The Effect of Heated, Humidified High-flow Air in COPD Patients With Chronic Bronchitis
Phase: NA
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Spyridon Fortis

Cover Page for Protocol 
 
 
Sponsor-Investigator: 
Spyridon Fortis 
NCT Number: 
NCT03959982 
Unique Protocol ID: 
201905817 
Official Title: 
The Effect of Heated, Humidified 
High-flow Air in COPD Patients 
With Chronic Bronchitis 
Date of Document: 
08 October 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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Principal Investigator (PI):  
 
 
Spyridon Fortis, MD 
Co-Investigators: 
 
 
 
Alejandro Comellas, MD 
 
 
 
 
 
 
Eric Hoffman, Ph.D 
 
 
 
 
 
 
 
Title of Study:  
The effect of heated, humidified high-flow air in COPD 
patients with chronic bronchitis 
Study Center:  
University of Iowa  
Estimated number of subjects:  
30 subjects (50% male, 50% female) will be recruited 
and enrolled in this study.  
Study Period:    
 
 
 
June 2019 until completion 
Estimated date of first enrollment:  
June 2019 will be the earliest day of enrollment.  
Estimated date of last enrollment:   
We estimate that all subjects will be enrolled by June 
2021. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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I. 
Introduction 
 
 
3 
II. 
Background 
 
 
5 
III. 
Statement of Compliance 
 
 
8 
IV. 
IRB Oversight 
 
 
9 
V. 
Location of Study Procedures 
 
10 
VI. 
Main Hypothesis 
 
 
11 
VII. 
Main Screening Criteria 
 
 
12 
VIII. 
Recruitment procedures 
 
 
13 
IX. 
Inclusion Criteria 
 
 
14 
X. 
Exclusion Criteria 
 
 
14 
XI. 
Schedule of events 
 
 
15 
XII. 
Study Procedures 
 
 
18 
XIII. 
Possible Risks of the Study  
 
20 
XIV. 
Adverse Event assessment  
 
21 
XV. 
Adverse Event Reporting 
 
 
21 
XVI. 
Data Management 
 
 
21 
XVII. Subject Safety 
 
 
21 
XVIII. Statistical Analysis Considerations 
22 
XIX. 
References 
 
 
23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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I. 
Introduction 
Chronic obstructive pulmonary disease (COPD) is characterized by respiratory exacerbations which 
increase in frequency as the severity of the disease progresses. COPD exacerbations may lead to 
hospitalizations, which make up the largest proportion of the total direct health-care cost of the disease 
and are a significant burden for patients and family. Chronic bronchitis, defined as chronic cough with 
sputum production for at least 3 months a year for 2 consecutive years, is one of the clinical 
manifestations of COPD. Chronic bronchitis doubles the risk of COPD exacerbations and 
hospitalizations, and is associated with increased dyspnea, worse health-related quality of life, and poorer 
quality of sleep. Chronic bronchitis also results in increased air trapping and hyperinflation, which 
decreases exercise capacity. Unfortunately, other than traditional inhaled pharmacological agents, there 
are no treatment options for COPD patients with chronic bronchitis. 
Heated, humidified high-flow air (HHHFA) devices improve airway clearance. HHHFA use for an 
average of 1.6 hours a day in COPD patients with chronic bronchitis improves health-related quality of 
life, lung function, and delays the first respiratory exacerbation. However, HHHFA for an average of 1.6 
hours a day had no effect on COPD exacerbation frequency or hospitalization, dyspnea, or exercise 
capacity, likely due to short duration of the treatment. Conversely, the effect of HHHFA for longer time 
periods on chronic bronchitis patients has not been studied. Moreover, the effect of HHHFA on sleep 
quality has not been studied. A prior study in COPD patients showed that use of HHHFA for more than 7 
hours during sleep can be achieved. The overall objective of this research is to examine the effect of 
HHHFA during sleep on COPD patients with chronic bronchitis. In this pilot study, we will examine the 
effect of HHHFA during sleep on clinically relevant short-term outcomes including: respiratory 
symptoms, quality of life and sleep, lung function and exercise capacity. 
Hypothesis 1: HHHFA during sleep in COPD patients with chronic bronchitis improves respiratory 
symptoms, sleep quality, lung function, and exercise capacity. 
Aim 1: To examine the effect of HHHFA during sleep on respiratory symptoms, sleep quality, lung 
function, and exercise capacity in COPD patients with chronic bronchitis. 
The effect of HHHFA on air trapping and hyperinflation has not been studied. Air trapping and 
hyperinflation as well as other radiographic measurements associated with chronic bronchitis (e.g. airway 
wall thickness) can be measured using chest CT. 
Hypothesis 2: HHHFA during sleep in COPD patients with chronic bronchitis improves air trapping and 
hyperinflation. 
Aim 2: To examine the effect of HHHFA in COPD patients with chronic bronchitis during sleep on air 
trapping and hyperinflation through chest CT imaging.  
Design: We will include COPD subjects with a post-bronchodilator FEV1%predicted below 70% and 
chronic bronchitis. We will include subjects with at least 2 exacerbations in the last year to identify 
patients with significant burden due to chronic bronchitis. We will exclude subjects with recent 
respiratory events or procedures as we want to capture the benefit of HHHFA on chronic, stable COPD 
participants. Subjects who meet eligibility criteria will be randomized to HHHFA(intervention arm) or 
usual care (usual care arm). At baseline we will perform measurements in all subjects that include 
dyspnea, cough,  health-related quality of life, and sleep quality questionnaires, spirometry, a 6-minute 
walk test, and chest CT. The HHHFA device will be provided to participants at the baseline visit. 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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Subjects will use the device during sleep for 6 weeks and return for an end-of-study visit. At the follow-
up visit (6 weeks), participants will repeat all baseline evaluations. At the follow-up visit, participants 
using the HHHFA will be asked whether they want to continue to participate in the sub-study. For 
participants that have consented to participate in the sub-study, they will use the HHHFA device for an 
additional 42 weeks. We will follow these participants who continue to use the HHHFA for 42 additional 
weeks (total 48 weeks) to assess for respiratory exacerbations.   
We will compare changes in variables (e.g. FEV1 etc) over time in each treatment group. We will also 
compare changes in variables over time between groups. To evaluate the effect of treatment, we will use 
linear mixed effect models controlling for demographics and lung function. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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II. 
Background 
COPD is a leading cause of mortality in the U.S.[1] and worldwide[2] and is associated with high 
morbidity[3] and resource utilization[3], including costs due to clinic visits, chronic therapy, and frequent 
hospitalizations.[3, 4] COPD patients experience respiratory exacerbations defined as acute worsening of 
dyspnea, cough, and sputum production.[5] 
Severe acute COPD exacerbations require hospitalization and have a 5-year mortality of 50-76%.[6-10] 
Fifty percent of patients admitted to the intensive care unit (ICU) with COPD exacerbations are re-
hospitalized within 6 months of discharge.[9] COPD exacerbations also reduce patients’ quality of 
life.[11] Moreover, direct health care expenditures for COPD in 2010 were $32.1 billion and projected to 
increase to $49 billion by 2020.[12] Hospitalizations due to COPD exacerbations alone are responsible 
for more than 70% of these direct health care costs.[4, 13] Preventing COPD exacerbations, in particular 
those requiring hospitalizations, would improve patients’ quality of life and decrease health care costs of 
the disease. Therefore, preventing COPD exacerbations is of major importance. 
Chronic bronchitis is associated with worse quality of life, exacerbations, and mortality 
COPD is a heterogenous disease with various phenotypes.[14] Identifying those COPD phenotypes is 
critical to individualizing treatment for COPD and improving outcomes.[15] Chronic bronchitis, defined 
as chronic cough with sputum production for at least 3 months a year for 2 consecutive years, accelerates 
lung function decline, is associated with more dyspnea and worse health-related quality of life,[16] 
increases exacerbations and hospitalizations,[16-20] and may increase mortality.[21, 22] Prior studies 
have shown that COPD patients with chronic bronchitis experience twice as many exacerbations and 
hospitalizations than COPD patients without chronic bronchitis.[16, 19, 23] Chronic bronchitis is a risk 
factor for exacerbations independent of lung function impairment.[24] More than half of COPD patients 
with chronic bronchitis have more than 2 exacerbations every year.[18] Even in smokers with normal 
lung function, sputum production is associated with increased risk for respiratory exacerbations.[25] 
In addition, chronic bronchitis is associated with poor quality of sleep and awakening during the 
night.[16, 26] Poor quality sleep is very common among COPD patients. Sputum production is the most 
prominent factor associated with poor sleep in COPD.[27] Thus, more effective treatment of COPD 
patients with chronic bronchitis would have a great impact on disease burden and likely reduce associated 
health care costs. 
Chronic bronchitis is associated with air trapping and hyperinflation 
Chronic bronchitis is associated with increased dynamic hyperinflation during exercise[28] likely due to 
airway secretions. COPD patients with chronic bronchitis have been shown to cover shorter distances in a 
6-minute walk test compared to COPD patients without chronic bronchitis.[28] COPD patients with 
chronic bronchitis have larger function residual capacity (FRC) and total lung capacity (TLC), and greater 
airway wall thickness on chest CT than COPD patients without chronic bronchitis[16], again likely due to 
increased airway secretions. Airway mucus plugging is considered a characteristic of COPD.[29] 
Nevertheless, quantification of mucus plugging in COPD patients with chronic bronchitis using chest CT 
is understudied. 
 
 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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Current treatment of chronic bronchitis 
Treatment of chronic bronchitis is not different than treatment of COPD in general. Apart from smoking 
cessation, inhaled pharmacological agents are the mainstay of treatment. Long-acting bronchodilators 
reduce respiratory exacerbations by 15-20%.[30] Adding inhaled corticosteroids have a similar effect on 
exacerbations.[31] In a selected group of COPD patients, oral pharmacological agents and non-
pharmacological therapies are also associated with decrease in COPD exacerbations.[32] However, the 
effect of those medications in every daily life may be less.[33] Other than common inhaled 
pharmacological agents, treatment options specifically for chronic bronchitis are limited.[34] 
Randomized, placebo-controlled trials examining N-acetylcysteine, the most-known mucolytic, have 
shown disappointing results.[35, 36] 
Heated humidified high flow oxygen/air in chronic obstructive pulmonary disease 
Recently, novel nasal cannula systems have become available that can deliver a heated and humidified 
air/oxygen mixture with a flow rate up to 60 L/minute.[37] Although the main use of these devices is to 
provide oxygen supplementation in hypoxemic respiratory failure, high-flow nasal cannula devices can be 
used without oxygen supplementation, providing only heating and humidification in the inspiratory gases 
(heated humidified high flow air; HHHFA). It is known that proper humidification improves airway 
clearance[38] and may preserve mucosal integrity and function, facilitate gas exchange, reduce the 
metabolic cost of breathing, and improve airway host defense.[37] The warm and humidified gas also 
provides comfort and reduces costs of breathing.[37] The metabolic cost to warm and humidify the cold 
and dry gas provided by regular oxygen supplementation devices is not negligible. [37] Moreover, 
HHHFA can wash out the dead space, facilitating CO2 removal[39] and has a positive end-expiratory 
pressure (PEEP) effect[40] and, as a result, the cost of breathing is reduced. 
HHHFA may be more beneficial in patients with chronic bronchitis as it facilitates airway clearance, 
improves host defense, and decreases the metabolic cost of breathing,[37] particularly in those patients 
with recent hospitalizations who are at high risk for subsequent readmissions.[41] 
Heated humidified high flow oxygen in patients with stable chronic obstructive pulmonary disease 
In a randomized, prospective trial conducted in Denmark, 200 COPD outpatients with chronic hypoxemic 
respiratory failure were randomized to high-flow nasal cannula or usual care.[42] The average high-flow 
nasal cannula was 20 L/minute for an average of 6 hours per day. Exacerbation rates were lower in the 
high-flow nasal cannula group (3.12 per year) relative to the usual care group (4.95 per year; p<0.001). 
Although there was no difference in hospital admission rates between the two groups, increasing duration 
of high-flow nasal cannula was associated with reduction in COPD hospitalizations. One-year use of 
high-flow nasal cannula treatment was associated with a statistically significant reduction of 
hospitalizations, from 1.39 to 0.79 per year (p<0.001). 
In a multicenter crossover trial, 32 stable COPD patients with hypoxemic and hypercapnic respiratory 
failure were randomized to receive either HHHFA with oxygen supplementation for 6 weeks followed by 
oxygen supplementation alone for another 6 weeks, or oxygen supplementation alone for 6 weeks 
followed by HHHFA plus oxygen supplementation for another 6 weeks.[43] HHHFA was used during the 
night at flow rates between 30 and 40 L/minute. The flow rate was allowed to be decreased down to 
20L/minute for patient comfort. The average usage time was above 7 hours per night. Oxygen could be 
blended in the HHHFA device and was adjusted to maintain the peripheral oxygen saturation above 88%. 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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HHHFA improved health-related quality of life and reduced PaCO2 by an average of 4.1 mmHg 
compared to oxygen supplementation alone. 
 
HHHFA improves outcomes in chronic bronchitis 
HHHFA improves airway clearance in patients with bronchiectasis and chronic sputum production.[38] In 
a prospective study in New Zealand, 108 patients with at least moderate COPD or non-cystic fibrosis 
bronchiectasis, who had ≥2 respiratory exacerbations in the last year and daily sputum production, were 
randomized to either HHHFA at 25 L/minute or standard care for 12 months.[44] Patients randomized to 
HHHFA were instructed to use the device for at least 2 hours per day. HHHFA increased FEV1 and FVC 
by 0.12 and 0.28L, respectively. HHHFA did not affect the rate of decline in 6-minute walk distances. In 
the HHHFA group, there was a 14.1 meter (4%) decline whereas in the control group, there was a 29 
meter (8.6%) decline (p=0.485). The study showed that rate of decline of the 6-minute walk distance was 
inversely correlated with improvement of FVC. HHHFA increased the time to the first exacerbation from 
a median of 27 days to 52 days (p=0.0495). Patients using the HHHFA had 18.2 annual exacerbation days 
whereas patients in the standard of care group had 33.5 annual exacerbation days (p=0.045). However, 
exacerbation frequency was not different between the HHHFA (2.97 exacerbations per year) and regular 
treatment groups (3.63 exacerbations per year; p=0.067). Similarly, hospital admission rates in the 
HHHFA group (0.39 hospitalizations per year) did not differ from those in the regular treatment group 
(0.47 hospitalizations per year; p=0.439). The modest effect of HHHFA can be explained by the short 
duration of treatment. The authors acknowledged that the goal of treatment adherence was 2 hours a day 
but the average treatment was only 1.6 hours a day. The short duration of treatment is likely the reason 
that HHHFA did not improve 6-minute walk distances and inspiratory capacity.  
Use of HHHFA for longer time periods can be achieved during sleep. In study by Nagata et al, patients 
were instructed to use HHHFA for at least 4 hours during sleep and patients used it an average above 7 
hours a night.[43] Adherence was confirmed by device records. The effect of HHHFA for longer time 
periods during the night on COPD with chronic bronchitis is unknown. Moreover, the effect HHHFA on 
COPD patients’ sleep is unknown. In this pilot study, we will focus on clinically relevant short-term 
outcomes that include symptoms, quality of life, quality of sleep, lung function and exercise capacity. 
 
 
 
 
 
 
 
 
 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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III. 
Statement of Compliance 
This study will be conducted in compliance with the protocol, Good Clinical Practice and the 
applicable Food and Drug Administration and other Department of Health and Human Services 
regulatory requirements. 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection and Good Clinical Practice training. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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IV. 
IRB Oversight 
 
Human Subjects Office / IRB 
J. Andrew Bertolatus, MD 
Hardin Library, Office 105 
600 Newton Rd 
Iowa City, IA 52242 
FWA#: FWA00003007 
Voice: 319-335-6564 
Fax: 319-335-7310 
Email: irb@uiowa.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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V. 
Location of Study Procedures 
 
University of Iowa  
200 Hawkins Drive 
Iowa City, Iowa 52242 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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VI. 
Main Hypothesis 
HHHFA during sleep in COPD patients with chronic bronchitis improves respiratory symptoms, sleep 
quality, lung function, and exercise capacity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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VII. 
Main Screening Criteria 
We will recruit COPD men and non-pregnant women of any ethnic background with the age above 18 
years with the following characteristics: post-bronchodilator FEV1%predicted below 70%, chronic 
bronchitis defined as cough with daily sputum production, and at least 1 exacerbations in the last year.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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VIII. 
Recruitment procedures 
The study team will utilize email blasts and University of Iowa Noon News advertising to recruit subjects 
for this study. We will also advertise study at the Iowa City VAMC. Upon study beginning and ensuring 
the smooth operation of the protocol, we will apply to the VA for permission to recruit subjects from the 
Iowa City VAMC. To avoid any coercion all subjects are offered the opportunity to talk with their 
primary care provider or family prior to signing a consent form. Study participation has no influence on 
their medical care. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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IX. 
Inclusion Criteria 
• 
COPD diagnosis by health care provider 
• 
Smoking with at least 10 pack-years 
• 
Post-bronchodilator FEV1/FVC <0.7 
• 
Post-bronchodilator FEV1%predicted <70% 
• 
Chronic bronchitis, defined as chronic cough with daily sputum production 
• 
≥1 COPD exacerbations within the last year 
 
 
X. 
Exclusion Criteria 
• 
Obstructive sleep apnea or suspected obstructive sleep apnea that requires positive airway 
pressure treatment  
• 
Patients that use oxygen supplementation continuously (patients that use oxygen supplementation 
only at exertion, as needed, or at night will NOT be excluded) 
• 
Any planned procedure that makes ineligible according the PI clinical judgement 
• 
Unable to perform a spirometry, 6-minute walk test or chest CT 
• 
Recent diagnosis (<2 weeks prior to study entry) of pneumonia, respiratory infection, COPD 
exacerbation, or acute bronchitis requiring antibiotics and new/increased dose of systemic 
corticosteroids  
• 
Thoracic surgery or another procedure in the last six months that may result in instability of 
pulmonary status 
• 
Recent medical or surgical history of upper airway disease that may interfere with intervention 
(e.g., sinus surgery, significant nasal polyps) 
• 
Recent chest illness (trauma, pneumothorax etc). 
• 
Basal skull surgery in the last 6 months 
• 
Open skin ulcer or rash where the nasal cannula will be worn 
• 
Tracheostomy or laryngectomy 
• 
Pregnancy 
 
 
 
 
 
 
 
 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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XI. 
Schedule of events 
After obtaining informed consent, participants will perform a screening pre-bronchodilator and post-
bronchodilator spirometry using the  EasyOne Spirometer (Zurich, Switzerland) according to American 
Thoracic Society-European Respiratory Society standards. Participants who meet eligibility criteria will 
be randomized (2:1) to receive either HHHFA or usual care for 6 weeks. Randomization will be 
performed using sealed envelopes. 
Baseline visit. After randomization, participants will have baseline measurements and training in the 
device. Participants will provide information regarding demographics, medical history, COPD history 
including prior exacerbations, hospitalizations, and pertinent medication use. Weight, height, and vitals 
will be recorded. Participants will complete Medical Research Council dyspnea scale (MRC),[45] St. 
George's Respiratory Questionnaire (SGRQ),[46-48] COPD Assessment Test (CAT),[49], Pittsburgh 
Sleep Quality Index (PSQI),[50], and Cough and Sputum Assessment Questionnaire (CASA-Q).[51] 
Subsequently, participants will perform a 6-minute walk test follow by an inspiratory and expiratory chest 
CT. Chest CT will be performed based on quantitative CT lung protocols.[52] TLC and residual volume 
(RV) will be measured at maximal inspiration and maximal expiration, respectively. We will quantify % 
emphysema and % gas trapping based on chest CT images. Quantified % emphysema will be defined as 
the percentage of voxels less than -950 Hounsfield units at TLC. Quantified % gas trapping will be 
measured at TLC as the percentage of voxels less than -856 Hounsfield units at RV. A parametric 
response map (PRM) will be constructed to reduce the misclassification of emphysema as gas trapping. 
Voxels with emphysema on TLC will be eliminated from the voxel count of gas-trapped areas after image 
matching of TLC and RV images. Airway geometry including Pi10, wall thickness, and visual mucus 
plugs will also be assessed.[52, 53] Lastly, subjects will receive training and the HHHFA with 
information materials and a study personnel contact number.  
 
Phone Call at Week 1. Three to seven days after enrollment, a member of the research team will contact 
the participant to address any concerns or questions regarding the device (device training) and/or the 
study, and adverse events.  
Follow-up visit (6-weeks). After 6 weeks, participants will return to the CRU with the HHHFA device 
and perform the same procedures in the same order as at the baseline visit including weight, height, vitals, 
spirometry, MRC questionnaire, CAT questionnaire, PSQI questionnaire, CASA-Q questionnaire,  6-min 
walk test, inspiratory and expiratory chest CT. Information regarding changes in medication usage 
including frequency of rescue inhaler, exacerbation and hospitalizations since the last visit will also be 
collected. Participants in the HHHFA arm will be asked whether they want to continue to participate in 
the sub-study that will have them use the HHHFA for an additional 42 weeks. Participants that are not 
interested in participating in the sub-study, will return the device at the 6 week follow-up visit. 
Participants interested in participating in the sub-study can ship the device to the research team following 
their completion of the sub-study that will end at 48-weeks. 
Phone Call visit at 12-weeks Only participants in the HHHFA sub-study group will receive a phone call 
at 12 weeks. Assessment for respiratory exacerbations will be performed. 
 

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Phone Call visit at 24-weeks. Only participants in the HHHFA sub-study group will receive a phone call 
at 24 weeks. Assessment for respiratory exacerbations will be performed. 
Phone Call visit at 36-weeks. Only participants in the HHHFA sub-study group will receive a phone call 
at 36 weeks. Assessment for respiratory exacerbations will be performed. 
Phone Call visit at 48-weeks. Only participants in the HHHFA sub-study group will receive a phone call 
at 48weeks. Assessment for respiratory exacerbations will be performed. Patients will ship the HHHFA 
device back to the company. 
Table 1. Schedule of events summary 
Activity 
Visit 1  
Phone Call  
visit 
(week 1) 
Follow-up 
visit 
(6-weeks) 
Phone Call  
visit 
(12-weeks) 
Phone Call  
visit 
(24-weeks) 
Phone Call  
visit 
(36-weeks) 
Phone Call  
visit 
(48-weeks) 
Informed Consent  
X 
 
 
 
 
 
 
Screening evaluation and 
enrollment 
X 
 
 
 
 
 
 
Spirometry 
X 
 
X 
 
 
 
 
Demographics and 
medical history  
X 
 
X 
 
 
 
 
Respiratory condition-
related medications only 
X 
 
X 
 
 
 
 
Modified physical exam  
X 
 
X 
 
 
 
 
SaO2 at rest  
X 
 
X 
 
 
 
 
Randomization  
X 
 
 
 
 
 
 
HHHFA device training 
and support 
X 
X 
X 
X 
X 
X 
X 
MRC questionnaire 
X 
 
X 
 
 
 
 
SGRQ Questionnaire 
X 
 
X 
 
 
 
 
CAT score 
X 
 
X 
 
 
 
 
PSQI 
X 
 
 
 X 
 
 
 
 
CASA-Q 
X 
 
X 
 
 
 
 
6-MWT 
X 
 
X 
 
 
 
 
Chest CT 
X 
 
X 
 
 
 
 
Respiratory exacerbation 
assessment 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
HHHFA Return device 
 
 
X 
X 
X 
X 
X 
  
 

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XII. 
Study procedures 
Vitals, Height and Weight 
The subject will have vitals taken by a CRU nurse: Height, weight, blood pressure, SaO2 
(saturation of oxygen in the blood), heart rate, temperature, and breathing rate. This will take 
approximately 20 minutes. 
Six-min walk test 
The test measures the distance a patient can walk on a flat, hard surface in six minutes. 
Urine Pregnancy Test 
Women of childbearing potential will have a urine pregnancy test as well. Before beginning 
the CT and MRI scans, the urine pregnancy test for females of childbearing potential will be 
checked. If the result is positive for pregnancy subject will be withdrawn. 
 
Spirometry  
The subject’s FEV1, FVC and the FEV1/FVC ratio will be determined after three acceptable 
spirometry efforts are obtained. After prebronchodilator spirometric manoeuvres, two puffs 
of albuterol metered dose inhaler were administered using a spacer. Postbronchodilator 
manoeuvres were performed between 15 and 20 min. 
 
 
      CT Scans 
The subject will be then taken to the Research CT Imaging Suite for their CT scan. A CT 
scan combines a series of X-ray images taken from different angles and uses computer 
processing to create cross-sectional images of the lungs. The CT scan will provide more 
detailed information than a standard x-ray. Once in the CT lab, the subject will be asked to 
remove any metallic items from their person (jewelry, piercings that can be removed easily, 
etc.). If the items to be removed involve clothing, the subject will be allowed to change in a 

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private restroom within the CT Suite and will be given a hospital scrub top to wear. We will 
explain the scanning procedures again to the subject and they will be reminded that they may 
ask questions at any time during the procedure(s). The subject will then be placed on the 
movable exam table of the CT scanner.  
Three scans will be done in the CT scanner. One scout scan will be done to position the 
subject and then a total of two non-contrast CT scans will be done: Total Lung Capacity 
(TLC) and Residual Volume (RV). 
The first scan that will be done is called a scout scan. This brief scan, which is similar to an 
x-ray, is simply used to help the technologists make sure that the subject is positioned 
correctly.  The subject will then be told to take in as deep of a breath as they can and hold it 
while the scout scan is done.  
Total Lung Capacity (TLC) the subject will be asked to take a deep breath and blow out 
completely two times, they will then be asked to take a deep breath and hold their breath 
while the CT scan is being done. This breath hold will last approximately 5-8 seconds.  
Residual Volume (RV). For this scan, we will tell the subject to take in a deep breath and 
blow it out twice before instructing them to take another deep breath in and blowing all of 
their air out until we see they've reached 0-10% of their SVC and then we will tell them to 
hold their breath while an image is being taken at RV (5-10 seconds). 
Subjects will be asked to bring their cigarettes or electronic cigarettes with them to the visit.  
They will be asked to smoke one of their cigarettes or vape with their electronic cigarette.  
They will then repeat the same CT scans.  
The spiral volumetric scan protocols use dose modulation with 36 reference mAs, 120kV, 
pitch of 1, & rotation time of 0.5sec. The CTDIvol for one scan at 36mAs is 2.41mGy, with 
total DLP of 81.5mGycm for a 30cm scan. 
Total effective dose equivalents (HE) for one spiral volumetric scan is estimated to be 
160mrem  
Total effective dose equivalents (HE) for TLC and RV spiral volumetric scan combined is 
estimates to be 320mrem  
320mrem is ~8% of annual radiation limit for a medical worker.   
Total mrem is 640 or ~16% of annual radiation limit for a medical worker.  
Heated humidified high flow air (HHHFA) 
Participants will be provided the HHHFA at baseline visit (time 0). At follow-up visit (6 
weeks), participants using the HHHFA that are not interested in participating in the sub-
study, they can return the device at the follow-up visit (6 weeks) . Participants that will 
participate the sub-study they can ship the device back to the research team at the end of the 
sub-study(48 weeks).  

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Participants will be instructed to use the HHHFA for at least 4 hours during their sleep but 
will be allowed to use it as long as they want during sleep.[43] HHHFA will be administered 
using myAIRVO 2 device (Fisher & Paykel Healthcare), which provided humidified high-
flow gas via Optiflow nasal cannula interface (Fisher & Paykel Healthcare). The temperature 
will be set at 32-37˚C and flow will be set at 35L/minute but can be titrated down to 
20L/minute for comfort based on a previous study.[44] Subjects use oxygen at night can 
blend the oxygen at the same flow through the device. Adherence of the device will be 
recorded using the device log.  
 
XIII. 
Possible Risks of the Study 
 
Spirometry: The subject may become short of breath or experience chest tightness while doing the 
pulmonary function tests. 
CT scans: The subject will be exposed to radiation from the CT scans. 
Heated humidified high flow air (HHHFA): According to a previous randomized control trials, that 
HHHFA applied during the night, six of 32 participants experienced adverse effects related to 
HHHFA.[43] Four participants experience night sweat, one had nasal discharge, one had insomnia, 
and one had a skin rash. Other adverse effects associated with the HHHFA device include but are not 
limited to the following: fire, burns, nosebleed, dry mouth and throat, headache, tripping over the 
equipment, electrical shock and injury, noise irritation, low oxygen due to improper use of device, 
skin irritation and injury/damage. 
Possible Loss of Confidentiality: To reduce risk of a loss of confidentiality, precautions will be 
taken to ensure privacy. The PI and study team will maintain appropriate medical and research 
records for this study, in compliance with ICH E6 GCP, Section 4.9 and regulatory and institutional 
requirements for the protection of confidentiality of subjects. Research records generated in this study 
will be stored in file cabinets in a locked room and/or on a secure electronic database. The text 
message server stores the minimum amount of data possible-participant phone numbers and text 
message responses, no other participant information will be stored on that server. Only authorized 
study team at the sites will have access to the data. Imaging collected during the study will be 
identified by a subject number, IRB protocol number, and date of collection.  
Abnormal findings: 
• 
False positive scan, which is an abnormality that initially is of concern that is later found 
not to be a concern. Anxiety may result from false positive results.  
• 
Detection of abnormalities that could lead to unnecessary testing or treatment.  
• 
Failure to detect an abnormality that is present and possibly miss an opportunity for care. 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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XIV. 
Adverse Event Assessment 
Adverse event information will be collected from all participants at every encounter throughout the study. 
The investigator and research team will inquire about adverse events until the end of the study at the 6-
week follow up study. Medical records will be reviewed for adverse effects. 
XV. 
Adverse Event Reporting 
Adverse events will be evaluated by the investigatory for severity and relatedness. Severe adverse events 
defined as those that interfere participant’s daily activity and/or require treatment will be reported to the 
manufacturer.  
XVI. 
Data Management 
The following people/agencies may have access to subject data/records: 
 
• 
Study team 
• 
Federal government regulatory agencies 
• 
Auditing departments of the University of Iowa 
• 
University of Iowa IRB 
• 
The National Institute of Health 
To protect confidentiality, we will assign each subject a study ID. All records will be in a locked 
cabinet in a locked office or password protected computer system. Data and records will be managed 
as follows: 
• 
Paper/hard copy records (hard copy surveys, questionnaires, case report forms, pictures, etc.) 
- Whenever possible, subject identifying information will be blacked out on all paper or hard 
copy records and replaced with the subject's unique study identifier. Paper records will be 
stored in a locked file cabinet in the study team's locked office.  
• 
Electronic records (computer files, electronic databases, etc.) – All electronic data bases will 
only be accessed by the study team and available only with a username and password 
assigned to study team by the PI.  

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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XVII. Subject Safety 
• 
To minimize risks all subjects are carefully pre-screened and screened trying to identify 
any factors that could contribute to increased risk. 
• 
All testing is completed at University of Iowa Hospitals and Clinics by a very 
experienced and well-trained staff and monitored by the Principal Investigator. 
• 
All confidential information is kept in locked offices and password protected computers 
only available to study team members.  
• 
The participant has contact information and study team members available 24/7.  
• 
A urine pregnancy test is done on all women of child bearing potential. 
 
XVIII. Statistical Analysis Considerations 
 
Primary outcomes: Sleep quality (PSQI) 
Secondary outcomes: Dyspnea (MRC), health-related quality of life (SGRQ and CAT), cough (CASA-
Q), lung function (Spirometry), and exercise capacity (6-min walk distance)Chest CT measurements. 
Variables will be collected: medical history, comorbidities, MRC, SGRQ, CAT, PSQI, CASA-Q, 
spirometric variables, 6-min walk distance, Chest CT measurements. 
Hypothesis 1: We expect that HHHFA will improve MRC, SGRQ, CAT, PSQI, CASA-Q scores in 
COPD patients with chronic bronchitis. It will also increase FEV1, and distanced covered in a 6-minute 
walk test. 
Hypothesis 2: We anticipate that HHHFA will reduce air trapping and hyperinflation. 
Decrease in air trapping and hyperinflation can explain the improvement in respiratory symptoms, lung 
function, and exercise capacity. The putative mechanism of that is that HHHFA improves airway 
clearance. 
Statistical considerations and power calculation. Prior studies have shown that HHHFA improves 
dyspnea, quality of life, and lung function in patients with COPD and daily sputum production. HHHFA 
has not been shown to improve quality of sleep. A prior study has shown that the average of PSQI in 
COPD patients with FEV1%predicted above 50% is 9.3 ± 3.8(SD).[54] To achieve a power of 80% at a 
2-sided 5% level of significance to detect a clinically significant improvement in PSQI (below 5), we 
need a sample size at least 27 subjects enrolling ratio of 2:1( HHHFA: usual care). To account for an 
increased rate of attrition, our goal will be a sample of 30. 
Statistical analysis. We will compare variables (e.g. MRC score, FEV1) between baseline and 6-week 
visits and changes over time in each group. We will use Fisher’s exact test for categorical variables and 
paired t-test or Wilcoxon signed-rank test for normal and non-normal continuous variables, respectively. 
We will also compare changes in those variables (e.g. change in FEV1 between baseline and 6-week 
visits) between groups. We will use Fisher’s exact test for categorical variables and t-test or Wilcoxon 
rank sum test for normal and non-normal continuous variables, respectively. To evaluate the effect of 
treatment, we will use linear mixed-effect models controlling for demographics and lung function. 

Protocol: Heated, humidified high-flow air in Chronic Bronchitis 
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Statistical analysis will be performed using SAS, version 9.4 and R statistical software (http://www.r-
project.org/). 
 
 
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