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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how inhaled nitric oxide affects individuals with idiopathic pulmonary fibrosis (IPF), a lung disease that makes breathing difficult during physical activities. The main goal is to determine if this gas can improve breathing and exercise capacity compared to a placebo (a harmless, inactive gas). Participants will undergo various tests to measure their breathing at rest and during exercise. Those with IPF who have mild breathing restrictions and a stable condition without recent hospital visits might be suitable candidates. This research could provide new insights into managing breathlessness in people with IPF. As an Early Phase 1 trial, the study focuses on understanding how inhaled nitric oxide works in people, offering participants a chance to be among the first to receive this innovative treatment.

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.

Is there any evidence suggesting that inhaled nitric oxide is likely to be safe for humans?

Research has shown that inhaled nitric oxide (iNO) is generally safe for individuals with lung diseases like idiopathic pulmonary fibrosis (IPF). In a small study involving seven IPF patients, inhaled nitric oxide reduced breathing problems during exercise without major side effects. Another study found that using inhaled nitric oxide for eight weeks was well-tolerated and improved physical activity in people with fibrotic lung diseases.

While these studies suggest that inhaled nitric oxide is safe and may aid exercise, individual reactions to treatments can vary. Clinical trial participants receive close monitoring for any potential side effects, allowing for quick intervention if issues arise. Those considering joining a trial should consult healthcare professionals to understand the treatment and its potential effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for idiopathic pulmonary fibrosis, which often involve antifibrotic drugs like nintedanib and pirfenidone, inhaled nitric oxide offers a unique approach. This treatment is administered directly to the lungs, using a specific concentration of 40 ppm from a KINOX gas cylinder system. Researchers are excited because nitric oxide is known for its ability to dilate blood vessels and improve oxygenation, potentially offering a new way to manage the condition's symptoms and improve quality of life for patients. This method targets the lungs directly, which could lead to more efficient results compared to systemic treatments.

What evidence suggests that inhaled nitric oxide might be an effective treatment for idiopathic pulmonary fibrosis?

Research has shown that inhaled nitric oxide (iNO) might help people with fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), become more active. Some studies suggest that iNO can enhance exercise performance for those with these lung conditions. However, other research indicates that iNO does not immediately alleviate breathing problems during exercise. This mixed evidence suggests that while iNO has potential, its exact benefits for IPF patients remain under investigation. In this trial, participants will receive either inhaled nitric oxide or a placebo to further explore its effects. The treatment might require more time or different conditions to reveal its full benefits. ^{1 2 4 6 7}

Who Is on the Research Team?

Denis E O'Donnell, MD

Principal Investigator

Principal Investigator, Professor

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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) 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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05052229

Inhaled Nitric Oxide (iNO) in Idiopathic Pulmonary Fibrosis ... These data suggest that patients with mild forms of IPF have significant exertional dyspnea, secondary to reduced ventilatory efficiency (high V̇E/V̇CO2), ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11084010/

The acute effect of inhaled nitric oxide on the exercise ... Our study revealed that iNO does not confer an immediate benefit, suggesting that the treatment may not be effective in ILD or that a longer ...

3. atsjournals.org atsjournals.org/doi/full/10.1513/AnnalsATS.202406-662OC?role=tab

Inhaled Nitric Oxide in Fibrotic Lung Disease Inhaled nitric oxide (iNO) has been shown to result in benefits in moderate to vigorous physical activity (MVPA) in patients with fibrotic interstitial lung ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05052229/inhaled-nitric-oxide-ino-in-idiopathic-pulmonary-fibrosis-ipf

Inhaled Nitric Oxide (iNO) in Idiopathic Pulmonary Fibrosis ... These data suggest that patients with mild forms of IPF have significant exertional dyspnea, secondary to reduced ventilatory efficiency ...

5. bmcpulmmed.biomedcentral.com bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-024-03051-4

The acute effect of inhaled nitric oxide on the exercise ... Our study revealed that iNO does not confer an immediate benefit, suggesting that the treatment may not be effective in ILD or that a longer ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03267108?intr=NCT03267108&rank=1

A Study to Assess Pulsed Inhaled Nitric Oxide in Subjects ... A randomized, double-blind, placebo-controlled dose escalation and verification study to assess the safety and efficacy of pulsed inhaled nitric oxide (iNO) ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0012369220303275

A Randomized, Double-Blind, Placebo-Controlled Study of ... In this double-blind randomized placebo-controlled study of ambulatory inhaled nitric oxide, we demonstrate that 8 weeks of iNO therapy can ameliorate the ...