Classifications

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• • A—HUMAN NECESSITIES
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• • G—PHYSICS
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  • G06Q99/00—Subject matter not provided for in other groups of this subclass
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
  • F17C—VESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
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• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
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  • F17C2203/0636—Metals
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• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
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  • F17C2221/00—Handled fluid, in particular type of fluid
  • F17C2221/01—Pure fluids
  • F17C2221/014—Nitrogen
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
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  • F17C2221/00—Handled fluid, in particular type of fluid
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• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
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• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
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Definitions

• INOmax® (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.
• 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.
• PCWP pulmonary capillary wedge pressure
• 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.
• AE adverse event
• SAE serious adverse event
• 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 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.
• 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.
• 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.
• step (c) may comprise further evaluating the risk versus benefit of utilizing iNO in a patient where the patients has clinically significant LVD before administering iNO to the patient.
• the method further comprises informing the medical provider that there is a risk associated with using inhaled nitric oxides 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.
• 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.
• a patient having pre-existing LVD is characterized as having PCWP greater than 20 mm Hg.
• the patients having pre-existing LVD demonstrate a PCWP ⁇ 20 mm Hg.
• the iNO treatment further comprises inhalation of oxygen (O 2 ) or concurrent ventilation.
• 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.
• the patient population comprises children.
• the patient population comprises adults.
• the patients who have pre-existing LVD are at risk of experiencing and increased rate of one or more AEs or SAEs selected from pulmonary edema, hypotension, cardiac arrest, electrocardiogram changes, hypoxemia, hypoxia, bradycardia or associations thereof.
• AEs or SAEs selected from pulmonary edema, hypotension, cardiac arrest, electrocardiogram changes, hypoxemia, hypoxia, bradycardia or associations thereof.
• 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 ⁇ 15 mm Hg, and, a pulmonary vascular resistance index (PVRI)>3 u ⁇ m 2 ; congenital heart disease with pulmonary hypertension repaired and unrepaired characterized by PAPm>25 mm Hg at rest and PVRI>3 u ⁇ m 2 ; cardiomyopathy characterized by PAPm>25 mm Hg at rest and PVRI>3 u ⁇ m 2 ; or, the patient is scheduled to undergo right heart catheterization to assess pulmonary vasoreactivity by acute pulmonary vasodilatation testing.
• PAPm mean pulmonary artery pressure
• PCWP ⁇ 15 mm Hg PCWP ⁇ 15 mm Hg
• PVRI pulmonary vascular resistance index
• 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.
• INOmax® nitric oxide
• INOmax® 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®, is a selective pulmonary vasodilator that increases the partial pressure of arterial oxygen (PaO 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® 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 current FDA-approved prescribing information for INOmax® is incorporated herein by reference in its entirety.
• INOmax® 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® is administered to a patient in conjunction with ventilatory support and O 2 . Delivery devices suitable for the safe and effective delivery of gaseous NO for inhalation include the INOvent®, INOmax DS®, INOpulse®, INOblender®, 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.
• Such devices deliver INOmax® 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.
• suitable delivery devices provide continuous integrated monitoring of inspired O 2 , NO 2 and NO, a comprehensive alarm system, a suitable power source for uninterrupted NO delivery and a backup NO delivery capability.
• children includes those being around 4 weeks to 18 years of age.
• adult includes those being over 18 years of age.
• AE adverse event
• 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.
• ADR reverse drug reaction
• SAE serious adverse event
• 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.
• 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.
• 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.
• 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 measure by inserting balloon-tipped, multi-lumen catheter (also known as a Swan-Ganz catheter). Measure 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.
• PVR pulmonary vascular resistance
• 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 only of direct relevance in the laboratory; in the clinic, the term end-systolic pressure is usually more appropriate, although not equivalent.
• left ventricular afterload refers to the pressure that the chamber of the heart has to generate in order to eject blood out of the chamber.
• aortic pressure since the pressure in the ventricle must be greater than the systemic pressure in order to open the aortic valve.
• cardiac output decreases.
• Disease processes that increase the left ventricular afterload include increased blood pressure and aortic valve disease.
• Hypertension Increased 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 increase pulse pressure. Mitral regurgitation decreases the afterload.
• 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.
• An intra-aortic balloon pump 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 thus, 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 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.
• INOmax® acts by preventing or treating reversible pulmonary vasoconstriction, reducing pulmonary arterial pressure and improving pulmonary gas exchange.
• INOmax® sales stem from its use by clinicians in a premature infant population.
• INOmax® is generally utilized by physicians as a rescue therapy primarily to vasodilate the lungs and improve pulmonary gas exchange.
• the precise mechanism(s) responsible for the benefits of INOmax® 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® to treat or prevent reversible pulmonary vasoconstriction.
• INOmax® In clinical practice, the use of INOmax® has reduced or eliminated the use of high risk systemic vasodilators for the treatment of PPHN.
• INOmax® 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.
• systemic vasodilators may increase blood flow to atelectatic (deflated or collapsed) alveoli, thereby increasing V/Q mismatch and worsening arterial oxygenation.
• INOmax® 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® allows INOmax® to exhibit rapid “on” and “off” responses relative to INOmax® dosing, in contrast to non-gaseous alternatives. In this way, INOmax® 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® in the blood significantly reduces or prevents vasodilatation of non-pulmonary vessels.
• ECMO extracorporeal membrane oxygenation
• MAS meconium aspiration syndrome
• PPHN idiopathic persistent pulmonary hypertension of the newborn
• pneumonia/sepsis (24%
• RDS respiratory distress syndrome
• NINOS study See Inhaled Nitric Oxide in Full-Term and Nearly Full-Term Infants with Hypoxic Respiratory Failure; NEJM, Vol. 336, No. 9, 597).
• 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%).
• MAS meconium aspiration syndrome
• PPHN idiopathic primary pulmonary hypertension of the newborn
• RDS respiratory distress syndrome
• the table below shows adverse reactions that occurred in at least 5% of patients receiving INOmax® in the CINRGI study. None of the differences in these adverse reactions were statistically significant when iNO patients were compared to patients receiving placebo.
• the INOT22 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 access the safety and effectiveness of INOmax® 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).
• 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 2 .
• PVRI pulmonary vascular resistance index
• 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 2 and NO for inhalation plus O 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.
• the primary objective was to compare the response frequency with iNO and O 2 vs. O 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 2 alone, and the alternate treatment in Period 3. All patients received the iNO and O 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.
• 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 2 and O 2 alone significantly increased systemic vascular resistance index (SVRI) (Table 4).
• the ideal pulmonary vasodilator should reduce PVRI and/or PAPm while having no appreciable effect on systemic blood pressure or SVRI.
• 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.
• NO plus O 2 appeared to provide the greatest reduction in the ratio, suggesting that NO plus O 2 was more selective for the pulmonary vasculature than either agent alone.
• the upper limit of normal PCWP in children is 10-12 mm Hg and 15 mm Hg in adults.
• a baseline PCWP value was not included as exclusion criteria.
• 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.
• 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 lead to discontinuation. A list of subjects who died, discontinued or experienced an SAE is provided in Table 5 below.
• 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 being rapidly acting, selective for the pulmonary vasculature, and well-tolerated in most patients.
• the INOT22 study results demonstrate that patients who had pre-existing LVD may experience an increased rate of SAEs (e.g., pulmonary edema).
• SAEs e.g., pulmonary edema
• 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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