Microsoft word - lung flute_therapeutic study manuscript_final.doc
Comparison of the Lung Flute® with the Acapella® in the Treatment of COPD with
Sanjay Sethi, M.D. 1,2 Jane Maloney, R.N. 2 Lori Grove, B.S. 2
1 VA WNY Health Care System, Buffalo, NY and 2 University at Buffalo, SUNY,
Corresponding Author: Sanjay Sethi, M.D.
Source of support: Medical Acoustics, Inc.
Chronic obstructive pulmonary disease (COPD) is characterized by mucus hypersecretion
that contributes to the morbidity and is associated with increased mortality. The Lung Flute® is a
new oscillatory positive expiratory pressure (OPEP) device that produces a low frequency
acoustic wave with vigorous exhalation that increases mucociliary clearance. We hypothesized
that the Lung Flute®, used on a twice daily basis will provide clinical benefit to patients with
COPD with chronic bronchitis. Acapella®, an OPEP device which is currently available and
approved for the clearance of respiratory secretions was used as a comparator in a randomized
open label eight week trial in 40 COPD patients. Thirty seven patients completed the study. For
the primary end point, change in 24 hour dry sputum weight from baseline, the two treatments
were equivalent. At 8 weeks, both devices improved symptoms as assessed by the Chronic
COPD questionnaire as well as quality of life as assessed by St. George Respiratory
questionnaire, with the Lung Flute® associated with larger changes than the Acapella®. There
was no change in baseline lung function over 8 weeks in both arms. Adverse effects were minor,
with only 1 patient discontinuing treatment because of musculoskeletal chest discomfort related
to blowing vigorously in the Lung Flute® in the initial week of treatment. The Lung Flute® is a
safe and effective OPEP treatment for mucus hypersecretion in COPD, and is equivalent to the
Mucus hyperesecretion and impaired mucociliary clearance is a common problem in
patients with COPD, and contributes significantly to the morbidity and mortality of this disease
(1, 2). In spite of the need for efficacious, convenient and safe treatment for mucus
hypersecretion, current choices are few with limited data to support their efficacy in COPD (3,
4). The Lung Flute® is a new small self-powered audio device that belongs to the family of
Oscillatory Positive Expiratory Pressure (OPEP) devices, which includes the Flutter and the
Acapella (5, 6). When blown into with an exhalation vigorous enough to make the reed
oscillate, the Lung Flute® generates a sound wave of 16 to 22Hz with an output of 110 to 115 dB
using 2.5cms H2O of pressure. This sound wave has the ability to travel down the
tracheobronchial tree and vibrate tracheobronchial secretions. This vibration enhances
mucociliary clearance of the lower respiratory tract thereby resulting in the induction of sputum.
This functionality of the Lung Flute® has been applied to sputum induction for diagnostic testing,
for which it is currently a Food and Drug Administration (FDA) approved device.
We hypothesized that the ability of the Lung Flute® to enhance mucus clearance from the
lower airways could be used for therapeutic purposes in COPD, if the device was used on a
chronic basis. This report is the first systematic evaluation of the therapeutic application of the
Lung Flute® in human subjects. The efficacy and safety of the Lung Flute® in a group of COPD
patients with chronic bronchitis was compared with a predicate device, the Acapella® (Smiths
Medical), which works on a similar principle and is available for therapeutic use in lung
hypersecretory disorders. The primary end point of the study was the comparison of 24 hr dry
sputum weights with the use of the Lung Flute® as compared to the Acapella®. Several
secondary end points were assessed for efficacy and safety, including COPD symptoms, health
status, spirometric lung function and daily albuterol use.
This was an eight-week, randomized, controlled, two arm parallel study that was powered to
demonstrate equivalency of the new device, the Lung Flute®, to the predicate device, the
Acapella®. The study was open label. The clinical trial registration number of this trial is
The study was approved by the Human Studies subcommittee for the VA WNY Healthcare
system. We planned to enroll 40 subjects with COPD with chronic bronchitis at a single center
(Buffalo VA Medical Center). Inclusion criteria were: a) at least 40 yrs of age, b) presence of
airflow obstruction by spirometry (GOLD Stage 2-4), c) presence of chronic bronchitis, i.e.
cough productive of sputum on most days of the week, d) current smoker or ex-smoker with at
least 10 pack yrs of smoking history (7). Exclusion criteria were a) exacerbation of COPD or
hospitalization for COPD within 8 weeks prior to enrollment, b) predominant asthma and
bronchiectasis by clinical assessment, c) history of cough syncope d) pregnant or nursing women
e) inability to comply with study procedures.
The study consisted of a screening visit, two weeks of intervention–free run-in, a
randomization visit and then on treatment clinic visits at 1, 2, 4, 6, and 8 weeks. Participants
who met the inclusion/exclusion criteria on screening were enrolled and provided with a daily
paper dairy to record symptoms and rescue albuterol use. In addition they were instructed to
provide two 24 hr sputum collections over the next 2 weeks. A randomization visit was done
within 2 weeks of the enrollment visit. Participants who were compliant with the 24 hr sputum
collection and at least 50% of the daily dairy entries were randomized to either the Lung Flute®
or the Acapella®. Randomization was done by a pre-specified randomization table. Detailed
instructions for the use of either device were provided as follows. For the Acapella®,
participants were instructed to watch the instructional video provided by the manufacturer, the
device was adjusted for the participant as per the manufacturer’s instructions, and they were
instructed to use the device twice a day for 2 cycles consisting of 20 breaths followed by 3 huff
coughs. For the Lung Flute®, participants were instructed to blow twice in to the device
vigorously enough to make the reed oscillate, followed by 5 normal breaths. This was repeated
10 times, followed by 3 huff coughs to complete 1 cycle. Two such cycles were recommended
twice a day. Baseline Spirometry, Clinical COPD questionnaire (CCQ) and St. George’s
Respiratory Questionnaire (SGRQ) were obtained at the randomization visit (8-10).
Participants were instructed to complete a daily dairy every evening in which they
recorded their breathlessness, cough and sputum severity on the breathlessness, cough and
sputum scale (BCSS), as well as the number of puffs of rescue albuterol used in the past 24 hrs
(11). At each subsequent on therapy clinic visit, 24 hour sputum samples were collected, a
clinical examination was performed, adverse effects were recorded and daily diaries were
collected. In addition, at the end of therapy 8 week visit, spirometry, CCQ and SGRQ were
completed. The Lung Flutes® were replaced at every visit and the patient was instructed to use
Twenty four hr sputum collections were transferred to pre-weighed centrifuge tubes and
weight of total sputum was measured. All samples were then centrifuged at 10,000g for 10mins
at 4oC, and the supernatant obtained was removed. The residual pellet and tube were re-weighed
and the dry sputum weight was obtained by subtracting the tube weight from the value obtained.
The primary endpoint of dry sputum weight was assessed by using mixed models. Mixed
models were also used to determine changes in daily BCSS scores and use of inhaled albuterol
from baseline in the two groups of patients. Secondary end-points of changes between baseline
and week 8 in spirometric measures, SGRQ and CCQ were assessed by paired t tests. A p<0.05
We enrolled 45 subjects, of which 5 subjects either did not meet the initial
inclusion/exclusion criteria (n=3) or did not meet the compliance criteria between the enrollment
and randomization visit (n=2). Of the 40 subjects who were randomized, 20 each were
randomized to the 2 devices. Of these 40 subjects, 37 completed the study. Of the 3 subjects
who did not complete the study, one was randomized to the Acapella® (participant was non-
compliant with study instructions) and 2 were randomized to the Lung Flute® (1 discontinued
Lung Flute® after 1 week of use because of musculoskeletal chest discomfort with use of the
device and 1 was non-compliant with study instructions).
Baseline clinical characteristics of the forty subjects randomized into the study are
described in Table 1. There were no statistically significant differences in the demographics,
smoke exposure history and lung function between the subjects enrolled in the two arms of the
Comparison of dry sputum weights between the Lung Flute® and the Acapella®
In order to test the overall treatment effect on dry sputum weight over the course of the
study, mixed effects analysis were performed. These models allow us to account for the
longitudinal nature of the data. We assumed that the observations collected within each patient
were correlated; however, observations collected across patients were assumed to be
independent. Dry sputum weights obtained prior to and at randomization were regarded as
baseline measurements, while those obtained at week 1, 2, 4, 6 and 8 were examined for
treatment effects. Neither device use had a statistically significant sustained effect on 24 hr
sputum volumes (Figure 1). Furthermore, we did not find any difference between the effects of
the Lung Flute® vs. Acapella® on the dry sputum weight over the course of the study (p = 0.94).
Spirometric data was collected primarily to document safety of the interventions. Pre-
and Post-bronchodilator spirometry was obtained at the randomization visit and at Week 8.
Though there were small improvements in the parameters in both arms, there were no
statistically significant differences in the post-bronchodilator values from baseline in any of the
The CCQ is an objective validated tool to assess COPD symptoms. CCQ was measured
at the randomization visit and at the end of the study visit at week 8. There was a significant
improvement in the CCQ (3.24 ± 0.30 at randomization, 2.82 ± 0.26, mean decrease of 0.41
units, p = 0.007, paired t-test) in patients who were using the Lung Flute®. A smaller and
statistically non-significant improvement in the CCQ (2.53 ± 0.20 at randomization, 2.29 ± 0.25,
mean decrease of 0.24 units, p = 0.16) was seen in patients who were using the Acapella®
(Figure 2). The change in CCQ was not statistically different between the two treatments
(p=0.44). The minimal important difference (MID) for the CCQ is 0.4 units, which was met on
an average by the patients in the Lung Flute® arm but not the Acapella® arm. These results
demonstrate a greater efficacy of the Lung Flute® in improving COPD symptoms as compared to
the Acapella and this efficacy was clinically meaningful.
SGRQ is a well validated, widely used health status questionnaire specific for COPD. Its
MID is 4 units. With the Lung Flute®, an improvement is health status of 4.71 ± 2.53 (SEM)
units in the total SGRQ score was seen at the end of study (8 weeks) visit as compared to the
randomization. This difference in total SGRQ score was however not statistically significant (p
=0.08). Improvements were noted in all 3 domains of symptoms, activity and impact of the
SGRQ (Table 3). With the use of the Acapella®, small non-statistically significant changes in
total SGRQ (0.44 ± 1.82 units), as well as in the domain scores were seen (Table 3). The change
in SGRQ total score was not statistically different between the two treatments (p=0.19). These
results suggest that the Lung Flute® had a larger effect on improvement of quality of life in
Breathlessness cough and sputum score is a well validated measure of daily symptoms of COPD,
with a MID of 0.3 units. In a mixed model analysis, with the Acapella®, a mean ± SEM decline
of 0.35 ± 0.18 units in the BCSS from 2.82 ± 0.10 units pre-treatment to 2.43 ± 0.05 units during
treatment was seen (p=0.05). Use of Lung Flute® resulted in a mean ± SEM decline of 0.26 ±
0.18 units in the BCSS from 3.79 ± 0.10 units pre-treatment to 3.63 ± 0.05 units during treatment
was seen (p=0.16). The changes were statistically similar in the two treatment arms (p= 0.72).
Both devices improved symptoms assessed by the BCSS score, with the Acapella® showing a
larger effect which reached the threshold of a minor clinically important improvement. Reported
daily albuterol use did not change significantly in either arm.
There were no serious adverse events or mortality in this study. Only 1 person dropped
out of the study at week 1, because of musculoskeletal chest discomfort with blowing in the
Lung Flute®. Three other patients complained of similar discomfort at week 1, however, these 3
patients continued in the study and the chest discomfort resolved spontaneously in spite of
continuing use of the device. The Acapella® was not associated with such chest discomfort. The
most common adverse effect were cold symptoms, 6 episodes were seen in the Acapella® arm
while 3 such episodes were seen in the Lung Flute® arm. Two COPD exacerbations occurred
during the study, both in patients using the Lung Flute®. Table 4 lists all the adverse effects
observed in the study that were respiratory or thought to be possibly related to the study devices.
The Lung Flute® has been shown to be efficacious in inducing sputum when used once
and is approved for such use to obtain diagnostic sputum samples. In this first study of repeated
use for therapeutic purposes, the Lung Flute® was equivalent to a similar device, the Acapella®,
in its effects on 24 hour dry sputum weight. However, a consistent increase in dry sputum
weight was not seen with either device in this study, which is consistent with observations made
in other studies with other mechanical treatments of lung hypersecretory disorders (3, 5, 6). In
this and other studies, patients do appear to benefit from these treatments. This would suggest
that dry sputum weight is not a good correlate of clinical efficacy of measures to improve lung
clearance. The measurement of dry sputum weight is confounded by salivary contamination, day
to day variability, swallowing, and its inability to detect changes in ease of expectoration.
Clinical benefit was also assessed in several secondary end points in this study. Both the
Lung Flute® and the Acapella® improved COPD symptoms, which were assessed with two
different measures, the CCQ and the BCSS. A larger reduction in symptoms was seen with the
Lung Flute® with the CCQ, while the reverse was true with the BCSS. However, the differences
between the two devices were not statistically significant. Disease related health status is an
important efficacy end point in COPD. The Lung Flute® did show larger improvements in health
status than the Acapella® as measured by the SGRQ, though the difference did not reach
statistical significance. Though dry sputum weight did not change, subjective benefit in health
status and symptoms is seen with OPEP treatment in COPD.
The Lung Flute® and Acapella® were both well tolerated. As the Lung Flute® required
vigorous exhalations to achieve oscillation of the reed, musculoskeletal discomfort was seen in
20% of patients in the first week. However, only 1 of 20 (5%) patients discontinued use of the
device because of this discomfort, while in the other 3 patients it was transient. Other adverse
events were minor and appeared to be unrelated to treatment. Transient throat irritation, which
was the most common adverse effect with single use of the Lung Flute®, was not seen with
The mechanism of action that results in clinical benefits of Lung Flute® and Acapella® in
COPD is presumed to be increased mucocilary clearance of tracheobronchial secretions.
However, a limitation of this study was the absence of measurement of mucociliary clearance.
Other limitations of this study include the lack of blinding, which is difficult in device studies.
The duration of the interventions was not long enough and the study was not large enough to
determine if other parameters such as lung function and exacerbation frequency were impacted
with the Lung Flute® or the Acapella®.
There is a paucity of treatments that have demonstrated efficacy in the treatment of
mucus hypersecretion in COPD. Currently available mucolytics and expectorants are of
unproven efficacy in COPD, and the beneficial effects of agents such as n-acetylcysteine and
carbocisteine are more likely related to their antioxidant effects rather than their mucolytic
effects (12, 13). Mechanical means to improve mucus clearance in hyperesecretory lung
conditions including Oscillatory PEP devices such as the Acapella® and Flutter, chest vibration
and percussion and breathing techniques have not been tested systematically in stable COPD .
This study demonstrates that oscillatory PEP devices are of potential benefit in COPD patients
with mucus hypersecretion. Further studies with the Lung Flute® should explore mechanisms
and clinical benefit with longer term use in COPD and other hypersecretory lung diseases.
FEV1 = Forced expiratory volume in 1 second, FVC = Forced vital capacity in1 second.
Table 2. Comparison of spirometric lung function at Randomization visit and Week 8 visit in the
Table 3. SGRQ total and domain scores at baseline and week 8 (End of treatment, EOT).
Table 4. Respiratory and treatment emergent adverse events during the course of the study.
Figure 1. Twenty four hours dry sputum weights (mean ± 1 SEM) during the course of the
study. Week 0 represents averaged values from 2 sputum collections obtained between the
Figure 2. Change in Chronic COPD questionnaire scores from Baseline to Week 8 (End of
treatment, EOT). Each horizontal bar represents an individual patient. The p values are from
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Deborah Yeh Chong, MD _____________________________________________________________________________________________________________ WORK EXPERIENCE Associate, Texas Retina Associates. Dallas, TX. Assistant Professor, Medical and Surgical Diseases of the Vitreous, Retina, and Macula. Department of Ophthalmology. University of Texas Southwestern Medical Center. TRAINING &