Inhaled Nitric Oxide (iNO) in Idiopathic Pulmonary Fibrosis (IPF).

NCT05052229 | Recruiting Early Phase 1 DMC

• 2 other identifiers: DMED 2495-21BI 1199.0477
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Idiopathic Pulmonary Fibrosis

Keywords

Exertional Dyspnea; Exercise; Nitric Oxide; Idiopathic Pulmonary Fibrosis

Outcome Measures

Primary Outcomes (2)

• Ventilatory efficiency (VE/VCO2)

  Ventilatory efficiency will be measured by expired gas analysis. Measurements will be collected on a breath-by breath basis and compared with predicted values based on age and height. Three main time points will be evaluated: "rest" will be defined as the steady-state period after at least 3 minutes of breathing on the mouthpiece before exercise starts; "isotime" will be defined as the last 30-sec increment of each minute (i.e. 1-min, 2-min, 3-min) during the incremental exercise test and at 2 minutes (or the longest time achieved by all subjects) during the constant load exercise tests, and; "end-exercise" will be defined as the last 30-sec of loaded pedaling.

  During exercise test on visit 4 and 5, every 1 minute, through end-exercise (average time 6-10minutes).

• Inspiratory Neural Drive (IND) as measured by Diaphragmatic electromyography (EMGdi)

  An esophageal electrode-balloon catheter consisting of 5 electrode pairs and two balloons, will be inserted nasally and positioned for optimal recoding. Electromyogram output of the diaphragm (used as an index of inspiratory neural drive to crural diaphragm or diaphragm activation; EMGdi) will be recorded continuously at rest and during exercise. Maximal EMGdi (EMGdi,max) will be determined from inspiratory capacity (IC) maneuvers. EMGdi/EMGdi,max will be used as an index of the inspiratory neural drive to the crural diaphragm.

  During exercise test on visit 4 and 5, every 1 minute, through end-exercise (average time 6-10minutes).

Secondary Outcomes (1)

• Dyspnea Intensity

  During exercise test on visit 4 and 5, every 1 minute, through end-exercise (average time 6-10minutes).

Study Arms (2)

Placebo

PLACEBO COMPARATOR

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

Drug: Medical air

Nitric Oxide

ACTIVE COMPARATOR

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

Drug: Nitric Oxide

Interventions

Nitric Oxide DRUG

Nitric oxide gas for inhalation

Also known as: KINOX

Nitric Oxide

Medical air DRUG

Medical grade air for inhalation (placebo)

Also known as: Medical grade air

Placebo

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• clinically stable, as defined by stable hemodynamic status, optimized medical treatment, no changes in medication dosage or frequency of administration with no hospital admissions in the preceding 6 weeks;
• Mild or absent mechanical restriction as determined by a total lung capacity (TLC) \>70% predicted;
• male or female non-pregnant adults \>40 years of age;
• ability to perform all study procedures and provide informed consent.

You may not qualify if:

• women of childbearing potential who are pregnant or trying to become pregnant;
• computed tomography evidence of any (significant) emphysema
• evidence of airway obstruction (forced expiratory volume in 1 s/forced vital capacity \<0.70,
• active cardiopulmonary disease (other than IPF) or other comorbidities that could contribute to dyspnea and exercise limitation;
• history/clinical evidence of asthma, atopy and/or nasal polyps;
• currently taking phosphodiesterase type 5 inhibitors;
• important contraindications to clinical exercise testing, including inability to exercise because of neuromuscular or musculoskeletal disease(s);
• body mass index (BMI) \<18.5 or ≥35.0 kg/m2;
• use of daytime oxygen or exercise-induced O2 desaturation (\<80% on room air).

Sponsors & Collaborators

• Dr. Denis O'Donnell: lead
• Boehringer Ingelheim: collaborator

Study Sites (1)

Respiratory Investigation Unit, Kingston General Hospital

Kingston, Ontario, K7L 2V7, Canada

RECRUITING

Related Publications (6)

• Milne KM, Ibrahim-Masthan M, Scheeren RE, James MD, Phillips DB, Moran-Mendoza O, Ja N, O'Donnell DE. Inspiratory neural drive and dyspnea in interstitial lung disease: Effect of inhaled fentanyl. Respir Physiol Neurobiol. 2020 Nov;282:103511. doi: 10.1016/j.resp.2020.103511. Epub 2020 Aug 3.

  PMID: 32758677 BACKGROUND

• Faisal A, Alghamdi BJ, Ciavaglia CE, Elbehairy AF, Webb KA, Ora J, Neder JA, O'Donnell DE. Common Mechanisms of Dyspnea in Chronic Interstitial and Obstructive Lung Disorders. Am J Respir Crit Care Med. 2016 Feb 1;193(3):299-309. doi: 10.1164/rccm.201504-0841OC.

  PMID: 26407036 BACKGROUND

• Farina S, Bruno N, Agalbato C, Contini M, Cassandro R, Elia D, Harari S, Agostoni P. Physiological insights of exercise hyperventilation in arterial and chronic thromboembolic pulmonary hypertension. Int J Cardiol. 2018 May 15;259:178-182. doi: 10.1016/j.ijcard.2017.11.023.

  PMID: 29579597 BACKGROUND

• Kolb M, Raghu G, Wells AU, Behr J, Richeldi L, Schinzel B, Quaresma M, Stowasser S, Martinez FJ; INSTAGE Investigators. Nintedanib plus Sildenafil in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018 Nov 1;379(18):1722-1731. doi: 10.1056/NEJMoa1811737. Epub 2018 Sep 15.

  PMID: 30220235 BACKGROUND

• Nathan SD, Flaherty KR, Glassberg MK, Raghu G, Swigris J, Alvarez R, Ettinger N, Loyd J, Fernandes P, Gillies H, Kim B, Shah P, Lancaster L. A Randomized, Double-Blind, Placebo-Controlled Study of Pulsed, Inhaled Nitric Oxide in Subjects at Risk of Pulmonary Hypertension Associated With Pulmonary Fibrosis. Chest. 2020 Aug;158(2):637-645. doi: 10.1016/j.chest.2020.02.016. Epub 2020 Feb 21.

  PMID: 32092321 BACKGROUND

• Phillips DB, Brotto AR, Ross BA, Bryan TL, Wong EYL, Meah VL, Fuhr DP, van Diepen S, Stickland MK; Canadian Respiratory Research Network. Inhaled nitric oxide improves ventilatory efficiency and exercise capacity in patients with mild COPD: A randomized-control cross-over trial. J Physiol. 2021 Mar;599(5):1665-1683. doi: 10.1113/JP280913. Epub 2021 Jan 25.

  PMID: 33428233 BACKGROUND

MeSH Terms

Conditions

Idiopathic Pulmonary Fibrosis; Motor Activity

Interventions

Nitric Oxide; Air

Condition Hierarchy (Ancestors)

Pulmonary Fibrosis; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Behavior

Intervention Hierarchy (Ancestors)

Reactive Nitrogen Species; Free Radicals; Inorganic Chemicals; Nitrogen Oxides; Nitrogen Compounds; Oxides; Oxygen Compounds; Organic Chemicals; Atmosphere; Environment; Ecological and Environmental Phenomena; Biological Phenomena; Meteorological Concepts; Environment and Public Health

Study Officials

• Denis E O'Donnell, MD

  Principal Investigator, Professor

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Devin Phillips, Ph.D.

CONTACT

6135496666; RIU@queensu.ca

Sandra G Vincent, MSc.

CONTACT

6135496666; RIU@queensu.ca

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Single center, randomized, double-blind, cross-over design

Study Record Dates

• First Submitted: September 2, 2021
• First Posted: September 22, 2021
• Study Start: April 21, 2022
• Primary Completion: December 30, 2024
• Study Completion: February 28, 2025
• Last Updated: April 3, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)