Non-invasive Positive Expiratory Pressure Mask (PEEP-Mask) for Tracheobronchomalacia Associated Cough
Phase: NA
Conditions: Tracheobronchomalacia
Sponsor: Duke University

Non-invasive Positive Expiratory Pressure (nPEP) Device for TBM-associated Cough 
 
NCT04169282 
Protocol version: 6/13/2019 

Non-invasive Positive Expiratory Pressure (nPEP) Device for TBM-associated Cough 
 
Abstract 
We aim to determine if an expiratory resistance device that delivers non-invasive positive 
expiratory pressure (nPEP) will abort coughing paroxysms, reduce airway resistance and 
improve quality of life in patients with tracheobronchomalacia (TBM) who are not candidates 
for tracheal stenting. 
 
Research Summary 
Patients at Duke University Hospital referred to General Pulmonary and Interventional 
Pulmonary services for evaluation of severe, debilitating TBM-related cough and possible 
tracheal stenting, but who are not candidates for tracheal stenting due to their airway 
anatomy, will be given the nPEP device. 
 
The nPEP device is assembled using mostly existing components with a history of 
respiratory applications. Specifically, a standard, adjustable (5-20 cm H2O) positive end 
expiratory pressure (PEEP) valve manufactured for attachment to a manual resuscitator 
(commonly known as bag-valve-mask) device is connected to a flexible respiratory mask. 
Patients will be instructed by the study team as to how to use the nPEP device. The patients 
will trial the nPEP device immediately during their clinical encounter and will be given a 
mask to take home for 2 weeks.  
 
Objectives-primary 
The primary objective is to determine if use of the nPEP device can decrease cough severity 
and improve cough related quality of life (QOL).  
 
Objectives-secondary 
The secondary objective is to determine if use of the nPEP device improves airway 
physiology by decreasing proximal airway resistance as assessed by impulse oscillometry. 
 
Objectives & hypothesis 
Background and significance- Tracheobronchomalacia (TBM) is a condition in which the 
cartilage and/or other connective tissue in the trachea and bronchi are weak, resulting in 
collapse of those large airways during exhalation, especially forceful exhalation as occurs with 
coughing [1]. The airway collapse with coughing leads to further, ongoing coughing, possibly 
because mechanical stimulation of the mucosa during collapse may cause localized mucosal 
inflammation or stimulation of neural circuits that control cough.  
 
TBM can cause a range of symptoms, including debilitating paroxysms of coughing, dyspnea, 
wheezing, and recurrent respiratory infections. In severe cases of TBM-related cough, patients 
experience morbidity including QOL impairment, social isolation, fatigue, loss of ability to work, 
recurrent hospital and even intensive care unit admissions.  
 
The only curative treatment for TBM is a surgical procedure called tracheobronchoplasty, in 
which the chest is opened and the posterior membrane of the trachea and/or bronchi are 
surgically affixed to nearby structures, with or without implantation of surgical mesh [2]. This is 
an approximately 6 hour procedure performed only at specialized centers with appropriate 
expertise, and only after patients have undergone and proven to benefit from temporary 
implantation of a tracheal/bronchial stent in the region of collapse. Many patients are not 
candidates for tracheobronchoplasty itself due to medical comorbidities, prefer to avoid the 

associated risks, or are not candidates for the required tracheal stenting due to trachea size or 
anatomy. These patients are left without a viable therapeutic option for their severe cough. 
 
Continuous positive airway pressure (CPAP) devices have been reported to stop or prevent 
cough in TBM, presumably through the pneumatic stenting of large airways to maintain their 
patency during exhalation [3]. CPAP devices, however, are not labeled for this indication and 
their functional utility is very limited given size of the device, need for a power source, and 
multiple steps to don the equipment that are not easily completed while actively and 
uncontrollably coughing. We hypothesize that use of the nPEP device will result in decreased 
cough severity and improve cough quality of life by decreasing proximal airway resistance as 
assessed using impulse oscillometry. 
 
Design 
Ten subjects with chronic cough and TBM diagnosed by bronchoscopy or computed 
tomography (CT) scan will be recruited. Comorbid conditions that can cause chronic cough, 
such as asthma, COPD, and GERD, must be treated if present, for subjects to qualify. At the 
pre-baseline visit (V-1), after obtaining written informed consent, each subject will complete 
validated cough questionnaires to quantify their cough severity and cough-related QOL at 
baseline. The baseline visit (V1) will occur approximately two weeks later, after a run-in period 
to minimize observation bias related to the cough questionnaires. At V1, the cough 
questionnaires will be repeated and subjects’ airway resistance and reactance will be measured 
with impulse oscillometry (IOS). Subjects will then be given the nPEP device by the study team 
and instructed on its use. Approximately two weeks after device delivery, at the follow-up visit 
(V2), cough questionnaires and IOS will be repeated and they will be asked for feedback 
regarding device design and user experience. Subjects may then be entered into a cohort for up 
to six additional months, during which there will be no study visits or procedures, but subjects 
may be contacted by investigators for additional narrative feedback on the device and its use.  
 
Inclusion and Exclusion Criteria 
 
Inclusion Criteria:   
- 
Age ≥18 years 
- 
Chronic cough for at least 8 weeks 
- 
Visualization of ≥50% collapse of the trachea or mainstem bronchus on CT scan or 
bronchoscopy 
- 
No upper or lower respiratory infection within 4 weeks 
- 
Negative evaluation or treatment response for cough: 
o Asthma (negative spirometry or treatment with oral corticosteroids or ≥moderate 
dose of inhaled corticosteroids) 
o GERD (negative pH probe or treatment with proton pump inhibitor) 
o Upper airway disease (nasal or oral corticosteroids, antihistamines) 
o COPD (negative spirometry or treatment with triple-inhaled therapy [≥moderate 
dose of inhaled corticosteroids, long-acting muscarinic antagonist, and long-
acting beta agonist]) 
- 
Having capacity to provide legal written informed consent  
 
Exclusion Criteria:   
- 
History of tracheobronchoplasty or chronic tracheal stenting 
- 
Current tracheostomy 
- 
History of external chest trauma 
- 
History of mediastinal goiter 

- 
Current smoking within 6 months 
- 
Current use of ACE inhibitor within 6 weeks 
- 
Primary parenchymal lung disease 
- 
History of: 
o Sarcoidosis 
o Interstitial lung disease 
o Chronic mycobacterial infection 
o Lung cancer 
o Lung transplantation 
- 
Unstable congestive heart failure 
- 
History of spontaneous pneumothorax 
- 
Other medical conditions that interfere with participation in the study 
 
Screening 
Potential subjects will be identified through two mechanisms: 
1. Potential subjects can be referred to the investigators by their physicians 
2. Study staff will identify qualifying subjects within the Duke electronic medical record (EMR) by 
searching for Duke patients with “tracheobronchomalacia” or its synonyms on their EMR 
problem list or in the text of a CT scan, discuss potential eligibility with each patient’s physician 
or provider, and, if appropriate, ask the patient’s physician to contact the patient regarding the 
study. 
 
Up to 20 patients will be screened to achieve a total of 10 enrolled participants. 
 
Study Interventions 
After informed consent is obtained, study subjects will be given an nPEP device to use for two 
weeks. During this time participants will be asked to remain on their current medical regimen 
and not to make any dose changes or add new drugs, unless indicated by their primary care 
provider. Impulse oscillometry will be measured at V1 and 2 weeks later at V2 to assess effect 
of the nPEP device on airway physiology.  
  
Description of assessments 
a. Medical history: Should include all medically significant events prior to enrollment, 
including surgical procedures. 
b. Physical exam (PE): Examination of the head, neck, chest, lungs, heart, abdomen, and 
extremities. 
c. Impulse oscillometry: A noninvasive and rapid technique in which small pressure 
oscillations are applied through a mouthpiece to measure pulmonary resistance and 
reactance, which are graphically displayed. 
d. Cough questionnaires: The Cough Specific Quality of Life Questionnaire (CQLQ), 
Leicester Cough Questionnaire (LCQ), and Cough Visual Analog Scale (Cough-VAS) 
Study visits 
Pre-baseline visit (V-1, -2 weeks [window -14 to -30 days]) 
• 
Review and sign informed consent 
• 
Medical history 
• 
Concomitant medication review 
• 
Physical exam 

• 
Cough questionnaires 
o 
Cough Specific Quality of Life Questionnaire (CQLQ) 
o 
Leicester Cough Questionnaire (LCQ) 
o 
Cough Visual Analog Scale (Cough-VAS) 
 
Baseline visit (V1) 
• 
Update medical history 
• 
Concomitant medication review 
• 
Impulse oscillometry 
• 
Cough questionnaires 
o 
Cough Specific Quality of Life Questionnaire (CQLQ) 
o 
Leicester Cough Questionnaire (LCQ) 
o 
Cough Visual Analog Scale (Cough-VAS) 
• 
Delivery of nPEP device and instruction on its use  
Visit 2 (V2, +2 weeks [window +11 to +28 days]) 
• 
Update medical history 
• 
Concomitant medication review 
• 
Impulse oscillometry 
• 
Cough questionnaires 
o 
Cough Specific Quality of Life Questionnaire (CQLQ) 
o 
Leicester Cough Questionnaire (LCQ) 
o 
Cough Visual Analog Scale (Cough-VAS) 
• 
Exit interview re: subject experience and preferences regarding device design and use 
 
Cohort for Ongoing Device Feedback 
Subjects may be entered into a cohort at the time of study completion, continuing for six 
months. During this time, no study procedures are planned, but subjects may be contacted and 
asked to give further opinions regarding any changes in device design and function that may 
occur after they have completed the study. Each communication or contact that occurs while in 
this cohort will be voluntary, and subjects may decline or opt out of these communications at 
any time.   
  
 
 

 
 
Pre-baseline 
Visit -1 (V-1) 
Week -2 
window -14 to -
30 days 
Baseline 
Visit 1 (V1) 
Day 0 
Follow-up 
Visit 2 (V2) 
Week +2 
window +11 to 
+28 days 
 
Unscheduled 
visit 
Consent 
X 
 
 
 
Medical History 
X 
 
 
 
Interval medical history 
 
X 
X 
X 
Concomitant 
medication review 
X 
X 
 
X 
X 
PE 
X 
 
 
X* 
IOS 
 
X 
X 
 
Cough/QOL 
Questionnaires: 
  CQLQ 
  LCQ 
  C-VAS 
X 
X 
X 
X 
Device demo and 
instructions 
 
X 
 
 
Adverse event review 
 
 
X 
X 
Exit interview 
 
 
X 
X* 
*At investigator’s discretion 
 
  
Device Description 
The nPEP device is intended as a single-patient, adjustable expiratory resistance device that 
provides positive pressure (5 to 20 cm H2O) during expiration. The device is assembled using 
mostly existing components with a history of respiratory applications. Specifically, a standard, 
adjustable (5-20 cm H2O) positive end expiratory pressure (PEEP) valve manufactured for 
attachment to a manual resuscitator (commonly known as bag-valve-mask) device is connected 
by a connector piece to a flexible respiratory mask. The connector piece contains a one-way 
valve to allow for inspiration through the mask. The user may adjust the resistance of the device 
by rotating the top of the PEEP valve, until the desired effect (cessation of coughing episodes) 
is obtained.  
 
 
 

 
 
 
 
 
 
 
Fig. 1. nPEP device 
 
Potential Benefits 
Subjects may experience direct benefit from the device, including reduction in cough symptom 
severity and increase in cough-related QOL. There is also a potential scientific and societal 
benefit in that this pilot study will enhance understanding of whether or not an nPEP device 
could be further studied in order to present a non-invasive alternative to tracheobronchoplasty 
for patients with TBM-related cough.  
 
Potential Risks  
Potential risks related to participation in this pilot study include risk to privacy, risk of skin 
irritation from device components, and risk of pneumothorax from positive pressure during 
cough. Privacy risk will be minimized by securing all personal health information in a locked 
cabinet or office, entering data into an electronic database protected by the Duke University 
firewall, and using only de-identified data in data exports. Risk of skin irritation from the device is 
minimal, given that the mask used is an approved, off-the-shelf component used in other 
medical applications, and contact dermatitis is a mild condition typically relieved by withdrawal 
of the offending agent; a literature review has indicated that contact dermatitis is very rare 
following use of medical facemasks. There is a potential theoretical risk of pneumothorax. The 
expectation is that this would be a rare occurance as the pathophysiology of TBM is such that 
central airway resistance likely prevents the pressure set at the device from being transmitted to 
the distal small airways or lung parenchyma. The maximum resistance applied by the device (20 
cm H2O) remains very small in comparison to the intrathoracic pressure generated through 
coughing itself, which has been shown to be in the range of 136-340 cm H2O [4]. Regardless, 
patients with personal history of prior pneumothorax or primary parenchymal lung disease will 
be excluded. 
 
Costs to subject 
There will be no additional costs to subjects of the study. Routine care will be charged to the 
participant or their insurance. 
 

Subject reimbursement 
Subjects will be reimbursed a total of $50 for study completion. This will be issued upon 
completion of Visit 2.   
 
Data analysis 
Statistical analyses include: a) descriptive and summary statistics of demographic and clinical 
variables, b) pre and post nPEP device treatment comparison of the primary and secondary 
outcomes (cough quality of life) using paired t-test for normally distributed and transformed data 
or Wilcoxon’s Signed Rank test for non-parametric paired data, and c) pre and post nPEP 
device assessment of airway physiology as assessed by impulse oscillometry. 
  
Data will be collected on paper forms and stored in each patient’s research binder on a secure 
location. Data will be entered into Redcap for subsequent analysis.  
 
Data and Safety Monitoring 
In accordance with federal regulations the PI will monitor for, review, and promptly report to the 
IRB, appropriate institutional officials, sponsor, coordinating center and the appropriate 
regulatory agency head all unanticipated problems involving risks to subjects or others that 
occur in the course of a subject’s participation in a research, all AE reports will be reported per 
the DUHS IRB policies. 
 
Role of external personnel 
No external personnel 
 
 
 

References 
  
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15764786.  
 
2 Ernst A, Odell DD, Michaud G, Majid A, Herth FFJ, Gangadharan SP. Central airway 
stabilization for tracheobronchomalacia improves quality of life inpatients with COPD. Chest. 
2011 Nov;140(5):1162-1168. PubMed PMID: 21868463.  
 
3 Kanter RK, Pollack MM, Wright WW, Grundfast KM. Treatment of severe 
tracheobronchomalacia with continuous positive airway pressure (CPAP). Anesthesiology. 1982 
Jul;57(1):54-6. PubMed PMID: 7046516. 
 
4 Sharpey-Schafer EP. Effects of coughing on intrathoracic pressure, arterial pressure and 
peripheral blood flow. J Physiol. 1953 Nov 28;122(2):351-7.