Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03522831 |
| Other study ID # |
H17-02029 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2018 |
| Est. completion date |
December 31, 2024 |
Study information
| Verified date |
December 2023 |
| Source |
University of British Columbia |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
It is estimated that one in every 3,600 children in Canada has cystic fibrosis (CF). CF is a
genetic disease that affects the glands that produce mucus and sweat. In CF, mucus production
increases and the mucus becomes thick and sticky. This can block the airways, making it
difficult to breathe. Mucus production also causes bacteria to grow, which can lead to
infections in the lungs. Individuals with CF suffer from shortness of breath, wheezing,
cough, and poor exercise capacity. There are limited treatment options to reduce shortness of
breath in these individuals. Some medications known as bronchodilators are commonly
prescribed to reduce breathlessness in patients with CF. These drugs help open the airways
making it easier to breathe. Unfortunately, there is limited scientific proof that these
drugs can reduce shortness of breath and improve exercise capacity in patients with CF. As a
result, some experts have recommended that these drugs should not be prescribed for patients
with CF. The purpose of this study is to examine the effects of a bronchodilator on shortness
of breath, exercise performance, and breathing responses compared to a placebo drug in adults
with CF.
Description:
BACKGROUND
Exertional dyspnea is a symptom that reduces quality of life and is associated with reduced
exercise tolerance in individuals with cystic fibrosis (CF). Lung hyperinflation has been
suggested to be an important factor contributing to dyspnea in CF. Dynamic hyperinflation
during exercise testing has been reported in up to 58% of CF patients with mild-to-moderate
CF lung disease and is associated with reduced exercise tolerance and increased exertional
dyspnea.
Dynamic lung hyperinflation also occurs in chronic obstructive pulmonary disease (COPD) and
is believed to be a major cause of exertional dyspnea and exercise limitation. Bronchodilator
use in COPD has been shown to reduce lung hyperinflation and improve exertional dyspnea and
exercise tolerance; however, there is limited data available in CF despite the
pathophysiological similarities between these conditions. Although a majority of individuals
six years and older with CF are prescribed bronchodilators, evidence to support the chronic
use of bronchodilators has been insufficient.
Unlike acute bronchodilator reversibility testing during routine spirometry, cardiopulmonary
exercise testing (CPET) is a highly sensitive and reproducible tool to assess the efficacy of
bronchodilators in CF. CPET can be used to identify significant physiological abnormalities
even in patients with mild CF lung disease with relatively normal spirometry. Compared to
healthy age-matched controls during exercise, adults with mild-to-moderate CF have: greater
exertional dyspnea; higher ventilatory requirements; earlier constraints on tidal volume
expansion; increased operating lung volumes; an earlier onset of unpleasant dyspnea
descriptors (i.e. unsatisfied inspiration); and are more likely to experience "chest
tightness". All of these abnormalities are, in theory, amenable to change following
bronchodilator therapy.
Very few studies have evaluated the effects of short-acting bronchodilators on exercise in CF
using CPET. In these studies, despite improvements in forced expiratory volume in one second
(FEV1), short-acting β2-agonists (SABA) failed to show any effect on maximal exercise
parameters including workload, oxygen uptake, dyspnea, and leg discomfort ratings.
Unfortunately, these studies used incremental exercise tests and focused on peak dyspnea
responses, which are often unresponsive to most pharmacological and non-pharmacological
interventions. A more clinically and physiologically relevant protocol is to use constant
work rate exercise tests and to evaluate dyspnea at standardized submaximal exercise times.
This approach has been highly effective in showing beneficial effects of bronchodilators in
COPD. Accordingly, the purpose of this study is to evaluate the acute effects of SABA on
sensory, physiological, and exercise performance outcomes in adults with CF. We hypothesize
that SABA will reduce dyspnea intensity ratings and ventilatory limitations, delay the onset
of unpleasant dyspnea descriptors, and will improve exercise performance compared to placebo.
These findings would support future guideline recommendations for the use of SABAs to improve
dyspnea and exercise tolerance in patients with CF.
METHODS
Experimental Overview: This randomized, double-blind, placebo-controlled, crossover study
will include a total of four visits to the Cardiopulmonary Exercise Physiology Laboratory at
St. Paul's Hospital.
Visit 1 will include medical history screening, chronic activity-related dyspnea, quality of
life, and physical activity questionnaires, anthropometric measurements, pulmonary function
assessment, and a symptom-limited incremental cycle exercise test to determine peak
incremental work rate. On visit 2, participants will perform a constant-load cycle exercise
test at 75% of peak incremental work rate (from visit 1) in order to familiarize participants
with the exercise protocol and experimental procedures. Visits 3 and 4 will include baseline
pulmonary function testing followed by inhalation of either 400 μg salbutamol or matched
placebo, in a 2x2 crossover randomized design. Approximately 10 minutes after administration
of salbutamol or placebo, subjects will undergo pulmonary function testing and the same
constant-load cycle exercise test performed on visit 2. All visits will take place at the
same time of day. Visits 1 and 2 will be separated by a minimum of 48 hours and visits 3 and
4 will be separated by a minimum of one week and a maximum of five weeks. Participants will
be instructed to perform their usual daily chest physiotherapy and will be required to
withhold SABAs, nebulized therapies, and caffeine for a minimum of 6 hours, and long-acting
bronchodilators and strenuous exercise for 24 h prior to each visit.
Randomization and Blinding: The random allocation sequence will be computer-generated in
blocks of four. Drugs will be prepared as two identical meter-dose inhalers, which will be
administered according to the blinded randomization sequence. Drug administration will be
performed using identical large-volume spacers. The unblinding code will be held by an
individual not involved in the study, and all data collection and analysis will be performed
before the treatment codes are broken. All investigators and staff will be unaware of
treatment allocations at all times.
Outcome Measures: Primary Efficacy Endpoint: Change in standardized dyspnea score at the
highest equivalent submaximal exercise time achieved on both constant load exercise tests
(i.e., iso-time) between salbutamol vs. placebo. Secondary Efficacy Endpoints: Exercise
endurance time, standardized leg discomfort score, qualitative dyspnea measurements,
spirometry, plethysmographic lung volumes, airways resistance, impulse oscillometry derived
variables, and metabolic and cardiopulmonary parameters (e.g. ventilatory responses,
inspiratory capacity/dynamic hyperinflation, operating lung volumes, expiratory flow
limitation, breathing patterns, metabolic responses, and arterial oxygen saturation).
Exercise Protocol: A symptom-limited incremental exercise test will be performed on visit 1
using an electronically braked cycle ergometer (Ergoselect 200P; Ergoline GmbH, Bitz,
Germany), according to recommended guidelines for cardiopulmonary exercise testing. The test
will consist of steady-state rest for six minutes, a one minute warm-up of unloaded pedaling,
and 10-20 watt stepwise increases in work rate, every minute until symptom-limitation using a
self-selected cadence. Constant-load exercise tests on visits 2, 3, and 4 will include rest
and warm-up periods followed by an immediate increase in work rate to 75% of maximal work
(determined on visit 1) until symptom-limitation, using a cadence >50 rpm.
Pulmonary Function: Spirometry, plethysmography, diffusing capacity of the lungs for carbon
monoxide, maximum respiratory pressures, and impulse oscillometry will be performed on visit
1, according to established recommendations. Pulmonary function testing on visits 3 and 4
will include spirometry, plethysmography, and impulse oscillometry performed before and ~10
minutes after administration of salbutamol and placebo. A commercially available
cardiopulmonary testing system will be used, and all measurements will be expressed as
percentage of predicted values.
Dyspnea Evaluation: Dyspnea intensity (defined as "the sensation of laboured or difficult
breathing") and perceived leg discomfort will be evaluated at rest, every minute during
exercise, and at peak exercise using the modified 0-10 category-ratio Borg scale, on all
testing visits. Participants will be asked to select the most applicable dyspnea
descriptor(s) after the intensity ratings using the following three descriptors: (1) "my
breathing requires more work and effort" (work and effort); (2) "I cannot get enough air in"
(unsatisfied inspiration); (3) "I cannot get enough air out" (unsatisfied expiration). None
to all three of the descriptors can be chosen at any one time. Upon exercise cessation,
participants will be asked to verbalize their main reason(s) for stopping exercise (i.e.,
breathing discomfort, leg discomfort, combination of breathing and legs, or some other
reason) and to select qualitative descriptors of breathlessness using an established
questionnaire.
Cardiorespiratory Responses to Exercise: Standard cardio-respiratory measures will be
recorded and averaged over 30-second epochs, including minute ventilation, oxygen
consumption, carbon dioxide production, tidal volume, and breathing frequency using a
commercially available system (Parvo Medics TrueOne 2400). Heart rate will be monitored using
a 12-lead electrocardiogram (ECG), blood pressure will be measured using a manual
sphygmomanometer, and arterial oxygen saturation will be monitored using pulse oximetry prior
to, during, and after all exercise testing.
Operating volumes (i.e., end-expiratory and end-inspiratory lung volumes) will be derived
from dynamic inspiratory capacity maneuvers as previously described. Expiratory flow
limitation will be measured by placing tidal flow-volume loops within the maximum flow-volume
loop. Briefly, a maximum flow-volume loop will be constructed by taking the highest
expiratory flows for any given lung volume from a series of graded vital capacity maneuvers
performed before and after exercise to account for both thoracic gas compression and
exercise-induced bronchodilation. Tidal flow-volume loops will be ensemble averaged and
placed within the maximum flow-volume loop according to the measured end-expiratory lung
volume. The degree of expiratory flow limitation will be calculated as the percentage overlap
between the expired portion of the ensemble averaged tidal flow-volume loop and the maximum
flow-volume loop.
Sample Size and Statistical Analyses: The primary endpoint for this study will be dyspnea
ratings during exercise at iso-time, defined as the highest equivalent submaximal time
achieved during both constant-load exercise tests by a given patient. Using a two-tailed
paired subject formula with α=0.05 and β=0.80, we estimate that 16 participants are needed to
detect a minimal clinically important difference of ±1 Borg 0-10 scale units at iso-time
between treatments, assuming a standard deviation of ±1 Borg 0-10 scale units. Assuming a 20%
rate of attrition, at least 20 participants will need to enter the study to ensure adequate
power for the primary and secondary endpoints.
Paired t-tests or Wilcoxon signed-rank tests will be used to identify changes in iso-time
dyspnea (primary outcome) and secondary outcome measures (e.g. endurance time; iso-time leg
discomfort ratings, operating volumes, etc.) comparing salbutamol to placebo. Possible
crossover and period effects for all outcomes will be assessed using paired t-tests according
to recommended guidelines for design and analysis of crossover trials. Qualitative
descriptors of dyspnea and reasons for stopping exercise will be compared using McNemar's
test. Multivariate models will be developed to identify predictors of between-test
differences in outcomes (e.g. iso-time Borg dyspnea scale and exercise endurance time) for
each individual. Predictor variables will include the between-test difference in operating
lung volumes, dynamic hyperinflation, and expiratory flow limitation at iso-time.
