U.S. patent application number 14/313767 was filed with the patent office on 2014-12-25 for methods of reducing the risk of mortality associated with a medical treatment.
This patent application is currently assigned to INO THERAPEUTICS LLC. The applicant listed for this patent is INO Therapeutics LLC. Invention is credited to Jim Potenziano, Joe Stauffer.
Application Number | 20140373836 14/313767 |
Document ID | / |
Family ID | 51210824 |
Filed Date | 2014-12-25 |
United States Patent
Application |
20140373836 |
Kind Code |
A1 |
Potenziano; Jim ; et
al. |
December 25, 2014 |
Methods of Reducing the Risk of Mortality Associated With a Medical
Treatment
Abstract
Disclosed are methods of treatment that permit a reduction of
risk of mortality in infants who are candidates for treatment with
inhaled nitric oxide, by identifying a subset of such infants who
are at an increased risk of mortality upon treatment with inhaled
nitric oxide; also disclosed are related systems for use in
administering inhaled nitric oxide and methods of distributing a
pharmaceutical product.
Inventors: |
Potenziano; Jim;
(Binghamton, NY) ; Stauffer; Joe; (Skillman,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INO Therapeutics LLC |
Hampton |
NJ |
US |
|
|
Assignee: |
INO THERAPEUTICS LLC
Hampton
NJ
|
Family ID: |
51210824 |
Appl. No.: |
14/313767 |
Filed: |
June 24, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61839352 |
Jun 25, 2013 |
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Current U.S.
Class: |
128/203.12 |
Current CPC
Class: |
A61M 2016/1035 20130101;
A61P 11/00 20180101; A61M 2202/0275 20130101; G16H 10/20 20180101;
G16H 50/30 20180101; A61M 2202/025 20130101; A61M 16/0096 20130101;
A61M 16/12 20130101; A61M 2202/0208 20130101; Y02A 90/10 20180101;
Y02A 90/26 20180101; A61K 33/00 20130101 |
Class at
Publication: |
128/203.12 |
International
Class: |
A61M 16/12 20060101
A61M016/12; G06F 19/00 20060101 G06F019/00; A61K 33/00 20060101
A61K033/00 |
Claims
1. A method of treatment comprising (a) identifying a plurality of
neonates as being candidates for treatment with inhaled nitric
oxide; (b) determining that the race of a first neonate of the
plurality is black; (c) administering inhaled nitric oxide to the
first neonate; (d) determining that the race of a second neonate of
the plurality is white; (e) determining that the gender of the
second neonate is male; (f) determining that the second neonate is
of less than 27 weeks gestational age; (g) determining that the
fact that the second neonate is a white male of less than 27 weeks
gestational age means the second neonate is at a higher risk of
mortality upon administration of inhaled nitric oxide compared to a
black male or female neonate of the same gestational age; and (h)
excluding the second neonate from treatment with inhaled nitric
oxide, based on the determination of (g).
2. A method of treatment comprising (a) identifying a plurality of
neonates as being candidates for treatment with inhaled nitric
oxide; (b) determining that the gender of a first neonate of the
plurality is female; (c) administering inhaled nitric oxide to the
first neonate; (d) determining that the gender of a second neonate
of the plurality is male; (e) determining that the race of the
second neonate is white; (f) determining that the second neonate is
of less than 27 weeks gestational age; (g) determining that the
fact that the second neonate is a white male of less than 27 weeks
gestational age means the second neonate is at a higher risk of
mortality upon administration of inhaled nitric oxide compared to a
black male or female neonate of the same gestational age; and (h)
excluding the second neonate from treatment with inhaled nitric
oxide, based on the determination of (g).
3. The method of claim 1, wherein the second neonate is treated
with ventilatory support, intravenous fluids, surfactant, and/or
bicarbonate therapy.
4. The method of claim 1, wherein the second neonate does not have
pulmonary hypertension.
5. The method of claim 1, wherein the second neonate is identified
as being at risk of developing bronchopulmonary dysplasia
(BPD).
6. The method of claim 1, wherein the second neonate is treated
with high-frequency oscillatory ventilation.
7. The method of claim 1, wherein the second neonate is not
identified as being dependent on right-to-left shunting of
blood.
8. The method of claim 1, wherein the second neonate does not have
left ventricular dysfunction.
9. A method of selecting a treatment for a pre-term neonate, the
method comprising (a) identifying a pre-term neonate of gestational
age less than 27 weeks; (b) treating the pre-term neonate with
mechanical ventilation or positive airway pressure support; (c)
determining that the pre-term neonate is at risk for BPD; (d)
determining that the pre-term neonate is a white male; (e)
determining that the fact that the pre-term neonate is a white male
means the pre-term neonate is at a higher risk of mortality upon
administration of inhaled nitric oxide for prevention of BPD
compared to a black pre-term neonate or female pre-term neonate of
the same gestational age; and (f) excluding the white, male,
pre-term neonate from treatment with inhaled nitric oxide for
prevention of BPD, based on the determination of (e).
10. The method of claim 9, wherein the white, male, pre-term
neonate is treated with supplemental oxygen, caffeine, vitamin A,
or one or more surfactants.
11. The method of claim 9, wherein the white, male, pre-term
neonate is treated with high-frequency oscillatory ventilation
instead of inhaled nitric oxide.
12. A method of selecting a treatment for a pre-term neonate, the
method comprising: (a) identifying a pre-term neonate of less than
27 weeks gestational age as being in need of inhaled nitric oxide
for treatment of a condition involving pulmonary hypertension; (b)
determining that the pre-term neonate is a white male; (c)
determining that the fact that the pre-term neonate is a white male
means the pre-term neonate is at a higher risk of mortality upon
administration of inhaled nitric oxide compared to a black pre-term
neonate or a female pre-term neonate of the same gestational age;
and (d) administering inhaled nitric oxide to the white, male,
pre-term neonate for a limited period of time not exceeding four
days, for treatment of the condition involving pulmonary
hypertension, where the limitation on the length of treatment is
due to a concern about the higher risk of mortality in white, male,
pre-term neonates of less than 27 weeks gestational age.
13. The method of claim 12, wherein the nitric oxide is
administered at 20 ppm.
14. The method of claim 12, wherein the white, male, pre-term
neonate is treated with ventilatory support, intravenous fluids,
surfactant, and/or bicarbonate therapy, both during the period of
inhaled nitric oxide administration and after the administration
ceases.
15. The method of claim 13, wherein the white, male, pre-term
neonate is a candidate for inhaled nitric oxide because of hypoxic
respiratory failure or because he is undergoing, or has just
undergone, cardiac surgery involving heart/lung bypass.
16. A method of treatment comprising (a) identifying a pre-term
neonate of less than 27 weeks gestational age as being in need of
inhaled nitric oxide for prevention of BPD; (b) determining that
the pre-term neonate is a white male; (c) determining that the fact
that the pre-term neonate is a white male means the pre-term
neonate is at a higher risk of mortality upon administration of
inhaled nitric oxide compared to a black pre-term neonate or female
pre-term neonate of the same gestational age; (d) deciding to
postpone inhaled nitric oxide treatment until the white, male,
pre-term neonate reaches 27 weeks gestational age, due to the
determination of (c); (e) administering a treatment other than
inhaled nitric oxide to the white, male pre-term neonate; and (f)
when the white, male, pre-term neonate reaches 27 weeks gestational
age, beginning administration of inhaled nitric oxide to the white,
male, pre-term neonate.
17. The method of claim 16, wherein the treatment administered
prior to beginning inhaled nitric oxide administration comprises
caffeine, vitamin A, supplemental oxygen, or one or more
surfactants.
18. The method of claim 16, wherein the day that the white, male,
pre-term neonate reaches 27 weeks gestational age and the
administration of inhaled nitric oxide begins is within 5-14 days
after birth.
19. A method of treatment comprising (a) identifying a neonate as
being a candidate for treatment with inhaled nitric oxide; (b)
determining that the neonate is a white male of less than 27 weeks
gestational age; (c) providing ventilatory support to the neonate;
(d) determining that the fact that the neonate is a white male of
less than 27 weeks gestational age means the neonate is at a higher
risk of mortality upon administration of inhaled nitric oxide
compared to a black neonate or female neonate of the same
gestational age; and (e) excluding the white, male neonate from
treatment with inhaled nitric oxide, based on the determination of
(d).
20. The method of claim 19, wherein the white, male neonate is less
than 27 weeks gestational age.
21. The method of claim 19, wherein the ventilatory support is
high-frequency oscillatory ventilation.
22. The method of claim 19, wherein the white, male neonate is
treated with intravenous fluids, surfactant, and/or bicarbonate
therapy.
23. The method of claim 9, wherein the white, male neonate or
white, male, pre-term neonate is not dependent on right-to-left
shunting of blood.
24. The method of claim 9, wherein the white, male neonate or
white, male, pre-term neonate does not have left ventricular
dysfunction.
25. A system for use in administering inhaled nitric oxide gas,
which system reduces the overall risk of mortality from inhalation
of nitric oxide, the system comprising: a source of
pharmaceutically acceptable nitric oxide gas for inhalation; a
delivery device suitable for delivering nitric oxide gas from the
source to a neonatal patient; and instructions for use in operating
the system, the instructions comprising a warning that nitric oxide
gas may have an increased risk of mortality in white, male,
pre-term infants of less than 27 weeks gestational age, wherein the
instructions do not contain a similar warning for pre-term infants
of less than 27 weeks gestational age who are not white males, and
wherein the instructions reduce the overall risk of mortality from
inhalation of nitric oxide compared to a similar system without the
instructions.
26. The system of claim 25, wherein the instructions include a
description of using the system to deliver 20 ppm inhaled nitric
oxide gas to treat a neonatal patient.
27. The system of claim 25, wherein the instructions also include a
contraindication for neonates who are dependent on right to left
shunting of blood.
28. The system of claim 25, wherein the instructions also include a
statement that a patient with pre-existing left ventricular
dysfunction, when treated with inhaled nitric oxide, may experience
increased pulmonary capillary wedge pressure (PCWP) leading to
pulmonary edema.
29. The system of claim 25, wherein the warning is effective in
excluding a population of white, male, pre-term infants less than
27 weeks gestational age from treatment with inhaled nitric oxide,
thereby reducing the overall risk of mortality resulting from
inhaled nitric oxide treatment.
30. A method of distributing a pharmaceutical product, the method
comprising: supplying a source of nitric oxide gas to a medical
provider responsible for treating a plurality of neonatal patients
who are candidates for treatment with inhaled nitric oxide;
informing the medical provider that a recommended dose of inhaled
nitric oxide is 20 ppm nitric oxide; and providing a warning to the
medical provider that white, male, pre-term infants of less than 27
weeks gestational age may have an increased risk of death, as
compared to non-white pre-term infants and female pre-term infants
of the same gestational age, upon treatment with inhaled nitric
oxide.
31. The method of claim 30, wherein the warning is effective in
reducing the use of inhaled nitric oxide in white, male, pre-term
infants of less than 27 weeks gestational age who are at risk of
developing BPD.
32. The method of claim 30, further comprising manufacturing the
source of nitric oxide gas by a process comprising diluting nitric
oxide gas with nitrogen gas to produce a gaseous mixture of nitric
oxide and nitrogen in a cylinder.
33. A method of distributing a pharmaceutical product, the method
comprising: supplying a source of nitric oxide gas to a medical
provider responsible for treating a plurality of infants who have
pulmonary hypertension or who are at risk of BPD; informing the
medical provider that a recommended dose of inhaled nitric oxide
gas is 20 ppm nitric oxide; providing a warning to the medical
provider that inhaled nitric oxide should not be administered to
white, male, pre-term infants less than 27 weeks gestational age
who are at risk of BPD.
34. The method of claim 33, wherein the warning is effective in
excluding from treatment with inhaled nitric oxide a population of
white, male, pre-term infants less than 27 weeks gestational age
who are at risk of BPD, thereby reducing the overall risk of
mortality resulting from inhaled nitric oxide treatment.
35. The method of claim 33, further comprising manufacturing the
source of nitric oxide gas by a process comprising diluting nitric
oxide gas with nitrogen gas to produce a gaseous mixture of nitric
oxide and nitrogen in a cylinder.
36. The method of claim 30, wherein the source of nitric oxide gas
comprises a container containing compressed nitric oxide or
nitrogen dioxide, and the method further comprises generating the
nitric oxide or nitrogen dioxide and introducing it into the
container in compressed form, prior to supplying it to the medical
provider.
37. The method of claim 30, wherein the source of nitric oxide gas
comprises a container of N.sub.2O.sub.4, and the method further
comprises generating the N.sub.2O.sub.4.
38. The method of claim 30, wherein supplying the source of nitric
oxide gas to the medical provider comprises manufacturing the
source of nitric oxide gas at a manufacturing location and
transporting the source from the manufacturing location to a site
where the medical provider administers inhaled nitric oxide
treatment to patients.
39. The method of claim 30, wherein supplying the source of nitric
oxide gas to the medical provider comprises transporting the source
from a manufacturing, distribution or storage site to a site where
the medical provider administers inhaled nitric oxide treatment to
patients.
40. A method of treatment comprising (a) identifying a plurality of
neonates as being candidates for treatment with inhaled nitric
oxide; (b) determining that the race of a first neonate of the
plurality is non-white; (c) administering inhaled nitric oxide to
the first neonate; (d) determining that the race of a second
neonate of the plurality is white; (e) determining that the gender
of the second neonate is male; (f) determining that the second
neonate is of less than 27 weeks gestational age; (g) determining
that the fact that the second neonate is a white male of less than
27 weeks gestational age means the second neonate is at a higher
risk of mortality upon administration of inhaled nitric oxide
compared to a non-white, male neonate or a female neonate of the
same gestational age; and (h) excluding the second neonate from
treatment with inhaled nitric oxide, based on the determination of
(g).
41. A system for use in administering inhaled nitric oxide gas,
which system reduces the overall risk of mortality from inhalation
of nitric oxide, the system comprising: a source of
pharmaceutically acceptable nitric oxide gas for inhalation; a
delivery device suitable for delivering nitric oxide gas from the
source to a neonatal patient; and instructions for use in operating
the system, the instructions comprising a warning that nitric oxide
gas may have an increased risk of mortality in white, male,
pre-term infants of less than 27 weeks gestational age who are at
risk of developing BPD and who do not have pulmonary hypertension,
wherein the instructions do not contain a similar warning regarding
an increased risk of mortality for pre-term infants of less than 27
weeks gestational age who are not white males, and wherein the
instructions reduce the overall risk of mortality from inhalation
of nitric oxide compared to a similar system without the
instructions.
42. A system for use in administering inhaled nitric oxide gas,
which system reduces the overall risk of mortality from inhalation
of nitric oxide, the system comprising: a source of
pharmaceutically acceptable nitric oxide gas for inhalation; a
delivery device suitable for delivering nitric oxide gas from the
source to a neonatal patient; and instructions for use in operating
the system, the instructions communicating that, in a subset of
white, male, pre-term infants less than 27 weeks gestational age,
without pulmonary hypertension and at risk of developing BPD, there
was seen in one study an imbalance in deaths in the INOmax treated
group as compared to placebo at doses of 20 ppm for 3 days reduced
to 10 ppm for 10 days and 5 ppm for remainder of 24 days; wherein
the instructions reduce the overall risk of mortality from
inhalation of nitric oxide compared to a similar system without the
instructions, by reducing use of inhaled nitric oxide in white,
male, pre-term infants less than 27 weeks gestational age.
Description
CLAIM OF PRIORITY
[0001] This application claims priority under 35 USC .sctn.119(e)
to U.S. Patent Application Ser. No. 61/839,352, filed on Jun. 25,
2013, the entire contents of which are hereby incorporated by
reference.
TECHNICAL FIELD
[0002] The present invention relates to methods for reducing the
incidence of mortality in infants undergoing medical treatment.
BACKGROUND
[0003] Bronchopulmonary dysplasia (BPD) is a chronic lung disease
(CLD) of pre-term neonates, attributable to lung immaturity with
associated surfactant deficiency, systemic inflammation, and the
adverse effects of ventilator and supplemental oxygen therapy for
acute respiratory problems. BPD is defined clinically as the need
for supplemental oxygen at 36 weeks' postmenstrual age (PMA) (.+-.3
days). There are an estimated 10,000 to 15,000 pre-term neonates
diagnosed with BPD in the United States (US) each year. The risk of
developing BPD is related to the degree of prematurity, with the
highest risk of BPD occurring in pre-term neonates born prior to 26
weeks gestation and .ltoreq.750 g body weight at birth. Pre-term
neonates who develop BPD may consequently need long-term breathing
support, such as with the use of nasal continuous positive airway
pressure (NCPAP) machines or ventilators. Prediction of which
pre-term neonates are considered to be at risk of developing BPD
can be done by standard methods, e.g., as described in Laughon et
al., (2011) Am J Respir Crit Care Med 183:1715-1722.
[0004] BPD can develop for several reasons. Pre-term
neonates--especially those who develop respiratory distress
syndrome (RDS)--frequently require supplemental oxygen therapy
(oxygen given through nasal prongs, a mask, or a breathing tube).
Preterm neonates with RDS require mechanical ventilation, but
over-ventilation of this patient population often results in BPD,
due to injury to the lungs. See Northway et al., (1967) New Engl J
Med 276:357-368. Infections that occur before or shortly after
birth also can contribute to BPD. Lack of lung maturation can also
affect a pre-term neonate's chance of developing BPD. Pre-term
neonates as young as 22 weeks gestational age are surviving, but
generally exhibit immature lungs, with large and simplified alveoli
with dysmorphic capillaries, negligible airway epithelial lesions,
and mild interstitial fibroproliferation. The younger the pre-term
neonate, the less-developed are his or her lungs, leaving him or
her more likely to develop BPD.
[0005] Pre-term neonates with BPD are at greater risk for poor
developmental outcomes, acute and chronic lung disease, an
increased susceptibility to infections, and more frequent
hospitalization for respiratory illness during the first year of
life. Antenatal infections, such as chorioamnionitis and acquired
pneumonias, are additional potentially complicating and
contributing factors in the development of BPD. Late clinical
sequelae of BPD result in recurrent respiratory hospitalizations
(50% in the first year) and frequent emergency room visits,
pulmonary hypertension, late asthma and structural airway disease,
exercise intolerance, apnea, sudden death, systemic hypertension,
left ventricular hypertrophy, growth failure, feeding difficulties,
and developmental delays.
[0006] Currently, there are no approved medicinal products in the
US or globally to prevent the development of BPD in pre-term
neonates. Following FDA approval of inhaled nitric oxide (a potent
and selective pulmonary vasodilator) for the treatment of pulmonary
hypertension secondary to hypoxic respiratory failure (HRF) in the
term/near term neonate, it has been suggested that inhaled nitric
oxide might also benefit the sick pre-term neonate and, in
particular, reduce the incidence and/or severity of BPD.
Radiographic evidence suggests prolonged inhaled nitric oxide
therapy improves lung vascular growth after VEGF inhibition and
improves alveolarization in experimental BPD in preterm lambs. The
potential therapeutic targets for the use of inhaled nitric oxide
in the pre-term neonate include: improved gas exchange and reduced
FiO.sub.2, lower pulmonary artery pressure, anti-inflammatory and
antioxidant effects, sustained surfactant production, and
preservation or stimulation of angiogenesis and alveolarization in
the developing lung.
[0007] Several studies have been directed to use of inhaled nitric
oxide to prevent (reduce the incidence of) BPD.
[0008] Kinsella et al., (1999) Lancet 354:1061-1065, was a
randomized, double-blind, placebo-controlled, multi-center study in
80 pre-term neonates that was terminated early for enrollment
issues. Inhaled nitric oxide was administered at a dose of 5 ppm
for 7 days. The results of this study demonstrated a 15.4%
reduction in death or BPD (77% inhaled nitric oxide vs 91% placebo;
p=0.14), with no increase in severe intraventricular haemorrhage
(IVH).
[0009] Schreiber et al., N Engl J Med (2003) 349:2099-2107, was a
randomized, double-blind, placebo-controlled, single-center study
in 207 pre-term neonates administered a starting dose of inhaled
nitric oxide 10 ppm for 1 day, then 5 ppm for 6 days. The results
of the Schreiber study demonstrated a 24% reduction in CLD/death
(48.6% inhaled nitric oxide vs 63.7% placebo; p=0.03), a 47%
reduction in severe IVH/PVL (PVL=periventricular leukomalacia)
(12.4% inhaled nitric oxide vs 23.5% placebo; p=0.04), and a 47%
reduction in "abnormal or delayed" development (p=0.01).
[0010] Van Meurs et al., Pediatrics (2004) 113:559-564, was a
randomized, double-blind, placebo-controlled, multi-center study in
420 (800 planned) pre-term neonates. Inhaled nitric oxide was
administered at a starting dose of 5 ppm and increased to 10 ppm if
no response (Mean 3 days therapy). The study was stopped
prematurely. The results of this study showed overall no difference
vs placebo in death or BPD and no difference in IVH.
[0011] Kinsella et al., N Engl J Med (2006) 355:354-364, designated
the "INOT 25" study, was a randomized, double-blind,
placebo-controlled, multi-center study in 793 subjects. Inhaled
nitric oxide was administered at a dose of 5 ppm while the patient
was intubated, with a median treatment duration of 14 days. The
results of the INOT 25 study showed overall no difference vs
placebo in CLD or death (71.6% vs 75.3%) and a 27% reduction in
IVH/PVL (17.5% vs 23.9%).
[0012] Mercier et al., Lancet (2010) 376:346-54, designated the
"INOT 27" study, was a randomized, double-blind,
placebo-controlled, multi-center study in 35 centers in nine
European Union countries (800 subjects). Inhaled nitric oxide was
administered at a dose of 5 ppm for 7-21 days (treatment duration
Mean 16.3 days). The results of the INOT 27 study showed overall no
difference in survival without BPD at 36 weeks postmenstrual age
(placebo 65.5% vs inhaled nitric oxide 65% (p=0.73)).
[0013] Ballard et al., N Engl J Med (2007) 357:1444-1445, and
Ballard et al., N Engl J Med (2006) 355:343-353, report a
randomized, double-blind, placebo-controlled, multicenter study in
which 537 pre-term neonates received either inhaled nitric oxide or
placebo. Therapy was initiated between Day 7 and Day 21. Patients
were administered inhaled nitric oxide 20 ppm for 2 to 4 days, then
stepped-down in weekly intervals. All patients were treated for 24
days. The results of this study showed a 20% improvement in
survival without CLD at 36 weeks postmenstrual age with inhaled
nitric oxide (inhaled nitric oxide 43.9% vs placebo 36.8%,
p=0.042). Patients were discharged (p=0.04) or off all ventilator
support sooner on study drug (40 weeks, inhaled nitric oxide 65% vs
placebo 53%, p=0.01; 44 weeks, inhaled nitric oxide 82% vs placebo
76%, p=0.03).
SUMMARY
[0014] It has now been discovered that a particular subset of
patients is at an increased risk of mortality when treated with
inhaled nitric oxide, and that this subset is defined in part by
one or more of race, gender, and gestational age, and also by
determination of risk of developing BPD. The affected subset of
patients is white, male, pre-term neonates; more specifically,
white, male, pre-term neonates less than 27 weeks gestational age;
and even more specifically, white, male, pre-term neonates less
than 27 weeks gestational age that are at risk of developing BPD.
The same risk was not observed in pre-term neonates (male or
female) of other races, specifically American Indian/Alaska Native,
Asian, black, and Hispanic pre-term neonates, nor in female
pre-term neonates of any race (including white), nor in neonates of
gestational age greater than 27 weeks. Non-white pre-term neonates
as a class and female pre-term neonates as a class, even those of
gestational age less than 27 weeks, were able to safely receive
inhaled nitric oxide administered as a means to prevent development
of BPD. The newly discovered risk can be described as follows: in
white males <27 weeks gestational age, inhaled nitric oxide may
have an increased risk of death as compared to other subgroups.
Another way to describe the risk is: in white male pre-term infants
<27 weeks gestational age, without pulmonary hypertension and at
risk of developing BPD, inhaled nitric oxide may have an increased
risk of death as compared to other subgroups. There was seen in one
study an imbalance in deaths in this subgroup when treated with
nitric oxide as compared to placebo at doses of 20 ppm for 3 days
reduced to 10 ppm for 10 days and 5 ppm for remainder of 24 days.
This was not seen in other subgroups.
[0015] In one aspect, the invention is directed to a method of
treatment that includes identifying a plurality of neonates (i.e.,
two or more) as being candidates for treatment with inhaled nitric
oxide (preferably for a reason--such as prevention of BPD--other
than treatment of a condition involving pulmonary hypertension);
determining that the race of a first neonate of the plurality is
black or another non-white race such as American Indian/Alaska
Native, Asian, or Hispanic; administering inhaled nitric oxide to
the first neonate; determining that the race of a second neonate of
the plurality is white; determining that the gender of the second
neonate is male; determining that the second neonate is of less
than 27 weeks gestational age; determining that the fact that the
second neonate is a white male of less than 27 weeks gestational
age means the second neonate is at a higher risk of mortality upon
administration of inhaled nitric oxide compared to a black (or
other non-white) male neonate or a female neonate of the same
gestational age; and excluding the second neonate from treatment
with inhaled nitric oxide, based on the determination that the
second neonate has the higher risk of mortality. Thus, neonates who
are determined not to have that higher risk of mortality (e.g.,
because they are non-white, or are female, or are not less than 27
weeks gestational age) are treated with inhaled nitric oxide, while
those who have the higher risk of mortality are not treated with
inhaled nitric oxide. The reason that the neonates are candidates
for treatment with inhaled nitric oxide may be that they are at
risk for developing BPD. The reason is preferably not that the
neonates have a condition associated with pulmonary hypertension,
since such a condition may itself be acutely life-threatening and,
in the judgment of the physician, require treatment with inhaled
nitric oxide even where the neonate is a white male of less than 27
weeks gestational age. Thus, a further determination that may be
made prior to deciding not to treat with inhaled nitric oxide is
that the neonate does not have pulmonary hypertension.
[0016] In another aspect, the second neonate is identified (e.g.,
diagnosed) as being at risk of incurring BPD, e.g., from damage
attributable to supplemental oxygen therapy that is frequently
given to pre-term neonates. Such a neonate may be excluded from
treatment of inhaled nitric oxide at a dosing regimen typically
used to prevent BPD because of the mortality risk specific to
white, male, pre-term neonates of less than 27 weeks gestational
age.
[0017] Administration of inhaled nitric oxide to pre-term neonates
who are candidates for inhaled nitric oxide therapy because they
have been identified as being at risk for developing BPD typically
begins no less than five days after birth, due at least in part to
risk of brain hemorrhage. Treatment of these pre-term neonates may
begin at a point during the period that is 5 to 14 days after
birth, 5 to 10 days after birth, 5 to 21 days after birth, 7 to 21
days after birth, or 5 to 7 days after birth. Administration of
inhaled nitric oxide for the purpose of preventing BPD in
susceptible pre-term neonates generally continues for 20-30 days
after it is initiated. In specific treatment protocols,
administration of inhaled nitric oxide may be continued for at
least 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24
days, 25 days, 26 days, 27 days, 28 days, 29 days or 30 days, and
may involve a stepwise decrease in nitric oxide concentration
(e.g., in two, three, or four steps) over that time period.
Treatments requiring inhaled nitric oxide for prevention or
treatment of a different disorder or underlying condition may have
a different dosing regimen.
[0018] The second neonate may have an underlying condition, such as
pulmonary hypertension or hypoxic respiratory failure, that may
benefit from inhaled nitric oxide treatment at a very different
dosing regimen than suggested for prevention of BPD. Thus, in one
aspect, a neonate who is male, white, less than 27 weeks
gestational age, and at risk of BPD may indeed safely receive
inhaled nitric oxide for the underlying condition, but for a
limited duration less than that typically utilized to prevent BPD
(e.g., a limited duration of approximately one, two, three, four,
five, or six hours, 12 hours, 18 hours, 24 hours, 36 hours, 48
hours, three days, or four days). The duration will typically be
long enough to relieve, at least temporarily, the underlying
condition, but will usually be less than 96 hours (e.g., less than
80 hours, or less than 70 hours, or less than 60 hours. In some
embodiments, the treatment will last for a period between
approximately 40 hours and 70 hours.
[0019] One or more of the neonates may have, or be at risk of
incurring, pulmonary hypertension that can be relieved at least in
part with inhaled nitric oxide at a specific dosing regimen
(timing, duration, amount, and manner of dosing) different from
that typically used to prevent BPD. The second neonate may be given
an alternate acceptable treatment for his/her underlying condition.
The second neonate may also be at risk of mortality due to an
underlying condition, such pulmonary hypertension, and may be
administered inhaled nitric oxide at a specific dosing regimen that
is different (much shorter duration) from the dosing regimen that
is used for the prevention of BPD. If the underlying condition is
hypoxic respiratory failure, the alternate treatment could be, for
example, ventilatory support (e.g., high-frequency oscillatory
ventilation) with supplemental oxygen, extracorporeal membrane
oxygenation (ECMO), intravenous fluids, surfactant, and/or
bicarbonate therapy. In some embodiments, the first and/or second
neonate is a potential candidate for inhaled nitric oxide at least
in part because he/she is identified as being at risk of BPD. In
other embodiments, the first and/or second neonate is a candidate
for inhaled nitric oxide because the neonate has a condition that
can lead to pulmonary hypertension, or is undergoing, or has just
undergone, a procedure that can lead to pulmonary hypertension,
such as cardiac surgery involving heart/lung bypass.
[0020] In another aspect, the method of treatment includes
identifying a plurality of neonates as being candidates for
treatment with inhaled nitric oxide; determining that the race of a
first neonate of the plurality is black or another non-white race
or that the gender of the first neonate is female; administering
inhaled nitric oxide to the first neonate; determining that the
race of a second neonate of the plurality is white; determining
that the gender of the second neonate is male; determining that the
fact that the second neonate is a white male means the second
neonate is at a higher risk of mortality upon administration of
inhaled nitric oxide compared to a nonwhite (e.g., black) or female
neonate of the same gestational age; and excluding the second
neonate from treatment with inhaled nitric oxide, based on the
determination that the second neonate has the higher risk. In some
embodiments, the neonate is less than 27 week gestational age
and/or is at risk of developing BPD. One or more of the neonates
may have, or be at risk of incurring, pulmonary hypertension that
can be relieved at least in part with inhaled nitric oxide. The
second neonate may be given an alternate acceptable treatment (or
inhaled nitric oxide at a specific dosing regimen dissimilar from
the dosing regimen that would typically be used to prevent BPD) for
his/her underlying condition. If the underlying condition is
pulmonary hypertension or hypoxic respiratory failure, the second
neonate may be given one or more alternate acceptable treatment(s),
such as ventilatory support (e.g., high-frequency oscillatory
ventilation) with supplemental oxygen, ECMO, intravenous fluids,
surfactant, and/or bicarbonate therapy, instead of inhaled nitric
oxide. In other embodiments, the second neonate is a candidate for
inhaled nitric oxide at a specific dosing regimen different than
the dosing regimen administered to the first neonate for prevention
of BPD because he has a condition that can lead to pulmonary
hypertension, or is undergoing, or has just undergone, a procedure
that can lead to pulmonary hypertension, such as cardiac surgery
involving heart/lung bypass. In this instance, the dosing regimen
of inhaled nitric oxide received by the second neonate is for a
shorter duration than would typically be used to prevent BPD.
[0021] In another aspect, the method of treatment includes
performing at least one diagnostic process (which may include
performing echocardiography) to identify a plurality of neonates
who have an underlying condition, such as hypoxic respiratory
failure or being at risk of BPD, that makes them candidates for
inhaled nitric oxide treatment; determining that the race of a
first neonate of the plurality is black (or another non-white race)
or the gender is female; administering inhaled nitric oxide to the
first neonate; determining that a second neonate of the plurality
is a white male of less than 27 weeks gestational age; determining
that the fact that the second neonate is a white male of less than
27 weeks gestational age means the second neonate is at a higher
risk of mortality upon administration of inhaled nitric oxide
compared to a black or female neonate patient of the same
gestational age; and either providing an alternative treatment to
the second neonate or administering inhaled nitric oxide at a
shorter duration than what would typically be used for prevention
of BPD. Such duration for the second neonate may be less than 1
day, 1 day, 2 days, 3 days, or 4 days, or an increment of hours
that is less than 96 hours, e.g., 6 hours, 12 hours, 18 hours, 24
hours, 36 hours, 40 hours, 48 hours, 50 hours, 60 hours, 72 hours,
or 84 hours. The second neonate may be given an alternate
acceptable treatment for his underlying condition, such as one or
more of ventilatory support (e.g., high-frequency oscillatory
ventilation) with supplemental oxygen, ECMO, intravenous fluids,
surfactant, and/or bicarbonate therapy, instead of inhaled nitric
oxide.
[0022] Also within the invention is a method of selecting a
treatment for a neonate, the method encompassing performing at
least one diagnostic process (which may include echocardiography)
to identify a neonate (e.g., a premature infant of less than 27
weeks gestational age who may be at risk of BPD) with pulmonary
hypertension and/or hypoxic respiratory failure; determining that
the neonate is a white male; determining that the fact that the
neonate is a white male means he is at a higher risk of mortality
upon administration of inhaled nitric oxide compared to a black or
other non-white neonate or a female neonate of the same gestational
age when administered inhaled nitric oxide in a fashion consistent
with preventing BPD; and either excluding the white male neonate
from treatment with inhaled nitric oxide or treating the white male
neonate with inhaled nitric oxide at a dosing regimen of a
significantly shorter duration than the 20-30 days that would
typically be used for preventing BPD in pre-term neonates
susceptible to BPD, based on the determination that the white male
neonate is at a higher risk of mortality than a black neonate or
female neonate of the same gestational age if treated with a dosing
regimen suitable for preventing BPD. Alternatives to treatment with
inhaled nitric oxide for treating or preventing hypoxic respiratory
failure or pulmonary hypertension may include one or more of
ventilatory support (e.g., with supplemental oxygen), ECMO,
intravenous fluids, surfactant, and/or bicarbonate therapy or other
acceptable treatment. The ventilatory support may involve
high-frequency oscillatory ventilation. In some embodiments, the
white male neonate is considered to be at risk of BPD. In other
embodiments, the neonate is a candidate for inhaled nitric oxide
because he has a condition that can lead to pulmonary hypertension,
or is undergoing, or has just undergone, a procedure that can lead
to pulmonary hypertension, such as cardiac surgery involving
heart/lung bypass.
[0023] Also within the invention is a method of selecting a
treatment for a pre-term neonate, the method encompassing
identifying a pre-term neonate of less than 27 weeks gestational
age; treating the pre-term neonate with mechanical ventilation or
positive airway pressure support; determining that the pre-term
neonate is at risk of BPD; determining that the pre-term neonate is
a white male; determining that the fact that the pre-term neonate
is a white male means the pre-term neonate is at a higher risk of
mortality upon administration of inhaled nitric oxide for
prevention of BPD compared to a black or other non-white pre-term
neonate or a female pre-term neonate of the same gestational age;
and, based on the determination of higher risk, excluding the
white, male, pre-term neonate from treatment with inhaled nitric
oxide for prevention of BPD. The white, male, pre-term neonate may
be treated with high-frequency oscillatory ventilation instead of
inhaled nitric oxide.
[0024] In another aspect, the method of treatment includes
identifying a pre-term neonate of less than 27 weeks gestational
age as being in need of treatment for prevention of BPD;
determining that the race of the pre-term neonate is white and the
gender is male; determining that the fact that the pre-term neonate
is a white male means the pre-term neonate is at a higher risk of
mortality upon administration of inhaled nitric oxide compared to a
black or other non-white pre-term neonate or a female pre-term
neonate of the same gestational age; deciding to postpone inhaled
nitric oxide treatment until the white, male, pre-term neonate
reaches 27 weeks gestational age; administering a treatment other
than inhaled nitric oxide to the white, male, pre-term neonate;
and, when the white, male, pre-term neonate reaches 27 weeks
gestational age, beginning administration of inhaled nitric oxide
to the white, male, pre-term neonate, where the decision to
postpone inhaled nitric oxide treatment until 27 weeks gestational
age is based on the higher risk of mortality in white, male,
pre-term neonates of less than 27 weeks gestational age. The nitric
oxide will typically be administered initially at 20 ppm, and may
be decreased gradually to 10 ppm, then 5 ppm, and finally 2 ppm
over the course of treatment. The treatment administered prior to
beginning inhaled nitric oxide administration may be, for example,
ventilatory support (e.g., with supplemental oxygen).
[0025] In another aspect, the method of treatment includes
identifying a pre-term neonate of less than 27 weeks gestational
age (e.g., less than 26 weeks) as being in need of inhaled nitric
oxide for prevention or treatment of a condition involving
pulmonary hypertension (e.g., hypoxic respiratory failure);
determining that the race of the pre-term neonate is white;
determining that the gender of the pre-term neonate is male;
determining that the fact that the pre-term neonate is a white male
means the pre-term neonate is at a higher risk of mortality upon
administration of inhaled nitric oxide compared to a black or other
non-white pre-term neonate or a female pre-term neonate of the same
gestational age; administering a treatment other than inhaled
nitric oxide to the white, male, pre-term neonate; and, when the
white, male, pre-term neonate reaches 27 weeks gestational age,
beginning administration of inhaled nitric oxide to the white,
male, pre-term neonate, where the decision to postpone inhaled
nitric oxide treatment until 27 weeks gestational age is because of
the higher risk of mortality in white, male, pre-term neonates of
less than 27 weeks gestational age. The nitric oxide will typically
be administered at 20 ppm. The treatment administered prior to
beginning inhaled nitric oxide administration may be, for example,
ventilatory support (e.g., with supplemental oxygen), ECMO,
intravenous fluids, surfactant, and/or bicarbonate therapy, or
another alternative therapy. Such treatment (except ECMO) may
optionally be continued during the period that inhaled nitric oxide
is administered. The ventilatory support may involve high-frequency
oscillatory ventilation. Treatment of any pre-term neonate with
ECMO may be possible only if the pre-term neonate's blood vessels
are of adequate size. In some embodiments, the white, male,
pre-term neonate is considered to be at risk of BPD, in addition to
having a condition involving pulmonary hypertension. The pre-term
neonate may be a candidate for inhaled nitric oxide because he has
a condition that can lead to pulmonary hypertension, or is
undergoing, or has just undergone, a procedure that can lead to
pulmonary hypertension, such as cardiac surgery involving
heart/lung bypass.
[0026] In another aspect, the method of treatment includes
identifying a pre-term neonate of less than 27 weeks gestational
age as being a candidate for treatment with inhaled nitric oxide
because of an underlying condition; determining that the race of
the pre-term neonate is white and the gender is male; providing
ventilatory support to the pre-term neonate; determining that the
fact that the pre-term neonate is a white male means the pre-term
neonate is at a higher risk of mortality upon administration of
inhaled nitric oxide compared to a black or other non-white
pre-term neonate or a female pre-term neonate of the same
gestational age; and, based on the determination of higher risk,
either excluding the white, male, pre-term neonate from treatment
with inhaled nitric oxide, or treating the white, male, pre-term
neonate with inhaled nitric oxide, but using a treatment regimen
shorter than typically used to treat the underlying condition. The
ventilatory support may be continued after the pre-term neonate is
excluded from treatment with inhaled nitric oxide, or may be
substituted with ECMO at that point if the underlying condition
involves hypoxia and if ECMO is appropriate for the patient. The
ventilatory support may be high-frequency oscillatory ventilation.
The white, male, pre-term neonate may also be treated with
intravenous fluids, surfactant, and/or bicarbonate therapy. In some
embodiments, the white, male, pre-term neonate is a candidate for
inhaled nitric oxide at least in part because he is identified as
being at risk of BPD. In other embodiments, the pre-term neonate is
a candidate for inhaled nitric oxide because he has a condition
that can lead to pulmonary hypertension, or is undergoing, or has
just undergone, a procedure that can lead to pulmonary
hypertension, such as cardiac surgery involving heart/lung bypass.
Alternatively or in addition, the pre-term neonate may have
pulmonary hypertension (e.g., associated with hypoxic respiratory
failure) that can be relieved at least in part with inhaled nitric
oxide.
[0027] In certain embodiments of any of the above methods, the
neonates (in particular, the white, male, pre-term neonates) are
not dependent on right-to-left shunting of blood, and/or do not
have left ventricular dysfunction. The methods may include steps of
carrying out standard tests (such as echocardiography) to determine
whether the neonates have either or both of those conditions, prior
to making a decision about administration of inhaled nitric
oxide.
[0028] In certain embodiments of the above methods, the non-white
neonates and female neonates, and also the white, male neonates who
are more than 27 weeks gestational age, who are not excluded from
treatment with inhaled nitric oxide (because the above-described
increased risk of mortality does not apply to them), are treated
with inhaled nitric oxide as a means to prevent BPD. This treatment
typically begins at least five days after birth of a pre-term
(<30 weeks gestational age) neonate, e.g., five to fourteen days
after birth, five to ten days after birth, five to seven days after
birth, or five to 21 days after birth. A typical protocol for
inhaled nitric oxide treatment of a pre-term neonate at risk of BPD
involves administering decreasing concentrations of nitric oxide
over the course of administration, beginning at 20 ppm. In certain
embodiments, the initial dose of 20 ppm nitric oxide is decreased
to 10, then 5, and then 2 ppm over the course of administration. In
specific embodiments, the administration of nitric oxide is for at
least 20 days, preferably at least 24 days, and can be up to 30
days. In a specific example of nitric oxide administration, the
initial administration of 20 ppm nitric oxide lasts for a period of
48 to 96 hours, followed by a week at 10 ppm, a week at 5 ppm, and
then a week at 2 ppm.
[0029] In certain embodiments, an alternative treatment for a
pre-term neonate who is at risk of BPD, but who is not treated with
inhaled nitric oxide because the pre-term neonate is a white male
of less than 27 weeks gestational age, is one or more of any
acceptable treatment, including but not limited to caffeine,
vitamin A, supplemental oxygen, and one or more surfactants,
antenatal steroid, etc. (Any of these alternative treatments (e.g.,
vitamin A or supplemental oxygen) may also be used in conjunction
with inhaled nitric oxide for the prevention of BPD in appropriate
patients.)
[0030] The invention also includes a system for use in
administering inhaled nitric oxide gas. The system reduces the
overall risk of mortality from inhalation of nitric oxide by
providing instructions for use of nitric oxide that include a
warning about a specific risk to a specific population of pre-term
neonates. The system also includes a source of pharmaceutically
acceptable nitric oxide gas for inhalation and a delivery device
suitable for delivering nitric oxide gas from the source to a
neonatal patient. The instructions may include, for example, a
description of operating the system to deliver 20 ppm inhaled
nitric oxide to treat a condition such as one or more of hypoxic
respiratory failure or BPD or pulmonary arterial hypertension, a
contraindication for neonates who are dependent on right to left
shunting of blood, and/or a contraindication or warning regarding
patients who have pre-existing left ventricular dysfunction. The
instructions also include a warning that inhaled nitric oxide may
produce an increased risk of death in white, male, pre-term infants
of less than 27 weeks gestational age (and do not include a similar
warning for pre-term infants of less than 27 weeks gestational age
who are female or are not white). The latter warning may also
specify that the white, male, pre-term infants of less than 27
weeks gestational age are ones who are at risk of developing BPD,
may say the white, male, pre-term infants do not have pulmonary
hypertension, and may be effective in reducing the overall risk of
mortality from inhalation of nitric oxide compared to a similar
system without the instructions, and may be effective in excluding
a population of white, male, pre-term infants less than 27 weeks
gestational age from treatment with inhaled nitric oxide, thereby
reducing the overall risk of mortality resulting from inhaled
nitric oxide treatment. In addition or instead, the instructions
may communicate that, in a subset of white, male, pre-term infants
less than 27 weeks gestational age, without pulmonary hypertension
and at risk of developing BPD, there was seen in one study an
imbalance in deaths in the INOmax treated group as compared to
placebo, and may specify that the study used doses of 20 ppm for 3
days reduced to 10 ppm for 10 days and 5 ppm for remainder of 24
days.
[0031] In other embodiments, the white male neonate who is excluded
is less than 30 weeks gestational age, or less than 29 weeks, 28
weeks, 26 weeks, 25 weeks, 24 weeks, or 23 weeks.
[0032] Also disclosed is a method of distributing a pharmaceutical
product. This method includes supplying a source of nitric oxide or
any material that can be converted to nitric oxide to a medical
provider responsible for treating a plurality of neonatal patients
who are candidates for treatment with inhaled nitric oxide (e.g.,
neonates with hypoxic respiratory failure and/or pulmonary
hypertension, or those at risk of BPD), including pre-term neonates
such as those of less than 27 weeks gestational age; informing the
medical provider than a recommended dose of inhaled nitric oxide
gas is 20 ppm nitric oxide; and providing a warning to the medical
provider that the risk of mortality from inhalation of nitric oxide
is higher in white, male, pre-term neonates less than 27 weeks
gestational age (e.g., those who are at risk of BPD and so might
otherwise be treated with inhaled nitric oxide to help prevent BPD)
than in non-white pre-term neonates or female pre-term neonates of
the same gestational age. In preferred embodiments, the warning is
effective to cause a medical provider considering inhaled nitric
oxide treatment in a white, male, pre-term neonate less than 27
weeks gestational age (e.g., for prevention of BPD) to forego use
of inhaled nitric oxide in that pre-term neonate in order to avoid
putting the pre-term neonate at increased risk of mortality, or
otherwise to reduce the use of inhaled nitric oxide in such white,
male, pre-term neonates, including those at risk of developing BPD.
The medical provider may choose to substitute another appropriate
treatment. The various instructions and warnings may be supplied to
the medical provider in the form of a label attached to and/or
shipped with the source of nitric oxide, or in materials otherwise
supplied to the medical provider. The medical provider who is so
informed may use the source of nitric oxide (or any material that
can be converted to nitric oxide gas that is then delivered to and
inhaled by a patient) to treat patients who are candidates for
treatment with inhaled nitric oxide, including pre-term neonates.
Prior to treating a given pre-term neonate, the medical provider
may assess whether the pre-term neonate falls within one of the
populations described in the instructions as being at increased
risk of harm. This assessment includes determining whether the
patient is a white, male, pre-term neonate of less than 27 weeks
gestational age, and may include determining whether the patient is
at risk of BPD. In accordance with the warning regarding that
population, the medical provider will likely avoid treating such a
patient with inhaled nitric oxide, and may utilize another suitable
alternative treatment instead. If the patient is a non-white or a
female, the warning does not apply, so the medical provider can
treat such a patient with inhaled nitric oxide, even though the
latter patient is of less than 27 weeks gestational age and can be
characterized as at risk of BPD.
[0033] The method of distributing the pharmaceutical product may
also include steps of manufacturing the source of nitric oxide gas
before it is supplied to the medical provider. If the source of
nitric oxide gas is a cylinder of compressed gas, it may be
manufactured by a process comprising diluting nitric oxide gas with
nitrogen gas to produce a compressed gaseous mixture of nitric
oxide and nitrogen in a cylinder. The pharmaceutical product may
instead include N.sub.2O.sub.4 (in liquid form) or nitrogen dioxide
(in gaseous form); such a product is supplied in a form that is
ultimately converted to nitric oxide at the patient's bedside. If
the source of nitric oxide gas is a container containing compressed
nitric oxide or nitrogen dioxide, the method may further comprise
generating the nitric oxide or nitrogen dioxide and introducing it
into the container in compressed form, prior to supplying it to the
medical provider. By "supplying to the medical provider" is meant
causing the source of nitric oxide gas to be delivered to the
medical supplier, e.g., by transporting it from one site (such as
the manufacturing location or a distributer or storage building) to
another site (e.g., where the medical provider administers inhaled
nitric oxide treatment to patients).
DETAILED DESCRIPTION
[0034] Several exemplary embodiments of the claimed methods and
systems are described below. It is to be understood that what is
claimed is not limited to the details of set forth in the following
description. The methods and systems are capable of other
embodiments and of being practiced or being carried out in various
ways.
[0035] INOmax.RTM. (nitric oxide) for inhalation is an approved
drug product. The FDA-approved prescribing information for INOmax
dated 2013 is attached as Appendix 1, and so forms part of the
present disclosure, and also is incorporated by reference herein in
its entirety. INOmax.RTM. is a selective pulmonary vasodilator,
which, in conjunction with ventilatory support or other appropriate
agents, is indicated for the treatment of term and near-term
(>34 weeks gestation) neonates with hypoxic respiratory failure
associated with clinical or echocardiographic evidence of pulmonary
hypertension, where it improves oxygenation and reduces the need
for extracorporeal membrane oxygenation. The recommended dose of
INOmax for the approved indication is 20 ppm, maintained for up to
14 days or until the underlying oxygen desaturation has resolved.
Weaning should occur gradually. Adverse reactions per the label
include methemoglobinemia and nitrogen dioxide levels, both which
can be dose dependent.
[0036] Inhaled nitric oxide may be administered via a delivery
device such as INOmax DSIR.RTM., INOmax.RTM. DS or INOvent.RTM.,
each of which delivers operator-determined concentrations of nitric
oxide in conjunction with a ventilator or breathing gas
administration system after dilution with oxygen or an oxygen/air
mixture. A nitric oxide delivery system includes a nitric oxide
administration apparatus, a nitric oxide gas analyzer and a
nitrogen dioxide gas analyzer.
[0037] The source of nitric oxide used in any of the presently
disclosed methods can be a cylinder of compressed gas containing
nitric oxide, typically as a mixture with an inert gas such as
nitrogen or helium. Nitric oxide is generated by manufacturing the
gases separately, mixing them in an appropriate ratio, and
introducing them into an appropriate cylinder under pressure. The
mixing may occur in two steps: first diluting bulk nitric oxide
with nitrogen to a concentration of, e.g., 5,000 ppm or 28,600 ppm
in interim cylinders, and then diluting that mixture further by
introducing the mixture into the final cylinders and filling them
with more nitrogen to produce a concentration of, e.g., 100 ppm or
800 ppm in the final cylinders. Care is taken not to introduce any
water or oxygen into the cylinders. The cylinders are equipped with
an appropriate valve, shipped to the point of use, and attached to
a delivery device (as described above) to facilitate inhalation of
the gas by the patient.
[0038] The source of nitric oxide can instead be a nitric
oxide-generating device that generates nitric oxide from a suitable
nitrogen source, such as air (see for reference U.S. Pat. No.
5,396,882, incorporated herein by reference) or nitrogen dioxide.
The source of nitrogen dioxide can be, for example, a canister of
compressed nitrogen dioxide gas or a container of N.sub.2O.sub.4
(which, when treated under appropriate conditions, will give off
nitrogen dioxide). Manufacturing a source of nitrogen dioxide
includes steps of compressing nitrogen dioxide gas into a suitable
container or introducing N.sub.2O.sub.4 in liquid form into a
suitable container. The container is supplied in a device that
includes a filter containing a reducing agent or antioxidant, such
as ascorbic acid, which reduces the nitrogen dioxide to form nitric
oxide at the patient's bedside. At the point of administration,
such a nitric oxide-generating device is typically attached to a
gas-delivery device (such as a ventilator) to facilitate inhalation
of the newly formed nitric oxide gas by the patient.
[0039] Inhaled nitric oxide is contraindicated in the treatment of
neonates known to be dependent on right-to-left shunting of
blood.
[0040] Patients with left ventricular dysfunction who are treated
with nitric oxide may experience pulmonary edema, increased
pulmonary capillary wedge pressure, worsening of left ventricular
dysfunction, systemic hypotension, bradycardia and cardiac arrest.
If this occurs, the medical provider is advised to discontinue
inhaled nitric oxide while providing symptomatic care. The medical
provider may choose to forego use of inhaled nitric oxide
altogether in patients who are determined to have pre-existing left
ventricular dysfunction, or may administer inhaled nitric oxide
while monitoring carefully for adverse events related to the left
ventricular dysfunction (such as pulmonary edema), and
discontinuing use of the gas only if necessary.
[0041] "Neonate" or "neonatal" refers to an infant within 4 weeks
of birth.
[0042] "Pre-term neonate" or "preterm neonate" refers to a neonate
who is less than 34 weeks gestational age.
[0043] Despite multiple trials indicating the safety of inhaled
nitric oxide in full-term, near-term, and pre-term neonates
(several clinical trials in the latter group are summarized in the
"Data Review and Bibliography--Use in Premature Neonates" document
attached as Appendix 2, which forms part of the present disclosure
and also is incorporated by reference in its entirety), it has been
unexpectedly discovered that there is a specific neonatal patient
population that is at increased risk of mortality (i.e., death) if
treated with inhaled nitric oxide, compared to the same population
that does not receive inhaled nitric oxide. The increased mortality
rate was unexpectedly observed in white, male, pre-term neonates of
gestational age less than 27 weeks who were being treated with
inhaled nitric oxide because they were at risk of BPD, on the
theory that inhaled nitric oxide may be useful in preventing
(reducing the incidence of) BPD. The increased mortality rate was
not observed in non-white, male pre-term neonates of gestational
age less than 27 weeks, or in female pre-term neonates of any race
who were of the same gestational age. Once an individual white,
male pre-term neonate born at less than 27 weeks gestation age
reaches a point corresponding to 27 weeks gestation age and at
least 5 days after birth, he can safely receive inhaled nitric
oxide.
[0044] Alternative preventative treatments for white, male,
pre-term neonates initially identified as candidates for inhaled
nitric oxide treatment intended for the prevention of BPD, but who
are now excluded from that preventative treatment because of the
newly discovered risk of mortality, include one or more of
caffeine, vitamin A, supplemental oxygen, and/or surfactant. Oxygen
is generally administered at 21-60% of the inhaled gas, but can be
administered at a higher level if necessary. It is considered to be
supplemental oxygen if the patient's inhalation gas contains a
level of oxygen higher than in air, i.e., at least 22% oxygen
(e.g., 22-60%), and up to 90%, 99% or even 100% oxygen. Caffeine
therapy can be, e.g., 20-25 mg/kg every 24 hours as citrate orally
or IV (intravenous) over 10 minutes, beginning 24 hours after
loading dose. Alternatively, 18-30 mg/kg every 12 or more hours may
be administered. Vitamin A therapy includes, for example,
7,500-15,000 IU intramuscularly daily for up to 10 days. Surfactant
treatment generally depends on the type of surfactant being
administered, but is typically administered in three doses: first
dose is 3 cc/kg, then if FiO.sub.2 (fraction of inspired oxygen)
six hours after the first dose is greater than 60%, the second dose
of 3 cc/kg is administered. If FiO.sub.2 six hours after the second
dose is greater than 40%, then the third dose of 3 cc/kg is
administered.
[0045] Certain risk calculators may be used to assist in
identifying if a patient is at risk of BPD. Risk calculator
software known in the art may take into account a pre-term
neonate's gestational age, weight and ventilator support needs,
among other factors. Such a risk calculator may help a clinician or
therapist to assist in determining if a given pre-term neonate is
at risk of developing BPD. See, e.g., Laughon et al., (2011) Am J
Respir Crit Care Med 183:1715-1722.
[0046] As in other situations where the race of the patient has an
effect on treatment options, determining whether the patient is
white or non-white is generally accomplished by visual assessment
coupled with querying the patient's parent or other relative,
and/or reviewing the patient's records. Self-identification of the
patient's race by the patient's biological mother or father is
typically the means by which race is determined for this purpose.
Biological markers (such as genetic markers) indicative of race may
also be useful, where such markers have been validated as accurate
predictors of whether a patient is white vs. non-white. As the
heightened risk in white males, compared to non-white males, is
theorized to be due to a recessive trait present in white males and
not in non-white males, a male pre-term neonate of mixed white and
non-white ancestry is (according to this theory) likely to carry
the dominant trait that is protective in non-whites. Thus, if there
is a question as to how to categorize a male pre-term neonate of
mixed white and non-white ancestry for purposes of the presently
claimed methods, a physician may choose to categorize the pre-term
neonate as non-white and thus eligible for treatment with inhaled
nitric oxide.
[0047] In general, administration of inhaled nitric oxide to
pre-term neonates that have been identified as at risk for
developing BPD and/or as likely to have a therapeutic response to
the inhaled nitric oxide should begin no less than five days after
birth. Treatment of these pre-term neonates may begin at some point
within the period of 5 to 14 days after birth, 7 to 21 days after
birth, 5 to 21 days after birth, or 5 to 7 days after birth.
Administration of inhaled nitric oxide for this purpose generally
continues for 20-30 days after it is initiated. In specific
treatment protocols, administration of inhaled nitric oxide may be
continued for at least 20 days, 21 days, 22 days, 23 days, 24 days,
25 days, 26 days, 27 days, 28 days, 29 days or 30 days.
EXAMPLES
[0048] A multi-center, double blind, placebo-controlled randomized
clinical trial designated the "BPD-301" study was conducted to
examine the efficacy of inhaled nitric oxide in preventing BPD in
preterm neonates less than 30 weeks gestational age and less than
1250 grams who required mechanical ventilation or positive pressure
support. Patients were identified as (1) American Indian or Alaska
Native, (2) Asian, (3) Black, (4) Hispanic, (5) White, or (6)
Other. Continuous inhaled nitric oxide or placebo gas
administration into the inspiratory limb of the ventilator circuit
in the mechanically ventilated subject was accomplished using an
INOvent.RTM. delivery device. The placebo group received the same
dose of nitrogen that the active or treatment group received of
inhaled nitric oxide. Administration of inhaled nitric oxide or
placebo was begun at a point during the window of time 5 to 14 days
after the subject's birth and continued for 24 days thereafter. The
starting dose was 20 ppm. A dose reduction schedule was followed:
after 72 hours of treatment at 20 ppm, reducing to 10 ppm, and then
reducing to 5 ppm on day 10. If an infant was extubated before 24
days, therapy was continued via nasal continuous positive airway
pressure or nasal cannula to complete the protocol. 451 infants
less than 30 weeks of gestation age were included in this trial, of
which 449 were randomized and 2 were not randomized. There was a
1:1 randomization with 220 infants treated with placebo and 229
treated with inhaled nitric oxide.
[0049] It is believed that pre-term neonates that enrolled in and
completed the BPD 301 study did not have pulmonary hypertension,
since one of the exclusionary criteria was prior treatment with
inhaled nitric oxide for any reason, and pulmonary hypertension in
infants is routinely treated with inhaled nitric oxide. In order to
enroll in the BPD 301 study and receive inhaled nitric oxide for
the prevention of BPD, a pre-term neonate could not have already
previously been administered inhaled nitric oxide. If a pre-term
neonate exhibited at birth characteristics associated with
pulmonary hypertension, he or she would have likely been treated
with commercial inhaled nitric oxide, and if treated with
commercial inhaled nitric oxide, he or she would not have been
eligible for the study.
[0050] Additionally, if the pre-term neonate had undiagnosed
pulmonary hypertension and happened to be placed on placebo
(nitrogen) for purposes of the BPD-301 study, the pre-term
neonate's hypoxic respiratory failure would have worsened and would
have likely required immediate treatment with commercial inhaled
nitric oxide. This administration of commercial inhaled nitric
oxide would have failed the subject from the trial, both reducing
the power of the trial and eliminating the subject from the study
analysis.
[0051] A synopsis of the BPD-301 protocol follows.
TABLE-US-00001 Name of Sponsor/Company: INO Therapeutics LLC Name
of Investigational Product: INOmax .RTM. (nitric oxide) for
inhalation Name of Active Ingredient: Nitric Oxide for Inhalation
Title of Study: Inhaled nitric oxide for the prevention of
bronchopulmonary dysplasia (BPD) in preterm infants requiring
mechanical ventilation or positive pressure support on days 5 to 14
after birth Study center(s): Approximately 25 Studied period
(years): Phase of development: 3 Estimated date first subject
enrolled: Dec. 30, 2009 Estimated date last subject completed: Aug.
2, 2012 Estimated end of follow up: Aug. 2, 2014 Objectives:
Primary: The primary objective of this trial is to examine the
efficacy of inhaled nitric oxide (iNO) in preterm infants <30
weeks gestational age (GA) and <1250 grams who require
mechanical ventilation or positive pressure support on days 5 to 14
after birth. Secondary: The secondary objectives are to examine the
safety of iNO on premature infants as measured by survival, adverse
events, and outcomes at 18 months to 24 months of age, to evaluate
the pharmacokinetics (PK) of iNO in preterm infants, and to measure
the pharmacoeconomic (PE) impacts of iNO use on the management of
preterm infants. Assessment will be: To examine the safety of
inhaled nitric oxide (iNO) on premature infants as measured by
survival and adverse events. To evaluate the pharmacokinetics (PK)
of nitric oxide (NO) in preterm infants using plasma nitrite and
nitrate (NOx) as surrogates To evaluate the relationship between
NOx and methemoglobin (MetHb) To explore the relationship between
NO exposure and clinical outcomes To evaluate the economic
implications of using nitric oxide for inhalation (iNO) to prevent
BPD Methodology: Multi-center, double blind, placebo-controlled,
randomized clinical trial. Infants who meet all enrollment criteria
at any point during days 5 to 14 after birth will be randomized to
inhaled NO starting at 20 ppm, or matching placebo, by means of a
blinded INOvent .RTM. delivery device. All infants will receive 24
days of therapy, following a dose reduction schedule. Infants who
are extubated before 24 days will continue therapy via nasal
continuous positive airway pressure (CPAP) or nasal cannula to
complete 24 days' of therapy. The primary outcome measure will be
survival without BPD at 36 weeks GA using a physiologic assessment
of BPD. Sparse pharmacokinetic (PK) samples will be collected from
participating infants (3 samples each) on a randomized schedule.
This study will include a 12 month and 18 to 24 month follow-up
visits to assess safety and efficacy. All infants will be followed
up to 18 to 24 months of corrected age for adverse events, somatic
growth and neurologic development. Number of subjects (planned):
450 Diagnosis and main criteria for inclusion: Inclusion: Preterm
infants who are: 1. <1250 grams at birth 2. <30 weeks
gestational age 3. 5 to 14 days of age (inclusive) at the time of
entry 4. Requiring mechanical ventilation or for those infants
.ltoreq.800 grams, positive pressure support (including CPAP) for
primary respiratory insufficiency on days 5 to 14 days of age
(inclusive) Exclusion: 1. Preterm infants with life-threatening
anomalies (cranial, cardiac, thoracic, chromosomal) or congenital
diaphragmatic hernia with lung hypoplasia, or any subject who will
not receive complete intensive care 2. Preterm infants with
bilateral Grade 4 intraventricular hemorrhage (IVH) 3. Subjects who
are dependent on right to left shunting to maintain the systemic
circulation 4. Preterm infants who received prior iNO therapy 5.
Use of another investigational agent Investigational product,
dosage and mode of administration: Nitric oxide for inhalation (or
matching placebo) starting at 20 ppm (and following a dose
reduction schedule) will be administered continuously into the
inspiratory limb of the ventilator circuit in mechanically
ventilated subject using a blinded version of the INOvent .RTM.
delivery system, or by nasal CPAP or nasal cannula, as needed to
complete 24 days of therapy. Duration of treatment: Study drug will
be weaned from 20 ppm to 10 ppm after 72 hours of treatment. The
next wean will be to 5 ppm on Day 10. If the infant deteriorates
after any dose reduction, he/she may be put back on the previous
treatment and weaning re-attempted as tolerated. Duration of
treatment is 24 days. Reference therapy, dosage and mode of
administration: Placebo consisting of 100% Grade 5 Nitrogen
(N.sub.2) gas will be administered in a blinded manner identical to
that of the active treatment. Criteria for evaluation: Efficacy:
Survival without BPD at 36 weeks gestational age (GA) using a
physiologic assessment Severity of BPD (as defined by FiO.sub.2
requirement at week 36) among survivors as determined by the level
of support needed to remain SaO.sub.2 .gtoreq.90% Status at 40 and
44 weeks (GA) Hospitalization Need for oxygen Need for airway
pressure support Need for mechanical ventilation Days of air
pressure support for lung disease (birth hospitalization) Days of
hospitalization (birth hospitalization) Use of postnatal
corticosteroids for respiratory insufficiency (including dose and
duration of therapy) (birth hospitalization) Use of respiratory
medications, oxygen, and days of all hospitalizations at 12 months
and 18 to 24 months of corrected age. Safety: Examine the safety of
iNO in preterm infants at risk of BPD. Incidence of
methemoglobinemia and elevated nitrogen dioxide concentrations
Incidence and types of adverse events including: Adverse events of
interest will include intracranial hemorrhage of any type, patent
ductus arteriosus requiring intervention, necrotizing entercolitis,
intestinal perforations, air leaks of any type, pulmonary
hemorrhage, retinopathy of prematurity and sepsis of any type.
Incidence of death after 36 weeks GA to 12 month and 18 to 24 month
of corrected age, stratified by gestational age at birth. Long-term
neurodevelopmental outcome assessed by age appropriate
developmental assessments at 18 to 24 months of corrected age.
Neurologic assessments at 18 to 24 months will include the
cognitive and language components of the Bayleys-3, a structured
neurologic examination, and a parental questionnaire.
Pharmacoeconomics (PE): Assessments of resource utilization will be
made to determine if INOmax therapy is cost effective or cost
saving. Pharmacokinetics (PK): Concentration data of NOx from
sparse samples will be pooled to evaluate the following PK
parameters. Individual parameters may be estimated based on
simulated results. Demographic covariates may be evaluated using a
population PK analysis approach if sufficient data is available.
C.sub.max: observed maximum plasma concentration T.sub.max: time at
C.sub.max AUC: area under plasma concentration-time curve from 0 to
last quantifiable time point (AUC.sub.0-t) and from 0 to infinity
(AUC.sub.0-inf) T.sub.1/2: terminal half-life V.sub.ss: volume of
distribution at steady state CL: total clearance PK Analyses:
Linear correlation between NOx and MetHb will be evaluated.
Exposure-response relationship (PK vs. clinical outcomes) may be
evaluated when sufficient data available. Statistical methods: All
efficacy analyses will be performed on an intent-to-treat (ITT)
population that consists of all randomized subjects. Safety
analyses will be performed on a safety population that includes all
randomized subjects who receive study drug. The primary efficacy
endpoint is survival without BPD at 36 weeks GA. The primary method
of analysis will use the generalized estimating equation (GEE) for
logistic regression. In addition, the Cochran-Mantel-Haenszel (CMH)
test will be performed to further evaluate the primary endpoint.
For the secondary efficacy endpoints, GEE for logistic regression
will be used to analyze the binary response variables and
mixed-effects model with repeated-measures will be used to analyze
continuous variables. Additional statistical analyses will be
performed using CMH test and van Elteren test as appropriate. All
statistical tests will be two-sided with a significance level of
0.05.
[0052] A safety analysis of the randomized population in the
BPD-301 study revealed an unexpected anomalous finding in a
subpopulation of white, male, preterm infants of less than 27
weeks. Data from this study indicate that white, male, preterm
infants of less than 27 weeks gestational age are at significant
risk of death when treated with inhaled nitric oxide for the
prevention of BPD, as compared to placebo. The placebo and
treatment groups were matched for the following characteristics:
gestational age, age at the start of treatment, sex, length at
birth, weight, head circumference, respiratory severity scores,
apgar scores, and physical exam results. There were no anomalous
findings to indicate that there was any particular reason, other
than the inhaled nitric oxide itself, that caused this result.
[0053] The overall mortality rate in the trial was low. The
mortality rate was not significantly different between inhaled
nitric oxide and placebo groups (11.35% vs. 8.64%, p=0.436),
evaluated with Fisher's exact test. See Table 1. Analysis of the
mortality rates in different race groups demonstrated that, among
the white population, the inhaled nitric oxide-treated pre-term
infants had an unexpected higher mortality rate than those from the
placebo group [Table 1].
TABLE-US-00002 TABLE 1 SUMMARY OF MORTALITY BY RACE PLACEBO INO N =
220 N = 229 n (%) n (%) P-VALUE.sup.(1) ALL 19 (8.64%) 26 (11.35%)
0.436 American Indian or 1 (0.45%) 0 (0.00%) Alaska Native Asian 2
(0.91%) 0 (0.00%) Black 9 (4.09%) 6 (2.62%) Hispanic 4 (1.82%) 3
(1.31%) Native Hawaiian or 0 (0.00%) 0 (0.00%) other Pacific
Islander Other 1 (0.45%) 2 (0.87%) White 2 (0.91%) 15 (6.55%)
.sup.(1)Fisher's exact test.
[0054] In the subgroup of white preterm infants of less than 27
weeks, deaths were a statistically significant 15 (12.5%) for the
treatment group versus only 2 (2.4%) in the placebo group [Tables 1
and 2]. There was no similar difference in mortality between
treatment and placebo groups for any other racial category [Table
1].
TABLE-US-00003 TABLE 2 MORTALITY FOR WHITE PRETERM INFANTS LESS
THAN 27 WEEKS GESTATIONAL AGE PLACEBO INO N = 84 N = 120 ALIVE n
(%) n (%) P-VALUE.sup.(1) Yes 82 (97.6%) 105 (87.5%) 0.010 No 2
(2.4%) 15 (12.5%) .sup.(1)Fisher's exact test.
[0055] Additional analyses were performed to assess role of gender
on mortality in the subset population of white infants less than 27
weeks gestational age. The mortality rate of the inhaled nitric
oxide-treated white infants was significantly higher in the male
group than in the female group (21.4% (3 of 15) vs. 4.7% (12 of
15), p=0.011) [Table 3]. All the white male infants that died were
less than 27 weeks gestational age. One white male in the placebo
group died and one white female in the placebo group died. Out of
the 84 total placebo population, 37 were female and 47 were male.
At the end of the study evaluation period, there was a highly
statistically significant finding of death/mortality in the
active/treatment arm as compared to the placebo. In sum, the BPD
301 trial unexpectedly identified an increased risk of mortality
for white males less than 27 weeks gestational age, treated with
inhaled nitric oxide for the prevention of BPD, than was shown in
treated white females of the same gestational age. This gender
discrepancy and unexpected mortality risk were not witnessed in
other race groups.
TABLE-US-00004 TABLE 3 MORTALITY BY GENDER FOR INHALED NITRIC
OXIDE-TREATED WHITE INFANTS LESS THAN 27 WEEKS GESTATIONAL AGE MALE
FEMALE N = 56 N = 64 ALIVE n (%) n (%) P-VALUE.sup.(1) Yes 44
(78.6%) 61 (95.3%) 0.011 No 12 (21.4%) 3 (4.7%) .sup.(1)Fisher's
exact test.
[0056] Reference throughout this specification to "one embodiment,"
"certain embodiments," "one or more embodiments" or "an embodiment"
means that a particular feature, structure, material, or
characteristic described in connection with the embodiment is
included in at least one embodiment of the invention. Thus, the
appearances of the phrases such as "in one or more embodiments,"
"in certain embodiments," "in one embodiment" or "in an embodiment"
in various places throughout this specification are not necessarily
referring to the same embodiment of the invention. Furthermore, the
particular features, structures, materials, or characteristics may
be combined in any suitable manner in one or more embodiments.
[0057] Although the inventions herein have been described with
reference to particular embodiments, it is to be understood that
these embodiments are merely illustrative of the principles and
applications of the present inventions. It will be apparent to
those skilled in the art that various modifications and variations
can be made to the methods and system of the present invention
without departing from the spirit and scope of the inventions.
Thus, it is intended that the present inventions include
modifications and variations that are within the scope of the
appended claims and their equivalents.
* * * * *