Inhaled Nitrite in Subjects With Pulmonary Hypertension

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Dose Escalation Study to Evaluate the Effect of Inhaled Nitrite on Cardiopulmonary Hemodynamics in Subjects With Pulmonary Hypertension

Conditions
-----------------
Pulmonary Hypertension, Heart Failure, Diastolic

Intervention / Treatment
-----------------
* Drug: Inhaled Nitrite


Participation Criteria
=================
Eligibility Criteria
-----------------
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 Has WHO functional class II through IV symptoms Had the diagnosis of PH confirmed by a cardiac catheterization Both WHO Group I PAH and WHO Group III PH 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled Nitrite<br>Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. | Drug: Inhaled Nitrite<br>* 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<br>* Other names: Sodium Nitrite;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pulmonary hypertension, heart failure