Dose Determination Safety and Activity Study of Inhaled NX1011 to Treat Pulmonary Arterial Hypertension

• To evaluate the safety, tolerability, and activity of inhalation therapy with NX1011 based on right heart catheterization (RHC) measures, pulse oximetry, and hemodynamic response
• To establish maximum tolerated dose (MTD) levels of NX1011 based on predefined criteria for dose-limiting toxicity (DLT)
• To qualify the delivery apparatus
• To generate descriptive data on the concentration-response relationship in order to choose a range of concentrations (e.g., low, medium, high) for the follow-up, fixed-dose, placebo-controlled study
• To summarize correlation data between echocardiography and RHC measures with respect to activity and methemoglobin levels documented via the visible light spectroscopy

• To evaluate the safety, tolerability, and activity of inhalation therapy with ethyl nitrite (ENO) based on RHC measures, pulse oximetry, and hemodynamic response
• To establish maximum tolerated dose (MTD) levels of ENO based on predefined criteria for dose-limiting toxicity (DLT)
• To qualify the delivery apparatus
• To generate descriptive data on the concentration-response relationship in order to choose a range of concentrations (e.g., low, medium, high) for the follow-on, fixed-dose, placebo-controlled study
• To summarize correlation data between echocardiography and RHC measures with respect to activity
• To summarize correlation data between methemoglobin levels documented using blood gas measurements (co-oximetry) and continuous methemoglobin monitoring documented via the visible light spectroscopy device

The purpose of this study is to determine the safety and maximum tolerated dose of inhaled NX1011 for the treatment of pulmonary arterial hypertension (PAH).

Inclusion Criteria:

• Patient must either:

  • meet the PAH diagnostic criteria at Screening (based on a documented history of diagnosis as outlined in the American College of Chest Physicians [ACCP] 2004 Evidence-Based Clinical Practices Guidelines)15; or
  • have elevated pulmonary pressure with a suspected PAH diagnosis based on a clinical referral at Screening for a RHC.
• Patient must have PAH as defined by a mean pulmonary artery pressure (PAP) > 25 mmHg.
• Patient must have symptoms of pulmonary hypertension (PH) according to the World Health Organization (WHO) Functional Classification of Pulmonary Hypertension Class II through IV.
• Patient must consent to, be able to tolerate, and have adequate venous and arterial access for Swan-Ganz catheterization (SGC) and an arterial line.

Exclusion Criteria:

• Clinically significant right-to-left intracardiac shunts based on Doppler echocardiography with bubble study.
• History of pulmonary veno-occlusive disease or clinically significant aortic or mitral stenosis.
• History of sustained ventricular tachycardia (VT-S) or ventricular fibrillation (VF) and cardiac arrest, or presence of atrial fibrillation.

• Active cardiac disease meeting the following criteria:

  • Patient with elevated pulmonary capillary wedge pressures (PCWPs) > 25 mmHg.
  • Patient with a history of myocardial infarction or coronary intervention within the last 60 days.
  • Patient with a history of pacemaker, cardiac defibrillator, or biventricular pacemaker insertion within 4 weeks of Baseline.
  • Patient who cannot be withdrawn from nitrate therapy.