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

• ClinicalTrials.gov Identifier: NCT03727451
• Recruitment Status: Completed
• First Posted: November 1, 2018
• Last Update Posted: August 10, 2022
• Sponsor: Bellerophon
• Information provided by (Responsible Party): Bellerophon

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Pulmonary Hypertension; Pulmonary Fibrosis; Sarcoidosis, Pulmonary	Combination Product: iNO	Phase 2

Detailed Description:

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 17 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: January 30, 2019
• Actual Primary Completion Date: September 7, 2021
• Actual Study Completion Date: June 15, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: PH-Pulmonary Fibrosis; 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; inhaled nitric oxide; Other Name: iNOPulse
Experimental: PH-Sarcoidosis; 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; inhaled nitric oxide; Other Name: iNOPulse

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Incidence and Severity of Treatment Emergent Adverse Events [ Time Frame: During a single right heart catheterization procedure ]
   Including adverse events related to device deficiency
2. Pulmonary Rebound [ Time Frame: During a single right heart catheterization procedure ]
   Symptoms associated with acute withdrawal of iNO: systemic arterial oxygen desaturation, hypoxemia, bradycardia, tachycardia, systemic hypotension, shortness of breath, near-syncope and syncope
3. Distance Saturation Product (DSP) [ Time Frame: 16 weeks ]

   Difference in DSP from baseline to Week 16

   Difference in DSP from baseline to 16 weeks

4. Dyspnea [ Time Frame: 16 weeks ]
   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
5. Quality of Life Assessment [ Time Frame: 16 weeks ]
   Difference in disease specific Quality of Life as measured by St. George's Respiratory Questionnaire
6. Incidence of Adverse Events and Serious Averse Events [ Time Frame: Through study completion; an average of 1 year ]
   Evaluation of adverse events and serious adverse events
7. Integral Distance Saturation Product (IDSP) [ Time Frame: 16 weeks ]
   Difference in IDSP from baseline to Week 16

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Signed informed consent

2. 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

3. 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:

   1. Pulmonary vascular resistance (PVR) ˃3 Wood Units (WU) (320 dynes.sec.cm-5)
   2. A left ventricular end diastolic pressure (LVEDP) or pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg
   3. A mean pulmonary arterial pressure (mPAP) of ≥ 25 mmHg
4. 6MWD ≥ 100 meters and ≤ 450 meters
5. WHO Functional Class II-IV
6. Forced Vital Capacity ≥ 40% predicted within last 6 weeks prior to screening
7. Females of childbearing potential must have a negative pre-treatment pregnancy test (urine).
8. Age between 18 and 85 years (inclusive)
9. Clinically stable for at least 4 weeks prior to Baseline in the opinion of the Investigator
10. 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:

1. Use of any type of PAH specific therapies
2. Episodes of disease worsening within 3 months prior to Baseline
3. Pregnant or breastfeeding females at Screening
4. Administered L-arginine within 1 month prior to Screening
5. Any subject who has been enrolled in any previous clinical study with inhaled NO administered through pulsed delivery
6. On more than 6 L/min of oxygen at rest by nasal cannula for less than 4 weeks
7. 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
8. 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
9. 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
10. For subjects continuing on open label therapy, the concurrent use of the INOpulse device with a CPAP/BiPAP, or any other positive pressure device

11. Significant heart failure in the opinion of the Investigator

    1. LVEF<40% or
    2. PCWP on last RHC>15 mmHg (unless concurrent LVEDP <15 mmHg) or
    3. Significant diastolic dysfunction on echocardiogram

Contacts and Locations

Locations

United States, Florida

University of Miami

Miami, Florida, United States, 33125

United States, Ohio

University of Cincinnati

Cincinnati, Ohio, United States, 45219

United States, Pennsylvania

Temple University

Philadelphia, Pennsylvania, United States, 19140

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

United States, Virginia

Inova Heart and Lung Vascular Institute

Falls Church, Virginia, United States, 22042

United States, Washington

University of Washington Medical Center

Seattle, Washington, United States, 98195

Sponsors and Collaborators

Bellerophon

Investigators

• Study Director: Edward Parsley, DO; Bellerophon Pulse Technologies

More Information

• Responsible Party: Bellerophon
• ClinicalTrials.gov Identifier: NCT03727451
• Other Study ID Numbers: PULSE-PHPF-002
• First Posted: November 1, 2018
• Last Update Posted: August 10, 2022
• Last Verified: February 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Bellerophon:

Pulmonary Hypertension; Pulmonary Fibrosis; Sarcoidosis

Additional relevant MeSH terms:

Hypertension, Pulmonary; Pulmonary Fibrosis; Sarcoidosis, Pulmonary; Hypertension; Sarcoidosis; Fibrosis; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Lung Diseases, Interstitial; Lymphoproliferative Disorders; Lymphatic Diseases; Hypersensitivity, Delayed; Hypersensitivity; Immune System Diseases