Study in Subjects With PAH and PH Secondary to IPF Using Inhaled GeNOsyl.

Study Overview
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Brief Summary
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A Phase 2 open label, dose escalation study to find the minimally and maximum effective dose (dose beyond which no further effect on PVR is seen) of inhaled nitric oxide generated by the GeNOsyl® System compared to placebo.

Detailed Description
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Up to 54 subjects undergoing RHC are planned in this study, and shall include subjects meeting eligibility criteria classified as WHO Group 1 PAH or WHO Group 3 IPF-PH. Subjects will receive inhaled nitric oxide from the GeNOsyl® System to characterize the hemodynamic response and evaluate safety and tolerability. Dose cohorts of approximately 5, 15, and 20 ppm nitric oxide in air will be studied. Different dose levels will be achieved by varying the flow rate of the drug substance (80 ppm NO2 in balance air) delivered to the subject via nasal cannula. Each subject will receive two different doses of inhaled nitric oxide separated by a placebo (medical grade air or supplemental oxygen) washout. Eligible subjects will be assigned to a dosing cohort in an escalating manner to receive study drug (80 ppm nitric oxide in air.)

Official Title
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A Phase 2, Open-Label, Dose-Escalation Study in Subjects With Pulmonary Arterial Hypertension, (PAH, WHO Group 1) and Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis, (PH-IPF WHO Group 3) Using Inhaled GeNOsyl.

Conditions
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Pulmonary Arterial Hypertension, Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: Inhaled Nitric Oxide
* Drug: Inhaled Nitric Oxide
* Drug: Inhaled Nitric Oxide


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: PAH and PH-IPF WHO Functional Class (or equivalent classification) II - IV. Subjects using supplemental oxygen must be receiving a stable course of therapy for a minimum of 14 days prior to study drug administration. All subjects' oxygen saturation must be > or = to 88% at time of treatment Echocardiogram within 6 months of baseline showing no signs of clinically significant left sided heart disease Females of child-bearing potential with a negative urine pregnancy test, or a documented surgical sterilization, or is post-menopausal prior to administration of investigational product. Females of childbearing potential must be practicing adequate birth control. PAH (WHO Group 1) ONLY-Inclusion Documented diagnosis of WHO Group 1 PAH, (limited to, idiopathic, heritable, drug and toxin induced, associated with connective tissue disease, portal hypertension, repaired congenital heart disease, HIV); documented by a previous RHC and hemodynamics consistent with PAH, WHO Group 1 Pulmonary Function Testing within 6 months prior to screening/enrollment shows no evidence of interstitial lung disease (TLC<70%) or obstructive lung disease (FEV1/FVC ratio <50%) Receiving a stable course of approved PAH oral mono therapies for a minimum of 14 days prior to treatment period Must be 18-80 year of age PH-IPF (WHO Group 3) ONLY-Inclusion Documented diagnosis of probable or definite IPF using ATS/ERS criteria Previous transbronchial biopsy, if performed, shows no features to support a definitive alternative diagnosis Previous bronchoalveolar lavage, if performed, shows no features that provides an alternative diagnosis FVC > or = 40% within 6 months of baseline visit Diagnosis of PH based on hemodynamic requirements Age 40-85. Diagnosis of IPF > or = 3 months prior to study drug administration Diagnosis of PH based on the following hemodynamic criteria (PAPm > or = 25 mmHg (at rest) / PCWP or LVED < or =15 mmHg and / PVR >3 Wood Units) EXCLUSION CRITERIA: PAH and PH-IPF Have any other disease associated with pulmonary hypertension (i.e. Group II, IV or V). Documented uncontrolled systemic hypertension. Left ventricular ejection fraction (LVEF) < 40%. Have chronic kidney disease stage IV or worse, or requires dialysis. Be receiving an investigational drug, have in place an investigational device, or have participated in an investigational drug study within past 30 days. Have had an atrial septostomy. Have anemia or any other ongoing condition that would interfere with the interpretation of study assessments. Have any serious or life-threatening disease other than conditions associated with PAH or PH-IPF (e.g. malignancy requiring aggressive chemotherapy, renal dialysis, etc.) Significant, ongoing alcohol or drug abuse, or unstable psychiatric status. Receiving inhaled or parenteral prostacyclins or a non-approved combination of approved oral PAH therapy. Pregnant or lactating subjects PAH (WHO Group 1) ONLY-Exclusion Have had any changes to chronic therapy (including but not limited to oxygen, a different category of vasodilator, a diuretic, digoxin) for PAH added within 14 days of study drug administration. Anticoagulants are allowed to be discontinued per institutional standard of care. History of untreated sleep apnea within three months of study drug administration. History of hemodynamically significant left-sided heart disease or evidence of left-sided heart disease. PH-IPF (WHO Group 3) ONLY-Exclusion Diagnosis of PH primarily due to etiology other than IPF. FEV/FVC ratio < 60% documented within 6 months of baseline visit. Hospitalization for acute exacerbation of IPF within 30 days of baseline visit. Recent active pulmonary or upper respiratory tract infection. Receiving any approved PAH therapy within 30 days of study drug administration.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dosing Group 1<br>1 Liter per Minute (LPM)of inhaled nitric oxide via nasal cannula: approximately 5 parts per million (ppm) | Drug: Inhaled Nitric Oxide<br>* Inhaled nitric oxide 80 ppm via nasal cannula at 1 LPM for 15 minutes followed by placebo washout of 15 minutes inhalation of medical grade air (or prescribed supplemental oxygen), and then inhaled nitric oxide 80 ppm via nasal cannula at 1 LPM<br>* Other names: GeNOsyl;|
| Experimental: Dosing Group 2<br>2 LPM of inhaled nitric oxide via nasal cannula: approximately 15 ppm | Drug: Inhaled Nitric Oxide<br>* Inhaled nitric oxide 80 ppm via nasal cannula at 1 LPM for 15 minutes followed by placebo washout of 15 minutes inhalation of medical grade air (or prescribed supplemental oxygen), and then inhaled nitric oxide 80 ppm via nasal cannula at 2 LPM<br>* Other names: GeNOsyl;|
| Experimental: Dosing Group 3<br>4 LPM of inhaled nitric oxide via nasal cannula: approximately 20 ppm | Drug: Inhaled Nitric Oxide<br>* Inhaled nitric oxide 80 ppm via nasal cannula at 1 LPM for 15 minutes followed by placebo washout of 15 minutes inhalation of medical grade air (or prescribed supplemental oxygen), and then inhaled nitric oxide 80 ppm via nasal cannula at 4 LPM<br>* Other names: GeNOsyl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify the minimally and maximum effective doses of inhaled nitric oxide generated by the GeNOsyl® System compared to placebo. | Assess mean change in pulmonary vascular resistance (PVR) for study drug dose 2 compared to placebo. Assess change from pre-dose to end-of-hemodynamic assessment for study drug dose 1. Assess change from placebo to end-of-hemodynamic assessment for study drug dose 2. | through end of Right Heart Catheterization procedure (Treatment Phase approximately 3 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the safety and tolerability of nitric oxide generated by the GeNOsyl® System in subjects with WHO Group 1 PAH and WHO Group 3 PH-IPF. |  | through end of study (approximately 30 days after treatment visit) | 
| Evaluate the pharmacokinetics of total nitrates/nitrites and methemoglobin produced following inhalation of nitric oxide via the GeNOsyl® System. | Individual pharmacokinetic parameters for total nitrates/nitrites and methemoglobin will be summarized with descriptive characteristics. | up through 24 hrs after treatment period for subjects participating in PK sub-study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAH, PH IPF