A Dose Escalation Study to Assess the Safety and Efficacy of Pulsed Inhaled Nitric Oxide in Subjects With Pulmonary Fibrosis or Sarcoidosis

Study Overview
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Brief Summary
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A phase 2b, open label study to assess the safety and efficacy of increasing doses of pulsed, inhaled nitric oxide (iNO) in subjects with pulmonary fibrosis and sarcoidosis on long term oxygen therapy followed by a long term extension study

Detailed Description
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A phase 2b, open label study to assess the hemodynamic effects of increasing doses of pulsed, inhaled nitric oxide (iNO) in subjects with pulmonary hypertension associated with pulmonary fibrosis or sarcoidosis on long term oxygen therapy followed by an open label extension study

Official Title
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A Dose Escalation Study to Assess the Safety and Efficacy of Pulsed, Inhaled Nitric Oxide in Subjects With Pulmonary Hypertension Associated With Pulmonary Fibrosis or Sarcoidosis on Long Term Oxygen Therapy Followed by an Optional Open-Label Long Term Extension Safety Study

Conditions
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Pulmonary Hypertension, Pulmonary Fibrosis, Sarcoidosis, Pulmonary

Intervention / Treatment
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* Combination Product: iNO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent A primary diagnosis of sarcoidosis as defined by the ATS/ERS/WASOG statement or pulmonary fibrosis associated with one of the following conditions: 2.1 Major IIPs (idiopathic interstitial pneumonias) diagnosed or suspected as one of the following: Idiopathic pulmonary fibrosis Idiopathic nonspecific interstitial pneumonia Respiratory bronchiolitis-interstitial lung disease Desquamative interstitial pneumonia Cryptogenic organizing pneumonia Acute interstitial pneumonia Rare IIPs diagnosis by one of the following: Idiopathic lymphoid interstitial pneumonia Idiopathic pleuroparenchymal fibroelastosis Unclassifiable idiopathic interstitial pneumonias 2.2 Chronic hypersensitivity pneumonitis 2.3 Occupational lung disease 2.4 Connective tissue disease with evidence of significant pulmonary fibrosis Intermediate or high probability of PH by echocardiogram as assessed by local Radiologist/Investigator, or PH as determined by a right heart catheterization (RHC) within 5 years prior to Baseline with the following parameters: Pulmonary vascular resistance (PVR) ˃3 Wood Units (WU) (320 dynes.sec.cm-5) A left ventricular end diastolic pressure (LVEDP) or pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg A mean pulmonary arterial pressure (mPAP) of ≥ 25 mmHg 6MWD ≥ 100 meters and ≤ 450 meters WHO Functional Class II-IV Forced Vital Capacity ≥ 40% predicted within last 6 weeks prior to screening Females of childbearing potential must have a negative pre-treatment pregnancy test (urine). Age between 18 and 85 years (inclusive) Clinically stable for at least 4 weeks prior to Baseline in the opinion of the Investigator If on therapy for their parenchymal lung disease and/or sarcoidosis, then the subject should be on a stable well-tolerated dose of the medication(s) for at least 4 weeks prior to enrollment. Exclusion Criteria: Use of any type of PAH specific therapies Episodes of disease worsening within 3 months prior to Baseline Pregnant or breastfeeding females at Screening Administered L-arginine within 1 month prior to Screening Any subject who has been enrolled in any previous clinical study with inhaled NO administered through pulsed delivery On more than 6 L/min of oxygen at rest by nasal cannula for less than 4 weeks Evidence of any connective tissue disease with FVC > 60% in the last 6 months prior to screening unless there is evidence of moderate to severe fibrosis on CT scan in the opinion of the local radiologist/Investigator Evidence of clinically significant combined pulmonary fibrosis with emphysema (CPFE) if > 15% of lung fields by CT scan show evidence of emphysema in the opinion of the local radiologist/Investigator For subjects with sarcoidosis, clinically significant evidence of pulmonary fibrosis on CT scan in the opinion of the local radiologist/Investigator and FVC ≥80% predicted For subjects continuing on open label therapy, the concurrent use of the INOpulse device with a CPAP/BiPAP, or any other positive pressure device Significant heart failure in the opinion of the Investigator LVEF<40% or PCWP on last RHC>15 mmHg (unless concurrent LVEDP <15 mmHg) or Significant diastolic dysfunction on echocardiogram

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PH-Pulmonary Fibrosis<br>Part 1: 1st 4 subjects will be treated with iNO 30, 45, 75 mcg/kg IBW/hr 2nd 4 subjects will be treated with iNO 45, 75, 125 mcg/kg IBW/hr Part 2: Optional open label long term extension at the optimal dose as identified in Part 1 | Combination Product: iNO<br>* inhaled nitric oxide<br>* Other names: iNOPulse;|
| Experimental: PH-Sarcoidosis<br>Part 1: 1st 4 subjects will be treated with iNO 30, 45, 75 mcg/kg IBW/hr 2nd 4 subjects will be treated with iNO 45, 75, 125 mcg/kg IBW/hr Part 2: Optional Open label long term extension at the optimal dose as identified in Part 1 | Combination Product: iNO<br>* inhaled nitric oxide<br>* Other names: iNOPulse;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of mean PAP | Mean pulmonary arterial pressure (mPAP) will be measured at iNO 30, 45, 75 and 125 mcg/kg IBW/hr | During a single right heart catheterization procedure | 
| Measurement of PCWP | Pulmonary capillary wedge pressure (PCWP) will be measured at iNO 30, 45, 75 and 125 mcg/kg IBW/hr | During a single right heart catheterization procedure | 
| Measurement of PVR | Pulmonary vascular resistance (PVR) will be measured at iNO 30, 45, 75 and 125 mcg/kg IBW/hr | During a single right heart catheterization procedure | 
| Measurement of CO | Cardiac output (CO) will be measured at iNO 30, 45, 75 and 125 mcg/kg IBW/hr | During a single right heart catheterization procedure | 
| Change in 6MWD from Baseline to 16 Weeks | Change in 6 minute walk distance | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Treatment Emergent Adverse Events | Including adverse events related to device deficiency | During a single right heart catheterization procedure | 
| Pulmonary Rebound | Symptoms associated with acute withdrawal of iNO: systemic arterial oxygen desaturation, hypoxemia, bradycardia, tachycardia, systemic hypotension, shortness of breath, near-syncope and syncope | During a single right heart catheterization procedure | 
| Distance Saturation Product (DSP) | Difference in DSP from baseline to Week 16 Difference in DSP from baseline to 16 weeks | 16 weeks | 
| Dyspnea | Difference in dyspnea as measured by UCSD Medical Center Pulmonary Rehabilitation Program Shortness of Breath Questionnaire on a scale from 0 (none at all) to 5 (maximal or unable to do because of breathlessness) from baseline to Week 16 | 16 weeks | 
| Quality of Life Assessment | Difference in disease specific Quality of Life as measured by St. George's Respiratory Questionnaire | 16 weeks | 
| Incidence of Adverse Events and Serious Averse Events | Evaluation of adverse events and serious adverse events | Through study completion; an average of 1 year | 
| Integral Distance Saturation Product (IDSP) | Difference in IDSP from baseline to Week 16 | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sarcoidosis, Pulmonary Hypertension, Pulmonary Fibrosis