Idiopathic Pulmonary FibrosisEarly Phase 1NCT05052229
Inhaled Nitric Oxide (iNO) in Idiopathic Pulmonary Fibrosis (IPF).
A Early Phase 1 study testing Nitric Oxide and Medical air in people with Idiopathic Pulmonary Fibrosis, run by Dr. Denis O'Donnell at 1 site in Canada.
Trial 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). Read more about this study
- Who is it for?
- Ages 40 years and olderHealthy volunteers can take part
- Conditions the study is for
- Idiopathic Pulmonary Fibrosis
- What is being tested?
- Nitric Oxide and Medical air
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteCanada
- Study dates
- 21 Apr 2022to 28 Feb 2025
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
- A key IPF inclusion criterion includes, in addition to the above, a clinical diagnosis of idiopathic pulmonary fibrosis.
Who cannot join
- 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;
Show all 9Show fewer
- 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).
Trial locations and contacts
1 site in 1 country.
Canada1 site, 1 recruiting
- Recruiting
Respiratory Investigation Unit, Kingston General Hospital
Kingston, Ontario, K7L 2V7
Denis E O'Donnell, MD, 6135482339, RIU@queensu.ca
Sandra G Vincent, MSc, 6135496666 ext. 4890, RIU@queensu.ca
About this study
Official title: Pulmonary Gas Exchange and Neuro-sensory Abnormalities in Patients With Idiopathic Pulmonary Fibrosis and Mild Mechanical Restriction. Implications for Dyspnea and Exercise Intolerance
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.
Read the detailed description
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease characterized by bi-basilar sub-pleural honeycombing, septal thickening, and traction bronchiectasis. Patients with IPF, even in mild cases, have a reduced exercise capacity which is strongly associated with exertional breathlessness (dyspnea). Our previous work in IPF has shown that dyspnea during exercise is associated with increased inspiratory neural drive (IND) compared with healthy controls. High IND, in turn, is related to a combination of 1) reduced ventilatory efficiency (i.e. increased ventilation relative to carbon dioxide production (V̇E/V̇CO2)); 2) abnormal dynamic breathing mechanics (blunted tidal volume (VT) and critically low inspiratory reserve volume (IRV)), especially in more advanced disease, and; 3) impaired pulmonary gas-exchange (i.e. diffusion limitation and arterial hypoxemia).
Preliminary work from our laboratory in patients with IPF but only mild restriction (total lung capacity (TLC) >70% predicted) demonstrated elevated IND and dyspnea during exercise, when compared to healthy age- and sex-matched controls. The increased IND appeared to be largely the result of the excess ventilation (high V̇E/V̇CO2), as dynamic respiratory mechanics (VT and operating lung volumes) during exercise were similar to healthy controls, when accounting for ventilation. Importantly, these patients showed only minor decreases in arterial O2 saturation. These data suggest that patients with mild forms of IPF have significant exertional dyspnea, secondary to reduced ventilatory efficiency (high V̇E/V̇CO2), although the exact mechanisms of elevated V̇E/V̇CO2 in mild IPF remains unclear.
Increased chemosensitivity has been linked to elevated V̇E/V̇CO2 in cardiopulmonary diseases. It is reasonable to postulate that persistent V̇A/Q̇ mismatch with elevated total physiological dead space and possible sympathetic over-excitation may alter central medullary chemoreceptor characteristics in patients with IPF, at least partially explaining elevated exercise V̇E/V̇CO2. Pulmonary microvascular abnormalities may also be a key contributor to the increased dead space and V̇E/V̇CO2 during exercise in IPF. Patients with IPF and mild mechanical restriction have relatively preserved gas transfer between the alveoli and capillaries, even in fibrotic lung regions with interstitial thickening. This suggests that regional capillary hypoperfusion in IPF with mild restriction, despite a relatively preserved alveolar-capillary interface, may lead to V̇A/Q̇ mismatch (specifically an increased proportion of high V̇A/Q̇ lung units), which would increase total physiologic dead space and V̇E/V̇CO2. The relative contribution of increased chemosensitivity and/or pulmonary microvascular abnormalities to elevated exercise V̇E/V̇CO2 in patients mild IPF has not been determined and are the primary focus of this study.
Treatment options for dyspnea management in IPF are limited. Recent work from the INSTAGE trial showed that a combination of nintedanib (anti-fibrotic) and sildenafil (pulmonary vasodilator) showed minimal improvement in dyspnea. However, improvements in physical activity and gas-exchange in patients with IPF following 8-week treatment of inhaled nitric oxide (iNO), a selective pulmonary vasodilator have been demonstrated in other, more recent studies. Since patients with mild forms of IPF are thought to have a relatively intact capillary bed but a relatively high physiological dead space due to attenuation of regional pulmonary perfusion, inhaled selective vasodilation may be more beneficial than in advanced disease with fixed microvascular destruction. This is supported by recent work demonstrating a reduced V̇E/V̇CO2 (reflecting a decrease in physiological dead space) and dyspnea during exercise in patients with mild chronic obstructive pulmonary disease with minimal or no emphysema. Importantly, arterial O2 saturation was normal throughout exercise and unaffected by iNO, which suggests no deleterious effects of iNO on overall gas-exchange. The reduction in V̇E/V̇CO2 during exercise with iNO suggests that iNO increases pulmonary microvascular perfusion heterogeneity, leading to improved V̇A/Q̇ matching, reduced dead space and therefore a lower ventilation for a given metabolic demand.
As an exploratory outcome, we will determine whether iNO improves V̇A/Q̇ and reduces dead space and attendant dyspnea, in patients with IPF and mild mechanical restriction. Moreover, this would clearly establish if partially reversible vascular dysfunction contributes to V̇A/Q̇ mismatch, elevated V̇E/V̇CO2, inspiratory neural drive and dyspnea exists in non-hypoxemic patients with IPF and minimal mechanical abnormalities.
Rationale: It has been well established that patients with advanced IPF have mechanical and pulmonary gas exchange abnormalities which require compensatory increases in inspiratory neural drive and an exaggerated ventilatory response to exercise with consequent increase in activity-related dyspnea. However, very little work has been done to understand mechanisms of exertional dyspnea in patients IPF in whom restrictive mechanics and hypoxemia are not prominent. The proposed work has the potential to not only provide important physiological insight into the underlying mechanisms for increased V̇E/V̇CO2 and inspiratory neural drive, but also to examine therapeutic avenues to improve ventilatory efficiency, dyspnea, exercise capacity and ultimately quality of life in patients with IPF.
- Conditions
- Idiopathic Pulmonary Fibrosis
- Being tested
- Nitric Oxide, Medical air
- Keywords
- Exertional Dyspnea, Exercise, Nitric Oxide, Idiopathic Pulmonary Fibrosis
- Medical subject headings
- Idiopathic Pulmonary Fibrosis, Motor Activity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nitric OxideDrug
Also called KINOX
Nitric oxide gas for inhalation
Medical airDrug
Also called Medical grade air
Medical grade air for inhalation (placebo)
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Inhaled medical grade normoxic gas (FiO2 = 0.21; DIN 02238755 Air Liquide Healthcare, Montreal, Quebec, Canada). Receives: 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). Receives: Drug: Nitric Oxide |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: During exercise test on visit 4 and 5, every 1 minute, through end-exercise (average time 6-10minutes).
Secondary outcomes (1)
Dyspnea Intensity
Dyspnea (respiratory discomfort) will be defined as the "sensation of breathing discomfort" experienced at rest and during pedaling. Measurements will be made at rest (the steady-state period after at least 3 minutes of breathing on the mouthpiece before exercise starts), at two-minute intervals during exercise, and at end-exercise (at 2 minutes or the last 30-sec of loaded pedaling achieved by all the participants). The intensity (strength) of sensations will be rated using the modified 10-point Borg scale.
Measured: During exercise test on visit 4 and 5, every 1 minute, through end-exercise (average time 6-10minutes).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Sep 2021
- Study start21 Apr 2022
- Primary completion30 Dec 2024 (estimated)
- Study completion28 Feb 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Idiopathic Pulmonary FibrosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Single center, randomized, double-blind, cross-over design
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Dr. Denis O'Donnell
- Sponsor type
- University, hospital or other
- Collaborators
- Boehringer Ingelheim
- Responsible party
- Sponsor-investigator, Dr. Denis O'Donnell, Queen's University
- Investigators
- Denis E O'Donnell, MD, Principal investigator, Principal Investigator, Professor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05052229
- Sponsor's protocol ID
- DMED 2495-21
- Other IDs
- BI 1199.0477
- Status last verified
- Apr 2024
- First submitted
- 2 Sep 2021
- Last updated
- 3 Apr 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 32758677Faisal 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.
PubMed 26407036Farina 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.
PubMed 29579597Kolb 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.
PubMed 30220235Nathan 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.
PubMed 32092321Phillips 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.
PubMed 33428233
Study at a glance
From the registry record, last updated by the sponsor on 3 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pulmonary Gas Exchange and Neuro-sensory Abnormalities in Patients With Idiopathic Pulmonary Fibrosis and Mild Mechanical Restriction. Implications for Dyspnea and Exercise Intolerance
- ClinicalTrials.gov ID
- NCT05052229
- Acronym / sponsor ID
- DMED 2495-21
- Conditions
- Idiopathic Pulmonary Fibrosis
- Keywords
- Exertional Dyspnea, Exercise, Nitric Oxide, Idiopathic Pulmonary Fibrosis
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Dr. Denis O'DonnellUniversity, hospital or other
- Collaborators
- Boehringer Ingelheim
- Study start
- 21 Apr 2022 (actual)
- Primary completion
- 30 Dec 2024 (estimated)
- Study completion
- 28 Feb 2025 (estimated)
- First posted
- 22 Sep 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease characterized by bi-basilar sub-pleural honeycombing, septal thickening, and traction bronchiectasis. Patients with IPF, even in mild cases, have a reduced exercise capacity which is strongly associated with exertional breathlessness (dyspnea). Our previous work in IPF has shown that dyspnea during exercise is associated with increased inspiratory neural drive (IND) compared with healthy controls. High IND, in turn, is related to a combination of 1) reduced ventilatory efficiency (i.e. increased ventilation relative to carbon dioxide production (V̇E/V̇CO2)); 2) abnormal dynamic breathing mechanics (blunted tidal volume (VT) and critically low inspiratory reserve volume (IRV)), especially in more advanced disease, and; 3) impaired pulmonary gas-exchange (i.e. diffusion limitation and arterial hypoxemia).
Preliminary work from our laboratory in patients with IPF but only mild restriction (total lung capacity (TLC) >70% predicted) demonstrated elevated IND and dyspnea during exercise, when compared to healthy age- and sex-matched controls. The increased IND appeared to be largely the result of the excess ventilation (high V̇E/V̇CO2), as dynamic respiratory mechanics (VT and operating lung volumes) during exercise were similar to healthy controls, when accounting for ventilation. Importantly, these patients showed only minor decreases in arterial O2 saturation. These data suggest that patients with mild forms of IPF have significant exertional dyspnea, secondary to reduced ventilatory efficiency (high V̇E/V̇CO2), although the exact mechanisms of elevated V̇E/V̇CO2 in mild IPF remains unclear.
Increased chemosensitivity has been linked to elevated V̇E/V̇CO2 in cardiopulmonary diseases. It is reasonable to postulate that persistent V̇A/Q̇ mismatch with elevated total physiological dead space and possible sympathetic over-excitation may alter central medullary chemoreceptor characteristics in patients with IPF, at least partially explaining elevated exercise V̇E/V̇CO2. Pulmonary microvascular abnormalities may also be a key contributor to the increased dead space and V̇E/V̇CO2 during exercise in IPF. Patients with IPF and mild mechanical restriction have relatively preserved gas transfer between the alveoli and capillaries, even in fibrotic lung regions with interstitial thickening. This suggests that regional capillary hypoperfusion in IPF with mild restriction, despite a relatively preserved alveolar-capillary interface, may lead to V̇A/Q̇ mismatch (specifically an increased proportion of high V̇A/Q̇ lung units), which would increase total physiologic dead space and V̇E/V̇CO2. The relative contribution of increased chemosensitivity and/or pulmonary microvascular abnormalities to elevated exercise V̇E/V̇CO2 in patients mild IPF has not been determined and are the primary focus of this study.
Treatment options for dyspnea management in IPF are limited. Recent work from the INSTAGE trial showed that a combination of nintedanib (anti-fibrotic) and sildenafil (pulmonary vasodilator) showed minimal improvement in dyspnea. However, improvements in physical activity and gas-exchange in patients with IPF following 8-week treatment of inhaled nitric oxide (iNO), a selective pulmonary vasodilator have been demonstrated in other, more recent studies. Since patients with mild forms of IPF are thought to have a relatively intact capillary bed but a relatively high physiological dead space due to attenuation of regional pulmonary perfusion, inhaled selective vasodilation may be more beneficial than in advanced disease with fixed microvascular destruction. This is supported by recent work demonstrating a reduced V̇E/V̇CO2 (reflecting a decrease in physiological dead space) and dyspnea during exercise in patients with mild chronic obstructive pulmonary disease with minimal or no emphysema. Importantly, arterial O2 saturation was normal throughout exercise and unaffected by iNO, which suggests no deleterious effects of iNO on overall gas-exchange. The reduction in V̇E/V̇CO2 during exercise with iNO suggests that iNO increases pulmonary microvascular perfusion heterogeneity, leading to improved V̇A/Q̇ matching, reduced dead space and therefore a lower ventilation for a given metabolic demand.
As an exploratory outcome, we will determine whether iNO improves V̇A/Q̇ and reduces dead space and attendant dyspnea, in patients with IPF and mild mechanical restriction. Moreover, this would clearly establish if partially reversible vascular dysfunction contributes to V̇A/Q̇ mismatch, elevated V̇E/V̇CO2, inspiratory neural drive and dyspnea exists in non-hypoxemic patients with IPF and minimal mechanical abnormalities.
Rationale: It has been well established that patients with advanced IPF have mechanical and pulmonary gas exchange abnormalities which require compensatory increases in inspiratory neural drive and an exaggerated ventilatory response to exercise with consequent increase in activity-related dyspnea. However, very little work has been done to understand mechanisms of exertional dyspnea in patients IPF in whom restrictive mechanics and hypoxemia are not prominent. The proposed work has the potential to not only provide important physiological insight into the underlying mechanisms for increased V̇E/V̇CO2 and inspiratory neural drive, but also to examine therapeutic avenues to improve ventilatory efficiency, dyspnea, exercise capacity and ultimately quality of life in patients with IPF.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- Model description
- Single center, randomized, double-blind, cross-over design
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: Medical airInhaled medical grade normoxic gas (FiO2 = 0.21; DIN 02238755 Air Liquide Healthcare, Montreal, Quebec, Canada). |
| Nitric Oxide | Active comparator | Drug: Nitric OxideInhaled 40 ppm nitric oxide from a KINOX gas cylinder system (Air Liquid Healthcare, Montreal, Quebec, Canada; DIN 02451328). |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
- A key IPF inclusion criterion includes, in addition to the above, a clinical diagnosis of idiopathic pulmonary fibrosis.
Key exclusion criteria (9 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nitric OxideAlso: KINOXNitric oxide gas for inhalation | Drug | Nitric Oxide |
| Medical airAlso: Medical grade airMedical grade air for inhalation (placebo) | Drug | Placebo |
Primary outcome
Ventilatory efficiency (VE/VCO2)
Time frame: During exercise test on visit 4 and 5, every 1 minute, through end-exercise (average time 6-10minutes).
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.
Inspiratory Neural Drive (IND) as measured by Diaphragmatic electromyography (EMGdi)
Time frame: During exercise test on visit 4 and 5, every 1 minute, through end-exercise (average time 6-10minutes).
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.
1 secondary outcome
Dyspnea Intensity
Time frame: During exercise test on visit 4 and 5, every 1 minute, through end-exercise (average time 6-10minutes).
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Apr 2024.
- Background: PubMed 32758677Milne 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.
- Background: PubMed 26407036Faisal 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.
- Background: PubMed 29579597Farina 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.
- Background: PubMed 30220235Kolb 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.
- Background: PubMed 32092321Nathan 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.
- Background: PubMed 33428233Phillips 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Denis E O'Donnell, MD principal investigator
Principal Investigator, Professor
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Nitric Oxide and Medical air in people with Idiopathic Pulmonary Fibrosis, run by Dr. Denis O'Donnell at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 3 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Devin Phillips, Ph.D. (6135496666 ext. 4950, RIU@queensu.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Ventilatory efficiency (VE/VCO2) (time frame: During exercise test on visit 4 and 5, every 1 minute, through end-exercise (average time 6-10minutes).). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05052229, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Apr 2024.