, pp. 369-378 at
372-73).
[0037] INOmax.RTM. also possesses highly desirable pharmacokinetic
properties as a lung-specific vasodilator when compared to other
ostensibly "pulmonary-specific vasodilators." For example, the
short half-life of INOmax.RTM. allows INOmax.RTM. to exhibit rapid
"on" and "off" responses relative to INOmax.RTM. dosing, in
contrast to non-gaseous alternatives. In this way, INOmax.RTM. can
provide physicians with a useful therapeutic tool to easily control
the magnitude and duration of the pulmonary vasodilatation desired.
Also, the nearly instantaneous inactivation of INOmax.RTM. in the
blood significantly reduces or prevents vasodilatation of
non-pulmonary vessels.
[0038] The pivotal trials leading to the approval of INOmax.RTM.
were the CINRGI and NINOS study.
[0039] CINRGI study. (See Davidson et al., March 1998, Inhaled
Nitric Oxide for the Early Treatment of Persistent Pulmonary
Hypertension of the term Newborn; A Randomized, Double-Masked,
Placebo-Controlled, Dose-Response, Multicenter Study; PEDIATRICS
Vol. 101, No. 3, p. 325).
[0040] This study was a double-blind, randomized,
placebo-controlled, multicenter trial of 186 term and near-term
neonates with pulmonary hypertension and hypoxic respiratory
failure. The primary objective of the study was to determine
whether INOmax.RTM. would reduce the receipt of extracorporeal
membrane oxygenation (ECMO) in these patients. Hypoxic respiratory
failure was caused by meconium aspiration syndrome (MAS) (35%),
idiopathic persistent pulmonary hypertension of the newborn (PPHN)
(30%), pneumonia/sepsis (24%), or respiratory distress syndrome
(RDS) (8%). Patients with a mean PaO.sub.2 of 54 mm Hg and a mean
oxygenation index (OI) of 44 cm H.sub.2O/mm Hg were randomly
assigned to receive either 20 ppm INOmax.RTM. (n=97) or nitrogen
gas (placebo; n=89) in addition to their ventilatory support.
Patients that exhibited a PaO.sub.2>60 mm Hg and a pH<7.55
were weaned to 5 ppm INOmax.RTM. or placebo. The primary results
from the CINRGI study are presented in Table 1. ECMO was the
primary endpoint of the study.
TABLE-US-00001 TABLE 1 Summary of Clinical Results from CINRGI
Study Placebo INOmax .RTM. P value Death or ECMO 51/89 (57%) 30/97
(31%) <0.001 Death 5/89 (6%) 3/97 (3%) 0.48
[0041] Significantly fewer neonates in the ECMO group required
ECMO, and INOmax.RTM. significantly improved oxygenation, as
measured by PaO.sub.2, OI, and alveolar-arterial gradient.
[0042] NINOS study. (See Inhaled Nitric Oxide in Full-Term and
Nearly Full-Term Infants with Hypoxic Respiratory Failure; NEJM,
Vol. 336, No. 9, 597).
[0043] The Neonatal Inhaled Nitric Oxide Study (NINOS) group
conducted a double-blind, randomized, placebo-controlled,
multicenter trial in 235 neonates with hypoxic respiratory failure.
The objective of the study was to determine whether iNO would
reduce the occurrence of death and/or initiation of ECMO in a
prospectively defined cohort of term or near-term neonates with
hypoxic respiratory failure unresponsive to conventional therapy.
Hypoxic respiratory failure was caused by meconium aspiration
syndrome (MAS; 49%), pneumonia/sepsis (21%), idiopathic primary
pulmonary hypertension of the newborn (PPHN; 17%), or respiratory
distress syndrome (RDS; 11%). Infants.ltoreq.14 days of age (mean,
1.7 days) with a mean PaO.sub.2 of 46 mm Hg and a mean oxygenation
index (OI) of 43 cm H.sub.2O/mmHg were initially randomized to
receive 100% O.sub.2 with (n=114) or without (n=121) 20 ppm NO for
up to 14 days. Response to study drug was defined as a change from
baseline in PaO.sub.2 30 minutes after starting treatment (full
response=>20 mmHg, partial=10-20 mm Hg, no response=<10 mm
Hg). Neonates with a less than full response were evaluated for a
response to 80 ppm NO or control gas. The primary results from the
NINOS study are presented in Table 2.
TABLE-US-00002 TABLE 2 Summary of Clinical Results from NINOS Study
Control NO (n = 121) (n = 114) P value Death or ECMO*, .dagger. 77
(64%) 52 (46%) 0.006 Death 20 (17%) 16 (14%) 0.60 ECMO 66 (55%) 44
(39%) 0.014 *Extracorporeal membrane oxygenation .dagger. Death or
need for ECMO was the study's primary end point
[0044] Adverse Events from CINRGI & NINOS. Controlled studies
have included 325 patients on INOmax.RTM. doses of 5 to 80 ppm and
251 patients on placebo. Total mortality in the pooled trials was
11% on placebo and 9% on INOmax.RTM., a result adequate to exclude
INOmax.RTM. mortality being more than 40% worse than placebo.
[0045] In both the NINOS and CINRGI studies, the duration of
hospitalization was similar in INOmax.RTM. and placebo-treated
groups.
[0046] From all controlled studies, at least 6 months of follow-up
is available for 278 patients who received INOmax.RTM. and 212
patients who received placebo. Among these patients, there was no
evidence of an AE of treatment on the need for re-hospitalization,
special medical services, pulmonary disease, or neurological
sequelae.
[0047] In the NINOS study, treatment groups were similar with
respect to the incidence and severity of intracranial hemorrhage,
Grade IV hemorrhage, per ventricular leukomalacia, cerebral
infarction, seizures requiring anticonvulsant therapy, pulmonary
hemorrhage, or gastrointestinal hemorrhage.
[0048] The table below shows adverse reactions that occurred in at
least 5% of patients receiving INOmax.RTM. in the CINRGI study.
None of the differences in these adverse reactions were
statistically significant when iNO patients were compared to
patients receiving placebo.
TABLE-US-00003 TABLE 3 ADVERSE REACTIONS ON THE CINRGI TRIAL
Adverse Reaction Placebo (n = 89) Inhaled NO (n = 97) Atelectasis 5
(4.8%) 7 (6.5%) Bilirubinemia 6 (5.8%) 7 (6.5%) Hypokalemia 5
(4.8%) 9 (8.3%) Hypotension 3 (2.9%) 6 (5.6%) Thrombocytopenia 20
(19.2%) 16 (14.8%)
[0049] Post-Marketing Experience. The following AEs have been
reported as part of the post-marketing surveillance. These events
have not been reported above. Given the nature of spontaneously
reported post-marketing surveillance data, it is impossible to
determine the actual incidence of the events or definitively
establish their causal relationship to the drug. The listing is
alphabetical: dose errors associated with the delivery system;
headaches associated with environmental exposure of INOmax.RTM. in
hospital staff; hypotension associated with acute withdrawal of the
drug; hypoxemia associated with acute withdrawal of the drug;
pulmonary edema in patients with CREST syndrome.
[0050] An analysis of AEs and SAEs from both the CINRGI and NINOS
studies, in addition to post-marketing surveillance, did not
suggest that patients who have pre-existing LVD could experience an
increased risk of AEs or SAEs. Nor was it predictable to physicians
skilled in the art that patients having pre-existing LVD (possibly
identified as those patients having a PCWP greater than 20 mmHg)
should be evaluated in view of the benefit versus risk of using iNO
in patients with clinically significant LVD, and that these
patients should be evaluated on a case by case basis.
Example 1
INOT22 Study
[0051] The INOT22 study, entitled "Comparison of supplemental
oxygen and nitric oxide for inhalation plus oxygen in the
evaluation of the reactivity of the pulmonary vasculature during
acute pulmonary vasodilatory testing" was conducted both to assess
the safety and effectiveness of INOmax.RTM. as a diagnostic agent
in patients undergoing assessment of pulmonary hypertension
(primary endpoint), and to confirm the hypothesis that iNO is
selective for the pulmonary vasculature (secondary endpoint).
[0052] During, and upon final analysis of the INOT22 study results,
applicants discovered that rapidly decreasing the pulmonary
vascular resistance, via the administration of iNO to a patient in
need of such treatment, may be detrimental to patients with
concomitant, pre-existing LVD. Therefore, a precaution for patients
with LVD was proposed to be included in amended prescribing
information for INOmax.RTM.. Physicians were further informed to
consider reducing left ventricular afterload to minimize the
occurrence of pulmonary edema in patients with pre-existing
LVD.
[0053] In particular, the INOT22 protocol studied consecutive
children undergoing cardiac catheterization that were prospectively
enrolled at 16 centers in the US and Europe. Inclusion criteria: 4
weeks to 18 years of age, pulmonary hypertension diagnosis, i.e.
either idiopathic pulmonary hypertension (IPAH) or related to
congenital heart disease (CHD) (repaired or unrepaired) or
cardiomyopathy, with pulmonary vascular resistance index
(PVRI)>3 u-m.sup.2. Later amendments, as discussed herein, added
an additional inclusionary criterion of a PCWP less than 20 mm Hg.
Patients were studied under general anaesthesia, or with conscious
sedation, according to the practice of the investigator. Exclusion
criteria: focal infiltrates on chest X-ray, history of intrinsic
lung disease, and/or currently taking PDE-5 inhibitors,
prostacyclin analogues or sodium nitroprusside. The study involved
supplemental O.sub.2 and NO for inhalation plus O.sub.2 in the
evaluation of the reactivity of the pulmonary vasculature during
acute pulmonary vasodilator testing. Consecutive children
undergoing cardiac catheterization were prospectively enrolled at
16 centers in the US and Europe. As hypotension is expected in
these neonatal populations, the comparison between iNO and placebo
groups is difficult to assess. A specific secondary endpoint was
evaluated in study INOT22 to provide a more definitive
evaluation.
[0054] The primary objective was to compare the response frequency
with iNO and O.sub.2 vs. O.sub.2 alone; in addition, all subjects
were studied with iNO alone. Patients were studied during five
periods: Baseline 1, Treatment Period 1, Treatment Period 2,
Baseline 2 and Treatment Period 3. All patients received all three
treatments; treatment sequence was randomized by center in blocks
of 4; in Period 1, patients received either NO alone or O.sub.2
alone, and the alternate treatment in Period 3. All patients
received the iNO and O.sub.2 combination treatment in Period 2.
Once the sequence was assigned, treatment was unblinded. Each
treatment was given for 10 minutes prior to obtaining hemodynamic
measurements, and the Baseline Period 2 was at least 10
minutes.
[0055] Results for the intent-to-treat (ITT) population, defined as
all patients who were randomized to receive drug, indicated that
treatment with NO plus O.sub.2 and O.sub.2 alone significantly
increased systemic vascular resistance index (SVRI) (Table 4). The
change from baseline for NO plus O.sub.2 was 1.4 Woods Units per
meter.sup.2 (WUm.sup.2) (p=0.007) and that for O.sub.2 was 1.3
WUm.sup.2 (p=0.004). While the change from baseline in SVRI with NO
alone was -0.2 WUm.sup.2 (p=0.899) which demonstrates a lack of
systemic effect.
TABLE-US-00004 TABLE 4 SVRI Change From Baseline by Treatment
(Intent-to-Treat) Treatment NO Plus O.sub.2 O.sub.2 NO SVRI (WU
m.sup.2) (n = 109) (n = 106) (n = 106) Baseline (room air) Mean
17.2 17.6 18.0 Standard Deviation 8.86 9.22 8.44 (SD) Median 15.9
16.1 16.2 Minimum, maximum -7.6, 55.6 -7.6, 55.6 1.9, 44.8
Post-treatment Mean 18.7 18.9 17.8 SD 9.04 8.78 9.40 Median 17.1
17.1 15.4 Minimum, maximum 3.0, 47.4 3.9, 43.6 3.3, 50.7 Change
From Baseline Mean 1.4 1.3 -0.2 SD 5.94 5.16 4.65 Median 1.2 1.0
0.2 Minimum, maximum -20.5, 19.1 -18.1, 17.7 -12.5, 12.7
p-value.sup.a 0.007 0.004 0.899 Pairwise comparisons NO plus
O.sub.2 versus O.sub.2, p = 0.952 NO plus O.sub.2 versus NO, p =
0.014 O.sub.2 versus NO, p = 0.017 .sup.ap-value from a Wilcoxon
Signed Rank Test. Only patients with data to determine response at
both treatments are included in this analysis. Source: INOT22 CSR
Table 6.4.1 and Appendix 16.2.6 (ATTACHMENT 1)
[0056] The ideal pulmonary vasodilator should reduce PVRI and/or
PAPm while having no appreciable effect on systemic blood pressure
or SVRI. In this case, the ratio of PVRI to SVRI would decrease,
given some measure of the selectivity of the agent for the
pulmonary vascular bed. The change in the ratio of PVRI to SVRI by
treatment is shown in Table 5.
TABLE-US-00005 TABLE 5 Change in Ratio of PVRI to SVRI by Treatment
(Intent-to-Treat) Treatment NO Plus O.sub.2 O.sub.2 NO Ratio
PVRI/SVRI (n = 108) (n = 105) (n = 106) Baseline Mean 0.6 0.5 0.6
SD 0.60 0.45 0.56 Median 0.5 0.5 0.4 Minimum, Maximum -1.6, 4.7
-1.6, 1.8 0.0, 4.7 Post Treatment Mean 0.4 0.4 0.5 SD 0.31 0.31
0.46 Median 0.3 0.4 0.3 Minimum, 0.0, 1.3 0.0, 1.4 -1.2, 2.2
Maximum Change from Baseline Mean -0.2 -0.1 -0.1 SD 0.52 0.31 0.54
Median -0.1 -0.1 0.0 Minimum, -4.4, 2.0 -1.6, 2.0 -4.4, 1.6 Maximum
P Value.sup.1 <0.001 <0.001 0.002 .sup.1Wilcoxon Signed Rank
Test Source: INOT22 CSR Table 6.5.1 (ATTACHMENT 2)
[0057] All three treatments have a preferential effect on the
pulmonary vascular bed, suggesting that all three are selective
pulmonary vasodilators. The greatest reduction in the ratio was
during treatment with NO plus O.sub.2, possibly due to the decrease
in SVRI effects seen with O.sub.2 and NO plus O.sub.2. These
results are displayed as percent change in the ratio (See Table
6).
TABLE-US-00006 TABLE 6 Percent Change in Ratio of PVRI to SVRI by
Treatment (Intent-to-Treat) Treatment NO Plus O.sub.2 O.sub.2 NO
Ratio PVRI/SVRI (n = 108) (n = 105) (n = 106) Baseline Mean 0.6 0.5
0.6 SD 0.60 0.45 0.56 Median 0.5 0.5 0.4 Minimum, Maximum -1.6, 4.7
-1.6, 1.8 0.0, 4.7 Post Treatment Mean 0.4 0.4 0.5 SD 0.31 0.31
0.46 Median 0.3 0.4 0.3 Minimum, 0.0, 1.3 0.0, 1.4 -1.2, 2.2
Maximum Percent Change from Baseline Mean -33.5 -19.3 -6.2 SD 36.11
34.59 64.04 Median -34.0 -21.3 -13.8 Minimum, -122.2, 140.1 -122.7,
93.3 -256.1, 294.1 Maximum P Value.sup.1 <0.001 <0.001 0.006
.sup.1Wilcoxon Signed Rank Test Source: INOT22 CSR Table 6.5.2
(ATTACHMENT 3)
[0058] NO plus O.sub.2 appeared to provide the greatest reduction
in the ratio, suggesting that NO plus O.sub.2 was more selective
for the pulmonary vasculature than either agent alone.
[0059] Overview of Cardiovascular Safety. In the INOT22 diagnostic
study, all treatments (NO plus O.sub.2, O.sub.2, and NO) were
well-tolerated. Seven patients of 124 treated experienced an AE
during the study. These included cardiac arrest, bradycardia, low
cardiac output (CO) syndrome, elevated ST segment (the portion of
an electrocardiogram between the end of the QRS complex and the
beginning of the T wave) on the electrocardiography (ECG) decreased
O.sub.2 saturation, hypotension, mouth hemorrhage and pulmonary
hypertension (PH). The numbers of patients and events were too
small to determine whether risk for AEs differed by treatment,
diagnosis, age, gender or race. Eight patients are shown in Table 7
due to the time period in which events are reported. AEs were
reported for 12 hours or until hospital discharge (which limits the
period in which such events can be reported). There is technically
no time limit in which SAEs are to be reported. So, there were 7
AEs during the study and at least one SAE after the study.
[0060] A total of 4 patients had AEs assessed as being related to
study drug. These events included bradycardia, low CO syndrome, ST
segment elevation on the ECG, low O.sub.2 saturation, PH and
hypotension. All but 2 AEs were mild or moderate in intensity and
were resolved. Study treatments had slight and non-clinically
significant effects on vital signs including heart rate, systolic
arterial pressure and diastolic arterial pressure. When an
investigator records an AE, they are required to say if (in their
opinion) the event is related to the treatment or not. In this
case, 4 of 7 were considered by the investigator to be related to
treatment.
[0061] The upper limit of normal PCWP in children is 10-12 mm Hg
and 15 mm Hg in adults. In INOT22, a baseline PCWP value was not
included as exclusion criteria. However, after the surprising and
unexpected identification of SAEs in the early tested patients, it
was determined that patients with pre-existing LVD had an increased
risk of experiencing an AE or SAE upon administration (e.g.,
worsening of left ventricular function due to the increased flow of
blood through the lungs). Accordingly, the protocol for INOT22 was
thereafter amended to exclude patients with a baseline PCWP greater
than 20 mm Hg after one patient experienced acute circulatory
collapse and died during the study. The value "20 mm Hg" was
selected to avoid enrollment of a pediatric population with LVD
such that they would be most likely at-risk for these SAEs.
[0062] SAEs were collected from the start of study treatment until
hospital discharge or 12 hours, whichever occurred sooner. Three
SAEs were reported during the study period, and a total of 7 SAEs
were reported. Three of these were fatal SAEs and 4 were nonfatal
(one of which led to study discontinuation). In addition, one
non-serious AE also led to discontinuation. A list of subjects who
died, discontinued or experienced an SAE is provided in Table 7
below.
TABLE-US-00007 TABLE 7 Subjects that died, discontinued or
experienced SAEs Patient Discontinued number AE Serious? Fatal?
treatment? 01020 Desaturation (hypoxia) No No Yes 02002 Pulmonary
edema Yes No No 04001 Hypotension and Yes Yes No cardiac arrest
04003 Hypotension and Yes No Yes ECG changes 04008 Hypotension and
Yes Yes No hypoxemia 05002 Hypoxia and bradycardia Yes Yes No (also
pulmonary edema) 07003 Cardiac arrest Yes No No 17001 Hypoxia Yes
No No
[0063] Two of the 3 fatal SAEs were deemed related to therapy. All
4 non-fatal SAEs were also considered related to therapy. The
numbers of patients and events were too small to determine whether
risk for SAEs differed by treatment, diagnosis, age, gender or
race. At least two patients developed signs of pulmonary edema
(subjects 05002 and 02002). This is of interest because pulmonary
edema has previously been reported with the use of iNO in patients
with LVD, and may be related to decreasing PVRI and overfilling of
the left atrium. (Hayward C S et al., 1996, Inhaled Nitric Oxide in
Cardiac Failure: Vascular Versus Ventricular Effects, J
Cardiovascular Pharmacology 27:80-85; Bocchi E A et al., 1994,
Inhaled Nitric Oxide Leading to Pulmonary Edema in Stable Severe
Heart Failure, Am J Cardiology 74:70-72; and, Semigran M J et al.,
1994, Hemodynamic Effects of Inhaled Nitric Oxide in Heart Failure,
J Am Coll Cardiology 24:982-988).
[0064] Although the SAE rate is within range for this population,
it appears that patients with the most elevated PCWP at baseline
had a disproportionately high number of these events. (Bocchi E A
et al., 1994; Semigran M J et al., 1994).
[0065] In the INOT22 study, 10 of the total 124 patients had a
baseline PCWP.gtoreq.18 mm Hg (7.5%), of which 3 subjects (04001,
02002 and 04003) had a SAE or were prematurely discontinued from
the study (30%), compared to 6.5% for the entire cohort.
[0066] Although there were very few significant AEs in the INOT22
study, these events are consistent with the expected physiologic
changes in patients with severe LVD. The events also corroborate
prior observations that iNO is rapidly acting, selective for the
pulmonary vasculature, and well-tolerated in most patients. The
actual incidence of acute LVD during acute ventricular failure
(AVT) is unknown. However, it is reasonable to expect that a
significant number of patients are at-risk for an increased
incidence of SAEs upon iNO treatment based upon the nature of the
underlying nature of the illness, i.e., pulmonary hypertension and
cardiovascular disease more generally. Thus, it would be
advantageous to have physicians identify these patients prior to
beginning iNO treatment, so that the physicians are alerted to this
possible outcome.
[0067] Benefits and Risks Conclusions. The INOT22 study was
designed to demonstrate the physiologic effects of iNO in a well
defined cohort of children (i.e., intended patient population) with
pulmonary hypertension using a high concentration, 80 ppm, of iNO,
i.e., one that would be expected to have the maximal
pharmacodynamic effect. INOT22 was the largest and most rigorous
pharmacodynamic study of iNO conducted to date, and it confirms a
number of prior observations, such as iNO's being rapidly acting,
selective for the pulmonary vasculature, and well-tolerated in most
patients.
[0068] It is also acknowledged that rapidly decreasing the PVR may
be undesirable and even dangerous in patients with concomitant LVD.
In the INOT22 study, the overall numbers of SAEs and fatal SAEs are
within the expected range for patients with this degree of
cardiopulmonary disease. The overall rate is 7/124 (5.6%), which is
closely comparable to the rate of 6% recently reported in a very
similar cohort of patients. (Taylor C J et al., 2007, Risk of
cardiac catheterization under anaesthesia in children with
pulmonary hypertension, Br J Anaesth 98(5):657-61). Thus, the
overall rate of SAEs would seem to be more closely related to the
underlying severity of illness of the patients rather than to the
treatments given during this study.
[0069] The INOT22 study results demonstrate that patients who had
pre-existing LVD may experience an increased rate of SAEs (e.g.,
pulmonary edema). During the course of the study, the protocol was
amended to exclude patients with a PCWP>20 mmHg. The
benefit/risk of using iNO in patients with clinically significant
LVD should be evaluated on a case by case basis. A reduction in
left ventricular afterload may perhaps be applied to minimize the
occurrence of pulmonary edema.
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