Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT03679312 |
Other study ID # |
Pro00078715 |
Secondary ID |
|
Status |
Completed |
Phase |
Phase 1/Phase 2
|
First received |
|
Last updated |
|
Start date |
September 4, 2018 |
Est. completion date |
November 20, 2023 |
Study information
Verified date |
January 2024 |
Source |
University of Alberta |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Chronic Obstructive Pulmonary Disease (COPD) is a lung disorder commonly caused by smoking,
which makes breathing more difficult. When COPD patients exercise, they are not efficient
breathers and this leads to serious breathing difficulties, which often causes these patients
to stop exercise at low intensities. Even though patients with a mild form of COPD have
relatively well preserved lung function, they still have inefficient breathing during
exercise. The investigators think that these patients have problems exchanging fresh gas
(i.e., oxygen) into the blood stream because of poor lung blood vessel function. The
investigators will test whether inhaled medications, specifically nitric oxide, can improve
lung blood vessel function and decrease breathing difficulties during exercise. With this
research, the investigators will understand more about breathing efficiency and lung blood
vessel function in patients with COPD, and find out whether improving lung blood vessel
function helps COPD patients breathe easier and exercise longer. Understanding the reasons
behind the feeling of difficult breathing may lead to more effective therapy and improved
quality of life in COPD patients.
Description:
Chronic Obstructive Pulmonary Disease (COPD) is a respiratory disorder typically caused by
smoking and is characterized by airway obstruction. Exertional dyspnea (perceived
breathlessness) is a hallmark of COPD regardless of severity and is the primary reason for
exercise intolerance even in patients with mild COPD (defined using spirometric criteria as a
forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.70 and a FEV1 ≥ 80%).
Dyspnea in COPD has been shown to profoundly reduce patient quality of life, physical
activity, and impair patients' ability to complete day-to-day tasks. Previous work in mild
COPD has demonstrated that exertional dyspnea is the result of increased work of breathing
during exercise, and that this increased work of breathing comes from: 1) an exaggerated
ventilatory response to exercise (i.e. increased minute ventilation relative to carbon
dioxide production, V̇E/V̇CO2), and 2) airflow limitation (i.e. expiratory flow limitation
and resulting dynamic hyperinflation). A great deal of work has focused on improving airflow
limitation in COPD; however, very little has been done to understand and treat the
exaggerated ventilatory response to exercise in COPD.
Several previous studies in COPD have consistently shown an elevated ventilatory response
(i.e. greater V̇E/V̇CO2) during exercise. The elevated V̇E/V̇CO2 response to exercise appears
to be clinically important, as it independently predicts mortality in COPD and indicates that
physiological abnormalities beyond airflow obstruction are important in determining disease
severity, dyspnea, and risk of death. This increased V̇E/V̇CO2 in COPD appears to be
secondary to increased deadspace ventilation(i.e. sections of the lung with ventilation, but
no perfusion), and this increased deadspace ventilation results in a compensatory increase in
total minute ventilation (i.e. increased V̇E/V̇CO2) to maintain effective alveolar
ventilation and arterial blood gas homeostasis.
The underlying mechanism(s) for the increased deadspace ventilation and V̇E/V̇CO2 during
exercise in mild to moderate COPD is currently unclear; however, pulmonary microvascular
abnormalities and hypoperfusion of pulmonary capillaries are potential pathophysiologic
mechanisms. Mild to moderate COPD patients have reduced pulmonary microvascular blood flow in
nonemphysematous lung regions, which has led researchers to conclude that the low pulmonary
perfusion in an intact pulmonary vascular bed is likely the result of pulmonary vascular
dysfunction. Ventilation-perfusion (V̇A/Q̇) data in mild and moderate COPD shows substantial
V̇A/Q̇ inequality at rest, with the V̇A/Q̇ distribution skewed towards regions of high
V̇A/Q̇, which is indicative of increased deadspace. Consistent with this capillary
hypoperfusion hypothesis, our recent work has shown a blunted pulmonary capillary blood
volume response to exercise in mild COPD, when compared to age- and height-matched
non-smoking controls. Importantly, the low pulmonary capillary blood volume was associated
with increased V̇E/V̇CO2 during exercise, suggesting that low pulmonary perfusion (i.e.
reduced pulmonary capillary blood volume) leads to increased deadspace.
Inhaled nitric oxide (NO) is commonly used to test for pulmonary vasodilatory responses in
patients with pulmonary arterial hypertension (PAH), as it increases NO bioavailability and
improves pulmonary vascular function. Previous work in PAH and heart failure (HF) patients
has shown that standard doses (20-40 parts per million (ppm)) of inhaled NO can reduce
pulmonary vascular resistance and increase peak oxygen consumption (V̇O2peak). If inhaled NO
can reduce vascular dysfunction and increase perfusion in mild and moderate COPD, this would
result in a reduction in V̇E/V̇CO2 and improved exercise tolerance.
STUDY PURPOSE
Purpose: To examine the effect of inhaled NO on exercise capacity (V̇O2peak) ventilation and
dyspnea in in patents with COPD.
Hypothesis: Inhaled NO will improve exercise capacity, secondary to reduced V̇E/V̇CO2 and
dyspnea, in mild and moderate COPD, while no change will be observed in healthy controls and
severe COPD.
Study Design: Randomized double-blind cross-over design.
All participants will have a pulmonary function and cardiopulmonary exercise test. The study
procedure is briefly outlined below and is further outlined in the attached University
Hospital Foundation Grant.
Study Protocol: Seven sessions will be completed over a 3-week period in the following order:
Day 1) Participant enrollment, medical history, standard pulmonary function (PFT) and
cardiopulmonary exercise test (CPET).
Days 2 & 3) Randomly-ordered experimental CPETs while either breathing room air or inhaled
nitric oxide (room air with 40 ppm NO).
Days 4 & 5) Randomly-ordered constant load exercise tests, at 75% peak power output, while
either breathing room air or inhaled nitric oxide (room air with 40 ppm NO).
Day 6) Ultrasonography doppler measurements will be completed to determine pulmonary arterial
systolic pressure (at rest and during exercise) while breathing room air or inhaled nitric
oxide. Doppler measurements of systemic vascular endothelial function will be measured at
rest while breathing room air. To enhance doppler signal during the cardiac ultrasound,
agitated saline contrast will be used. A small sample of venous blood will be taken to
analyze inflammatory levels. Additionally, participants will breathe into a small tube so
that expelled saliva can be analyzed to determine airway inflammation.
Day 7) Prospective quantitative computed tomography (CT) imaging will be completed to obtain
lung density, heterogeneity, tissue, vascular and airway measurements.
Each visit will take approximately 3 hours. The total time duration for each participant will
be approximately 21 hours.