Use of inhaled nitric oxide therapy (iNO) to improve activity levels in patients with pulmonary conditions

Abstract

Methods for maintaining or improving activity levels in a patient with a pulmonary-related condition are described.

Description

[Technical Field]

[0001]

[0001] This application relates generally to devices and methods for administering nitric oxide, particularly to pulsed delivery of nitric oxide to patients in need of therapeutic treatment, and also generally to methods for administering nitric oxide, particularly to pulsed delivery of nitric oxide to patients with pulmonary-related conditions to maintain and / or increase activity levels. [Background technology]

[0002] Nitric oxide (NO) is a gas that, when inhaled, dilates pulmonary blood vessels, improving blood oxygenation and reducing pulmonary hypertension. Therefore, nitric oxide is provided as a therapeutic gas during the inspiration phase in patients experiencing shortness of breath (dyspnea) due to conditions such as pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), chronic pulmonary fibrosis with emphysema (CPFE), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), emphysema, interstitial lung disease (ILD), chronic thromboembolic pulmonary hypertension (CTEPH), chronic mountain sickness, or other pulmonary diseases.

[0003]

[0003] When administered under appropriate conditions, NO can be therapeutically effective, but it can also be toxic if administered improperly. NO reacts with oxygen to form nitrogen dioxide (NO2), which can form if oxygen or air is present in the NO delivery tubing. NO2 is a toxic gas that can cause many side effects, and the Occupational Safety & Health Administration (OSHA) has set a permissible exposure limit of only 5 ppm in general industry. Therefore, it is desirable to limit exposure to NO2 during NO therapy. Summary of the Invention [Means for solving the problem]

[0004] In some embodiments of the present invention, methods of administering a dose of nitric oxide are described. In some embodiments of the present invention, at least a single pulse dose is administered to a patient and is therapeutically effective to treat or alleviate symptoms of pulmonary disease. In some embodiments of the present invention, the total amount of two or more pulse doses is therapeutically effective to treat or alleviate symptoms of pulmonary disease.

[0005] In some embodiments of the invention, nitric oxide is delivered periodically, for a minimum of 5 minutes per day to 24 hours per day. In some embodiments of the invention, nitric oxide may be delivered over a period of time that is convenient for the patient, for example, while sleeping. In some embodiments of the invention, pulsed administration of nitric oxide may be evenly or unevenly spaced over a period of time (e.g., 10 minutes, 1 hour, or 24 hours). In other embodiments, administration of a therapeutically effective dose of nitric oxide may be continuous for a period of time.

[0006] In one embodiment, a method includes detecting a patient's breathing pattern. In an embodiment of the invention, the breathing pattern includes total inspiration time (e.g., the duration of a single exhalation of the patient). In an embodiment of the invention, the breathing pattern is detected using a device including a breath sensitivity control. In an embodiment of the invention, the breathing pattern is correlated with an algorithm for calculating timing of administration of a dose of nitric oxide. In an embodiment of the invention, a volume of nitric oxide-containing gas required to administer an amount of nitric oxide per pulse is calculated. In an embodiment, nitric oxide is delivered to the patient in a pulsed manner over a portion of the total inspiration time.

[0007] In some embodiments of the invention, the nitric oxide dose is delivered to the patient for a time sufficient to deliver a therapeutic dose of nitric oxide to the patient. In some embodiments of the invention, the device calculates a total time sufficient to deliver a therapeutic dose of nitric oxide to the patient. In some embodiments of the invention, the total time required to deliver a therapeutic dose of nitric oxide to the patient depends, at least in part, on the breathing pattern of the patient.

[0008] In some embodiments of the present invention, nitric oxide is delivered during the first one-third of the total inhalation time. In some embodiments, nitric oxide is delivered during the first one-half of the total inhalation time. In some embodiments, nitric oxide is delivered during the first two-thirds of the total inhalation time.

[0009] In some embodiments of the invention, at least fifty percent (50%) of the dose of nitric oxide is delivered to the patient during the first one-third of the total inhalation time. In some embodiments of the invention, at least seventy percent (70%) of the dose of nitric oxide is delivered to the patient during the first one-half of the total inhalation time. In some embodiments, at least ninety percent (90%) of the dose of nitric oxide is delivered to the patient during the first two-thirds of the total inhalation time. In some embodiments of the invention, at least ninety percent (90%) of the dose of nitric oxide is delivered to the patient during the first one-third of the total inhalation time. In some embodiments of the invention, the entire dose of nitric oxide is delivered to the patient during the first one-half of the total inhalation time.

[0010] In some embodiments of the invention, the breath sensitivity control of the device is adjustable. In some embodiments of the invention, the breath sensitivity control is fixed. In some embodiments of the invention, the breath sensitivity control is adjustable ranging from least sensitive to most sensitive, whereby the most sensitive setting is more sensitive to detecting breaths than the least sensitive setting.

[0011] In one embodiment of the present invention, a method for treating or alleviating symptoms of cardiopulmonary disease is described. In one embodiment of the present invention, the method includes detecting a patient's breathing pattern using a device including a breath sensitivity control. In one embodiment of the present invention, the breathing pattern includes a measurement of total inhalation time. In one embodiment of the present invention, the breathing pattern is correlated with an algorithm for calculating the timing of administration of a dose of nitric oxide. In one embodiment of the present invention, at least fifty percent (50%) of the dose of nitric oxide is delivered over the first one-third of the total inhalation time. In one embodiment of the present invention, at least seventy percent (70%) of the dose of nitric oxide is delivered to the patient over the first one-half of the total inhalation time. In one embodiment of the present invention, at least ninety percent (90%) of the dose of nitric oxide is delivered over the first two-thirds of the total inhalation time.

[0012] In one embodiment of the invention, the device calculates the total time required to deliver a therapeutically effective amount of nitric oxide to the patient. In one embodiment of the invention, the total time required to deliver a therapeutically effective amount of nitric oxide depends on one or more of breathing pattern, nitric oxide concentration in the gas delivered to the patient, pulse dose volume, and duration of a pulse.

[0013] In one embodiment of the present invention, the pulmonary disease and / or lung-related condition is selected from idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis (PF), interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), emphysema, pulmonary fibrosis with emphysema (CPFE), chronic thromboembolic pulmonary hypertension (CTEPH), chronic mountain sickness, or other pulmonary diseases. In one embodiment of the present invention, the pulmonary disease is pulmonary hypertension associated with other pulmonary diseases, such as groups I-V pulmonary hypertension (PH). In another embodiment, the pulmonary disease and / or lung-related condition is pulmonary hypertension associated with interstitial lung disease. In one embodiment of the present invention, the pulmonary disease and / or lung-related condition is pulmonary hypertension associated with pulmonary fibrosis. In one embodiment of the present invention, the pulmonary disease and / or lung-related condition is pulmonary hypertension associated with idiopathic pulmonary fibrosis. In one embodiment of the present invention, patients suffering from ILD are at increased risk of developing pulmonary hypertension. In another embodiment of the present invention, a patient suffering from ILD has a low risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from ILD has a moderate risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from IPF has a high risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from IPF has a moderate risk of developing pulmonary hypertension. In another embodiment of the present invention, a patient suffering from IPF has a low risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from ILD has a high risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from PF has a high risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from PF has a moderate risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from PF has a low risk of developing pulmonary hypertension.

[0014] In one embodiment of the present invention, a programmable device for delivering a dose of nitric oxide is described. In one embodiment of the present invention, the device includes a nasal delivery portion, a drug cartridge containing nitric oxide, an oxygen source, a breath sensing portion for detecting a patient's breathing pattern, a breath detection algorithm for determining a dose of nitric oxide to be delivered to the patient, and a portion for administering the dose of nitric oxide to the patient via a series of pulses correlated with the inhalation portion of the breathing pattern. In one embodiment of the present invention, the breath sensing portion of the device includes an adjustable or fixed breath sensitivity setting. In one embodiment of the present invention, the nasal delivery portion is a nasal cannula, a face mask, a nebulizer, or a nasal inhaler. In one embodiment of the present invention, the breath detection algorithm uses a threshold sensitivity and a slope algorithm. In one embodiment of the present invention, the slope algorithm counts breaths detected when the rate of pressure drop reaches a threshold level.

[0015] In one embodiment of the present invention, a method for maintaining or increasing activity level in a patient with pulmonary hypertension is described. In one embodiment, the patient's pulmonary hypertension is associated with interstitial lung disease. In one embodiment of the present invention, the method comprises administering inhaled nitric oxide (iNO). In another embodiment, iNO is administered continuously in a pulsed manner for a period of at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, or at least 24 hours. In another embodiment, iNO is administered at 30 mcg / kg IBW / hr. In another embodiment, iNO is administered at 45 mcg / kg IBW / hr. In another embodiment, iNO is administered at 75 mcg / kg IBW / hr. In one embodiment of the present invention, iNO is administered in combination with supplemental oxygen.

[0016]

[0016] In another embodiment, the method includes administering iNO by the steps of: first detecting a breathing pattern in the patient, including a total inhalation time; associating the breathing pattern with an algorithm for calculating the timing of administering a dose of nitric oxide; and administering a dose of nitric oxide to the patient in a pulsed manner for a portion of the total inhalation time.

[0017] In another embodiment of the present invention, a method for treating pulmonary hypertension associated with interstitial lung disease is described. In one embodiment, the method comprises administering inhaled nitric oxide to a patient.

[0018] In yet another embodiment, a method is described for preventing a decrease in activity level in a patient with pulmonary hypertension associated with interstitial lung disease. In one embodiment, the method comprises administering inhaled nitric oxide to the patient.

[0019] In one embodiment of the present invention, actigraphy is used to measure activity parameters.

[0020] In one embodiment of the present invention, a method for improving activity levels in a patient with pulmonary hypertension associated with a pulmonary condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis is described, comprising administering inhaled nitric oxide to the patient. In one embodiment, the inhaled nitric oxide is administered by detecting a breathing pattern in the patient, including a total inhalation time; correlating the breathing pattern with an algorithm for calculating timing for administering a dose of nitric oxide; and administering a dose of nitric oxide to the patient in a pulsed manner over a portion of the total inhalation time.

[0020]

[0021] In one embodiment of the present invention, a method is described for treating pulmonary hypertension associated with a pulmonary condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis, comprising administering inhaled nitric oxide to the patient. In one embodiment, the inhaled nitric oxide is administered by detecting a breathing pattern in the patient, including a total inhalation time; correlating the breathing pattern with an algorithm for calculating timing for administering a dose of nitric oxide; and administering a dose of nitric oxide to the patient in a pulsed manner over a portion of the total inhalation time.

[0021]

[0022] In one embodiment of the present invention, a method for preventing a decrease in activity level in a patient with pulmonary hypertension associated with a pulmonary condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis is described, comprising administering inhaled nitric oxide to the patient. In one embodiment, the inhaled nitric oxide is administered by detecting a breathing pattern in the patient, including a total inhalation time; correlating the breathing pattern with an algorithm for calculating the timing of administering a dose of nitric oxide; and administering a dose of nitric oxide to the patient in a pulsed manner over a portion of the total inhalation time.

[0022]

[0023] In one embodiment of the present invention, a method for maintaining activity levels in a patient with pulmonary hypertension associated with a pulmonary condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis is described, comprising administering inhaled nitric oxide to the patient. In one embodiment, the inhaled nitric oxide is administered by detecting a breathing pattern in the patient, including a total inhalation time; correlating the breathing pattern with an algorithm for calculating timing for administering a dose of nitric oxide; and administering a dose of nitric oxide to the patient in a pulsed manner over a portion of the total inhalation time.

[0023]

[0024] In one embodiment of the present invention, a method for improving activity levels in a patient with a pulmonary condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis is described, comprising administering inhaled nitric oxide to the patient. In one embodiment, the inhaled nitric oxide is administered by detecting a breathing pattern in the patient, including a total inhalation time; correlating the breathing pattern with an algorithm for calculating timing for administering a dose of nitric oxide; and administering a dose of nitric oxide to the patient in a pulsed manner over a portion of the total inhalation time.

[0024]

[0025] In one embodiment of the present invention, a method is described for improving activity levels in a patient having a pulmonary condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis, comprising administering inhaled nitric oxide to the patient by detecting a breathing pattern in the patient, including a total inhalation time; correlating the breathing pattern with an algorithm for calculating timing for administering a dose of nitric oxide; and administering a dose of nitric oxide to the patient in a pulsed manner over a portion of the total inhalation time.

[0025]

[0026] In one embodiment of the present invention, a method is described for preventing a decrease in activity level in a patient with a pulmonary condition, the method comprising administering inhaled nitric oxide to the patient. In another embodiment, a method is described for maintaining activity level in a patient with a pulmonary condition, the method comprising administering inhaled nitric oxide to the patient. In yet another embodiment, a method is described for improving activity level in a patient with pulmonary hypertension associated with a pulmonary condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis, the method comprising administering a vasodilator to the patient. In one embodiment, the vasodilator is a systemic vasodilator. In another embodiment, the vasodilator is a locally acting vasodilator. In another embodiment, the vasodilator is inhaled nitric oxide.

[0026]

[0027] In one embodiment of the invention, inhaled nitric oxide is administered at a dose ranging from about 25 mcg / kg IBW / hr to about 50 mcg / kg IBW / hr. In another embodiment, inhaled nitric oxide is administered at a dose ranging from about 30 mcg / kg IBW / hr to about 45 mcg / kg IBW / hr. In another embodiment, inhaled nitric oxide is administered at a dose of about 30 mcg / kg IBW / hr. In another embodiment, inhaled nitric oxide is administered at a dose of about 45 mcg / kg IBW / hr.

[0027]

[0028] Various embodiments have been described above and will be explained in more detail below, and it will be understood that the described embodiments may be combined not only as described below but in any other suitable combinations consistent with the scope of the present invention.

[0028]

[0029] The foregoing has outlined, rather broadly, certain features and technical advantages of the present invention. It should be appreciated by those skilled in the art that the specific embodiments disclosed may be readily utilized as a basis for modifying or designing other structures or processes within the scope of the invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims.

[0029]

[0030] In addition to the summary set forth above, the following detailed description will be better understood when read in conjunction with the accompanying drawings.

[0031] So that the above-enumerated features of the present invention may be understood in detail, a more particular description of the invention briefly summarized above may be had by reference to embodiments, some of which are illustrated in the accompanying drawings. It should be noted, however, that the accompanying drawings illustrate only typical embodiments of the invention and, therefore, are not to be considered as limiting the scope of the invention, since the invention may include other equally effective embodiments. [Brief explanation of the drawings]

[0030] [Figure 1]

[0032] 1 is a graph showing single breath measurements. [Figure 2]

[0033] 1 is a graph showing measurements of pulses of nitric oxide delivered to a patient in accordance with the present invention. [Figure 3]

[0034] 1 is a graph showing breath detection as a percentage of nitric oxide delivery relative to total inhalation time. The orange line represents a breath sensitivity setting of 8 out of 10 (e.g., 80% of maximum sensitivity) in Embodiment 1, the blue line represents a breath sensitivity setting of 10 out of 10 (e.g., maximum sensitivity) in Embodiment 1, and the green line represents a breath sensitivity setting fixed at 10 in Embodiment 2. The green line shows that approximately 93% of the nitric oxide dose is delivered during the first 33% (i.e., first one-third) of the total inhalation time, and 100% of the nitric oxide dose is delivered during the first 50% (i.e., first one-half) of the total inhalation time. The blue lines indicate that approximately 62% of the nitric oxide dose is delivered during the first 33% (i.e., first one-third) of the total inhalation time, approximately 98% is delivered during the first 50% (i.e., first half) of the total inhalation time, and 100% is delivered during the first 67% (i.e., first two-thirds) of the total inhalation time. The orange lines indicate that approximately 17% of the nitric oxide dose is delivered during the first 33% (i.e., first one-third) of the total inhalation time, approximately 72% is delivered during the first 50% (i.e., first half) of the total inhalation time, and approximately 95% is delivered during the first 67% (i.e., first two-thirds) of the total inhalation time. [Figure 4]

[0035] FIG. 4 is a diagram representing a combination of the results described in FIG. 3. [Figure 5A]

[0036] Figures 5A and 5B are diagrams depicting the algorithms for breath detection and nitric oxide delivery: Figure 5A shows the threshold algorithm; Figure 5B shows the slope algorithm. [Figure 5B]

[0036] Figures 5A and 5B are diagrams depicting the algorithms for breath detection and nitric oxide delivery. Figure 5A shows the threshold algorithm. Figure 5B shows the slope algorithm. [Figure 6A]

[0037] Figures 6A-6C show the percent change in activity parameters over time in iNO-treated and placebo-treated patients: Figure 6A shows the percent change in moderate intensity activity, Figure 6B shows the percent change in non-sedentary activity, and Figure 6C shows the percent change in total activity. [Figure 6B] 6A-6C show the percent change in activity parameters over time in iNO-treated and placebo-treated patients: Figure 6A shows the percent change in moderate-intensity activity, Figure 6B shows the percent change in non-sedentary activity, and Figure 6C shows the percent change in total activity. [Figure 6C] 6A-6C show the percent change in activity parameters over time in iNO-treated and placebo-treated patients: Figure 6A shows the percent change in moderate-intensity activity, Figure 6B shows the percent change in non-sedentary activity, and Figure 6C shows the percent change in total activity. [Figure 7A]

[0038] Figures 7A-7D show the percent change in activity parameters over time in iNO-treated and placebo-treated patients: Figure 7A shows the percent change in moderate-to-vigorous physical activity (MVPA), Figure 7B shows the percent change in total activity, Figure 7C shows the percent change in non-sedentary activity, and Figure 7D shows the percent change in daily caloric intake. [Figure 7B] 7A-7D show the percent change in activity parameters over time in iNO-treated and placebo-treated patients. Figure 7A shows the percent change in moderate-to-vigorous physical activity (MVPA) activity, Figure 7B shows the percent change in total activity, Figure 7C shows the percent change in non-sedentary activity, and Figure 7D shows the percent change in daily caloric intake. [Figure 7C] 7A-7D show the percent change in activity parameters over time in iNO-treated and placebo-treated patients. Figure 7A shows the percent change in moderate-to-vigorous physical activity (MVPA) activity, Figure 7B shows the percent change in total activity, Figure 7C shows the percent change in non-sedentary activity, and Figure 7D shows the percent change in daily caloric intake. [Figure 7D] 7A-7D show the percent change in activity parameters over time in iNO-treated and placebo-treated patients. Figure 7A shows the percent change in moderate-to-vigorous physical activity (MVPA) activity, Figure 7B shows the percent change in total activity, Figure 7C shows the percent change in non-sedentary activity, and Figure 7D shows the percent change in daily caloric intake. [Figure 8A]

[0039] Figures 8A and 8B show comparative data for mean weekly change in MVPA (Figure 8A) and general activity (Figure 8B) from the blinded portion of the study compared to the open-label extension (OLE) portion of the study. [Figure 8B]

[0039] Figures 8A and 8B show comparative data for mean weekly change in MVPA (Figure 8A) and general activity (Figure 8B) from the blinded portion of the study compared to the open-label extension (OLE) portion of the study. [Figure 9A]

[0040] Figures 9A and 9B show Cohort 2 (iNO45) comparison data for normalized MVPA change from baseline over months 1-4 (Figure 9A) and general activity change from baseline over months 1-4 (Figure 9B). In Figure 9A, baseline MVPA was 74 min / day, with an improvement of 14 min / day at month 4. In Figure 9B, baseline general activity was 1476 counts per minute, with an improvement of 100 counts per minute at month 4. [Figure 9B]Figures 9A and 9B show Cohort 2 (iNO45) comparison data for normalized MVPA change from baseline over months 1-4 (Figure 9A) and general activity change from baseline over months 1-4 (Figure 9B). In Figure 9A, baseline MVPA was 74 min / day, with an improvement of 14 min / day at month 4. In Figure 9B, baseline general activity was 1476 counts per minute, with an improvement of 100 counts per minute at month 4. [Figure 10AB]

[0041] Figures 10A-10C show comparative data for Cohort 2 (iNO45) on the St. George's Respiratory Questionnaire (SGRQ) at 4 months. Because the SGRQ is reversed-item, higher total points indicate worsening disease status. Figure 10A shows a 3-point improvement in the SGRQ Total, which measures health status and quality of life. Figure 10B shows a 5-point improvement in the SGRQ Activity, which measures the patient's impairment to physical activity. Figure 10C shows a 6-point improvement in the SGRQ Impact, which measures the psychological and social impact of the disease / condition. [Figure 10C]

[0041] Figures 10A-10C show comparative data for Cohort 2 (iNO45) on the St. George's Respiratory Questionnaire (SGRQ) at 4 months. Because the SGRQ is reversed-item, higher total points indicate worsening disease status. Figure 10A shows a 3-point improvement in the SGRQ Total, which measures health status and quality of life. Figure 10B shows a 5-point improvement in the SGRQ Activity, which measures the patient's impairment to physical activity. Figure 10C shows a 6-point improvement in the SGRQ Impact, which measures the psychological and social impact of the disease / condition. [Figure 11]

[0042] Comparative data from Cohort 2 (iNO45) on the University of California, San Diego (UCSD) Shortness of Breath Questionnaire (SOBQ) are shown, demonstrating benefit in dyspnea. Again, increasing scores indicate worsening disease. A 5-point improvement was demonstrated, which measures shortness of breath while patients perform daily physical activities. [Figure 12A]

[0043] Log-transformed estimated changes in MVPA ( Fig. 12A ) and total activity ( Fig. 12B ) at 2 months (iNO30 and iNO45, cohorts 1 and 2) and 4 months (iNO45, cohort 2) are shown. [Figure 12B]

[0043] Log-transformed estimated changes in MVPA (Figure 12A) and total activity (Figure 12B) at 2 months (iNO30 and iNO45, Cohorts 1 and 2) and 4 months (iNO45, Cohort 2) are shown. [Figure 13]

[0044] Log-transformed predicted marginal effects of MVPA on a monthly (Figure 13A) and weekly (Figure 13B) basis for Cohort 2 are shown. DETAILED DESCRIPTION OF THE INVENTION

[0031]

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

[0032]

[0046] Before describing several exemplary embodiments, it is to be understood that the invention is not limited to the details of construction or process steps set forth in the following description. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0033]

[0047] References throughout this specification to "one embodiment," "a particular embodiment," "one or more embodiments," or "an embodiment" mean that a particular feature, structure, material, or characteristic described in connection with an embodiment is included in at least one embodiment of the invention. Thus, the appearances of phrases such as "in one or more embodiments," "a particular embodiment," "in one embodiment," or "in an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Furthermore, particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0034]

[0048] Although the present invention has been described herein with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the method and apparatus of the present invention without departing from the spirit and scope of the invention. Thus, it is intended that the present invention cover modifications and variations that come within the scope of the appended claims and their equivalents. definition

[0049] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein sufficient to effect its intended use, including, but not limited to, the treatment of disease. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), the subject and condition being treated (e.g., the subject's weight, age, and sex), the severity of the condition, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that will elicit a specific response in target cells (e.g., decreased platelet adhesion and / or decreased cell migration). The specific dose will vary depending on the particular compound selected, the administration regimen followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which the compound is delivered.

[0035]

[0050] As used herein, the term "therapeutic benefit" encompasses therapeutic benefit and / or prophylactic benefit. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0036]

[0051] "Interstitial lung disease" or "ILD" conditions include all subtypes of ILD, including, but not limited to, idiopathic interstitial pneumonia (IIP), chronic hypersensitivity pneumonitis, occupational or environmental lung disease, idiopathic pulmonary fibrosis (IPF), non-IPF IIP, granulomatous (e.g., sarcoidosis), connective tissue diseases associated with ILD, and other forms of ILD.

[0037]

[0052] When ranges are used herein to describe aspects of the invention, such as dosage ranges, amounts of components of a formulation, etc., all combinations and subcombinations of ranges and specific embodiments thereof are intended to be included. The use of the term "about" when referring to a number or numerical range means that the stated number or numerical range is approximate within experimental variation (i.e., within statistical experimental error), and thus, the number or numerical range may vary. This variation is typically 0% to 15%, preferably 0% to 10%, and more preferably 0% to 5% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes embodiments such as, for example, any composition of matter, any method, or any process "consisting of" or "consisting essentially of" the described features.

[0038]

[0053] For the avoidance of doubt, it is intended herein that a particular feature (e.g., integer, property, value, use, disease, formula, compound, or group) described in connection with a particular aspect, embodiment, or example of the invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless inconsistent therewith. Accordingly, such feature may be used where appropriate in connection with any of the definitions, claims, or embodiments defined herein. All features disclosed herein (including any accompanying claims, abstract, and figures), and / or all method or process steps similarly disclosed, may be combined in any combination, except combinations in which at least some of the features and / or steps are mutually exclusive. The invention is not limited to any details of any disclosed embodiment. The invention extends to any novel or any novel combination of features disclosed herein (including any accompanying claims, abstract, and figures), or any novel or any novel combination of method or process steps similarly disclosed.

[0039]

[0054] Effective administration of NO depends on many different variables, including the amount of drug and the timing of delivery. Several patents related to NO delivery have been issued, including U.S. Patent Nos. 7,523,752, 8,757,148, 8,770,199, and 8,803,717, and Design Patent No. D701,963 for the design of NO delivery devices, all of which are incorporated herein by reference. Additionally, there are pending applications related to NO delivery, including U.S. Patent Nos. US2013 / 0239963 and US2016 / 0106949, both of which are incorporated herein by reference. Despite these patents and pending publications, there remains a need for methods and devices that deliver NO in a precisely controlled manner to maximize the benefits of therapeutic doses and minimize potentially harmful side effects.

[0040]

[0055] In certain embodiments of the present invention, a dose of gas (e.g., NO) is administered to a patient in pulses during the patient's inhalation. Surprisingly, it has been discovered that delivery of nitric oxide can be precise and accurate within the first two-thirds of the total respiratory inhalation time, and that patients benefit from such delivery. Such delivery, which minimizes the risk of drug loss and adverse side effects, increases the effectiveness of pulse administration, thereby reducing the overall amount of NO that needs to be administered to a patient to be effective. Such delivery is useful for the treatment of various diseases, including, but not limited to, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), including groups I-V of pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and emphysema, and is also useful as an antibacterial agent, for example, in the treatment of pneumonia.

[0041]

[0056] Such precision has the added advantage that only portions of poorly ventilated lung regions are exposed to NO. Hypoxia and hemoglobin disturbances may also be reduced using such pulsed delivery, but exposure to NO2 is also more limited. Devices of the Invention

[0057] In certain embodiments, the invention includes a device, e.g., a programmable device for delivering a dose of gas (e.g., nitric oxide) to a patient in need thereof. The device may include a delivery portion, a drug cartridge containing compressed gas for delivery to the patient, a breath sensing portion for detecting the patient's breathing pattern including a breath sensitivity setting, at least one breath detection algorithm for determining when to administer compressed gas to the patient, and a portion for administering the dose of nitric oxide to the patient via a series of one or more pulses.

[0042]

[0058] In certain embodiments, the medication cartridge is replaceable.

[0059] In certain embodiments, the delivery portion includes one or more of a nasal cannula, a face mask, a nebulizer, and a nasal inhaler. In certain embodiments, the delivery portion can further include a second delivery portion that allows for simultaneous administration of one or more other gases (e.g., oxygen) to the patient.

[0043]

[0060] In certain embodiments, and as detailed elsewhere herein, the device includes an algorithm that uses one or both of a threshold sensitivity and a slope algorithm, where the slope algorithm detects a breath when the rate of pressure drop reaches a predetermined threshold.

[0044]

[0061] In some embodiments of the present invention, the pulsed dose of gas can mechanically reduce the Venturi effect that, if not vented, typically causes problems in other gas sensors. For example, without the pulsed dose of the present invention, an O2 backpressure sensor can disable the delivery of O2 when O2 is administered simultaneously with another gas, such as NO. Breathing Pattern, Detection, and Triggering

[0062] Breathing patterns vary based on the individual, time of day, level of activity, and other variables. This makes it difficult to predetermine an individual's breathing pattern. Therefore, a delivery system that delivers therapy to a patient based on breathing patterns should be able to accommodate a range of possible breathing patterns to be effective.

[0045]

[0063] In certain embodiments, the patient or individual can be of any age, but in more particular embodiments, the patient is 16 years of age or older.

[0064] In one embodiment of the invention, a breathing pattern, as used herein, includes a measurement of total inspiration time determined for a single breath. However, depending on the context, "total inspiration time" may also refer to the sum of all inspiration times for all breaths detected during therapy. Total inspiration time may be observed or calculated. In another embodiment, total inspiration time is a time verified based on a simulated breathing pattern.

[0046]

[0065] In certain embodiments of the present invention, breath detection includes at least one trigger, and in some embodiments includes at least two separate triggers that work together: a breath level trigger and / or a breath slope trigger.

[0047]

[0066] In one embodiment of the invention, a breath level trigger algorithm is used for breath detection. The breath level trigger detects a breath when a threshold level of pressure (e.g., a threshold negative pressure) is reached during inspiration.

[0048]

[0067] In one embodiment of the invention, a respiratory slope trigger detects a breath when the slope of the pressure waveform indicates inspiration. A respiratory slope trigger can, in some cases, be more accurate than a threshold trigger, especially when used to detect short, shallow breaths.

[0049]

[0068] In certain embodiments of the present invention, the combination of these two triggers provides a generally more accurate breath detection system, especially when multiple therapeutic gases are being administered to the patient simultaneously.

[0050]

[0069] In some embodiments of the invention, the respiration sensitivity control for detecting respiration level and / or respiration slope is fixed. In some embodiments of the invention, the respiration sensitivity control for detecting either respiration level or respiration slope is adjustable or programmable. In some embodiments of the invention, the respiration sensitivity control for detecting respiration level and / or respiration slope is adjustable ranging from minimum sensitivity to maximum sensitivity, where the maximum sensitivity setting is more sensitive to detecting breaths than the minimum sensitivity setting.

[0051]

[0070] In certain embodiments where at least two triggers are used, the sensitivity of each trigger is set at a different relative level. In one embodiment where at least two triggers are used, one trigger is set to maximum sensitivity and the other trigger is set to less than maximum sensitivity. In one embodiment where at least two triggers are used and one trigger is a breath level trigger, the breath level trigger is set to maximum sensitivity.

[0052]

[0071] Often, not all of a patient's inhalations / halts are detected and classified as inhalation / halt events for pulsed administration of gas (e.g., NO). Detection errors can occur, especially when multiple gases are administered to the patient simultaneously, for example, in combination NO and oxygen therapy.

[0053]

[0072] Embodiments of the present invention, and particularly those incorporating a respiratory slope trigger, either alone or in combination with another trigger, can maximize the correct detection of inhalation events, thereby maximizing the effectiveness and efficiency of therapy while minimizing waste due to misidentification or errors in timing.

[0054]

[0073] In certain embodiments, greater than 50% of the patient's total inspirations over the time frame for gas delivery to the patient are detected. In certain embodiments, greater than 75% of the patient's total inspirations are detected. In certain embodiments, greater than 90% of the patient's total inspirations are detected. In certain embodiments, greater than 95% of the patient's total inspirations are detected. In certain embodiments, greater than 98% of the patient's total inspirations are detected. In certain embodiments, greater than 99% of the patient's total inspirations are detected. In certain embodiments, 75%-100% of the patient's total inspirations are detected. Dosage and Administration Regimen

[0074] In certain embodiments of the present invention, nitric oxide delivered to a patient is formulated at a concentration of about 3 to about 18 mg NO per liter, about 6 to about 10 mg NO per liter, about 3 mg NO per liter, about 6 mg NO per liter, or about 18 mg NO per liter. NO may be administered alone or in combination with an alternative gas therapy. In certain embodiments, oxygen (e.g., concentrated oxygen) may be administered to a patient in combination with NO.

[0055]

[0075] In some embodiments of the invention, a volume of nitric oxide is administered in an amount of about 0.350 mL to about 7.5 mL per breath (e.g., in a single pulse). In some embodiments, the volume of nitric oxide in each pulse dose may be the same over the course of a single session. In some embodiments, the volume of nitric oxide in several pulse doses may vary over the course of a single time frame for delivering gas to a patient. In some embodiments, the volume of nitric oxide in each pulse dose may be adjusted while monitoring breathing patterns over the course of a single time frame for delivering gas to a patient. In some embodiments of the invention, the amount of nitric oxide (ng) delivered to a patient per pulse ("pulse dose") for purposes of treating or alleviating symptoms of pulmonary disease is calculated as follows, rounded to the nearest nanogram: Dose mcg / kg-IBW / hour x ideal body weight kg (kg-IBW) x ((1 hour / 60 minutes) / (1 minute / respiration rate (bpm)) x (1,000ng / ug).

[0056]

[0076] As an example, patient A on a dose of 100 mcg / kg IBW / hr has an ideal body weight of 75 kg and a respiratory rate of 20 breaths per minute (or 1200 breaths per hour): 100mcg / kg-IBW / hr x 75kg x (1hr / 1200 breaths) x (1,000ng / ug) = 6250ng per pulse

[0077] In certain embodiments, the variable 60 / respiratory rate (min) may be referred to as the administration event time. In another embodiment of the invention, the administration event time is 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, or 10 seconds.

[0057]

[0078] In some embodiments of the invention, a single pulse dose provides a therapeutic benefit (e.g., a therapeutically effective amount of NO) to a patient. In other embodiments of the invention, the total amount of two or more pulse doses provides a therapeutic benefit (e.g., a therapeutically effective amount of NO) to a patient.

[0058]

[0079] In certain embodiments of the invention, at least about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, about 490, about 500, about 510, about 520, about 530, about 540, about 550, about 560, about 570, about 580, about 590, about 600, about 625, about 650, about 675, about 700, about 750, about 800, about 850, about 900, about 950, or about 1000 pulses of nitric oxide are administered to a patient every hour.

[0059]

[0080] In certain embodiments of the invention, nitric oxide therapy sessions occur over a time frame that is, in one embodiment, at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 24 hours per day.

[0060]

[0081] In some embodiments of the present invention, nitric oxide therapy is administered for a minimum treatment course time frame. In some embodiments of the present invention, the minimum treatment course is about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, or about 90 minutes. In some embodiments of the present invention, the minimum treatment course is about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 24 hours. In certain embodiments of the invention, the minimum course of treatment is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8 weeks, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 18, or about 24 months.

[0061]

[0082] In some embodiments of the invention, nitric oxide therapy sessions are administered one or more times per day. In some embodiments of the invention, nitric oxide therapy sessions may be administered one, two, three, four, five, six, or more than six times per day. In some embodiments of the invention, therapy sessions may be administered monthly, biweekly, weekly, every other day, daily, or multiple times per day. NO pulse timing

[0083] In one embodiment of the invention, breathing patterns are correlated with an algorithm to calculate when to administer a dose of nitric oxide.

[0062]

[0084] The accuracy of detecting inhalation / inhalation events is further maximized by timing the gas (e.g., NO) pulse to administer gas at a specific time window within the total inhalation time of a single detected breath.

[0063]

[0085] In some embodiments of the invention, at least fifty percent (50%) of the pulse dose of gas is delivered over the first third of the total inspiratory time of each breath. In some embodiments of the invention, at least sixty percent (60%) of the pulse dose of gas is delivered over the first third of the total inspiratory time. In some embodiments of the invention, at least seventy-five percent (75%) of the pulse dose of gas is delivered over the first third of the total inspiratory time of each breath. In some embodiments of the invention, at least eighty-five percent (85%) of the pulse dose of gas is delivered over the first third of the total inspiratory time of each breath. In some embodiments of the invention, at least ninety-two percent (92%) of the pulse dose of gas is delivered over the first third of the total inspiratory time. In some embodiments of the invention, at least ninety-five percent (95%) of the pulse dose of gas is delivered over the first third of the total inspiratory time. In some embodiments of the invention, at least ninety-nine percent (99%) of the pulse dose of gas is delivered over the first third of the total inhalation time. In some embodiments of the invention, 90% to 100% of the pulse dose of gas is delivered over the first third of the total inhalation time.

[0064]

[0086] In some embodiments of the invention, at least 70 percent (70%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In yet other embodiments, at least 75 percent (75%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In some embodiments of the invention, at least 80 percent (80%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In some embodiments of the invention, at least 90 percent (90%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In some embodiments of the invention, at least 95 percent (95%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In some embodiments of the invention, 95% to 100% of the pulse dose of gas is delivered over the first half of the total inspiration time.

[0065]

[0087] In some embodiments of the invention, at least ninety percent (90%) of the pulse dose is delivered over the first two-thirds of the total inhalation time. In some embodiments of the invention, at least ninety-five percent (95%) of the pulse dose is delivered over the first two-thirds of the total inhalation time. In some embodiments of the invention, 95%-100% of the pulse dose is delivered over the first two-thirds of the total inhalation time.

[0066]

[0088] When aggregated, administration of multiple pulse doses over a therapy session / time frame may also fall within the above ranges. For example, when aggregated, more than 95% of all pulse doses administered during a therapy session were administered over the first two-thirds of the total inhalation time of all detected breaths. In a more accurate embodiment, when aggregated, more than 95% of all pulse doses administered during a therapy session were administered over the first one-third of the total inhalation time of all detected breaths.

[0067]

[0089] Given the high accuracy of the detection method of the present invention, pulse doses can be administered during any specific time window of inspiration. For example, pulse doses can be administered during the first third, middle third, or last third of a patient's inspiration. Alternatively, the first half or second half of inspiration can be targeted for pulse dose administration. Furthermore, the target for administration can be changed. In one embodiment, the first third of inspiration time can be targeted for one or a series of inspirations, and the second third or second half can be targeted for a subsequent one or a series of inspirations during the same or a different therapy session. Alternatively, pulse administration can be initiated after the first quarter of inspiration time has elapsed, continued through the middle half (the next two quarters), and terminated at the beginning of the last quarter of inspiration time. In some embodiments, the pulse may be delayed by 50, 100, or 200 milliseconds (ms), or may be delayed in the range of about 50 to about 200 ms.

[0068]

[0090] Utilizing pulsed administration during inhalation reduces exposure of underventilated lung regions and alveoli to the pulsed gas, e.g., NO. In one embodiment, less than 5% of the underventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 10% of the underventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 15% of the underventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 20% of the underventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 25% of the underventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 30% of the underventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 50% of the underventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 60% of the inadequately ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 70% of the inadequately ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 80% of the inadequately ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 90% of the inadequately ventilated (a) lung regions or (b) alveoli are exposed to NO. Treatment method

[0091] In one embodiment of the present invention, a method for increasing the activity level of a patient with a lung-related condition is described. The method includes administering iNO, optionally supplementing the iNO administration with oxygen. In one embodiment of the present invention, iNO is administered according to the pulsed regimen discussed herein. In one embodiment of the present invention, iNO is delivered to the patient using an INOpulse® device (Bellerofon Therapeutics). In one embodiment, the patient is administered iNO for a period of at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours per day for a period of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. In one embodiment, the patient is administered iNO for 8 weeks. In another embodiment, the patient is administered iNO for 16 weeks. In one embodiment of the present invention, the nitric oxide therapy sessions occur over a time frame. In one embodiment, the time frame is at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 24 hours per day.

[0069]

[0092] In some embodiments of the invention, nitric oxide therapy is administered within a minimum therapeutic course time frame. In some embodiments of the invention, the minimum therapeutic course is about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, or about 90 minutes. In some embodiments of the invention, the minimum therapeutic course is about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 24 hours. In certain embodiments of the invention, the minimum course of treatment is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8 weeks, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 18, or about 24 months.

[0070]

[0093] In certain embodiments of the present invention, iNO is administered at a dose of 10 mcg / kg ideal body weight (IBW) / hour to 200 mcg / kg IBW / hour or more. In one embodiment, iNO is administered at about 20 mcg / kg IBW / hour to about 150 mcg / kg IBW / hour. In one embodiment, iNO is administered at about 25 mcg / kg IBW / hour to about 100 mcg / kg IBW / hour. In one embodiment, iNO is administered at about 30 mcg / kg IBW / hour to about 75 mcg / kg IBW / hour. In one embodiment, iNO is administered at about 25 mcg / kg IBW / hour to about 50 mcg / kg IBW / hour. In one embodiment, iNO is administered at about 30 mcg / kg IBW / hour to about 45 mcg / kg IBW / hour. In one embodiment, iNO is administered at 25 mcg / kg IBW / hr. In one embodiment, iNO is administered at 30 mcg / kg IBW / hr. In one embodiment, iNO is administered at 35 mcg / kg IBW / hr. In one embodiment, iNO is administered at 40 mcg / kg IBW / hr. In one embodiment, iNO is administered at 45 mcg / kg IBW / hr. In one embodiment, iNO is administered at 50 mcg / kg IBW / hr. In one embodiment, iNO is administered at 55 mcg / kg IBW / hr. In one embodiment, iNO is administered at 60 mcg / kg IBW / hr. In one embodiment, iNO is administered at 65 mcg / kg IBW / hr. In one embodiment, iNO is administered at 70 mcg / kg IBW / hr. In one embodiment, iNO is administered at 75 mcg / kg IBW / hr. In one embodiment, iNO is administered at 80 mcg / kg IBW / hr. In one embodiment, iNO is administered at 85 mcg / kg IBW / hr. In one embodiment, iNO is administered at 90 mcg / kg IBW / hr. In one embodiment, iNO is administered at 95 mcg / kg IBW / hr. In one embodiment, iNO is administered at 100 mcg / kg IBW / hr. In one embodiment, iNO is administered at 105 mcg / kg IBW / hr. In one embodiment, iNO is administered at 110 mcg / kg IBW / hr.In one embodiment, iNO is administered at 115 mcg / kg IBW / hr. In one embodiment, iNO is administered at 120 mcg / kg IBW / hr. In one embodiment, iNO is administered at 125 mcg / kg IBW / hr. In one embodiment, iNO is administered at 130 mcg / kg IBW / hr. In one embodiment, iNO is administered at 135 mcg / kg IBW / hr. In one embodiment, iNO is administered at 140 mcg / kg IBW / hr. In one embodiment, iNO is administered at 145 mcg / kg IBW / hr. In one embodiment, iNO is administered at 150 mcg / kg IBW / hr. In one embodiment, iNO is administered at 155 mcg / kg IBW / hr. In one embodiment, iNO is administered at 160 mcg / kg IBW / hr. In one embodiment, iNO is administered at 165 mcg / kg IBW / hr. In one embodiment, iNO is administered at 170 mcg / kg IBW / hr. In one embodiment, iNO is administered at 175 mcg / kg IBW / hr. In one embodiment, iNO is administered at 180 mcg / kg IBW / hr. In one embodiment, iNO is administered at 185 mcg / kg IBW / hr. In one embodiment, iNO is administered at 190 mcg / kg IBW / hr. In one embodiment, iNO is administered at 190 mcg / kg IBW / hr. In one embodiment, iNO is administered at 200 mcg / kg IBW / hr.

[0071]

[0094] In some embodiments of the invention, the patient is also administered oxygen in conjunction with iNO. In some embodiments of the invention, oxygen is administered at a rate of up to 20 L / min. In some embodiments of the invention, oxygen is administered at a rate of up to 1 L / min, 2 L / min, 3 L / min, 4 L / min, 5 L / min, 6 L / min, 7 L / min, 8 L / min, 9 L / min, 10 L / min, 11 L / min, 12 L / min, 13 L / min, 14 L / min, 15 L / min, 16 L / min, 17 L / min, 18 L / min, 19 L / min, or 20 L / min. In some embodiments of the invention, oxygen is administered as prescribed by a physician.

[0072]

[0095] In one embodiment of the present invention, the lung-related condition useful in the present invention is selected from idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis (PF), interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and emphysema. In one embodiment of the present invention, the lung disease is pulmonary hypertension associated with other lung diseases, such as groups I-V of pulmonary hypertension (PH). In another embodiment, the lung disease and / or lung-related condition is pulmonary hypertension associated with interstitial lung disease. In one embodiment of the present invention, the lung disease and / or lung-related condition is pulmonary hypertension associated with pulmonary fibrosis. In one embodiment of the present invention, the lung disease and / or lung-related condition is pulmonary hypertension associated with idiopathic pulmonary fibrosis. In one embodiment of the present invention, patients suffering from ILD are at increased risk of developing pulmonary hypertension. In another embodiment of the present invention, patients suffering from ILD are at reduced risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from ILD has a moderate risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from IPF has a high risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from IPF has a moderate risk of developing pulmonary hypertension. In another embodiment of the present invention, a patient suffering from IPF has a low risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from ILD has a high risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from PF has a high risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from PF has a moderate risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from PF has a low risk of developing pulmonary hypertension.

[0073]

[0096] Notably, patients with pulmonary hypertension associated with interstitial lung disease showed statistically significant improvements in activity levels, as measured by actigraphy (a wearable, medical-grade activity monitor). Actigraphy is currently being used as the primary endpoint in multiple late-stage clinical programs for pulmonary hypertension and other cardiopulmonary diseases. Patients receiving iNO showed an increase in moderate-intensity activity compared with a decrease in patients receiving placebo. Patients receiving iNO therapy also showed no decline in overall activity compared with a decline in patients receiving placebo. Patients also experienced clinically meaningful improvements in other areas. NT-ProBNP, a peptide marker of right ventricular failure, was measured, and patients receiving iNO therapy showed only a small increase in NT-ProBNP compared with a large increase in patients receiving placebo. These results are consistent with the activity results, as higher NT-ProBNP levels indicate worsening disease (i.e., more severe deterioration in placebo patients). Patients receiving iNO also showed improvements in oxygen saturation. Nadir SpO2 improved in patients receiving iNO therapy, whereas nadir SpO2 worsened in patients receiving placebo. Furthermore, in certain embodiments of the invention, oxygen desaturation worsened in patients receiving placebo while improving in patients receiving iNO therapy. As measured by another method, in certain embodiments of the invention, oxygen desaturation worsened in patients receiving placebo while improving in patients receiving iNO therapy. Unlike other systemic vasodilators, such as those approved for the treatment of pulmonary arterial hypertension, targeted delivery of INOpulse to the lungs improves oxygen saturation during exercise.

[0074]

[0097] In certain embodiments of the invention, other parameters useful for assessing the efficacy of iNO include time to clinical improvement and time to clinical deterioration. Patients treated with iNO are expected to experience a shorter time to clinical improvement and a longer time to clinical deterioration. Patient-related outcome measures (PROs) are also useful for assessing the efficacy of iNO. PROs are measured in the form of questionnaires and provide a subject's perspective on overall quality of life. In certain embodiments of the invention, these PROs include the St. George Respiratory Questionnaire (SGRQ) and the University of California, San Diego Shortness of Breath Questionnaire (UCSD SOBQ). Both of these questionnaires are standard questionnaires used in the art and are well known and clinically accepted. Improvements in both scores of these PROs are expected for patients receiving iNO therapy. Actigraphy

[0098] The present invention relates to a method for improving or maintaining activity levels or preventing decline in activity levels in patients with cardiopulmonary or lung-related conditions, which method involves monitoring and measuring changes in activity levels using actigraphy.

[0075]

[0099] Actigraphy involves the use of a wearable activity monitor, similar to a pedometer or accelerometer, or a triaxial accelerometer, such as the Actigraph GT9X or FITBIT®, to measure activity parameters. Such activity monitors assess activity and measure a user's activity parameters. Measured activity parameters include overall activity, sedentary activity, moderate-intensity activity, moderate-vigorous physical activity (MVPA), steps, calories, metabolic equivalent units (METs), sleep, heart rate, oxygen saturation, calories burned, and other types of activity parameters.

[0076]

[0100] In some embodiments of the present invention, activity levels are monitored and measured continuously over a period of time. In some embodiments of the present invention, activity levels are monitored and measured intermittently over a period of time. In one embodiment, activity levels are monitored and measured for a period of at least about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours per day for a period of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks. In another embodiment, activity levels are monitored and measured for a period of at least about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours per day for a period of at least about 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In another embodiment, activity levels are monitored only during the patient's awake hours. In one embodiment, activity levels are measured in a continuous manner throughout the awake period. In another embodiment, the patient can remove the device for certain activities, and thus activity levels are measured in a discontinuous manner throughout the awake period. In another embodiment, the awake period is at least 10 hours. In another embodiment, the awake period is at least 8 hours. In another embodiment, the awake period is at least 12 hours. In another embodiment, the awake period is at least 14 hours.

[0077]

[0101] In some embodiments of the present invention, the activity level is improved compared to the baseline activity level. In some embodiments, the baseline activity level is monitored and measured for at least one week prior to administration of the vasodilator. In other embodiments, the baseline activity level is monitored or measured for about 1 to about 14 days, about 1 to about 10 days, about 1 to about 7 days, or about 1 to about 5 days. In other embodiments, the baseline activity level is monitored or measured for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In some embodiments of the present invention, the baseline activity is monitored or measured for about 7 days. In some embodiments of the present invention, the baseline activity level is monitored or measured over a period of about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours per day. In some embodiments of the present invention, the baseline activity is monitored or measured while the subject is awake. In some embodiments of the present invention, the baseline activity is monitored or measured while the subject is asleep. In some embodiments of the present invention, the baseline activity is monitored or measured during the time the subject is awake and asleep.

[0078]

[0102] In one embodiment, the activity level is improved compared to the baseline activity level. In one embodiment, the activity level is improved by about 1% to about 50%. In another embodiment, the activity level is improved by about 1% to about 25%. In another embodiment, the activity level is improved by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%. In another embodiment, the activity level is improved by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0079]

[0103] In another embodiment of the present invention, activity levels are maintained compared to baseline activity levels. In another embodiment, activity levels do not decrease compared to baseline activity levels. In another embodiment, activity levels decrease less over time in treated patients than in untreated or placebo patients. In one embodiment, activity levels decrease by about 5% in treated patients, while activity levels decrease by about 20% or more in placebo or untreated patients.

[0080]

[0104] In one embodiment of the present invention, a subject wears an actigraphy monitor on their non-dominant arm. Wrist acceleration is continuously measured by the monitor. The monitor records triaxial acceleration at 30 Hz. An algorithm converts acceleration measurements into minutes of activity. Each minute is classified as an activity level based on established and validated cutpoints. The algorithm can also determine wear time, calories, and other parameters. Daily activity data is converted to weekly activity levels to allow for data comparison. Predefined filters are utilized to ensure only adherence data is analyzed. Such filters can include a minimum number of "wake-to-wear" minutes to ensure adherence (e.g., at least 600 minutes) and at least three adherence days per complaint week. Filters can be based on industry standards used for actigraphy analysis.

[0081]

[0105] Counts can be converted to activity levels in several ways. For example, the average count provides a direct measure of physical activity. As shown in Table 1, each minute of the day can be converted to an activity intensity to determine the amount of time spent in sedentary, light-intensity, moderate-intensity, and vigorous-intensity activity.

[0082] [Table 1]

[0083] Cardiopulmonary and pulmonary-related conditions

[0106] The methods of the invention are useful in patients with cardiopulmonary and / or lung-related conditions, including, but not limited to, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension, pulmonary arterial hypertension (PAH), including groups I-V pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), emphysema, asthma, interstitial lung disease, and pulmonary fibrosis.

[0084]

[0107] In one embodiment of the present invention, the lung disease is pulmonary hypertension associated with other lung diseases, such as group I-V pulmonary hypertension (PH). In another embodiment, the lung disease and / or lung-related condition is pulmonary hypertension associated with interstitial lung disease. In one embodiment of the present invention, the lung disease and / or lung-related condition is pulmonary hypertension associated with pulmonary fibrosis. In one embodiment of the present invention, the lung disease and / or lung-related condition is pulmonary hypertension associated with idiopathic pulmonary fibrosis. In one embodiment of the present invention, a patient suffering from an ILD has a high risk of developing pulmonary hypertension. In another embodiment of the present invention, a patient suffering from an ILD has a low risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from an ILD has a moderate risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from IPF has a high risk of developing pulmonary hypertension. In one embodiment of the present invention, a patient suffering from IPF has a moderate risk of developing pulmonary hypertension. In another embodiment of the present invention, a patient suffering from IPF has a low risk of developing pulmonary hypertension. In one embodiment of the present invention, patients suffering from ILD have a high risk of developing pulmonary hypertension. In one embodiment of the present invention, patients suffering from PF have a high risk of developing pulmonary hypertension. In one embodiment of the present invention, patients suffering from PF have a moderate risk of developing pulmonary hypertension. In one embodiment of the present invention, patients suffering from PF have a low risk of developing pulmonary hypertension. Administration of other vasodilators and oxygen

[0108] The present invention relates to a method for improving or maintaining activity levels, or preventing a decline in activity levels, in patients with cardiopulmonary or lung-related conditions, comprising administering a vasodilator to the patient and then monitoring and measuring changes in activity levels using actigraphy.

[0085]

[0109] In certain embodiments of the invention, the vasodilator is administered to the patient as directed by the treating physician.

[0110] In certain embodiments of the present invention, vasodilators useful in the present invention include, but are not limited to, systemic vasodilators and topical vasodilators. In one embodiment, systemic vasodilators include, but are not limited to, nitrates. In another embodiment, topical vasodilators include, but are not limited to, oxygen, nitric oxide, iNO, sildenafil, tadalafil, and nitroprusside.

[0086]

[0111] In one embodiment of the present invention, the patient is also administered oxygen in conjunction with a vasodilator according to the present invention. In one embodiment of the present invention, oxygen is administered at a maximum of 20 L / min. In one embodiment of the present invention, oxygen is administered at a maximum of 1 L / min, 2 L / min, 3 L / min, 4 L / min, 5 L / min, 6 L / min, 7 L / min, 8 L / min, 9 L / min, 10 L / min, 11 L / min, 12 L / min, 13 L / min, 14 L / min, 15 L / min, 16 L / min, 17 L / min, 18 L / min, 19 L / min, or 20 L / min. In one embodiment of the present invention, oxygen is administered as prescribed by a physician. In another embodiment, the patient is receiving long-term oxygen therapy (LTOT). In another embodiment, the patient is administered oxygen 24 hours per day. In another embodiment, the patient is administered oxygen for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours per day, hi another embodiment, the patient is administered oxygen for at least 12 hours per day. [Example]

[0087]

[0112] Embodiments encompassed herein will now be described with reference to the following examples, which are provided for illustrative purposes only, and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather as encompassing any and all variations that become evident as a result of the teachings presented herein.

[0088]

[0113] Example 1 Measuring Precise Respiratory Sensitivity for Appropriate Trigger / Arming Thresholds

[0114] A device using a threshold algorithm to detect breaths was used in this example (Embodiment 1). The threshold algorithm detects breaths using pressure, meaning that a pressure drop below a certain threshold must be observed for inspiration in order for a breath to be detected and counted. The pressure threshold can be modified to change the detection sensitivity of the device of Embodiment 1. Several breath sensitivity settings were tested in this example. Settings from 1 to 10 were tested, with 1 being the least sensitive and 10 being the most sensitive. The trigger threshold, shown in cmH2O, is the threshold level at which nitric oxide is delivered. The arming threshold, also shown in cmH2O, is the threshold level at which the device is ready for the next delivery of nitric oxide. This data is shown in Table 1 below.

[0089]

[0115] Table 1 below shows the data set collected in this example. Varying the breath sensitivity setting resulted in an increase in the trigger threshold (measured in cm HO) from -1.0 at the lowest sensitivity setting (1) to -0.1 at the highest sensitivity setting (10). Furthermore, the arming threshold (measured in cm HO) maintained a value of 0.1 from sensitivity setting 1 to setting 6, and then decreased by 0.02 at each sensitivity setting up to 10. This suggests that the most sensitive breath sensitivity setting allows for more accurate breath detection, thereby resulting in more accurate pulse delivery of nitric oxide within a shorter time window, i.e., earlier in the inspiratory portion of the breath. Based on these data, additional testing was performed at sensitivity settings 8 and 10.

[0090] [Table 2]

[0091]

[0116] In conclusion, higher breath sensitivity settings correlate with lower trigger thresholds and higher arming thresholds, tuning the device to deliver short, precise pulses of nitric oxide over the course of therapy.

[0092]

[0117] Example 2 Testing the device for different breathing patterns

[0118] As mentioned above, precise and timely delivery of nitric oxide is critical to the present invention. To verify that the device delivers precise doses of gas within a precise time window, 10 different breathing patterns were tested using an artificial lung and nose model. The 10 different simulated breathing patterns were analyzed, and variations in breathing rate (8-36 bpm), ventilation volume (316-912 mL), and inhalation:exhalation (I / E) ratio (1:1-1:4) were observed. These variable breathing patterns are expected for subjects aged 16 years or older and are summarized in Table 2. Real-world conditions were mimicked as closely as possible.

[0093] [Table 3]

[0094]

[0119] Two device embodiments were tested—Embodiment 1, tested at sensitivity levels 8 and 10, and the other device embodiment (Embodiment 2, also including a slope algorithm) tested at sensitivity level 10. This study consisted of two parts. In Part 1, the delay time between the start of inspiration breath and the start of nitric oxide delivery was measured using 10 different simulated breathing patterns. This delay time is measured using two data points—the time from the start of inspiration (FIG. 1, point A) to breath detection with simultaneous delivery valve opening (FIG. 1, point B). In Part 2, the duration and volume of the delivered pulse were measured across the same breathing patterns in Table 2. The duration of the gas pulse is measured from the simultaneous opening of the delivery valve, corresponding to breath detection and the start of gas delivery (FIG. 2, point A), to the completion of gas delivery (FIG. 2, point B). The volume of the delivered pulse is measured by integrating the gas flow rate over the duration of the pulse. Additionally, the data from Part 1, which measures the delay time, and the data from Part 2, which measures the pulse duration, are added together to calculate the dose delivery time, sometimes referred to as the "delivered pulse width."

[0095]

[0120] Part 1: Measurement of the delay time between the start of inspiration and the onset of NO delivery. This part of the study was performed at a dose of 75 mcg / kg-IBW / h, with a drug concentration entered as 6 mg / L (4880 ppm). This study was performed using nitrogen only. The primary output for Part 1 was the duration between the start of inspiration and the indication of valve opening / breath detection. Point A in Figure 1 is the point at which pulmonary airflow rose just above the resting line. The moment of valve opening is shown as point B in Figure 1 and is displayed as a sudden voltage drop at the detector. The time interval between points A and B is the valve delay time, or trigger delay, and is calculated for each breathing pattern. The total inspiration time corresponds to the interval from point A to point C, which is the end of inspiration.

[0096]

[0121] Part 2: Measurement of Delivered Pulse Duration and Volume. The same breathing pattern was used in this part of the study. Doses of 10, 15, 30, and 75 mcg / kg-IBW / h were tested. The device was programmed for each dose, patient IBW, and respiratory rate (breaths per minute). The resulting pulse gas flow was determined by the flow meter. The pulse duration is the time between the point at which the valve opens, indicated by a sudden voltage drop at the detector and corresponding to point A in Figure 2, and the point at which the gas flow returns to baseline at point B in Figure 2. The delivered pulse volume is the integrated gas flow during the pulse duration. The pulse duration was added to the pulse delay time from Part 1 to obtain the dose delivery time, i.e., the "delivered pulse width." Figure 1 shows the results of Part 1. Four panels are shown in Figure 1. The second and fourth panels show breath detection and depiction of the breathing pattern, respectively, corresponding to actuation of the flow control valve. Point A indicates the start of inspiration, point B indicates breath detection corresponding to the opening of the flow valve, and point C indicates the end of inspiration. From this data, the delay between points A and B can be calculated.

[0097]

[0122] Figure 2 shows the results of Part 2. Figure 2 shows four panels. The second and third panels show depictions of breath detection and pulsed gas flow, respectively, which correspond to actuation of the flow control valve. Point A represents breath detection, which corresponds to opening of the flow valve, and point B represents the end of pulsed flow. From this data, the duration of the pulse between points A and B can be calculated.

[0098] [Table 4]

[0099]

[0123] FIG. 3 depicts the breath detection results for each device listed in Table 3. Example 2, i.e., the green data in FIG. 3, shows that at least 93% of nitric oxide is delivered within the first one-third of the inhalation portion of the breath. 100% of nitric oxide is delivered within the first half of the inhalation portion of the breath. In comparison, Example 1 with sensitivity setting 8 showed that at least 17% of nitric oxide was delivered within the first one-third of the inhalation portion of the breath, at least 77% within the first half of the inhalation portion of the breath, and at least 95% within the first two-thirds of the inhalation portion of the breath. Example 1 with sensitivity setting 10 showed that at least 62% of nitric oxide was delivered within the first one-third of the inhalation portion of the breath, at least 98% within the first half of the inhalation portion of the breath, and 100% within the first two-thirds of the inhalation portion of the breath. FIG. 4 depicts the data curve combining all three tests.

[0100]

[0124] From this data, it can be concluded that because more nitric oxide is delivered more precisely per pulse over a shorter period of time during the course of treatment, a smaller dose of nitric oxide is needed over the course of a single treatment, which translates into less drug use overall and a reduced risk of adverse side effects.

[0101]

[0125] Example 3: Evaluation of activity parameters in patients with pulmonary hypertension associated with interstitial lung disease (Cohort 1) - pulmonary fibrosis.

[0126] Patients were divided into two cohorts and randomized 1:1 (Cohort 1) or 2:1 (Cohort 2) for treatment:placebo. Patients received either 30 mcg / kg IBW / h (iNO30, Cohort 1) or 45 mcg / kg IBW / h (iNO45, Cohort 2) for up to 24 hours per day for a period of 8 weeks (Cohort 1) or 16 weeks (Cohort 2). Cohort 1 consisted of 41 patients and was extended into an open-label phase, which is currently ongoing. The open-label phase includes iNO patients receiving either iNO30 or iNO45. The following data represent the topline results from Cohort 1. Cohort 3 will be the pivotal Phase 3 arm using iNO45 administration.

[0102]

[0127] For the duration of the study, all patients received a level of background oxygen prescribed by their treating physician. Vital signs and a baseline 6MWD test were measured on day 0, and activity monitors were provided. Patient activity was measured throughout the treatment period using a wearable, medical-grade activity monitor (Actigraph GT9X). Vitals and another 6MWD test were measured at weeks 4 and 8 in Cohort 1 and at weeks 12 and 16 in Cohort 2.

[0103]

[0128] The Actigraph GT9X is a triaxial accelerometer that continuously monitors subject movement and acceleration at 30 Hz. Acceleration measurements are converted to minute-by-minute activity "counts." These counts can be converted to activity intensity based on established and validated daily cutpoints. Each minute record includes sleep / wake tags, wear / unwear tags, X-, Y-, and Z-axis counts, and classifications such as sedentary, light, moderate, or vigorous activity. Minute data are summarized for the daily record, including minutes of sedentary, light, moderate, or vigorous activity; cumulative counts (X-, Y-, and Z-axes); minutes in non-sedentary activity (light, moderate, or vigorous combined); minutes in VMPA (moderate and vigorous combined); and overall activity, which can be used to measure activity intensity.

[0104]

number

[0105] It is calculated as follows:

[0129] Monthly and weekly data are calculated by averaging the daily data output for all "adherence days" within a period. An adherence day includes ≥ 600 minutes of wear-and-wake time; an adherence month includes ≥ 14 adherence days within a period; and an adherence week includes ≥ 3 adherence days within a period. Non-adherence days, weeks, or months were not used in the analysis.

[0106]

[0130] Activities relevant to the pulmonary fibrosis population and relevant to this particular study were identified and reported by the IPF Voice of Patient-FDA Meeting and Report, 2015. These activities can be grouped by activity intensity based on estimated metabolic equivalent levels, as summarized in Table 5A below.

[0107]

[0131] Here, results from Cohort 1 are provided. Six-Minute Walk Distance (6MWD) Study Support Actigraphy Results. In Cohort 1, there were three times as many 6MWD improvers in the treatment group compared with placebo. Improvement in 6MWD is defined as a 15% or greater improvement in 6MWD above the patient's baseline level. Thirty-one percent of treated patients improved in 6MWD compared with approximately 11% of those receiving placebo, and patients with more severe pulmonary hypertension showed greater improvements above baseline levels (a +6-meter change in INOpulse patients and a -7-meter change in placebo). Additionally, in Cohort 1, patients who wore INOpulse for at least 12 hours experienced an overall change in 6MWD of +10 meters compared with a -6-meter change in those receiving placebo. The composite endpoints of distance-saturation product (DSP) and integrated DSP (IDSP) increased compared with 6MWD, validating a ventilation / perfusion (V / Q) benefit. Furthermore, iNO was well tolerated and no safety concerns were raised.

[0108]

[0132] In addition to certain specific actigraphy parameters (MVPA and general activity), the additional efficacy parameter of NT-proBNP change was also analyzed. NT-proBNP is a natriuretic peptide released by cardiac myocytes when the ventricles are placed under increased load and stretch (caused by pulmonary hypertension). Thus, pulmonary hypertension leads to elevated levels of NT-proBNP. Treatments targeting the pulmonary vasculature are predicted to maintain or reduce elevated levels of NT-proBNP. In general, the higher the baseline level, the greater the likelihood of reduction.

[0109]

[0133] The SpO2 nadir (or lowest oxygen saturation point) during the 6MWT was also measured.

[0110] [Table 5]

[0111] [Table 6]

[0112] [Table 7]

[0113] Tables 4 and 5 show the changes in key power and activity parameters for treated and placebo patients from Cohort 1. Table 4 shows statistically significant data for improvements in activity levels for treated and untreated patients. Table 5 shows data for treated and placebo patients, along with placebo-corrected changes.

[0114]

[0134] Table 6 shows subject demographic and disease characteristics.

[0115] [Table 8]

[0116]

[0135] Results show that iNO provides clinically and statistically significant improvements in activity as measured by a wearable activity monitor (Actigraph GT9X). Changes in NT-ProBNP were consistent with activity results, indicating greater deterioration in placebo patients. Unlike other approved PAH systemic vasodilators, targeted delivery of INOpulse improves oxygen saturation during exercise. Multiple actigraphy parameters were used to demonstrate consistent benefits for subjects receiving iNO30 versus those receiving placebo. Statistically significant benefits were seen in moderate and general activity and calories. See summary of results in Tables 7-10 below.

[0117] [Table 9]

[0118]

[0136] Table 7 shows actigraphy results from iNO-PF Cohort 1. Improvements in the iNO group were statistically significant compared to placebo for all parameters: MVPA (p=0.04), percentage of awake time in MVPA (p=0.04), overall activity (p=0.05), and calories (p=0.05). MVPA is the primary endpoint for the pivotal Phase 3 cohort of this study.

[0119]

[0137] 7A-7D show that iNO demonstrated consistent and sustained benefits in activity parameters of MVPA, general activity, non-sedentary activity, and daily calories. The data show a consistent split of approximately 4 weeks that was maintained for the remainder of the study (through week 8).

[0120] [Table 10]

[0121]

[0138] Table 8 shows the improvement in supportive parameters. The reduction in desaturations and increase in SpO2 nadir in the iNO group translates to improved oxygen saturation in that group. The peptide marker NT-ProBNP, an indicator of heart failure, showed a greater increase in the placebo group, indicating worsening of the condition.

[0122] [Table 11]

[0123]

[0139] Table 9 provides a summary of safety data. The safety study in Cohort 1 supports dose escalation for iNO45. There were no serious, unexpected suspected adverse reactions and no unexpected adverse events. All serious adverse events were reported as unrelated to the study. The incidence of AEs and SAEs was low and balanced across both treatment and placebo groups. Pulsed inhaled nitric oxide is safe and well tolerated with iNO30.

[0124] [Table 12]

[0125]

[0140] Table 10 shows that iNO30 treatment maintained MVPA compared to a consistent decline in the placebo group. A change in MVPA of 15% or greater was considered significant. Approximately 23% of patients receiving iNO showed a significant improvement in MVPA, while 71% of placebo patients showed a significant decline in MVPA.

[0126]

[0141] Finally, Figures 8A and 8B demonstrate consistent improvements for the 16 subjects in the open-label treatment study. Figure 8A shows the average weekly change in MVPA in minutes per day, and Figure 8B shows the average weekly change in general activity in counts per minute for treated and placebo patients in both the blinded study (left panel) and the open-label extension study (right panel). Blinded iNO patients showed little change in either MVPA or general activity, while blinded placebo patients showed a decline of approximately 3 minutes of MVPA and approximately 20 counts per minute of general activity. In contrast, in the open-label extension (OLE) study, both the OLE iNO and OLE placebo groups showed consistent improvements in both MVPA and general activity. The OLE iNO and OLE placebo groups showed an improvement of approximately 1 minute in MVPA and an improvement of approximately 20 counts per minute and 15 counts per minute, respectively, in general activity.

[0127]

[0142] In summary, consistent benefits were seen across multiple activity and other supportive parameters for subjects receiving iNO30 compared with placebo. MVPA demonstrated the greatest benefit, with a statistically significant placebo-corrected benefit of approximately 34%. General activity also demonstrated a statistically significant placebo-corrected benefit of approximately 12%. Other parameters, such as non-sedentary activity and calories, supported the benefit of general activity for subjects receiving iNO. Improvements in oxygen saturation and NT-ProBNP support the dual mechanism of action of INOpulse (regional vasodilation and V / Q matching). DSP demonstrated a greater benefit than 6MWD alone, consistent with INOpulse's ability to maintain oxygen saturation during exercise. Clinical studies are ongoing.

[0128]

[0143] The data presented for Cohort 1 above is raw data collected during the clinical study of Cohort 1 and does not represent a longitudinal analysis. The data presented in Example 4 for both Cohorts 1 and 2 includes data analyzed using a Mixed Effect Model Repeated Measure (MMRM) model and also includes pooled placebo data.

[0129]

[0144] Example 4: Evaluation of activity parameters in patients with pulmonary hypertension associated with interstitial lung disease (Cohort 2) - pulmonary fibrosis.

[0145] Example 4 presents data collected for Cohort 2 of Example 3, i.e., patients administered iNO45 (45 mcg / kg IBW / hr), and also includes MMRM analyses related to Cohorts 1 and 2. Cohort 2 included 44 subjects randomized 2:1 to either iNO45 or placebo for a 4-month (16-week) blinded treatment period followed by an open-label extension. Patients from Cohort 2 demonstrated statistically significant improvements in moderate-to-vigorous physical activity (MVPA), defined as walking, stair climbing, gardening, work, and similar activities, versus placebo. Figure 9A shows that treatment with iNO45 improved MVPA by 14 minutes per day, or a 20% overall improvement (p=0.02). Figure 9B shows that overall activity improved by 100 counts per minute, representing a 7% improvement.

[0130]

[0146] The actigraphy improvements were supported by improvements in two clinically relevant patient-reported outcome measures (PROs), which provide a subject's perspective on overall quality of life and dyspnea or shortness of breath. These PROs include the St. George Respiratory Questionnaire (SGRQ) and the University of California, San Diego Shortness of Breath Questionnaire (UCSD SOBQ). Both of these questionnaires are standard questionnaires used in the art, are well-known, and are clinically accepted. Figures 10A-10C show patient scores on the SGRQ. These data indicate that patients generally felt better on iNO45 treatment than on placebo. Figure 11 shows patient scores on the UCSD SOBQ, which indicate that patients felt less short of breath while receiving iNO45 treatment than on placebo.

[0131]

[0147] Table 11 shows safety data for Cohort 2 (iNO45). Pulsed iNO was well tolerated in Cohort 2. The incidence of adverse events (AEs) and serious adverse events (SAEs) was low in both the treatment and placebo groups. AEs were not serious overall, and there were no observable trends. All SAEs were reported as unrelated to study drug.

[0132]

[0148]

[0133] [Table 13]

[0134]

[0149] Table 12 provides an overview of the patient demographics for Cohort 2.

[0135] [Table 14]

[0136]

[0150] Table 13 shows data related to patient adherence to INOpulse administration for Cohorts 1 and 2. Patient adherence was similar for Cohorts 1 and 2, respectively, with both groups exceeding the target of 12 hours per day on average.

[0137] [Table 15]

[0138]

[0151] Table 14 shows patient adherence to wearing the activity monitor for at least 10 hours per day while awake to ensure an accurate assessment of their daytime activity levels. As noted in the table, both cohorts demonstrated average adherence to exceeding the required 10 hours per day, however, Cohort 2 saw an increase in the percentage of adherent days from 79% to 88%, indicating improved training in Cohort 2.

[0139] [Table 16]

[0140]

[0152] Figure 12 shows the log-transformed estimated change in MVPA (Figure 12A) and general activity (Figure 12B) at months 2 (iNO30 and iNO45) and 4 (iNO45). Month 2 data is based on pooled placebo data from weeks 4 to 8, and month 4 data is based on data collected between months 2 and 4. As noted in Figure 12A, the change from baseline in MVPA is smaller for Cohort 2 compared to Cohort 1. Furthermore, as shown in Figure 12B, the change from baseline in general activity for Cohort 2 is smaller at month 4 compared to Cohorts 1 and 2 at month 2.

[0141]

[0153] Figure 13 shows the log-transformed predicted marginal effect of MVPA on a monthly (Figure 13A) and weekly (Figure 13B) basis for Cohort 2. In both cases, patients treated with iNO45 maintain their activity levels, while subjects receiving placebo deteriorate over time. Importantly, the treatment effect is "slow," with differences between the two groups beginning in the second month of treatment and most pronounced in the second half of the study. While the shape of the decline is similar between monthly and weekly analyses, the monthly analysis shows less variability, with a standard deviation of the residuals of 0.14 compared to 0.20 for the weekly analysis.

[0142]

[0154] Table 15 shows that SpO2 nadir during 6MWD showed minimal differences between treatment and placebo groups for both Cohorts 1 and 2. The ability to maintain oxygen saturation is consistent with previous results showing that pulsed iNO can target well-ventilated alveoli and maintain V / Q (ventilation / perfusion balance) in this patient population.

[0143]

[0155]

[0144] [Table 17]

[0145]

[0156] Changes in NT-proBNP levels were analyzed for Cohorts 1 and 2. In Cohort 1, there was no difference in change from baseline between the iNO30 and placebo groups when analyzed using the MMRM model. Furthermore, no statistically significant difference was observed between the iNO30 group and pooled placebo in Cohort 1 until week 8 using the MMRM model. By week 8, there was a statistically significant difference between iNO45 and pooled placebo; however, this difference was lost when comparing iNO45 over 16 weeks, likely due to small sample sizes. Table 16 shows the change in NT-proBNP (pmol / L) over 8 weeks for Cohorts 1 and 2 and over 16 weeks for Cohort 2.

[0146] [Table 18]

[0147]

[0157] Time to clinical improvement was a composite endpoint consisting of a ≥15% improvement in 6MWD, or improvement on the SGRQ defined as a ≥4-point reduction, or a ≥15% improvement in the DSP / IDSP. There was minimal difference between Cohort 1 and pooled placebo over 8 weeks. Although not statistically significant, Cohort 2 showed a trend toward an increased percentage of subjects achieving clinical improvement in iNO45 when evaluated against the larger pooled placebo group. This effect was primarily driven by improvement in the SGRQ, further supporting the benefit seen in the overall SGRQ population.

[0148]

[0158] Time to clinical deterioration was also a composite endpoint consisting of mortality, hospitalization for cardiopulmonary deterioration, a ≥15% decline from baseline in 6MWD, or worsening functional class. If there were multiple events, only the first clinical deterioration event was counted. While differences in time to clinical deterioration between Cohort 1 or Cohort 2 were minimal, iNO45, evaluated against placebo in the larger pool, showed a trend toward less clinical deterioration with iNO45, supporting a potential signal that may become more apparent in larger trials.

[0149]

[0159] In summary, consistent benefits were seen across multiple activity and other supportive parameters for subjects receiving iNO45 compared to placebo. MVPA demonstrated the greatest benefit, with a statistically significant placebo-corrected benefit of approximately 20%. General activity also demonstrated a statistically significant placebo-corrected benefit of approximately 7%.

[0150]

[0160] Topline results indicate that iNO45 provides clear benefits over placebo in MVPA (moderate-vigorous physical activity) and overall activity over the 4-month treatment period. Subjects receiving iNO45 maintained their activity levels, while subjects receiving placebo showed consistent declines. Over 4 months, subjects receiving iNO45 demonstrated a 19% placebo-corrected benefit in MVPA and a 7% placebo-corrected benefit in overall activity. Comparison of iNO30 and iNO45 demonstrated that both treatments maintained overall activity levels, potentially providing benefits of iNO45 over iNO30 over 2 months. Because iNO30 was only tested for 2 months, a comparative assessment between treatments at 4 months was not available.

[0151]

[0161] There was a statistically significant improvement in NT-proBNP when iNO45 in Cohort 2 was compared to the pooled placebo group over 8 weeks; however, this effect was lost when iNO45 in Cohort 2 was compared to placebo over 16 weeks. The effect at 16 weeks may be due to the smaller sample size and fewer subjects with abnormal NT-proBNP values ​​at baseline. Oxygen saturation was maintained with both iNO30 and iNO45, consistent with the overall INOpulse mechanism of action, which is to provide pulmonary vasodilation without causing V / Q imbalance.

[0152]

[0162] In PROs, subjects in Cohort 2 maintained their SGRQ scores overall, while subjects receiving placebo worsened. In comparison, subjects in Cohort 1 showed minimal benefit compared to placebo on SGRQ measures.

[0153]

[0163] Pulsed iNO was well tolerated during the blinded treatment period, with iNO30 in Cohort 1 and iNO45 in Cohort 2. AEs were balanced between treatment groups, and the incidence of SAEs was low in both the treatment and placebo groups in Cohort 1. In Cohort 2, fewer subjects reported SAEs in the treatment group (10%) compared with the placebo group (21.4%). Furthermore, all SAEs occurring during the blinded treatment period in both Cohorts 1 and 2 were reported as unrelated to the drug. There were no unexpected AEs or suspected unexpected serious adverse reactions (SUSARs) reported, and the benefit / risk profile remains favorable. The consistency of benefit seen with iNO45, along with a clean safety profile, supports advancing this administration into a pivotal, confirmatory Phase 3 cohort, which will evaluate iNO45 versus placebo for a 4-month (16-week) blinded treatment period.

[0154]

[0164] While preferred embodiments of the present invention have been shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in practicing the invention.

Claims

1. 1. A device for improving activity levels in patients with pulmonary hypertension associated with interstitial lung disease, comprising: a) a breath sensing portion for detecting a breathing pattern in the patient, including a total inhalation time; b) a breath detection algorithm associated with said breathing pattern for calculating when to administer a dose of nitric oxide; c) for delivering a dose of nitric oxide to said patient in a pulsed manner over a portion of said total inhalation time; Devices containing:

2. 10. The device of claim 1, wherein the device allows the inhaled nitric oxide to be administered at a dose ranging from about 25 mcg / kg IBW / hr to about 50 mcg / kg IBW / hr.

3. 3. The device of claim 2, wherein the device allows the inhaled nitric oxide to be administered at a dose ranging from about 30 mcg / kg IBW / hr to about 45 mcg / kg IBW / hr.

4. 3. The device of claim 2, wherein the device allows the inhaled nitric oxide to be administered at a dose of about 30 mcg / kg IBW / hr.

5. 3. The device of claim 2, wherein the device allows the inhaled nitric oxide to be administered at a dose of about 45 mcg / kg IBW / hr.

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