A Dose Escalation Study to Assess the Safety and Efficacy of Pulsed iNO in Subjects With Pulmonary Fibrosis

A phase 2b, randomized, double-blind, placebo-controlled dose escalation clinical study to
assess the safety and efficacy of pulsed, inhaled nitric oxide (iNO) versus placebo in
subjects with and without pulmonary hypertension associated with pulmonary fibrosis on long
term oxygen therapy (Part 1 and Part 2).

Inclusion Criteria:

1. Signed Informed Consent

2. Diagnosed with pulmonary fibrosis by high resolution CT scan performed in the 6 months
prior to screening associated with one of the following conditions and confirmed using
guidelines, as per American Thoracic Society (ATS) / European Respiratory Society
(ERS) / Japanese Respiratory Society (JRS) / Latin American Thoracic Association
(ALAT):

Major IIPs (idiopathic interstitial pneumonias) diagnosis 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 Chronic hypersensitivity
pneumonitis Occupational lung disease

3. At least 50% of the subjects will have confirmed intermediate or high probability of
pulmonary hypertension as determined by echocardiography according to the 2015 ESC/ERS
Guidelines for Diagnosis and Treatment of Pulmonary Hypertension.

4. Have been using oxygen therapy by nasal cannula for at least 4 weeks prior to the
screening run-in period.

5. 6MWD ≥ 100 meters and ≤ 450 meters prior to randomization

6. WHO Functional Class II-IV

7. Forced Vital Capacity ≥ 40% predicted within last 6 months prior to screening the
screening run-in period.

8. For at least 1 week prior to Baseline/Randomization, subjects must demonstrate the
ability to consistently use the device greater than 12 hrs/day in the opinion of the
Investigator.

9. Female subjects of childbearing potential must have a negative pre-treatment pregnancy
test (serum or urine). All female subjects should take adequate precaution to avoid
pregnancy.

10. Subjects must have completed at least 1 week of activity monitoring prior to the
Baseline/Randomization visit.

11. Age between 18 and 85 years (inclusive)

12. Subject should be clinically stable for at least 4 weeks prior to
Baseline/Randomization in the opinion of the Principal Investigator.

Exclusion Criteria:

1. Demonstrate symptomatic rebound defined as significant cardiopulmonary instability,
such as systemic arterial oxygen desaturation, hypoxemia, bradycardia, tachycardia,
systemic hypotension, shortness of breath, near-syncope, and syncope, occurring within
1 hour of acute iNO during rebound testing

2. Episodes of disease worsening within 1 month prior to Baseline/Randomization

3. Use of any PAH-specific medications regardless of reason for use

4. Acute or chronic physical impairment (other than dyspnea due to PF) that would limit
the ability to comply with study procedures or adherence to therapy (i.e., 6MWT),
including carrying and wearing the pulsed delivery device per study protocol, or
medical problem(s) likely to preclude completion of the study

5. Pregnant or breastfeeding females at Screening

6. Administered L-arginine within 1 month prior to Screening

7. The concurrent use of the INOpulse device with a continuous positive airway pressure
(CPAP), Bilevel positive airway pressure (BPAP), or any other positive pressure
device.

8. Use of investigational drugs or devices within 1 month prior to Screening (other than
acute vasodilator testing with iNO)

9. Any underlying medical or psychiatric condition that, in the opinion of the
Investigator, makes the subject an unsuitable candidate for the study including unable
to complete 6MWT.

10. Any subject who has been enrolled in any previous clinical study with inhaled NO
administered through pulse delivery

11. In the last 6 months prior to screening, evidence of any connective tissue disease
with FVC > 60% unless there is evidence of moderate to severe fibrosis on CT scan in
the opinion of the Investigator

12. Evidence of clinically significant Combined Pulmonary Fibrosis and Emphysema (CPFE) if
> 15% of lung fields by CT scan show evidence of emphysema in the opinion of the
Investigator