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This is a single-center, open label phase II study to evaluate the effect of inhaled nitrite delivered in a dose escalation manner on the change in pulmonary vascular resistance (PVR) in subjects with pulmonary hypertension undergoing right heart catheterization.
A total of 50 subjects with a confirmed diagnosis of pulmonary hypertension and meet all inclusion/exclusion criteria will be enrolled in the study which will entail a single right heart catheterization and nebulized nitrite dose of 45mg with one subsequent dosage of 90 mg.
Screening Visit:Initial screening evaluations including physical examination, medical history, and clinical laboratory assessments will be conducted to determine study eligibilities during a routine clinic visit at the UPMC HVI, CLC or inpatient at UPMC Presbyterian. Subjects who meet the inclusion criteria and none of the exclusion criteria will be entered into the study.
Day 1: This study visit will occur on the same day subjects are scheduled for their clinically indicated right heart catheterization or who volunteer for a research right heart catheterization for this specific study. Subjects on oral background PAH therapy (ETRA or PDE5I) will be instructed to hold their regimen on the day of the study visit.
Subjects will receive nebulized AIR001 doses escalated based upon safety and tolerability. The dose of inhaled nitrite will be delivered via electronic nebulizer. During the study right heart/pulmonary artery hemodynamics will be measured as well as noninvasive systemic blood pressure monitoring. Subjects will be tested for the changes in pulmonary vascular resistance (PVR) using standard clinical protocol hemodynamic recordings of right atrial, right ventricular, and pulmonary artery pressures, in addition to cardiac output at time zero,
3 Day phone follow up
30 Day follow up visit: All subjects enrolled in the study will be followed for 30 days (+/- 5 day window) after completion of the study treatment. A physical exam and clinical labs will be obtained at this visit.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Inhaled Nitrite | Experimental | Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Inhaled Nitrite | Drug | Each patient will receive a starting dose of 45 mg of inhaled nitrite, with one planned subsequent planned dose of 90 mg of inhaled nitrite |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Pulmonary Vascular Resistance (PVR) | Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. Since pulmonary vascular resistance (PVR) was not normally distributed, it was transformed to natural log prior to analysis. The reported mean is the change from baseline of PVR over all subsequent times and doses (beta from the mixed effects model, converted back from natural log to Woods units), and is reported as the mean and 95% confidence interval. | Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Maximum Pulmonary Vascular Resistance (PVR) Decrease | Time in minutes to maximum PVR decrease. During study procedure, hemodynamics were measured at 0, 15, 30, 45, and 60 minutes after 45 mg followed by same times after 90 mg dose. The time point at which each patient's maximal decrease in PVR occurred was recorded and reported as the mean and standard deviation in each cohort. | 0, 15, 30, 45, and 60 minutes after 45 mg followed by same times after 90 mg dose |
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Inclusion Criteria:
Diagnosis of RHC confirmed WHO Group I PAH n=20
Idiopathic, primary or familial pulmonary arterial hypertension PAH associated with one of the following connective tissue diseases:
PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil Stable PAH for at least 3 months if on therapy This patient population is closed to enrollment. Target enrollment of 20 subjects has been met
WHO Group II Pulmonary Hypertension n=20 Pulmonary capillary wedge pressure PWCP greater than 15 AND Transpulmonary Gradient TPG greater than12
WHO Group III PH n = 10
WHO GROUP I PAH, II and III PH Age 18 and older Able to participate in right heart catheterization Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
Exclusion Criteria
Age less than 18 years
Baseline systemic hypotension, defined as MAP less than 50 mmHg
Required intravenous inotropes within 30 days prior to study participation;
Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure greater than160 mm Hg or sitting diastolic blood pressure greater than100 mm Hg at screening
Has a history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C with evidence of recent infection and/or active virus replication defined as moderate to severe hepatic impairment Child-Pugh Class B-C
Has chronic renal insufficiency as defined by serum creatinine greater than 2.5 mgdL at screening or requires dialytic support
Has a hemoglobin concentration less than 9 gdL at Screening
History of atrial septostomy within 6 months prior to Day 1 visit
Repaired or unrepaired congenital heart disease CHD
Pericardial constriction
Confirmed diagnosis of restrictive or congestive cardiomyopathy;
Left ventricular ejection fraction 40 percent by multiple gated acquisition scan MUGA, angiography or echocardiography
Symptomatic coronary disease with demonstrable ischemia;
Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study
Has a psychiatric, addictive or other disorder that compromises the ability to give informed consent for participating in this study. This includes subjects with a recent history of abusing alcohol or illicit drugs 30 days prior to study screening Day 0and for the duration of the study
Poorly controlled asthma defined by active wheezing and or cough with FEV1 less than 70 percent predicted, responsive to inhaled BD greater than 15 percent increase in FEV1 with BD
Investigators, study staff or their immediate families
Clinically significant intercurrent illness (including lower respiratory tract infection) or clinically significant surgery within 4 weeks before the administration of study drug
Personal or family history of congenital or acquired methemoglobinemia
Personal or family history of RBC CYP B5 reductase deficiency
Known or suspected hypersensitivity or allergic reaction to sodium nitrite Personal history of glucose-6-phosphate dehydrogenase G6PD deficiency or any contraindication to receiving methylene blue
If female, is pregnant or breast feeding, or has a positive pregnancy test result predose
Receipt of an investigational product or device, or participation in a drug research study within a period of 15 days or 5 half-lives of the drug, whichever is longer before the first dose of study drug
Blood loss or blood donation greater than 550 mL within 90 days or plasma donation greater than 500 mL within 14 days before administration of study drug
RHC less than 2 weeks from treatment visit unless clinically indicated
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| Name | Affiliation | Role |
|---|---|---|
| Marc A. Simon, MD | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pittsburgh | Pittsburgh | Pennsylvania | 15213 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30152056 | Background | DeMartino AW, Kim-Shapiro DB, Patel RP, Gladwin MT. Nitrite and nitrate chemical biology and signalling. Br J Pharmacol. 2019 Jan;176(2):228-245. doi: 10.1111/bph.14484. Epub 2018 Oct 3. | |
| 28069711 | Background | Gladwin MT. How Red Blood Cells Process Nitric Oxide: Evidence for the Nitrite Hypothesis. Circulation. 2017 Jan 10;135(2):177-179. doi: 10.1161/CIRCULATIONAHA.116.024752. No abstract available. |
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Subjects were enrolled in the trial between June 2012 and October 2017.
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| ID | Title | Description |
|---|---|---|
| FG000 | WHO Group I PAH | Idiopathic, primary or familial pulmonary arterial hypertension PAH associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. |
| FG001 | WHO Group II Pulmonary Hypertension (PH) | MPAP ≥ 25 mm Hg, PWCP > 15, and Transpulmonary Gradient (TPG) > 12. Additionally, LVEF ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. |
| FG002 | WHO Group III PH | MPAP ≥ 25 mm Hg, PCWP ≤ 15 mm Hg, and PVR ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | WHO Group I PAH | Idiopathic, primary or familial pulmonary arterial hypertension PAH associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Pulmonary Vascular Resistance (PVR) | Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. Since pulmonary vascular resistance (PVR) was not normally distributed, it was transformed to natural log prior to analysis. The reported mean is the change from baseline of PVR over all subsequent times and doses (beta from the mixed effects model, converted back from natural log to Woods units), and is reported as the mean and 95% confidence interval. | Posted | Mean | 95% Confidence Interval | Woods units | Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose |
|
30 days +/- 5 days from Right Heart Catheterization
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | WHO Group I Pulmonary Arterial Hypertension (PAH) | Idiopathic, primary or familial pulmonary arterial hypertension PAH associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upper respiratory infection | Infections and infestations | Non-systematic Assessment |
Small, early phase II pilot study, limited number of subjects. Exercise hemodynamics would be helpful in this population. Findings of acute changes in hemodynamics may or may not be translatable to chronic administration and longer-term outcomes.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Marc A. Simon, MD | University of Pittsburgh | 4128023131 | SIMONMA@UPMC.EDU |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 12, 2017 | Nov 19, 2018 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006976 | Hypertension, Pulmonary |
| D054144 | Heart Failure, Diastolic |
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D006973 | Hypertension |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D012977 | Sodium Nitrite |
| ID | Term |
|---|---|
| D009573 | Nitrites |
| D009608 | Nitrous Acid |
| D017672 | Nitrogen Compounds |
| D007287 | Inorganic Chemicals |
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|
| Change in Systemic Blood Pressure (Mean Arterial Pressure, MAP) | Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. The reported mean is the change from baseline of MAP over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval. | Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose |
| Change in Systemic Vascular Resistance (SVR) | Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. Since systemic vascular resistance was not normally distributed, it was transformed to natural log prior to analysis. The reported mean is the change from baseline of SVR over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval. | Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose |
| Change in Pulmonary Vascular Impedance / Wave Intensity | Characteristic impedance (Zc) which may be related to compliance effects in the large, conduit arteries. | Pre dose and 60 minutes post last dosage inhaled |
| Change in Plasma Nitrite Concentrations in Mixed Venous Blood | Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. The reported mean is the change from baseline of plasma nitrite concentrations in mixed venous blood over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval. | Pre-dose, 15 minutes post 45mg and 90mg inhalation |
| Change in Pulmonary Artery Occlusion (Capillary) Pullback Nitrite | Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. The reported mean is the change from baseline of pulmonary artery occlusion (capillary) pullback nitrite concentration over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval. | Pre-dose, 15 minutes post 45mg and 90mg inhalation |
| Change in Mitochondrial Oxygen Consumption Compared to Baseline After Each Dose of Nitrite | Basal platelet oxygen consumption measured in isolated platelets by extracellular flux analysis (XF24, Seahorse Biosciences, Billerica, MA). | Maximal effect at 15 minutes post 45mg or 90mg inhalation vs Pre dose |
| 26813102 | Background | Lai YC, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, St Croix CM, Garcia-Ocana A, Goncharova EA, Tofovic SP, Mora AL, Gladwin MT. SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction. Circulation. 2016 Feb 23;133(8):717-31. doi: 10.1161/CIRCULATIONAHA.115.018935. Epub 2016 Jan 26. |
| 26684248 | Background | Hon YY, Lin EE, Tian X, Yang Y, Sun H, Swenson ER, Taveira-Dasilva AM, Gladwin MT, Machado RF. Increased consumption and vasodilatory effect of nitrite during exercise. Am J Physiol Lung Cell Mol Physiol. 2016 Feb 15;310(4):L354-64. doi: 10.1152/ajplung.00081.2015. Epub 2015 Dec 18. |
| 25533965 | Background | Vanderpool R, Gladwin MT. Harnessing the nitrate-nitrite-nitric oxide pathway for therapy of heart failure with preserved ejection fraction. Circulation. 2015 Jan 27;131(4):334-6. doi: 10.1161/CIRCULATIONAHA.114.014149. Epub 2014 Dec 22. No abstract available. |
| 25421879 | Background | Rix PJ, Vick A, Attkins NJ, Barker GE, Bott AW, Alcorn H Jr, Gladwin MT, Shiva S, Bradley S, Hussaini A, Hoye WL, Parsley EL, Masamune H. Pharmacokinetics, pharmacodynamics, safety, and tolerability of nebulized sodium nitrite (AIR001) following repeat-dose inhalation in healthy subjects. Clin Pharmacokinet. 2015 Mar;54(3):261-72. doi: 10.1007/s40262-014-0201-y. |
| 22871207 | Background | Bueno M, Wang J, Mora AL, Gladwin MT. Nitrite signaling in pulmonary hypertension: mechanisms of bioactivation, signaling, and therapeutics. Antioxid Redox Signal. 2013 May 10;18(14):1797-809. doi: 10.1089/ars.2012.4833. Epub 2012 Oct 15. |
| 22685116 | Background | Totzeck M, Hendgen-Cotta UB, Luedike P, Berenbrink M, Klare JP, Steinhoff HJ, Semmler D, Shiva S, Williams D, Kipar A, Gladwin MT, Schrader J, Kelm M, Cossins AR, Rassaf T. Nitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation. Circulation. 2012 Jul 17;126(3):325-34. doi: 10.1161/CIRCULATIONAHA.111.087155. Epub 2012 Jun 9. |
| 22572912 | Background | Sparacino-Watkins CE, Lai YC, Gladwin MT. Nitrate-nitrite-nitric oxide pathway in pulmonary arterial hypertension therapeutics. Circulation. 2012 Jun 12;125(23):2824-6. doi: 10.1161/CIRCULATIONAHA.112.107821. Epub 2012 May 9. No abstract available. |
| 21177703 | Background | Zuckerbraun BS, George P, Gladwin MT. Nitrite in pulmonary arterial hypertension: therapeutic avenues in the setting of dysregulated arginine/nitric oxide synthase signalling. Cardiovasc Res. 2011 Feb 15;89(3):542-52. doi: 10.1093/cvr/cvq370. Epub 2010 Dec 22. |
| 18167491 | Background | Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008 Feb;7(2):156-67. doi: 10.1038/nrd2466. |
| 17893272 | Background | Dejam A, Hunter CJ, Tremonti C, Pluta RM, Hon YY, Grimes G, Partovi K, Pelletier MM, Oldfield EH, Cannon RO 3rd, Schechter AN, Gladwin MT. Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation. Circulation. 2007 Oct 16;116(16):1821-31. doi: 10.1161/CIRCULATIONAHA.107.712133. Epub 2007 Sep 24. |
| 14980746 | Background | Vangeneugden T, Laenen A, Geys H, Renard D, Molenberghs G. Applying linear mixed models to estimate reliability in clinical trial data with repeated measurements. Control Clin Trials. 2004 Feb;25(1):13-30. doi: 10.1016/j.cct.2003.08.009. |
| 27812547 | Result | Simon MA, Vanderpool RR, Nouraie M, Bachman TN, White PM, Sugahara M, Gorcsan J 3rd, Parsley EL, Gladwin MT. Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction. JCI Insight. 2016 Nov 3;1(18):e89620. doi: 10.1172/jci.insight.89620. |
| BG001 | WHO Group II PH | MPAP ≥ 25 mm Hg, PWCP > 15, and Transpulmonary Gradient (TPG) > 12. Additionally, LVEF ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. |
| BG002 | WHO Group III PH | MPAP ≥ 25 mm Hg, PCWP ≤ 15 mm Hg, and PVR ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG000 | WHO Group I Pulmonary Arterial Hypertension (PAH) | Idiopathic, primary or familial pulmonary arterial hypertension (PAH) associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. |
| OG001 | WHO Group II Pulmonary Hypertension (PH) | mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) > 15, and Transpulmonary Gradient (TPG) > 12. Additionally, left ventricular ejection fraction (LVEF) ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. |
| OG002 | WHO Group III Pulmonary Hypertension (PH) | mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. |
|
|
|
| Secondary | Time to Maximum Pulmonary Vascular Resistance (PVR) Decrease | Time in minutes to maximum PVR decrease. During study procedure, hemodynamics were measured at 0, 15, 30, 45, and 60 minutes after 45 mg followed by same times after 90 mg dose. The time point at which each patient's maximal decrease in PVR occurred was recorded and reported as the mean and standard deviation in each cohort. | Posted | Mean | Standard Deviation | minutes | 0, 15, 30, 45, and 60 minutes after 45 mg followed by same times after 90 mg dose |
|
|
|
| Secondary | Change in Systemic Blood Pressure (Mean Arterial Pressure, MAP) | Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. The reported mean is the change from baseline of MAP over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval. | Posted | Mean | 95% Confidence Interval | mmHg | Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose |
|
|
|
|
| Secondary | Change in Systemic Vascular Resistance (SVR) | Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. Since systemic vascular resistance was not normally distributed, it was transformed to natural log prior to analysis. The reported mean is the change from baseline of SVR over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval. | Posted | Mean | 95% Confidence Interval | mmHgâ‹…min/L | Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose |
|
|
|
|
| Secondary | Change in Pulmonary Vascular Impedance / Wave Intensity | Characteristic impedance (Zc) which may be related to compliance effects in the large, conduit arteries. | Data are reported in each group for the subset in whom this data was collected. | Posted | Median | 95% Confidence Interval | dyne*sec/cm5 | Pre dose and 60 minutes post last dosage inhaled |
|
|
|
|
| Secondary | Change in Plasma Nitrite Concentrations in Mixed Venous Blood | Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. The reported mean is the change from baseline of plasma nitrite concentrations in mixed venous blood over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval. | Data are reported in each group for the subset in whom this data was collected. | Posted | Mean | 95% Confidence Interval | micromolar | Pre-dose, 15 minutes post 45mg and 90mg inhalation |
|
|
|
|
| Secondary | Change in Pulmonary Artery Occlusion (Capillary) Pullback Nitrite | Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. The reported mean is the change from baseline of pulmonary artery occlusion (capillary) pullback nitrite concentration over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval. | Data are reported only for WHO Group I PAH and WHO Group III Pulmonary Hypertension (PH), as there was insufficient data for this analysis for WHO Group II PH. Data are reported in each group for the subset in whom this data was collected. | Posted | Mean | 95% Confidence Interval | micromolar | Pre-dose, 15 minutes post 45mg and 90mg inhalation |
|
|
|
|
| Secondary | Change in Mitochondrial Oxygen Consumption Compared to Baseline After Each Dose of Nitrite | Basal platelet oxygen consumption measured in isolated platelets by extracellular flux analysis (XF24, Seahorse Biosciences, Billerica, MA). | Data are reported in each group for the subset in whom this data was collected. | Posted | Mean | 95% Confidence Interval | picomoles O2/min | Maximal effect at 15 minutes post 45mg or 90mg inhalation vs Pre dose |
|
|
|
|
| 0 |
| 20 |
| 0 |
| 20 |
| 4 |
| 20 |
| EG001 | WHO Group II Pulmonary Hypertension (PH) | mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) > 15, and Transpulmonary Gradient (TPG) > 12. Additionally, left ventricular ejection fraction (LVEF) ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. | 0 | 20 | 0 | 20 | 6 | 20 |
| EG002 | WHO Group III Pulmonary Hypertension (PH) | mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. | 0 | 8 | 0 | 8 | 2 | 8 |
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
|
| shortness of breath | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Lightheaded/Dizziness | Cardiac disorders | Non-systematic Assessment |
|
| Headache | General disorders | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Back/neck pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| palpitations | Cardiac disorders | Non-systematic Assessment |
|
| increase in serum creatinine from baseline | Renal and urinary disorders | Non-systematic Assessment |
|
Not provided
Not provided
| D002318 |
| Cardiovascular Diseases |
| D006331 | Heart Diseases |
| D017670 |
| Sodium Compounds |
| Other |
Mixed effects model across all time points. |
| Mixed Models Analysis | <0.001 | Other | Mixed effects model across all time points. |
| Other |
Mixed effects model across all time points. |
| Mixed Models Analysis | 0.01 | Other | Mixed effects model across all time points. |
| Superiority |
| Wilcoxon (Mann-Whitney) | 0.17 | Superiority |
| <0.05 |
| Other |
Mixed effects model of concentrations measured at Pre-dose, 15 minutes post 45mg dose and 15 minutes post 90mg dose. |
| Mixed Models Analysis | <0.05 | Other | Mixed effects model of concentrations measured at Pre-dose, 15 minutes post 45mg dose and 15 minutes post 90mg dose. |
| <0.001 |
| Other |
Mixed effects model of concentrations measured at Pre-dose, 15 minutes post 45mg dose and 15 minutes post 90mg dose. |
| Other |
Mixed effects model across all doses. |
| Mixed Models Analysis | 0.59 | Other | Mixed effects model across all doses. |