Inhaled Nitric Oxide for Idiopathic Pulmonary Fibrosis

Overseen By Devin Phillips, Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Dr. Denis O'Donnell

Must not be taking: Phosphodiesterase inhibitors

Disqualifiers: Emphysema, Asthma, Cardiopulmonary disease, others

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

40 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications. However, you must be clinically stable with no changes in medication dosage or frequency in the past 6 weeks. If you are taking phosphodiesterase type 5 inhibitors, you cannot participate in the trial.

What data supports the idea that Inhaled Nitric Oxide for Idiopathic Pulmonary Fibrosis is an effective treatment?

The available research shows that inhaled nitric oxide can improve certain lung functions in patients with idiopathic pulmonary fibrosis. In one study, patients who inhaled a low dose of nitric oxide experienced a decrease in pressure in their lung arteries and a reduction in resistance to blood flow in the lungs. This suggests that inhaled nitric oxide can help improve breathing and blood flow in the lungs for these patients. However, more research is needed to confirm these findings and to compare its effectiveness to other treatments for idiopathic pulmonary fibrosis. ^{1 2 3 4 5}

What safety data exists for inhaled nitric oxide treatment?

Inhaled nitric oxide (iNO) has been studied for its safety and efficacy in various conditions. It is used in premature infants with hypoxemia, but concerns about side effects exist. iNO affects pulmonary vasoreactivity and has known side effects, including a 'rebound' phenomenon upon withdrawal. It is also associated with renal dysfunction in patients with acute respiratory distress syndrome (ARDS). The safety profile of iNO includes potential interactions with other drugs and its chemical reactions in the lungs, which can lead to both beneficial and harmful effects. ^{6 7 8 9 10}

Is the drug Nitric Oxide a promising treatment for Idiopathic Pulmonary Fibrosis?

Yes, Nitric Oxide shows promise as a treatment for Idiopathic Pulmonary Fibrosis. It can improve blood flow in the lungs and help with breathing by reducing pressure in the lung's blood vessels. Studies have shown that it can improve oxygen levels and reduce lung blood pressure, which are important for patients with this condition. ^{1 4 5 11 12}

What is the purpose of this trial?

Idiopathic Pulmonary Fibrosis (IPF) is a progressive lung disease marked by reduced exercise capacity and activity-related breathlessness (commonly termed dyspnea). Our previous work has shown that dyspnea during exercise is associated with an increased drive to breathe (inspiratory neural drive; IND). However, little work has been done to understand the mechanisms of exertional dyspnea in patients with mild IPF. The objectives of this study are to compare the acute effects of inhaled nitric oxide to placebo on ventilatory efficiency (VE/VCO2), and IND at rest and during a standard cardiopulmonary exercise test (CPET). Twenty patients with diagnosed IPF with mild (or absent) mechanical restriction and 20 healthy age- and sex-matched controls will be recruited from a database of volunteers and from the Interstitial Lung Disease and Respirology clinics at Hotel Dieu Hospital. Participants with cardiovascular, or any other condition that contributes to dyspnea or abnormal cardiopulmonary responses to exercise will be excluded. After giving written informed consent, all participants will complete 7 visits, conducted 2 to 7 days apart. Visit 1 (screening): medical history, pulmonary function testing and a symptom limited incremental CPET. Visit 2: Standard CT examination conducted at KGH Imaging. Visit 3: assessment of resting chemoreceptor sensitivity, followed by a symptom limited incremental CPET to determine peak work rate (Wmax). Visits 4 \& 5 (run-in): familiarization to standardized constant work rate (CWR) CPET to symptom limitation at 75% Wmax. Visits 6 \& 7 (Randomized \& Blinded): CWR CPET to symptom limitation while breathing a gas mixture with either 1) 40 ppm iNO or 2) placebo \[medical grade normoxic gas, 21% oxygen\]. The proposed work has the potential to provide important physiological insights into the underlying mechanisms of heightened dyspnea, as well as examine therapeutic avenues to improve quality of life in patients with IPF.

Research Team

Denis E O'Donnell, MD

Principal Investigator

Principal Investigator, Professor

Eligibility Criteria

Adults over 40 with a clinical diagnosis of mild Idiopathic Pulmonary Fibrosis (IPF) and no recent hospital admissions can join this trial. They must have minimal lung restriction, be clinically stable, able to perform study tasks, and not pregnant. Exclusions include significant emphysema, active heart/lung diseases other than IPF, severe obesity or underweight conditions, certain medication use, and exercise limitations due to neuromuscular issues.

Inclusion Criteria

I have been diagnosed with idiopathic pulmonary fibrosis.

My lung function is mostly normal.

My health condition has been stable, with no hospital visits or medication changes in the last 6 weeks.

Exclusion Criteria

You have a history of asthma, allergies, or nasal polyps.

Your body mass index (BMI) is either too low (less than 18.5) or too high (35.0 or more).

You have trouble breathing out air quickly.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Baseline Assessment

Standard CT examination and assessment of resting chemoreceptor sensitivity

1 week

2 visits (in-person)

Run-in

Familiarization to standardized constant work rate CPET to symptom limitation at 75% Wmax

1-2 weeks

2 visits (in-person)

Randomized Treatment

CWR CPET to symptom limitation while breathing a gas mixture with either 40 ppm iNO or placebo

1 week

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Nitric Oxide

Trial Overview The trial is testing the effects of inhaled nitric oxide (iNO) versus medical air placebo on breathing efficiency during rest and exercise in IPF patients compared to healthy controls. Participants will undergo several visits including pulmonary function tests, CT scans, chemoreceptor sensitivity assessments, familiarization exercises sessions followed by two blinded test sessions with either iNO or placebo.

Participant Groups

Group I: Nitric Oxide Active Control 1 Intervention

Inhaled 40 ppm nitric oxide from a KINOX gas cylinder system (Air Liquid Healthcare, Montreal, Quebec, Canada; DIN 02451328).

Group II: Placebo Placebo Group 1 Intervention

Inhaled medical grade normoxic gas (FiO2 = 0.21; DIN 02238755 Air Liquide Healthcare, Montreal, Quebec, Canada).

Nitric Oxide is already approved in United States for the following indications:

Approved in United States as Inomax for:

• Hypoxic respiratory failure in term and near-term neonates with pulmonary hypertension

Approved in United States as Noxivent for:

• Hypoxic respiratory failure in term and near-term neonates with pulmonary hypertension

Approved in United States as GeNOsyl for:

• Hypoxic respiratory failure in term and near-term neonates with pulmonary hypertension

Who Is Running the Clinical Trial?

Dr. Denis O'Donnell

Lead Sponsor

Trials

7

Recruited

240+

Dr. Denis O'Donnell

Lead Sponsor

Trials

6

Recruited

200+

Queen's University

Lead Sponsor

Trials

382

Recruited

122,000+

Boehringer Ingelheim

Industry Sponsor

Trials

2,566

Recruited

16,150,000+

Findings from Research

Inhalation of low-dose nitric oxide (2 ppm) significantly reduced pulmonary arterial pressure and pulmonary vascular resistance in 10 patients with stable idiopathic pulmonary fibrosis, indicating improved pulmonary hemodynamics.

Combining nitric oxide with oxygen not only further decreased pulmonary arterial pressure but also improved arterial oxygen tension, suggesting a potential new treatment strategy for patients with idiopathic pulmonary fibrosis and pulmonary hypertension, though safety and efficacy need further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of low-dose inhalation of nitric oxide in patients with pulmonary fibrosis. Yoshida, M., Taguchi, O., Gabazza, EC., et al.[2019]

Inhaled nitric oxide can improve oxygenation in patients with acute respiratory distress syndrome (ARDS) by vasodilating well-ventilated areas of the lung, making it a potential therapeutic option.

Despite its benefits, nitric oxide is a highly reactive molecule with both positive and negative biological effects, and its use in ARDS remains experimental, highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy of inhaled nitric oxide in the treatment of acute respiratory distress syndrome. An evidence-based medicine approach. Greene, JH., Klinger, JR.[2019]

A new rat model was developed to study acute exacerbations of idiopathic pulmonary fibrosis by administering bleomycin to induce lung fibrosis, followed by lipopolysaccharide to simulate exacerbation.

In this model, significant deterioration in oxygen levels and increased macrophage infiltration were observed, suggesting that nitric oxide production from these macrophages may contribute to decreased oxygen levels during acute exacerbations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute exacerbation of idiopathic pulmonary fibrosis model by small amount of lipopolysaccharide in rats. Miyamoto, H., Takemura, S., Minamiyama, Y., et al.[2022]

Patients with idiopathic interstitial pneumonias (IIP) exhibited significantly higher levels of exhaled nitric oxide (FeNO) and alveolar nitric oxide (CalvNO) compared to healthy individuals, indicating abnormal nitric oxide production likely due to lung fibrosis.

CalvNO levels were strongly correlated with pulmonary function test results and exercise capacity, suggesting that it could serve as a potential biomarker for assessing lung fibrosis and exercise tolerance in IIP patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exhaled nitric oxide in interstitial lung diseases. Cameli, P., Bargagli, E., Refini, RM., et al.[2015]

Inhaled nitric oxide is a promising treatment for pulmonary hypertension and respiratory failure, as it selectively dilates blood vessels in the lungs, which is crucial for improving blood flow and oxygen delivery.

Preliminary studies show encouraging results, but further controlled and randomized trials are necessary to confirm its effectiveness and safety in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic use of inhaled nitric oxide. Adatia, I., Wessel, DL.[2019]

In a study of 860 premature infants under 32 weeks, low-dose inhaled nitric oxide (iNO) did not significantly improve intact survival at 28 days compared to placebo, with survival rates of 61.4% for iNO and 61.1% for controls.

The use of iNO was found to be safe, showing no significant differences in major complications like intraventricular hemorrhage, necrotizing enterocolitis, or patent ductus arteriosus compared to controls, suggesting it does not increase the risk of these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of nitric oxide therapy in premature infants. Hascoet, JM., Fresson, J., Claris, O., et al.[2016]

Inhaled nitric oxide (NO) has established clinical uses due to its effects on pulmonary vasoreactivity, but careful management is needed to avoid withdrawal effects, known as the 'rebound' phenomenon.

Future research is essential to determine the optimal therapeutic dose, duration of treatment, and potential toxicity of inhaled NO, ensuring its safe and effective use in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide and pulmonary vasoreactivity. Aranda, M., Pearl, RG.[2019]

Nitrogen oxides (NOx), previously seen only as toxic pollutants, are now recognized as important bioactive molecules in the lungs, produced by an enzyme system called nitric oxide synthase (NOS) that plays roles in various lung cells.

Therapies involving inhaled nitric oxide (NO) may improve conditions like pulmonary hypertension and asthma, highlighting the dual nature of NOx as both beneficial and potentially harmful depending on their chemical interactions in the lung.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The biology of nitrogen oxides in the airways. Gaston, B., Drazen, JM., Loscalzo, J., et al.[2013]

Inhaled nitric oxide (iNO) therapy significantly increases the risk of renal dysfunction in patients with acute respiratory distress syndrome (ARDS), with an adjusted hazard ratio of 1.59 after accounting for confounding factors.

Older patients (aged 65 and above) are particularly vulnerable to kidney injury associated with iNO therapy, highlighting the need for careful monitoring in this demographic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide and the risk of renal dysfunction in patients with acute respiratory distress syndrome: a propensity-matched cohort study. Ruan, SY., Wu, HY., Lin, HH., et al.[2022]

In a study of 44 infants with hypoxic respiratory failure treated with inhaled nitric oxide (iNO), 31 responded to the therapy while 13 did not, highlighting the variability in treatment efficacy.

Key predictors of non-response to iNO included a decrease in oxygen levels (PaO2) and pH after treatment, as well as the need for pressor support before starting iNO, which can help clinicians identify at-risk patients early.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical characteristics and factors associated with term and late preterm infants that do not respond to inhaled nitric oxide (iNO). Morel, AA., Shreck, E., Mally, PV., et al.[2017]

Inhaled nitric oxide (NO) significantly reduced pulmonary vascular resistance and improved arterial oxygenation in a patient with severe interstitial pulmonary fibrosis and pulmonary hypertension, indicating its potential as a selective pulmonary vasodilator.

In contrast, intravenous PGE1 caused rapid arterial oxygen desaturation and worsened symptoms, highlighting the safety and efficacy of inhaled NO over PGE1 in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improvement in pulmonary hypertension and hypoxemia during nitric oxide inhalation in a patient with end-stage pulmonary fibrosis. Channick, RN., Hoch, RC., Newhart, JW., et al.[2016]

Inhaled nitric oxide (NO) effectively reduced pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) in patients with moderate pulmonary hypertension during one-lung ventilation, demonstrating its role as a selective pulmonary vasodilator.

Unlike intravenous vasodilators, inhaled NO did not impair oxygenation or increase venous admixture, preserving hypoxic pulmonary vasoconstriction and maintaining stable hemodynamic variables.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide selectively decreases pulmonary vascular resistance without impairing oxygenation during one-lung ventilation in patients undergoing cardiac surgery. Rich, GF., Lowson, SM., Johns, RA., et al.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

The effect of low-dose inhalation of nitric oxide in patients with pulmonary fibrosis. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

The efficacy of inhaled nitric oxide in the treatment of acute respiratory distress syndrome. An evidence-based medicine approach. [2019]

3. Japan pubmed.ncbi.nlm.nih.gov

Acute exacerbation of idiopathic pulmonary fibrosis model by small amount of lipopolysaccharide in rats. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Exhaled nitric oxide in interstitial lung diseases. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

Therapeutic use of inhaled nitric oxide. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

The safety and efficacy of nitric oxide therapy in premature infants. [2016]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide and pulmonary vasoreactivity. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

The biology of nitrogen oxides in the airways. [2013]

9. England pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide and the risk of renal dysfunction in patients with acute respiratory distress syndrome: a propensity-matched cohort study. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Clinical characteristics and factors associated with term and late preterm infants that do not respond to inhaled nitric oxide (iNO). [2017]

11. United States pubmed.ncbi.nlm.nih.gov

Improvement in pulmonary hypertension and hypoxemia during nitric oxide inhalation in a patient with end-stage pulmonary fibrosis. [2016]

12. United States pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide selectively decreases pulmonary vascular resistance without impairing oxygenation during one-lung ventilation in patients undergoing cardiac surgery. [2013]