USE OF INHALED NITRIC OXIDE (iNO) FOR IMPROVING ACTIVITY LEVEL IN PATIENT HAVING LUNG-RELATED STATE

Abstract

To provide a method for maintaining or improving an activity level in a lung-related state of a patient.SOLUTION: Nitric oxide may be delivered during certain time in sleep, for example, according to convenience of a patient. In an embodiment of the present invention, pulse administration of the nitric oxide may be performed with even or uneven intervals during certain time (for example, for 10 minutes, for 1 hour, or for 24 hours). In another embodiment, administration of nitric oxide of therapeutically effective dosage may be continuous for certain time.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001]

[0001] This application generally relates to devices and methods for administering nitric oxide, and more particularly to the pulsed delivery of nitric oxide to patients in need of therapeutic treatment, and also generally relates to methods of administering nitric oxide, and more particularly to the pulsed delivery of nitric oxide to patients having a lung-related condition for maintaining and / or increasing activity levels.

Background Art

[0002]

[0002] Nitric oxide (NO) is a gas that, when inhaled, causes the blood vessels in the lungs to dilate, improves blood oxygenation, and reduces pulmonary hypertension. For this reason, nitric oxide is provided as a therapeutic gas during the inspiratory respiratory phase for patients suffering from dyspnea (shortness of breath) due to a medical condition such as pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis and emphysema (CPFE), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), emphysema, interstitial lung disease (ILD), chronic thromboembolic pulmonary hypertension (CTEPH), chronic mountain sickness, or other lung diseases.

[0003]

[0003] When administered under appropriate conditions, NO can be therapeutically effective, but it can also be toxic if not administered correctly. NO reacts with oxygen to form nitrogen dioxide (NO2), and if oxygen or air is present in the NO delivery tube, there is a possibility of forming NO2. NO2 is a toxic gas that can cause many side effects, and the Occupational Safety & Health Administration (OSHA) has set its permissible exposure limit in general industry at only 5 ppm. For this reason, it is desirable to limit exposure to NO2 during NO therapy.

Summary of the Invention

Means for Solving the Problems

Means for Solving the Problems

[0004]

[0004] In certain embodiments of the present invention, a method of administering a certain dosage of nitric oxide is described. In certain embodiments of the present invention, at least a single pulse dosage is administered to a patient to treat or alleviate the symptoms of a lung disease and is therapeutically effective. In certain embodiments of the present invention, the total amount of two or more pulse dosages is therapeutically effective to treat or alleviate the symptoms of a lung disease.

[0005]

[0005] In certain embodiments of the present invention, nitric oxide is delivered periodically for at least 5 minutes per day up to 24 hours per day. In certain embodiments of the present invention, nitric oxide may be delivered at a time convenient for the patient, e.g., for a certain period of time during sleep. In certain embodiments of the present invention, the pulsed administration of nitric oxide may be spaced evenly or unevenly over a period of time (e.g., 10 minutes, 1 hour, or 24 hours). In another embodiment, the administration of a therapeutically effective dosage of nitric oxide may be continuous for a period of time.

[0006]

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

[0007]

[0007] In certain embodiments of the present invention, the nitric oxide dosage is a therapeutic dosage of nitric oxide for the patient ​is delivered to the patient over a time sufficient to effect delivery to the recipient. In certain embodiments of the invention, the device calculates a total time sufficient to deliver a therapeutic dose of nitric oxide to the patient. In certain embodiments of the invention, the total time required to deliver a therapeutic dose of nitric oxide to the patient is at least partially dependent on the respiratory pattern of said patient.

[0008]

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

[0009]

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

[0010]

[0010] In certain embodiments of the invention, the respiratory sensitivity control of the device is adjustable. In certain embodiments of the invention, the respiratory sensitivity control is fixed. In certain embodiments of the invention, the respiratory sensitivity control is adjustable over a range from a minimum sensitivity to a maximum sensitivity, whereby the maximum sensitivity setting is more sensitive to detecting respiration than the minimum sensitivity setting.

[0011]

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

[0012]

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

[0013]

[0013] In certain embodiments of the present invention, the pulmonary disease and / or pulmonary-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, combined pulmonary fibrosis and emphysema (CPFE), chronic thromboembolic pulmonary hypertension (CTEPH), chronic mountain sickness, or other pulmonary diseases. In certain embodiments of the present invention, the pulmonary disease is pulmonary hypertension of groups I-V It is pulmonary hypertension associated with other lung diseases such as pulmonary hypertension (PH). In another embodiment, the lung disease and / or lung-related condition is pulmonary hypertension associated with interstitial lung disease. In certain embodiments of the present invention, the lung disease and / or lung-related condition is pulmonary hypertension associated with pulmonary fibrosis. In certain embodiments of the present invention, the lung disease and / or lung-related condition is pulmonary hypertension associated with idiopathic pulmonary fibrosis. In certain embodiments of the present invention, patients suffering from ILD are at high risk of developing pulmonary hypertension. In another embodiment of the present invention, patients suffering from ILD are at low risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from ILD are at moderate risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from IPF are at high risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from IPF are at moderate risk of developing pulmonary hypertension. In another embodiment of the present invention, patients suffering from IPF are at low risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from ILD are at high risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from PF are at high risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from PF are at moderate risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from PF are at low risk of developing pulmonary hypertension.

[0014]

[0014] In certain embodiments of the present invention, a programmable device for delivering a certain dose of nitric oxide is described. In certain embodiments of the present invention, the device includes a nasal delivery portion, a drug cartridge containing nitric oxide, an oxygen source, a respiratory sensing portion for detecting a patient's breathing pattern, a respiratory detection algorithm for determining the 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 certain embodiments of the present invention, the respiratory sensing portion of the device includes an adjustable or fixed respiratory sensitivity setting. In certain embodiments of the present invention, the nasal delivery portion is a nasal cannula, a face mask, a nebulizer, or a nasal inhaler. In certain embodiments of the present invention, the respiratory detection algorithm uses a threshold sensitivity and a slope algorithm. In certain embodiments of the present invention, the slope algorithm counts breaths detected when the rate of pressure drop reaches a threshold level.

[0015]

[0015] In certain embodiments of the present invention, a method for maintaining or increasing an activity level in a patient having pulmonary hypertension is described. In one embodiment, the patient's pulmonary hypertension is associated with interstitial lung disease. In certain embodiments of the present invention, the method includes 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 / hour. In another embodiment, iNO is administered at 45 mcg / kg IBW / hour. In another embodiment, iNO is administered at 75 mcg / kg IBW / hour. In certain embodiments of the present invention, iNO is administered in combination with oxygen supplementation.

[0016]

[0016] In another embodiment, the method includes first detecting a respiratory pattern in the patient including a total inspiration time; associating the respiratory pattern with an algorithm for calculating a 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 inspiration time, thereby administering iNO.

[0017]

[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 includes administering inhaled nitric oxide to a patient. In one embodiment, the method includes administering inhaled nitric oxide to a patient.

[0018]

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

[0019]

[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 an activity level in a patient having pulmonary hypertension associated with a lung condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis, the method including administering inhaled nitric oxide to the patient. In one embodiment, the inhaled nitric oxide is administered by detecting a respiratory pattern in the patient including a total inspiration time; associating the respiratory pattern with an algorithm for calculating a 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 inspiration time.

[0020]

[0021] In one embodiment of the present invention, there is described a method for treating pulmonary hypertension associated with a lung condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis, the method comprising administering inhaled nitric oxide to a patient. In certain embodiments, the inhaled nitric oxide is administered by detecting a respiratory pattern in the patient including a total inspiratory time; associating the respiratory pattern with an algorithm for calculating a 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 inspiratory time.

[0021]

[0022] In one embodiment of the present invention, there is described a method for preventing a decrease in activity level in a patient having pulmonary hypertension associated with a lung condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis, the method comprising administering inhaled nitric oxide to the patient. In certain embodiments, the inhaled nitric oxide is administered by detecting a respiratory pattern in the patient including a total inspiratory time; associating the respiratory pattern with an algorithm for calculating a 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 inspiratory time.

[0022]

[0023] In one embodiment of the present invention, there is described a method for maintaining an activity level in a patient having pulmonary hypertension associated with a lung condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis, the method comprising administering inhaled nitric oxide to the patient. In certain embodiments, the inhaled nitric oxide is administered by detecting a respiratory pattern in the patient including a total inspiratory time; associating the respiratory pattern with an algorithm for calculating a 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 inspiratory time.

[0023]

[0024] In one embodiment of the present invention, there is described a method for improving the activity level in a patient having a lung condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis, the method comprising administering inhaled nitric oxide to the patient. In one embodiment, the inhaled nitric oxide comprises detecting a respiratory pattern in the patient including total inspiratory time; associating the respiratory pattern with an algorithm for calculating the 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 inspiratory time. is administered by:

[0024]

[0025] In one embodiment of the present invention, there is described a method for improving the activity level in a patient having a lung condition selected from the group consisting of interstitial lung disease, idiopathic pulmonary fibrosis, and pulmonary fibrosis, the method comprising detecting a respiratory pattern in the patient including total inspiratory time; associating the respiratory pattern with an algorithm for calculating the 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 inspiratory time, the method comprising administering inhaled nitric oxide to the patient.

[0025]

[0026] In certain embodiments of the present invention, a method for preventing a decrease in activity level in a patient having a pulmonary condition, the method comprising administering inhaled nitric oxide to the patient, is described. In another embodiment, a method for maintaining an activity level in a patient having a pulmonary condition, the method comprising administering inhaled nitric oxide to the patient, is described. In yet another embodiment, a method for improving an activity level in a patient having 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, is described. 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 certain embodiments of the present invention, inhaled nitric oxide is administered in the range of about 25 mcg / kg IBW / hour to about 50 mcg / kg IBW / hour. In another embodiment, inhaled nitric oxide is administered at a dose in the range of about 30 mcg / kg IBW / hour to about 45 mcg / kg IBW / hour. In another embodiment, inhaled nitric oxide is administered at a dose of about 30 mcg / kg IBW / hour. In another embodiment, inhaled nitric oxide is administered at a dose of about 45 mcg / kg IBW / hour.

[0027]

[0028] Various embodiments have been described and will be explained in more detail below. It will be understood that the described embodiments may be combined not only as described below but also in other suitable combinations according to the scope of the present invention.

[0028]

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

[0029]

[0030] In addition to the means for solving the above problems, the mode for carrying out the following invention will be better understood by being read together with the accompanying drawings.

[0031] To enable a more detailed understanding of the features of the present invention enumerated above, a more detailed description of the present invention, briefly summarized above, may be obtained by referring to the embodiments illustrated in some of the accompanying drawings. However, it should be noted that the accompanying drawings illustrate only typical embodiments of the present invention, and thus, it is not to be construed that the scope of the present invention is limited, since the present invention may include other equally effective embodiments.

Brief Description of the Drawings

[0030]

Figure 1

[0032] It is a graph showing the measurement of a single breath.

Figure 2

[0033] It is a graph showing the measurement of a pulse of nitric oxide delivered to a patient in accordance with the present invention.

Figure 3

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

Figure 4

[0035] A figure representing the combination of the results described in FIG. 3.

Figure 5A

[0036] FIGS. 5A and 5B are figures representing the algorithms for respiration detection and nitric oxide delivery. FIG. 5A shows a threshold algorithm. FIG. 5B shows a slope algorithm.

Figure 5B

[0036] FIGS. 5A and 5B are figures representing the algorithms for respiration detection and nitric oxide delivery. FIG. 5A shows a threshold algorithm. FIG. 5B shows a slope algorithm.

Figure 6A

[0037] Figures 6A - 6C show the percent change over time in activity parameters in patients receiving iNO treatment and placebo 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 overall activity.

Figure 6B

[0037] Figures 6A - 6C show the percent change over time in activity parameters in patients receiving iNO treatment and placebo 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 overall activity.

Figure 6C

[0037] Figures 6A - 6C show the percent change over time in activity parameters in patients receiving iNO treatment and placebo 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 overall activity.

Figure 7A

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

Figure 7B

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

Figure 7C

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

Figure 7D

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

Figure 8A

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

Figure 8B

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

Figure 9A

[0040] Figures 9A and 9B show cohort 2 (iNO45) comparative data on the normalized change in MVPA from baseline over 1 - 4 months (Figure 9A) and the change in overall activity from baseline over 1 - 4 months (Figure 9B). In Figure 9A, the baseline MVPA was 74 minutes / day, and a 14 - minute / day improvement was seen at 4 months. In Figure 9B, the baseline overall activity was 1476 counts per minute, and a 100 - counts - per - minute improvement was seen at 4 months.

Figure 9B

[0040] ]Figures 9A and 9B show the cohort 2 (iNO45) comparison data for the changes in normalized MVPA from baseline over 1 - 4 months (Figure 9A) and the changes in overall activity from baseline over 1 - 4 months (Figure 9B). In Figure 9A, the baseline MVPA was 74 minutes per day, and an improvement of 14 minutes per day was seen at the 4 - month mark. In Figure 9B, the baseline overall activity was 1476 counts per minute, and an improvement of 100 counts per minute was seen at the 4 - month mark.

Figure 10AB

[0041] Figures 10A - 10C show the cohort 2 (iNO45) comparison data for the 4 - month St. George’s Respiratory Questionnaire (SGRQ). Since the SGRQ is a reverse - scored item, a higher total score indicates a worse disease state. Figure 10A shows a 3 - point improvement in the SGRQ total, which measures health status and quality of life here. Figure 10B shows a 5 - point improvement in SGRQ activity, which measures the patient's impairment in physical activity here. Figure 10C shows a 6 - point improvement in SGRQ impact, which measures the psychological and social impact of the disease / condition here.

Figure 10C

[0041] ]Figures 10A - 10C show the cohort 2 (iNO45) comparison data for the 4 - month St. George’s Respiratory Questionnaire (SGRQ). Since the SGRQ is a reverse - scored item, a higher total score indicates a worse disease state. Figure 10A shows a 3 - point improvement in the SGRQ total, which measures health status and quality of life here. Figure 10B shows a 5 - point improvement in SGRQ activity, which measures the patient's impairment in physical activity here. Figure 10C shows a 6 - point improvement in SGRQ impact, which measures the psychological and social impact of the disease / condition here.

Figure 11

[0042] Comparative data for cohort 2 (iNO45) of the University of California, San Diego (UCSD) Shortness of Breath Questionnaire (SOBQ), showing benefits in dyspnea. Again, an increase in score indicates disease worsening. An improvement of 5 points is shown, where shortness of breath is measured while the patient is engaged in daily physical activity.

Figure 12A

[0043] Shows the log-transformed estimated changes in MVPA (Figure 12A) and overall activity (Figure 12B) at 2 months (iNO30 and iNO45, cohorts 1 and 2) and 4 months (iNO45, cohort 2).

Figure 12B

[0043] Shows the log-transformed estimated changes in MVPA (Figure 12A) and overall activity (Figure 12B) at 2 months (iNO30 and iNO45, cohorts 1 and 2) and 4 months (iNO45, cohort 2).

Figure 13

[0044] Shows the log-transformed MVPA predictive marginal effects on a monthly (Figure 13A) and weekly (Figure 13B) basis for cohort 2.

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 some exemplary embodiments, it should be understood that the present invention is not limited to the details of the configurations or process steps set forth in the following description. The present invention is capable of other embodiments and of being practiced or carried out in various ways.

[0033]

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

[0034]

[0048] The present invention is described herein with reference to particular embodiments, but it should be understood that these embodiments are merely illustrative of the principles and applications of the invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the methods and apparatuses of the invention without departing from the spirit and scope of the invention. Accordingly, the invention is intended to cover modifications and variations that are within the scope of the appended claims and their equivalents. Definitions

[0049] The terms "effective amount" or "therapeutically effective amount" refer to an amount of a compound or combination of compounds described herein that, without limitation, is sufficient to produce an effect for the intended use, including the treatment of a 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 gender), 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 the dosage that would cause a particular response (e.g., a decrease in platelet adhesion ability and / or a decrease in cell migration) in the target cells. Specific dosages will vary depending on the particular compound selected, the dosing regimen to which it conforms, 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 carried.

[0035]

[0050] As used herein, the term "therapeutic effect" encompasses therapeutic and / or prophylactic benefits. Prophylactic effects include delaying or precluding the onset of a disease or condition, delaying or precluding the development of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0036]

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

[0037]

[0052] For purposes of describing embodiments of the present invention, when ranges such as, for example, dosage ranges, amounts of components of a formulation, etc. are used herein, all combinations and subcombinations of the ranges as well as specific embodiments in that case are intended to be included. The use of the term "about" in reference to a number or numerical range means that the recited number or numerical range is an approximation within the variations of an experiment (i.e., within statistical experimental error), and thus, this number or numerical range may vary. This variation is typically 0% to 15%, preferably 0% to 10%, more preferably 0% to 5% of the recited number or numerical range. The term "comprising" (and related terms such as "comprise", "comprises", "having", "including") includes embodiments such as any composition of matter, any method, or any process embodiment that consists of or consists essentially of the features described.

[0038]

[0053] To avoid misunderstanding, it is intended herein that any specific features (e.g., integers, properties, values, uses, diseases, formulas, compounds, or groups) described in connection with a particular aspect, embodiment, or example of the present invention are applicable to any other aspect, embodiment, or example described herein, unless inconsistent therewith. Thus, such features may be used if appropriate in connection with any definition, claim, or embodiment defined herein. All of the features disclosed in this specification (including any appended claims, abstract, and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of the features and / or steps are mutually incompatible. The invention is not limited to any details of any disclosed embodiment. The invention extends to any novel one or any novel combination of any of the features disclosed in this specification (including any appended claims, abstract, and drawings), or to any novel one or any novel combination of any of the steps of any method or process so disclosed.

[0039]

[0054] Effective administration of NO is based on many different variables, including the amount of drug and the timing of delivery. A number of patents related to NO delivery have been granted, including U.S. Pat. Nos. 7,523,752, 8,757,148, 8,770,199, and 8,803,717, as well as Design Pat. No. D701,963 for the design of an NO delivery device, all of which are incorporated herein by reference. Additionally, there are pending applications related to NO delivery, including 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 for delivering NO in a precisely controlled manner to maximize the benefits of therapeutic dosing and minimize potentially harmful side effects.

[0040]

[0055] With respect to the present invention, in certain embodiments, a dose of a gas (e.g., NO) is administered to a patient in pulses during inhalation by the patient. Surprisingly, the delivery of nitric oxide can be performed precisely and accurately within the first two-thirds of the total respiratory inhalation time, and patients have been found to benefit from such delivery. Such delivery, which minimizes the risk of pharmaceutical loss and harmful side effects, enhances the effectiveness of pulsed administration and thus results in a good reduction in the overall amount of NO that needs to be administered to the patient in order to be effective. Such delivery is useful for the treatment of various diseases, such as, 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, for example, as an antibacterial in the treatment of pneumonia.

[0041]

[0056] Such precision is further advantageous in that it exposes only the portions of the lung regions with insufficient ventilation to NO. Hypoxia and hemoglobin impairment may also be reduced by using such pulsed delivery, but the exposure to NO2 is also more limited. The device of the present invention

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

[0042]

[0058] In certain embodiments, the drug 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 enables the simultaneous administration of one or more other gases (e.g., oxygen) to the patient.

[0043]

[0060] In certain embodiments, and as detailed elsewhere in this specification, the device is an algorithm that uses one or both of a threshold sensitivity and a slope algorithm, the slope algorithm including an algorithm that detects breathing when the rate of pressure drop reaches a predetermined threshold.

[0044]

[0061] In certain embodiments of the present invention, mechanically, the pulsed dose of gas, when not exhausted, can reduce the Venturi effect that typically causes problems in other gas sensors. For example, when not using the pulsed dose of the present invention, when administering O2 simultaneously with another gas such as NO, the O2 backpressure sensor may disable the delivery of O2. Respiratory Patterns, Detection, and Triggers

[0062] Respiratory patterns vary based on the individual, time of day, level of activity, and other variable factors. For this reason, it is difficult to predetermine an individual's respiratory pattern. Therefore, a delivery system that delivers a treatment to a patient based on the respiratory pattern should be able to address the range of possible respiratory patterns in order to be effective.

[0045]

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

[0064] In certain embodiments of the present invention, the respiratory pattern, as used herein, includes a measured value of the total inspiration time determined for a single breath. However, depending on the context, "total inspiration time" may refer to the sum of all inspiration times in all breaths detected during a therapy. The total inspiration time may be observed or calculated. In another embodiment, the total inspiration time is a time verified based on a simulated respiratory pattern.

[0046]

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

[0047]

[0066] In certain embodiments of the present invention, the breath level trigger algorithm is used for respiratory 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 certain embodiments of the present invention, the breath slope trigger detects a breath when the slope of the pressure waveform indicates inspiration. The breath slope trigger may be more accurate than a threshold trigger, particularly when used to detect particularly short and shallow breaths.

[0049]

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

[0050]

[0069] In certain embodiments of the present invention, the respiratory sensitivity control for detecting respiratory level and / or respiratory slope is fixed. In certain embodiments of the present invention, the respiratory sensitivity control for detecting either respiratory level or respiratory slope is adjustable or programmable. In certain embodiments of the present invention, the respiratory sensitivity control for detecting respiratory level and / or respiratory slope is adjustable in a range from a minimum sensitivity to a maximum sensitivity, where the maximum sensitivity setting is more sensitive to detect respiration 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 different relative levels. In one embodiment where at least two triggers are used, one trigger is set at maximum sensitivity and the other trigger is set lower than the maximum sensitivity. In one embodiment where at least two triggers are used and one trigger is a respiratory level trigger, this respiratory level trigger is set at maximum sensitivity.

[0052]

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

[0053]

[0072] Embodiments of the present invention and in particular embodiments incorporating the respiratory slope trigger alone or in combination with another trigger are capable of maximizing the correct detection of inhalation events, thereby minimizing waste due to misidentification or false positives in timing while maximizing the effectiveness and efficiency of the therapy.

[0054]

[0073] In certain embodiments, breaths are detected that exceed 50% of the patient's total number of breaths over a time frame for gas delivery to the patient. In certain embodiments, breaths are detected that exceed 75% of the patient's total number of breaths. In certain embodiments, breaths are detected that exceed 90% of the patient's total number of breaths. In certain embodiments, breaths are detected that exceed 95% of the patient's total number of breaths. In certain embodiments, breaths are detected that exceed 98% of the patient's total number of breaths. In certain embodiments, breaths are detected that exceed 99% of the patient's total number of breaths. In certain embodiments, 75% - 100% of the patient's total number of breaths 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 of NO per liter, about 6 to about 10 mg of NO per liter, about 3 mg of NO per liter, about 6 mg of NO per liter, or about 18 mg of NO per liter. NO may be administered alone or in combination with alternative gas therapies. In certain embodiments, oxygen (e.g., concentrated oxygen) may be administered to the patient in combination with NO.

[0055]

[0075] In certain embodiments of the present invention, a certain volume of nitric oxide is about 0.3 administered in an amount of 50 mL to about 7.5 mL per breath (e.g., in a single pulse). In some embodiments, during a single session, the volume of nitric oxide in each pulse dose may be the same. In some embodiments, during a single time frame for delivering gas to the patient, the volumes of nitric oxide in several pulse doses may be different. In some embodiments, during a single time frame for delivering gas to the patient, the volume of nitric oxide in each pulse dose may be adjusted while monitoring the breathing pattern. In certain embodiments of the present invention, for the purpose of treating or alleviating the symptoms of lung disease, the amount of nitric oxide (ng) delivered to the patient in pulse units ( "pulse dose") is calculated as follows and rounded to the nearest nanogram value: Dosage mcg / kg-IBW / hour × ideal body weight kg (kg-IBW) × ((1 hour / 60 minutes) / (1 minute / respiratory rate (bpm)) × (1,000 ng / μg).

[0056]

[0076] As an example, for patient A at a dosage of 100 mcg / kg IBW / hour, the ideal body weight is 75 kg and the respiratory rate is 20 breaths per minute (or 1200 breaths per hour): 100 mcg / kg-IBW / hour × 75 kg × (1 hour / 1200 breaths) × (1,000 ng / μg) = 6250 ng per pulse

[0077] In certain embodiments, the variable 60 / respiratory rate (min) is sometimes referred to as the administration event time. In another embodiment of the present 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 certain embodiments of the present invention, a single pulse dosage provides a therapeutic effect (e.g., a therapeutically effective amount of NO) to the patient. In another embodiment of the present invention, the total amount of two or more pulse dosages provides a therapeutic effect (e.g., a therapeutically effective amount of NO) to the patient.

[0058]

[0079] In certain embodiments of the present 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 the patient per hour.

[0059]

[0080] In certain embodiments of the present invention, a nitric oxide therapy session occurs 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 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 24 hours per day.

[0060]

[0081] In certain embodiments of the present invention, nitric oxide treatment is carried out during the time frame of the shortest treatment course. In certain embodiments of the present invention, the shortest 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 certain embodiments of the present invention, the shortest 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 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 24 hours. In certain embodiments of the present invention, the shortest treatment course 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 certain embodiments of the present invention, a nitric oxide therapy session is carried out once or multiple times per day. In certain embodiments of the present invention, a nitric oxide therapy session may be carried out 1, 2, 3, 4, 5, 6, or more than 6 times per day. In certain embodiments of the present invention, the therapy session may be carried out once a month, once every two weeks, once a week, once every other day, once a day, or multiple times a day. Timing of NO Pulses

[0083] In certain embodiments of the present invention, the breathing pattern correlates with an algorithm for calculating the timing of administering a certain dose of nitric oxide.

[0062]

[0084] The accuracy of detecting inhalation / inspiration events is further enhanced to its maximum effectiveness by the timing of the gas (e.g., NO) pulse by administering the gas over a specific time frame within the total inspiration time of a single detected breath.

[0063]

[0085] In certain embodiments of the present invention, at least 50 percent (50%) of the pulsed dose of the gas is delivered over the first one-third of the total inspiration time of each breath. In certain embodiments of the present invention, at least 60 percent (60%) of the pulsed dose of the gas is delivered over the first one-third of the total inspiration time. In certain embodiments of the present invention, at least 75 percent (75%) of the pulsed dose of the gas is delivered over the first one-third of the total inspiration time of each breath. In certain embodiments of the present invention, at least 85 percent (85%) of the pulsed dose of the gas is delivered over the first one-third of the total inspiration time of each breath. In certain embodiments of the present invention, at least 90 percent (90%) of the pulsed dose of the gas is delivered over the first one-third of the total inspiration time. In certain embodiments of the present invention, at least 92 percent (92%) of the pulsed dose of the gas is delivered over the first one-third of the total inspiration time. In certain embodiments of the present invention, at least 95 percent (95%) of the pulsed dose of the gas is delivered over the first one-third of the total inspiration time. In certain embodiments of the present invention, at least 99 percent (99%) of the pulsed dose of the gas is delivered over the first one-third of the total inspiration time. In certain embodiments of the present invention, 90% to 100% of the pulsed dose of the gas is delivered over the first one-third of the total inspiration time.

[0064]

[0086] In certain embodiments of the present invention, at least 70 percent (70%) of the pulsed dose is delivered to the patient over the first one-half of the total inspiration time. In yet another embodiment, at least 75 percent (75%) of the pulsed dose is delivered to the patient over the first one-half of the total inspiration time. In certain embodiments of the present invention, at least 80 percent (80%) of the pulsed dose is delivered to the patient over the first one-half of the total inspiration time. In certain embodiments of the present invention, at least 90 percent (90%) of the pulsed dose is delivered to the patient over the first one-half of the total inspiration time. In certain embodiments of the present invention, at least 95 percent (95%) of the pulsed dose is delivered to the patient over the first one-half of the total inspiration time. In certain embodiments of the present invention, 95% to 100% of the pulsed dose of gas is delivered over the first one-half of the total inspiration time.

[0065]

[0087] In certain embodiments of the present invention, at least 90 percent (90%) of the pulsed dose is delivered over the first two-thirds of the total inspiration time. In certain embodiments of the present invention, at least 95 percent (95%) of the pulsed dose is delivered over the first two-thirds of the total inspiration time. In certain embodiments of the present invention, 95% to 100% of the pulsed dose is delivered over the first two-thirds of the total inspiration time.

[0066]

[0088] When aggregated, multiple administrations of the pulsed dose over a therapy session / time frame may also fall within the above ranges. For example, when aggregated, more than 95% of the total pulsed dose administered during a therapy session is administered over the first two-thirds of the total inspiration time of all detected breaths. In a higher precision embodiment, when aggregated, more than 95% of the total pulsed dose administered during a therapy session is administered over the first one-third of the total inspiration time of all detected breaths.

[0067]

[0089] Based on the high accuracy of the detection method of the present invention, it is possible to administer a pulse dose during any specific time window of inspiration. For example, it is possible to define and administer the pulse dose during the first one-third, middle one-third, or last one-third of the patient's inspiration. Alternatively, it is possible to define the first one-half or the second one-half of inspiration as the target for administering the pulse dose. Further, the target for administration may be changed. In one embodiment, it is possible to target the first one-third of the inspiration time for one or a series of inspirations, where the second one-third or the second one-half may be the target for a subsequent one or a series of inspirations during the same or a different therapy session. Alternatively, after the first one-fourth of the inspiration time has elapsed, pulse administration is started and continues during the middle one-half (the next two one-fourths), such that the pulse administration is defined to end at the start of the last one-fourth of the 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 dosing during inhalation reduces exposure of poorly ventilated lung regions and alveoli to the pulsed dosed gas, e.g., NO. In one embodiment, less than 5% of (a) the poorly ventilated lung regions or (b) the alveoli are exposed to NO. In one embodiment, less than 10% of (a) the poorly ventilated lung regions or (b) the alveoli are exposed to NO. In one embodiment, less than 15% of (a) the poorly ventilated lung regions or (b) the alveoli are exposed to NO. In one embodiment, less than 20% of (a) the poorly ventilated lung regions or (b) the alveoli are exposed to NO. In one embodiment, less than 25% of (a) the poorly ventilated lung regions or (b) the alveoli are exposed to NO. In one embodiment, less than 30% of (a) the poorly ventilated lung regions or (b) the alveoli are exposed to NO. In one embodiment, less than 50% of (a) the poorly ventilated lung regions or (b) the alveoli are exposed to NO. In one embodiment, less than 60% of (a) the poorly ventilated lung regions or (b) the alveoli are exposed to NO. In one embodiment, less than 70% of (a) the poorly ventilated lung regions or (b) the alveoli are exposed to NO. In one embodiment, less than 80% of (a) the poorly ventilated lung regions or (b) the alveoli are exposed to NO. In one embodiment, less than 90% of (a) the poorly ventilated lung regions or (b) the alveoli are exposed to NO. Treatment method

[0091] In certain embodiments of the present invention, a method for increasing the activity level of a patient having a lung-related condition is described. The method includes administration of iNO, optionally supplemented with oxygen. In certain embodiments of the present invention, iNO is administered according to the pulsed regimen discussed herein. In certain embodiments 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 about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks, for a period of at least 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours per day. In one embodiment, the patient is administered iNO for 8 weeks. In another embodiment, the patient is administered iNO for 16 weeks. In certain embodiments 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 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 24 hours per day.

[0069]

[0092] In certain embodiments of the present invention, nitric oxide therapy is administered during the time frame of the shortest treatment course. In certain embodiments of the present invention, the shortest 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 certain embodiments of the present invention, the shortest 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 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 24 hours. In certain embodiments of the present invention, the shortest treatment course 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 any rate from 10 mcg / kg ideal body weight (IBW) / hour to 200 mcg / kg IBW / hour or more. In one embodiment, iNO is administered at a rate of about 20 mcg / kg IBW / hour to about 150 mcg / kg IBW / hour. In one embodiment, iNO is administered at a rate of about 25 mcg / kg IBW / hour to about 100 mcg / kg IBW / hour. In one embodiment, iNO is administered at a rate of about 30 mcg / kg IBW / hour to about 75 mcg / kg IBW / hour. In one embodiment, iNO is administered at a rate of about 25 mcg / kg IBW / hour to about 50 mcg / kg IBW / hour. In one embodiment, iNO is administered at a rate of about 30 mcg / kg IBW / hour to about 45 mcg / kg IBW / hour. In one embodiment, iNO is administered at 25 mcg / kg IBW / hour. In one embodiment, iNO is administered at 30 mcg / kg IBW / hour. In one embodiment, iNO is administered at 35 mcg / kg IBW / hour. In one embodiment, iNO is administered at 40 mcg / kg IBW / hour. In one embodiment, iNO is administered at 45 mcg / kg IBW / hour. In one embodiment, iNO is administered at 50 mcg / kg IBW / hour. In one embodiment, iNO is administered at 55 mcg / kg IBW / hour. In one embodiment, iNO is administered at 60 mcg / kg IBW / hour. In one embodiment, iNO is administered at 65 mcg / kg IBW / hour. In one embodiment, iNO is administered at 70 mcg / kg IBW / hour. In one embodiment, iNO is administered at 75 mcg / kg IBW / hour. In one embodiment, iNO is administered at 80 mcg / kg IBW / hour. In one embodiment, iNO is administered at 85 mcg / kg IBW / hour. In one embodiment, iNO is administered at 90 mcg / kg IBW / hour. In one embodiment, iNO is administered at 95 mcg / kg IBW / hour. In one embodiment, iNO is administered at 100 mcg / kg IBW / hour. In one embodiment, iNO is administered at 105 mcg / kg IBW / hour. In one embodiment, iNO is administered at 110 mcg / kg IBW / hour.In one embodiment, iNO is administered at 115 mcg / kg IBW / hour. In one embodiment, iNO is administered at 120 mcg / kg IBW / hour. In one embodiment, iNO is administered at 125 mcg / kg IBW / hour. In one embodiment, iNO is administered at 130 mcg / kg IBW / hour. In one embodiment, iNO is administered at 135 mcg / kg IBW / hour. In one embodiment, iNO is administered at 140 mcg / kg IBW / hour. In one embodiment, iNO is administered at 145 mcg / kg IBW / hour. In one embodiment, iNO is administered at 150 mcg / kg IBW / hour. In one embodiment, iNO is administered at 155 mcg. / kg IBW / hour. In one embodiment, iNO is 160 mcg / kg IBW / hour. In one embodiment, iNO is administered at 165 mcg / kg IBW / hour. In one embodiment, iNO is administered at 170 mcg / kg IBW / hour. In one embodiment, iNO is administered at 175 mcg / kg IBW / hour. In one embodiment, iNO is administered at 180 mcg / kg IBW / hour. In one embodiment, iNO is administered at 185 mcg / kg IBW / hour. In one embodiment, iNO is administered at 190 mcg / kg IBW / hour. In one embodiment, iNO is administered at 190 mcg / kg IBW / hour. In one embodiment, iNO is administered at 200 mcg / kg IBW / hour.

[0071]

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

[0072]

[0095] In certain embodiments of the present invention, lung-related conditions useful in the present invention are 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 certain embodiments 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 certain embodiments of the present invention, the lung disease and / or lung-related condition is pulmonary hypertension associated with pulmonary fibrosis. In certain embodiments of the present invention, the lung disease and / or lung-related condition is pulmonary hypertension associated with idiopathic pulmonary fibrosis. In certain embodiments of the present invention, patients suffering from ILD are at high risk of developing pulmonary hypertension. In another embodiment of the present invention, patients suffering from ILD are at low risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from ILD are at moderate risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from IPF are at high risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from IPF are at moderate risk of developing pulmonary hypertension. In another embodiment of the present invention, patients suffering from IPF are at low risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from ILD are at high risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from PF are at high risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from PF are at moderate risk of developing pulmonary hypertension. In certain embodiments of the present invention, patients suffering from PF are at low risk of developing pulmonary hypertension.

[0073]

[0096] In particular, patients with pulmonary hypertension associated with interstitial lung disease showed a statistically significant improvement in activity level as measured by actigraphy (a wearable, medical-grade activity monitor). Actigraphy is currently used as a primary outcome measure in multiple late-stage clinical programs for pulmonary hypertension and other cardiopulmonary diseases. Patients receiving iNO showed an increase in moderate-intensity activity relative to the decrease seen in placebo-treated patients. Patients receiving iNO therapy also did not show a decrease relative to the decrease in placebo-treated patients in overall activity. Patients also experienced clinically meaningful improvements in other areas. The peptide marker of right ventricular failure, NT-ProBNP, was measured, and patients receiving iNO therapy showed only a slight increase in NT-ProBNP relative to the large increase seen in placebo-treated patients. Higher levels of NT-ProB NP indicate worsening of the condition, and these results are consistent with the activity results (i.e., more severe worsening in placebo patients). Also, patients receiving iNO showed an improvement in oxygen saturation. The SpO2 nadir improved in patients receiving iNO therapy but worsened in placebo-treated patients. Further, in certain embodiments of the invention, oxygen saturation decline improved in patients receiving iNO therapy whereas it worsened in placebo-treated patients. Measured another way, in certain embodiments of the invention, oxygen saturation decline worsened in placebo-treated patients whereas it improved in patients receiving iNO therapy. Unlike other systemic vasodilators, such as those approved for the treatment of pulmonary arterial hypertension, the targeted delivery of INOpulse to the lungs results in improved oxygen saturation during exercise.

[0074]

[0097] In certain embodiments of the present invention, other parameters useful for evaluating the effect of iNO include the time to clinical improvement and the time to clinical deterioration. In patients receiving iNO treatment, it is expected that the time taken for clinical improvement will be shortened and the time taken for clinical deterioration will be lengthened. Patient related outcome (PRO) measurements are also useful for evaluating the effect of iNO. PRO is measured in the form of a questionnaire and provides the perspective of the subject regarding overall quality of life. In certain embodiments of the present invention, these PROs include the St. George's 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. Improvement in both scores of these PROs is expected for patients receiving iNO therapy. Actigraphy

[0098] The present invention relates to a method for improving or maintaining an activity level, or preventing a decrease in an activity level, in a patient having a cardiorespiratory condition or a lung-related condition. The method includes using actigraphy to monitor and measure changes in the activity level.

[0075]

[0099] Actigraphy involves the use of a wearable activity monitor similar to a pedometer or accelerometer, or a triaxial accelerometer, Actigraph GT9X, or FITBIT® to measure activity parameters. Such activity monitors are used to evaluate activity and measure the user's activity parameters. Activity parameters measured include general activity, non-seated activity, moderate-intensity activity, moderate-to-vigorous physical activity (MVPA), steps, calories, metabolic equivalent units (MET), sleep, heart rate, oxygen saturation, calories consumed, and other types of activity parameters.

[0076]

[0100] In certain embodiments of the present invention, the activity level is continuously monitored over a period of time is viewed and measured. In certain embodiments of the invention, the activity level is monitored and measured intermittently over a period of time. In one embodiment, the activity level is monitored and measured for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, or 26 weeks, for at least about 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours per day. In another embodiment, the activity level is monitored and measured for at least about 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, for at least about 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours per day. In another embodiment, the activity level is monitored only during the time the patient is awake. In one embodiment, the activity level is measured in a continuous manner over the entire waking period. In another embodiment, the patient can remove the device for a particular activity, and thus the activity level is measured in a discontinuous manner over the waking period. In another embodiment, the waking period is at least 10 hours. In another embodiment, the waking period is at least 8 hours. In another embodiment, the waking period is at least 12 hours. In another embodiment, the waking period is at least 14 hours.

[0077]

[0101] In certain embodiments of the invention, the activity level is compared to a baseline activity level is improved as compared. In certain embodiments, the baseline activity level is monitored and measured for at least one week prior to administration of the vasodilator. In another embodiment, the baseline activity level is monitored or measured for about 1 day to about 14 days, about 1 day to about 10 days, about 1 day to about 7 days, or about 1 day to about 5 days. In another embodiment, the baseline activity level is monitored or measured for about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In certain embodiments of the present invention, the baseline activity is monitored or measured for about 7 days. In certain embodiments of the present invention, the baseline activity level is monitored or measured over a period of about 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours 15 hours, 16 hours 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours per day. In certain embodiments of the present invention, the baseline activity is monitored or measured while the subject is awake. In certain embodiments of the present invention, the baseline activity is monitored or measured while the subject is asleep. In certain 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 as compared to the baseline activity level is. 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, the activity level is compared to the baseline activity level is maintained as compared. In another embodiment, the activity level does not decrease as compared to the baseline activity level. In another embodiment, the activity level decreases less over time in treated patients than in untreated or placebo patients. In one embodiment, the activity level decreases by about 5% in treated patients, while the activity level decreases by about 20% or more in placebo or untreated patients.

[0080]

[0104] In one embodiment of the present invention, the subject wears an actigraphy monitor on the non-dominant arm. The acceleration of the wrist is continuously measured by the monitor. The monitor records triaxial acceleration at 30 Hz. The algorithm converts the measured acceleration values into the number of activities per minute. Each minute is classified into an activity level based on established and validated cut-off points. The algorithm can also determine the wear time, calories, and other parameters. The daily activity data is converted into weekly activity levels so that the data can be compared. A predetermined filter is used to ensure that only compliant data is analyzed. Such a filter can include a minimum number of "wear-awake" minutes (e.g., at least 600 minutes) to ensure compliance, and can include at least 3 compliant days in a compliant week. The filter may be based on industry standards used in actigraphy analysis. based.

[0081]

[0105] The count can be converted into an activity level in a plurality of ways. For example, the average of the counts provides a direct measure of physical activity. As shown in Table 1, each minute of the day can be converted into an activity intensity to determine the amount of time spent in sedentary, light-intensity, moderate-intensity, and high-intensity activities.

[0082]

Table 1

[0083] Cardiopulmonary and pulmonary-related conditions

[0106] ​The method of the present invention is useful in patients having a cardio-pulmonary condition and / or a lung-related condition 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. In certain embodiments of the invention, the lung disease is pulmonary hypertension associated with other lung diseases such as groups 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 certain embodiments of the invention, the lung disease and / or lung-related condition is pulmonary hypertension associated with pulmonary fibrosis. In certain embodiments of the invention, the lung disease and / or lung-related condition is pulmonary hypertension associated with idiopathic pulmonary fibrosis. In certain embodiments of the invention, patients suffering from ILD are at high risk of developing pulmonary hypertension. In another embodiment of the invention, patients suffering from ILD are at low risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from ILD are at moderate risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from IPF are at high risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from IPF are at moderate risk of developing pulmonary hypertension. In another embodiment of the invention, patients suffering from IPF are at low risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from ILD are at high risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from PF are at high risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from PF are at moderate risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from PF are at low risk of developing pulmonary hypertension.

[0084]

[0107] In certain embodiments of the invention, the lung disease is pulmonary hypertension associated with other lung diseases such as groups 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 certain embodiments of the invention, the lung disease and / or lung-related condition is pulmonary hypertension associated with pulmonary fibrosis. In certain embodiments of the invention, the lung disease and / or lung-related condition is pulmonary hypertension associated with idiopathic pulmonary fibrosis. In certain embodiments of the invention, patients suffering from ILD are at high risk of developing pulmonary hypertension. In another embodiment of the invention, patients suffering from ILD are at low risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from ILD are at moderate risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from IPF are at high risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from IPF are at moderate risk of developing pulmonary hypertension. In another embodiment of the invention, patients suffering from IPF are at low risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from ILD are at high risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from PF are at high risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from PF are at moderate risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from PF are at low risk of developing pulmonary hypertension. risk. In certain embodiments of the invention, patients suffering from IPF are at high risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from IPF are at moderate risk of developing pulmonary hypertension. In another embodiment of the invention, patients suffering from IPF are at low risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from ILD are at high risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from PF are at high risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from PF are at moderate risk of developing pulmonary hypertension. In certain embodiments of the invention, patients suffering from PF are at low risk of developing pulmonary hypertension. Administration of other vasodilators and oxygen

[0108] The present invention relates to a method for improving or maintaining the activity level, or preventing a decrease in the activity level, in a patient having a cardiopulmonary condition or a lung-related condition. The method includes administering a vasodilator to the patient and then monitoring and measuring changes in the activity level using actigraphy. This method includes administering a vasodilator to the patient and then monitoring and measuring changes in the activity level using actigraphy.

[0085]

[0109] In certain embodiments of the present invention, the vasodilator is administered to the patient in accordance with instructions from the treating physician.

[0110] In certain embodiments of the present invention, the vasodilators useful in the present invention include, but are not limited to, systemic vasodilators and local vasodilators. In one embodiment, the systemic vasodilators include, but are not limited to, nitrates. In another embodiment, the local 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 along with the vasodilator according to the present invention. In certain embodiments of the present invention, the oxygen is administered at up to 20 L / min. In certain embodiments of the present invention, the oxygen is administered at 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 certain embodiments of the present invention, the 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 for 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. In another embodiment, the patient is administered oxygen for at least 12 hours per day.

EXAMPLE

[0087]

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

[0088]

[0113] Example 1 Precise measurement of respiration sensitivity for appropriate trigger / arming thresholds

[0114] A device that uses a threshold algorithm to detect breathing is shown in this example. Used in embodiment 1). The threshold algorithm uses pressure to detect breaths, meaning that a pressure drop below a certain threshold must be observed in an inhalation in order for a breath to be detected and counted. The pressure threshold can be modified as a result of changing the detection sensitivity of the device of embodiment 1. Several breath sensitivity settings were tested in this example. 1 is the least sensitive. Settings from 1 to 10 were tested, with 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 primed 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. Movement resulted in an increase in the trigger threshold (measured in cm H2O) 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 H2O) 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 highest respiratory sensitivity setting allows for more accurate detection of respiration, thereby resulting in a more accurate delivery of nitric oxide pulses earlier in the inspiratory portion of respiration, i.e., within a shorter time window. Based on these data, additional tests were conducted at sensitivity settings 8 and 10.

[0090]

Table 2

[0091]

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

[0092]

[0117] Example 2 Testing of the device against various respiratory patterns

[0118] As described above, accurate and timely delivery of nitric oxide is important for the present invention. To confirm that the device delivers precise dosages of gas within precise time windows, 10 different respiratory patterns were tested using an artificial lung and a nose model. The 10 different simulated respiratory patterns were analyzed and showed variations in respiratory rate (8 - 36 bpm), tidal volume (316 - 912 mL), and inspiratory:expiratory (I / E) ratio (1:1 - 1:4) across the respiratory patterns. These variable respiratory patterns are those expected from subjects aged 16 and above and are summarized in Table 2. Actual conditions were mimicked as closely as possible.

[0093]

Table 3

[0094]

[0119] Two device embodiments were tested - Embodiment 1 was tested at sensitivity levels 8 and 10, and the other device embodiment (Embodiment 2, including the tilt algorithm) was tested at sensitivity level 10. This investigation consisted of two parts. In Part 1, using 10 different simulated breathing patterns, the delay time between the start of inhalation and the start of nitric oxide delivery was measured. This delay time was measured using two data points - the time between the start of inhalation (Figure 1, point A) and the breathing detection at which the delivery valve opens simultaneously (Figure 1, point B). In Part 2, the duration and volume of the delivered pulses corresponding to the same breathing patterns in Table 2 were measured. The duration of the gas pulse was measured from the simultaneous opening of the delivery valve (Figure 2, point A), corresponding to the start of breathing detection and gas delivery, to the completion of gas delivery (Figure 2, point B). The volume of the delivered pulse was measured by integrating the gas flow rate over the duration of the pulse. Further, the data from Part 1 where the delay time was measured and the data from Part 2 where the pulse duration was measured were 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 inhalation and the start of NO delivery. This part of the test was carried out at a dose of 75 mcg / kg-IBW / hour using a drug concentration of 6 mg / L (4880 ppm) input. This test was carried out using only nitrogen. The main output of Part 1 is the duration between the start of inhalation and the valve opening / breathing detection indicator. Point A in Figure 1 is the point at which the air flow rate in the lungs rises just above the resting line. The valve opening time is shown as point B in Figure 1 and is displayed as a sharp voltage drop in the detector. The time interval between point A and point B is the valve delay time, i.e., the trigger delay, which is calculated for each breathing pattern. The total inhalation time corresponds to the interval from point A to point C (the end point of inhalation).​​

[0096]

[0121] Part 2: Measurement of delivered pulse duration and volume. This part of the study The same breathing pattern was used in Part 1 and Part 2. Doses of 10, 15, 30, and 75 mcg / kg-IBW / hr 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 duration of the pulse is the time between the point at which the valve opens, indicated by a sudden voltage drop at the detector, corresponding to point A in Figure 2, and the return of gas flow to baseline at point B in Figure 2. The volume of the delivered pulse is the integrated gas flow during the duration of the pulse. The duration of the pulse was calculated by multiplying the delay of the pulse from Part 1 by the time t1, t2, and t3. The dose delivery time was then added to the delay time to obtain the dose delivery time, i.e., "delivered pulse width." Figure 1 shows the results for part 1. Four panels are shown in Figure 1. The second and fourth panels show breath detection corresponding to actuation of the flow control valve and a depiction of the breath pattern, respectively. Point A indicates the start of inspiration, point B indicates breath detection corresponding to opening of the flow valve, and point C indicates the end of inspiration. From this data, the delay time between points A and B can be calculated.

[0097]

[0122] Figure 2 shows the results of part 2. Four panels are shown in Figure 2. 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. Embodiment 2, i.e., the green data in FIG. 3, indicates that at least 93% of nitric oxide is delivered within the first one-third of the inhalation portion of respiration. 100% of nitric oxide is delivered within the first half of the inhalation portion of respiration. In contrast, in Embodiment 1 with sensitivity setting 8, at least 17% of nitric oxide is delivered within the first one-third of the inhalation portion of respiration, at least 77% within the first half of the inhalation portion of respiration, and at least 95% within the first two-thirds of the inhalation portion of respiration. Embodiment 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 respiration, at least 98% within the first half of the inhalation portion of respiration, and 100% within the first two-thirds of the inhalation portion of respiration. FIG. 4 depicts the data curve combining all three tests.

[0100]

[0124] From this data, more nitric oxide is delivered more precisely per pulse over a shorter time during the treatment process, so it can be concluded that a lower dose of nitric oxide is required over the course of a single treatment. A lower dose of nitric oxide leads to an overall lower use of drugs and also to a reduction in the risk of harmful side effects.

[0101]

[0125] Example 3: Activity parameter evaluation in patients with pulmonary hypertension associated with interstitial lung disease (cohort 1) - pulmonary fibrosis. Patients were divided into two cohorts and randomized 1:1 (cohort 1) or 2:1 (cohort 2) to treatment: placebo. Patients were administered either 30 mcg / kg IBW / hour (iNO30, cohort 1) or 45 mcg / kg IBW / hour (iNO45, cohort 2) for a period of 8 weeks (cohort 1) or 16 weeks (cohort 2), up to 24 hours per day. Cohort 1 consisted of 41 patients and was a non-blind phase

[0126] ​​​Extended to the ones, which is currently in progress. The open-label phase includes iNO patients who were administered iNO30 or iNO45. The following data represent the topline results of cohort 1. Cohort 3 will be a critical phase 3 group using iNO45 administration.

[0102]

[0127] During the study period, all patients were administered a certain level of background ground oxygen by the treating physician. Vital signs and baseline 6MWD tests 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). Vital and another 6MWD test were measured at week 4 and 8 in cohort 1, and at week 12 and 16 in cohort 2.

[0103]

[0128] The Actigraph GT9X is a triaxial accelerometer that continuously monitors the movement and acceleration of the subject at 30 Hz. The measured acceleration values are converted into activity "counts" per minute. These counts can be converted into activity intensity based on established and validated daily cut-off points. Each 1-minute record includes sleep / wake tags, worn / not worn tags, X, Y, and Z axis counts, and classifications such as sitting, light intensity, moderate intensity, or high intensity. The minute data are summarized for a daily record that includes the fraction of sitting, light intensity, moderate intensity, or high intensity activity; cumulative counts (X, Y, and Z axes); fraction in non-sitting activity (total of light intensity, moderate intensity, or high intensity), fraction in VMPA (total of moderate intensity and high intensity); and overall activity, which is

[0104]

Number

[0105] calculated as follows.

[0129] Monthly and weekly data were output for all "compliance days" within the period on a daily basis It is calculated by averaging the data. A compliant day includes a wear-awake time of ≧600 minutes; a compliant month includes ≧14 compliant days within the period; a compliant week includes ≧3 compliant days within the period. Non-compliant days, weeks, or months were not used in the analysis.

[0106]

[0130] It is meaningful for the pulmonary fibrosis group, and the activities related to this specific study are IPF Identified and reported by Voice of Patient-FDA Meeting and Report, 2015. These activities can be grouped by activity intensity based on the estimated metabolic equivalent level, as summarized in Table 5A below.

[0107]

[0131] Here, the results of cohort 1 are provided. The 6-minute walk distance (6MWD) test sa Results of port actigraphy. In cohort 1, there were three times as many patients with improved 6MWD in the treatment group compared to the placebo. Improvement in 6MWD is defined as an improvement of more than 15% in 6MWD above the patient's baseline level. While it is about 11% when receiving placebo, 31% of the patients receiving treatment improved in 6MWD, and patients with more severe pulmonary hypertension showed a significant improvement compared to the baseline level (+6 meters change in INOpulse patients, -7 meters change in placebo). Furthermore, in cohort 1, in terms of 6MWD, there was a total change of +10 meters in patients who wore INOpulse for at least 12 hours compared to a change of -6 meters in those receiving placebo. The composite evaluation items of distance-saturation product (DSP) and integrated DSP (IDSP) showed an increase compared to 6MWD, which verifies the benefit of ventilation / perfusion (V / Q). Furthermore, iNO had good tolerance and there were no safety concerns.

[0108]

[0132] In addition to certain actigraphy parameters (MVPA and overall activity) In addition, additional efficacy parameters of the NT-proBNP change were analyzed. NT-proBNP is a natriuretic peptide released by cardiomyocytes when the ventricles are placed under increased load and stretch (caused by pulmonary hypertension). Therefore, pulmonary hypertension results in an increase in the level of NT-proBNP. Treatments targeting the pulmonary vasculature are predicted to maintain or decrease the increase in the level of NT-proBNP. Generally, the higher the baseline level, the higher the likelihood of a decrease.

[0109]

[0133] The nadir SpO2 (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 the main output and activity parameters of the treated and placebo patients from cohort 1. Table 4 shows statistically significant data regarding the improvement in the activity levels of the treated and untreated patients. Table 5 shows the data of the treated and placebo patients together with the placebo-corrected changes.

[0114]

[0134] Table 6 shows the population statistics and disease characteristics.

[0115]

Table 8

[0116]

[0135] The results were measured with a wearable activity monitor (Actigraph GT9X) Results show that iNO provides clinically and statistically significant improvements in activity when administered in a controlled setting. Changes in NT-ProBNP are consistent with activity outcomes, 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 placebo. Statistically significant benefits were seen for moderate and general activity and calories. See summary results in Tables 7-10 below.

[0117] [Table 9]

[0118]

[0136] Table 7 shows actigraphy results from iNO-PF cohort 1. iNO group Improvements in were statistically significant compared to placebo for all parameters: MVPA (p=0.04), percentage of waking time in MVPA (p=0.04), general 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 is associated with MVPA, general activity, non-sedentary activity, and daily The data show that the subjects demonstrated consistent and sustained benefits in calorie activity parameters over a period of approximately 4 weeks that was maintained over the remainder of the study (through week 8).

[0120] [Table 10]

[0121]

[0138] Table 8 shows the improvement in supportive parameters. Reduced desaturation in the iNO group. And an increase in the SpO2 nadir leads to an improvement in the oxygen saturation of that group. The peptide marker NT-ProBNP, which is an indicator of heart failure, showed a greater increase in the placebo group, indicating a worsening of the condition.

[0122]

Table 11

[0123]

[0139] Table 9 shows an overview of the safety data. The safety study of cohort 1 supports dose escalation for iNO45 There was no suspicion of serious, unexpected suspected adverse reactions, and there were no unexpected adverse events. All serious adverse events were reported to be unrelated to the study. The incidence of AEs and SAEs was low and balanced across both the treatment and placebo groups. Inhaled nitric oxide for pulse is safe, and tolerance is good at iNO30.

[0124]

Table 12

[0125]

[0140] Table 10 shows that iNO30 treatment maintains M compared to a consistent decrease in the placebo group. A change in MVPA of 15% or more is considered a significant change. Approximately 23% of the patients who received iNO showed a significant improvement in MVPA, while 71% of the placebo patients showed a significant decrease in MVPA.

[0126]

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

[0127]

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

[0128]

[0143] The data shown for the above Cohort 1 were collected during the clinical study of Cohort 1 Raw data that has not shown longitudinal analysis. For both Cohorts 1 and 2, the data shown in Example 4 includes data analyzed using the Mixed Effect Model Repeated Measure (MMRM) model and pooled placebo data.

[0129]

[0144] Example 4: Assessment of Activity Parameter in Patients with Pulmonary Hypertension Associated with Interstitial Lung Disease (Cohort 2) - Pulmonary Fibrosis.

[0145] Example 4 shows data collected for Cohort 2 of Example 3, i.e., patients administered iNO45 (45 mcg / kg IBW / hour), and also includes the MMRM analysis 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 non-blinded continuation. Patients from Cohort 2 showed a statistically significant improvement in moderate-to-vigorous physical activity (MVPA) defined as walking, climbing stairs, yard, work, and similar activities compared to 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 improvement in actigraphy provides perspectives of two clinically relevant patient-reported outcomes (patient related to overall quality of life and dyspnea or shortness of breath. supported in one direction by improvement in the measured value (PRO) of the reported outcome. These PROs include the St. George's 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 the patients' scores on the SGRQ. These data indicate that patients generally felt better on iNO45 treatment than on placebo. Figure 11 shows the patients' scores on the UCSD SOBQ, which indicates that patients felt less short of breath while receiving iNO45 treatment than on placebo.

[0131]

[0147] Table 11 shows the safety data for cohort 2 (iNO45). In cohort 2, the tolerance of pulsed iNO was good. The incidence of adverse events (AE) and serious adverse events (SAE) was low in both the treatment group and the placebo group. The AEs were generally not serious and there were no observable trends. All SAEs were reported to be unrelated to the study drug. were reported.

[0132]

[0148]

[0133]

Table 13

[0134]

[0149] Table 12 shows an overview of the patient demographics for cohort 2.

[0135]

Table 14

[0136]

[0150] Table 13 shows patient compliance with INOpulse administration for cohorts 1 and 2. Patient adherence was similar in 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 that a small amount of exercise should be done during wakefulness to ensure an accurate assessment of activity levels during the day. Figure 1 shows patient adherence to wearing the activity monitor for at least 10 hours per day. As noted in the table, both cohorts demonstrated mean adherence to greater than the required 10 hours per day, however, cohort 2 showed 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 results at 2 months (iNO30 and iNO45) and 4 months (iNO Figure 12 shows log-transformed estimated change in MVPA (Figure 12A) and general activity (Figure 12B) in the 45-week follow-up study. Month 2 data is based on pooled placebo data from weeks 4-8, and month 4 data is based on data collected between months 2-4. As noted in Figure 12A, the change from baseline MVPA is smaller for Cohort 2 compared to Cohort 1. Additionally, 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 logarithmic monthly (Figure 13A) and weekly (Figure 13B) data for cohort 2. Shows the transformed MVPA prediction limit effect. In both cases, patients being treated with iNO45 maintain their activity levels, while those receiving placebo deteriorate over time. Importantly, the treatment effect is "slow", and the difference between the two groups begins at the second month of treatment and is most pronounced in the second half of the study. The shape of the decline is similar between monthly and weekly analyses, but the monthly analysis has lower variability, and the standard deviation of the residuals is 0.14 compared to 0.20 for the weekly analysis. 14.

[0142]

[0154] Table 15 shows that the lowest SpO2 during the 6MWD showed the smallest difference between the 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 targets well-ventilated alveoli and can maintain V / Q (ventilation / perfusion balance) in this patient population.

[0143]

[0143]

[0155]

[0144]

Table 17

[0145]

[0156] Changes in NT-proBNP levels were analyzed for cohorts 1 and 2. In cohort 1, when analyzed using the MMRM model, there was no difference in the change from baseline between the iNO30 group and the placebo group. Furthermore, no statistically significant difference was observed between the iNO30 group of cohort 1 and the pooled placebo using the MMRM model until week 8. Until week 8, there was a statistically significant difference between iNO45 and the pooled placebo; however, when comparing iNO45 over 16 weeks, this difference was lost, probably due to the small sample size. 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] The time to clinical improvement was defined as a ≥15% improvement in 6MWD, or an improvement in SGRQ defined as a ≥4-point decrease, or a ≥15% improvement in DSP / IDSP, and was a composite evaluation item. There was a minimal difference between Cohort 1 pooled with placebo over 8 weeks. Although not statistically significant, Cohort 2 showed a tendency for an increased percentage of subjects achieving a clinical improvement in iNO45 when evaluated against the larger pooled placebo group. This effect was mainly promoted by the improvement in SGRQ, further supporting the benefit seen in the entire SGRQ population.

[0148]

[0158] The time to clinical worsening was also a composite evaluation item consisting of mortality, or hospitalization due to cardiopulmonary worsening, or a ≥15% decrease from baseline in 6MWD, or a worsening of functional class. If there were multiple events, only the first clinical worsening event was counted. The difference in the time to clinical worsening between Cohort 1 or Cohort 2 was minimal, but iNO45 evaluated against the larger pooled placebo showed a tendency for a decrease in the clinical worsening of iNO45, supporting a potential signal that may become clearer in a larger trial.

[0149]

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

[0150]

[0160] The topline results were that iNO45 achieved a statistically significant improvement in MVPA ( ​​​In moderate-to-high intensity physical activity) and overall activity, it has been shown to provide a clear benefit over placebo. Subjects receiving iNO45 maintained their activity levels, while subjects receiving placebo showed a consistent decline. Over four months or more, subjects receiving iNO45 showed a 19% placebo-corrected benefit in MVPA and a 7% placebo-corrected benefit in overall activity. The comparison between iNO30 and iNO45 showed that overall activity levels were maintained by both administrations, indicating a potential benefit of iNO45 over iNO30 over a two-month period. Since iNO30 was only tested for two months, a comparative evaluation between administrations at the fourth month was not available.

[0151]

[0161] When iNO45 in cohort 2 was compared with the pooled placebo group over eight weeks, there was a statistically significant improvement in NT-proBNP; however, when iNO45 in cohort 2 was compared with placebo over 16 weeks, this effect was lost. The effect at week 16 may be due to a 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 mechanism of action of INOpulse to provide pulmonary vasodilation without causing V / Q mismatch.

[0152]

[0152]

[0162] In PRO, subjects in cohort 2 generally maintained their SGRQ scores, while subjects receiving placebo deteriorated. In comparison, subjects in cohort 1 showed minimal benefit compared to placebo in SGRQ measurements.

[0153]

[0153]

[0163] Pulse iNO, during the blinded treatment period, iNO30 administration in cohort 1 and cohort With the administration of iNO45 in cohort 2, the tolerance was good. The AEs were balanced among the treatment groups, and the incidence of SAE was low in both the treatment group and the placebo group of cohort 1. In the case of cohort 2, the number of subjects who reported SAE was lower in the treatment group (10%) compared to the placebo group (21.4%). Furthermore, all SAEs that occurred in both cohorts 1 and 2 during the blinded treatment period were reported to be unrelated to the drug. There were no reported unexpected AEs or suspected unexpected serious adverse reactions (SUSAR), and the benefit / risk profile remained favorable. The consistency of the benefits seen with iNO45 administration, along with a clean safety profile, supports proceeding with this administration in a very important confirmatory phase 3 cohort that evaluates iNO45 against placebo for a 4-month (16-week) blinded treatment period.

[0154]

[0164] Preferred embodiments of the present invention are shown and described herein, but such embodiments are provided by way of example only and are not intended to limit the scope of the present invention otherwise. Various alternatives to the described embodiments of the present invention may be employed in practicing the present invention. The various alternatives to the described embodiments of the invention are contemplated as being employed in practicing the invention.

Claims

1. 1. A device for improving or maintaining activity levels in a patient, the device comprising: a breath sensing portion operable to detect a breathing pattern including a total breath time of the patient, the breath sensing portion including an algorithm configured to calculate timing of administration of a dose of nitric oxide; and a delivery portion operable to administer the dose of nitric oxide to the patient in a pulsed manner over a portion of the total inspiration time. Including, the algorithm includes a respiration level threshold and slope algorithm; The slope algorithm detects a breath when the rate of pressure drop reaches a predetermined threshold; the respiration level threshold detects a breath when the negative pressure threshold is exceeded; The dose of nitric oxide is adjusted based on the breathing pattern. The device.

2. 10. The device of claim 1, wherein the dose of nitric oxide is from about 25 micrograms (mcg) / kg ideal body weight (IBW) / hour to about 50 mcg / kg IBW / hour.

3. 10. The device of claim 1, wherein the dose of nitric oxide is from about 30 mcg / kg IBW / hr to about 45 mcg / kg IBW / hr.

4. 10. The device of claim 1, wherein the dose of nitric oxide is about 45 mcg / kg IBW / hr.

5. 10. The device of claim 1, wherein the patient has interstitial lung disease.

6. 6. The device of claim 5, wherein the interstitial lung disease comprises one or more subtypes selected from idiopathic interstitial pneumonia (IIP), chronic hypersensitivity pneumonitis, occupational or environmental lung disease, idiopathic pulmonary fibrosis (IPF), non-IPF IIP, granulomatous disease associated with ILD, and connective tissue disease associated with ILD.

7. The device of claim 5 , wherein the interstitial lung disease comprises idiopathic pulmonary fibrosis.

8. The device of claim 1 , wherein the patient is at high risk of developing pulmonary hypertension.

9. The device of claim 1 , further comprising a wearable activity monitor.

10. 10. The device of claim 9, wherein the wearable activity monitor is operable to monitor and measure changes in the patient's activity level.

11. The device of claim 1 , wherein the delivery portion comprises a nasal cannula, a face mask, a sprayer, or a nasal inhaler.

12. 1. A formulation comprising inhaled nitric oxide for use in a method for improving or maintaining activity levels in a patient, the method comprising: detecting a breathing pattern in the patient, the breathing pattern including a total inspiration time; correlating said breathing pattern with an algorithm for calculating the timing of administering a dose of inhaled nitric oxide; and administering the dose of inhaled nitric oxide to the patient in a pulsed manner over a portion of the total inspiration time. administering the inhalable nitric oxide to the patient by the algorithm uses a respiration level threshold and slope algorithm; The slope algorithm detects a breath when the rate of pressure drop reaches a predetermined threshold; the respiration level threshold detects a breath when the negative pressure threshold is exceeded; The dose of inhaled nitric oxide is adjusted based on the breathing pattern. The preparation

13. 13. The formulation of claim 12, wherein the dosage of inhaled nitric oxide is from about 25 micrograms (mcg) / kg ideal body weight (IBW) / hour to about 50 mcg / kg IBW / hour.

14. 13. The formulation of claim 12, wherein the dose of inhaled nitric oxide is from about 30 mcg / kg IBW / hr to about 45 mcg / kg IBW / hr.

15. 13. The formulation of claim 12, wherein the dose of inhaled nitric oxide is about 45 mcg / kg IBW / hr.

16. 13. The formulation of claim 12, wherein the patient has interstitial lung disease.

17. 17. The formulation of claim 16, wherein the interstitial lung disease comprises one or more subtypes selected from idiopathic interstitial pneumonia (IIP), chronic hypersensitivity pneumonitis, occupational or environmental lung disease, idiopathic pulmonary fibrosis (IPF), non-IPF IIP, granulomatous disease associated with ILD, and connective tissue disease associated with ILD.

18. 17. The formulation of claim 16, wherein the interstitial lung disease comprises idiopathic pulmonary fibrosis.

19. 13. The formulation of claim 12, wherein the patient is at high risk of developing pulmonary hypertension.

20. 13. The formulation of claim 12, wherein the method further comprises measuring changes in the activity level using actigraphy.

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