Use of ProAir Digihaler in Chronic Obstructive Pulmonary Disease (COPD) - Characterization of Inhalation Metrics From a Cohort of Patient At-risk for Acute Exacerbation of COPD (AECOPD) in an Outpatient Setting
Phase: NA
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: University of North Carolina, Chapel Hill

 
 
Use of ProAir Digihaler in COPD - Characterization of inhalation 
metrics from a cohort of patient at-risk for AECOPD in an outpatient 
setting 
 
 
NCT number NCT05241288 
Document Date 03/21/2022 
 

 
Use of ProAir Digihaler in COPD - Characterization of 
inhalation metrics from a cohort of patient at-risk for 
AECOPD in an outpatient setting  
 
Running Title: Digihaler in COPD 
National Clinical Trial (NCT) Identified Number:  N/A 
Principal Investigators:   
M. Bradley Drummond, MD (UNC) 
Jill Ohar, MD (Wake Forest University) 
Funded by: Teva 
Funding Agency Collaborators: Amanda Roe, Tanisha Hill 
Version Number:  v.1.2 
 21 March 2022 
 
 
I confirm that I have read this protocol and understand it.    
 
Principal Investigator Name:   
 
_________________  
 
Principal Investigator Signature:  
 
 
 
 
 
 
 
 
Date:   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

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Table of Contents 
STATEMENT OF COMPLIANCE .............................................................................................. 1 
1 
PROTOCOL SUMMARY .................................................................................................. 1 
1.1 
Synopsis ..................................................................................................................... 1 
1.2 
Schema ...................................................................................................................... 5 
1.3 
Schedule of Activities (SoA) .................................................................................... 5 
2 
INTRODUCTION ............................................................................................................... 6 
2.1 
Study Rationale ......................................................................................................... 6 
2.2 
Background ................................................................................................................ 6 
2.3 
Risk/Benefit Assessment ......................................................................................... 6 
2.3.1 
Known Potential Risks ............................................................................. 6 
2.3.2 
Known Potential Benefits ........................................................................ 7 
2.3.3 
Assessment of Potential Risks and Benefits ....................................... 7 
3 
OBJECTIVES ..................................................................................................................... 8 
4 
STUDY DESIGN ................................................................................................................ 8 
4.1 
Overall Design ........................................................................................................... 8 
4.2 
End of Study Definition ............................................................................................ 9 
5 
STUDY POPULATION ...................................................................................................... 9 
5.1 
Inclusion Criteria ....................................................................................................... 9 
5.2 
Exclusion Criteria ...................................................................................................... 9 
5.3 
Screen Failures ....................................................................................................... 10 
5.4 
Strategies for Recruitment and Retention ........................................................... 10 
6 
STUDY INTERVENTION ................................................................................................ 10 
6.1 
Study Intervention(s) Administration .................................................................... 10 
6.1.1 
Study Intervention Description ............................................................. 10 
6.1.2 
Dosing and Administration .................................................................... 12 
6.2 
Study Intervention Compliance ............................................................................. 12 
6.3 
Concomitant Therapy ............................................................................................. 12 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................................... 12 
7.1 
Discontinuation of Study Intervention .................................................................. 12 
7.2 
Participant Discontinuation/Withdrawal from the Study .................................... 12 
7.3 
Lost to Follow-Up .................................................................................................... 13 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................ 13 
8.1 
Outcome Assessments .......................................................................................... 13 
8.2 
Safety and Other Assessments ............................................................................ 13 
8.3 
Adverse Events and Serious Adverse Events ................................................... 13 
8.3.1 
Definition of Adverse Events (AE) and Adverse Device Effects ..... 14 
8.3.2 
Definition of Serious Adverse Events (SAE) ...................................... 14 
8.3.3 
Classification of an Adverse Event ...................................................... 15 
 
8.3.3.1 
 
Severity of Event ……………………………………………... 15 
8.3.3.2 
 
Relationship to Study Intervention…………...……………... 15 
8.3.3.3 
 
Expectedness ….……………………………………………... 16 
8.3.4 
Time Period and Frequency for Event Assessment & Follow-Up .. 16 
8.3.5 
Adverse Event Reporting ...................................................................... 17 
8.3.6 
Reporting Events to Participants ......................................................... 18 

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8.3.7 
Events of Special Interest ..................................................................... 18 
9 
STATISTICAL CONSIDERATIONS .............................................................................. 18 
9.1 
HypothesIs ............................................................................................................... 18 
9.2 
Sample Size RATIONALE ..................................................................................... 18 
9.3 
MISSING DATA ...................................................................................................... 18 
9.4 
Statistical Analyses ................................................................................................. 18 
9.4.1 
Safety Analyses ...................................................................................... 19 
9.4.4 
Planned Interim Analyses ..................................................................... 20 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS . 20 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................... 20 
10.1.1 
Informed Consent Process ................................................................... 20 
10.1.2 
Study Discontinuation and Closure ..................................................... 20 
10.1.3 
Confidentiality and Privacy ................................................................... 21 
10.1.4 
Future Use of Stored Specimens and Data ....................................... 21 
10.1.5 
Key Roles and Study Governance ...................................................... 21 
10.1.6 
Safety Oversight ..................................................................................... 22 
10.1.7 
Clinical Monitoring .................................................................................. 22 
10.1.8 
Quality Assurance and Quality Control ............................................... 22 
10.1.9 
Data Handling and Record Keeping .................................................... 22 
10.1.10 
Protocol Deviations ................................................................................ 23 
10.1.11 
Publication and Data Sharing Policy ................................................... 23 
10.1.12 
Conflict of Interest Policy....................................................................... 23 
10.2 
Additional Considerations ...................................................................................... 24 
10.3 
Abbreviations ........................................................................................................... 25 
10.4 
Protocol Amendment History ................................................................................ 25 
11 
REFERENCES ................................................................................................................. 25 

 
 
1 
STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the terms and 
conditions of the contract. The Principal Investigators will assure that no deviation from, or changes to 
the protocol will take place without prior agreement from the funding agency and documented approval 
from the Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) 
to the trial participants. All personnel involved in the conduct of this study have completed Human 
Subjects Protection. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title 
Use of ProAir Digihaler in COPD - Characterization of inhalation metrics 
from a cohort of patient at-risk for an acute exacerbation of COPD 
(AECOPD) in an outpatient setting  
Study Description 
The albuterol sulfate electronic multidose dry powder inhaler (Albuterol 
eMDPI) Digital System (DS) (ProAir® Digihaler®) is the first and only FDA 
approved inhaler rescue medication with a built-in sensor to detect and 
record inhaler use.  The inhaler device measures peak inspiratory flow 
(PIF) and the app groups PIF into categories that can help to highlight 
potential patient inhaler technique errors. This study will deploy this 
product in COPD patients to establish foundational data on Digihaler 
metrics in a COPD population at greater risk for COPD exacerbations.  
Adult subjects with COPD recruited from two sites (UNC and Wake Forest) 
will participate in a longitudinal study to collect data regarding the normal 
variation in Digihaler metrics (PIF, inhalation volume, # inhalations), a daily 
self-assessment asking “How are you feeling?” with responses provided on 
a Leikert scale as well as responses to a Digihaler metric algorithm-triggered 
digital automated questionnaire (DAQ) in a stable COPD population with 
history of an AECOPD,  to assess correlations of Digihaler metrics to daily 
self-assessment and DAQ responses, correlations of self-reported to actual 
short acting beta agonist (SABA) use and symptoms, and the changes in 
inhaler paramenters and SABA use around incidental AECOPD.  
Objectives 
 
Primary Objective.    
• 
To determine the variation in ProAir Digihaler metrics (PIF, inhalation 
volume, number of inhalation events) amongst COPD patients in the 
ambulatory setting.  
 

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Secondary Objectives.  
• 
To determine the correlation of self-reported SABA use with actual 
SABA use collected by the ProAir Digihaler.  
• 
To determine the correlation of inhaler metrics (PIF, inhalation 
volume, number of inhalation events) with monthly CAT score 
domains.  
• 
To determine the correlation of inhaler metrics (PIF, inhalation 
volume, number of inhalation events) with the  daily daily self-
assessment asking “How are you feeling?” with responses provided on 
a Leikert scale. 
 
Exploratory Objectives.    
• 
To determine the change in inhaler metrics in patients experiencing an 
AECOPD during study period.  
• 
To determine the correlation of inhaler metrics (PIF, inhalation 
volume, number of inhalation events) with the Digihaler metric 
algorithm-triggered DAQ. 
• 
To describe COPD-related health-care resource utilization (HRU): 
o Number of COPD exacerbations-associated hospitalizations 
 
Proportion of patients with 30-day COPD-related 
hospital re-admission 
o Number of COPD exacerbations-associated emergency room 
visits 
 
Proportion of patients with 30-day COPD-related 
emergency room re-admission 
o SABA utilization 
• 
To describe patient treatment/device satisfaction/ease of use. 
• 
To describe patient APP satisfaction/ease of use.  
Study Design 
Multicenter 3-month observational study 
Outcome Measures 
Primary Outcome Measure: 
1. Variability in Peak Inspiratory Flow (PIF) Measured via Digihaler 
Device (Time Frame: Three months) 
a. PIF is the maximal flow occurring during an inhalation 
effort, expressed in Liters/minute. Mean, standard 
deviation and coefficient of variation (calculated by 
dividing standard deviation of PIF by the mean of the PIF) 
of daily PIF measurement collected over three months will 
be calculated.  PIF will be measured using the Digihaler 
device.  
 
Secondary Outcome Measures: 
1. Correlation of Self-Reported Inhaler Use with Actual Inhaler Use 
(Time Frame: 3 months) 
a. Correlation between self-reported inhaler use and actual 
inhaler use over three months will be calculated with 
Spearman rank-order correlation coefficient. Self-reported 
inhaler use will be determined with an investigator-

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developed single question categorizing average use over 
the last four weeks with five groups (not at all, once a 
week or less, two or three times a week, one or two times 
a day, three or more times a day). Actual inhaler use will 
be directly measured via Digihaler device and categorized 
into one of the five groups described above.  
 
2. Variability in Inhalation Volume Measured via Digihaler (Time 
Frame: Three months) 
a. Inhalation volume is the volume of air inspired during an 
inhalation effort, expressed in Liters. The mean, standard 
deviation and coefficient of variation (calculated by 
dividing standard deviation of inhalation volume by the 
mean of the inhalation volume) of daily inhalation volume 
measurements collected daily over three months will be 
calculated. Inhalation volume will be measured using the 
Digihaler device. 
 
 
Analysis Strategy 
The primary analysis will be descriptive, with analytical plans as defined 
above for each primary and secondary outcome.  
 
Additional exploratory analysis will include linear regression (continuous) or 
negative binomial regression (count) of the clinical and demographic factors 
associated with inhaler from primary and secondary outcomes; descriptive 
statistics (mean, median, variance estimate and 95% confidence intervals) 
of number of inhalation events, correlation of inhaler metrics (PIF, 
inhalation volume, number of inhalation events) with CAT score, correlation 
of inhaler metrics (PIF, inhalation volume, number of inhalation events) with 
daily self-assessment asking “How are you feeling?” with responses 
provided on a Leikert scale,  correlation of inhaler metrics (PIF, inhalation 
volume, number of inhalation events) with responses to metric algorithm-
triggered DAQ; change in inhaler metrics (during the 7 days after and/or 
leading into  hospitalized AECOPD or home treatment of a moderate 
AECOPD defined by a prescription for steroids and/or antibiotics); 
descriptive 
statistics 
(proportion, 
95% 
CI) 
of 
COPD-associated 
hospitalizations and emergency room visits as well as SABA utilization; and 
patient satisfaction will be assessed with a post-study survey.  
Target Population 
Inclusion Criteria:  
• 
Age >40 years old 
• 
History of cigarette smoking >=10 pack-years 
• 
Established COPD defined as physician diagnosis along with spirometry 
confirmation (post-BD FEV1/FVC<0.70) within the last two years and an 
FEV1 ≤80% predicted 
• 
Regular albuterol use (defined as at least one puff weekly for each of 
the last four weeks) 
• 
Currently non-hospitalized 

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• 
Medical records confirmed history of two moderate AECOPD (defined 
as use of antibiotic or steroids to treat clinical event consistent with 
AECOPD) or one severe AECOPD (defined as ED/hospital visit) in prior 
12 months  
• 
Access to smartphone, tablet or computer and internet 
• 
Willingness to switch current rescue inhaler/device to ProAir Digihaler 
 
Exclusion Criteria:  
• 
Allergy or inability/contraindication to use Albuterol Sulfate 
• 
Any condition that, in the opinion of the site investigator, would 
compromise the subject’s ability to participate in the study 
Study Cohort 
 
Patients (n=60) with documented COPD and a history of two moderate or 
one severe AECOPD in prior 12 months.  
Phase 
This is an early-stage preparatory study that paves the way for this line of 
research moving forward into multicenter clinical trials.  
Research Sites 
This study will enroll patients who are currently followed at The University 
of North Carolina at Chapel Hill (N=30) or Wake Forest University in 
Winston-Salem, NC (N=30). Participants will be recruited from existing 
clinical pools at both sites including COPD registries, virtual and in-person 
outpatient clinics (routine or post-hospital discharge). 
Description of Study 
Intervention: 
In light of the COVID pandemic, this study is designed to be conducted 
entirely virtually to minimize any potential interruptions related to COVID. 
After identification and consenting, participants will be mailed the ProAir 
Digihaler (provided by Teva). The study coordinator will contact the 
participant to ensure set-up and correct usage. Participants will be asked to 
use the ProAir Digihaler as their primary mode of SABA therapy as they 
would in usual treatment and indicated in the product package insert and 
Instructions for Use. They will be provided a COPD Action Plan to ensure 
they have appropriate instructions to handle a possible AECOPD. They will 
answer a daily self-assessment asking “How are you feeling?” with 
responses provided on a Leikert scale on the DAQ App, as well as Digihaler 
metric algorithm-triggered DAQ on the DAQ app. The DAQ will collect 
yes/no responses to questions focused on change in respiratory symptoms, 
sleep disturbances, daily activity limitation, and anxiousness.. The 
participants will be contacted once per month to collect CAT score and self-
reported average albuterol use over the preceding month. They will also be 
asked about any AECOPD events requiring treatment with antibiotics 
and/or steroids or hospitalization in the prior month. Participants will be 
enrolled for three months duration. All individuals will be provided three 
inhalers at enrollment. In the event their ProAir Digihaler does not last three 
months, they will be prescribed another ProAir Digihaler (provided by Teva).  
  
Study Duration: 
This study is intended to last 18 months. 
Participant Duration: 
There will be no in-person visits. Participants will undergo a virtual 
screening/enrollment visit, followed by an initial check-in call to ensure 
device set up within one week of receipt. They will then receive three 
monthly calls during study. In the event the participant has an AECOPD 

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within two weeks of end of study, they will be followed for 14 days after 
AECOPD resolution. Total participant duration is three months (+21 days to 
account for 14 days in event of AECOPD and seven day window at end of 
study). 
 
 
1.2 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening 
& 
Enrollment 
Virtual Visit 
Confirmatory 
Phone Call 
Phone 
visit 
#1 
 
Phone 
visit 
#2 
 
Phone 
visit #3 
 
Time Window (days) 
-21 
0 
30±7 
60±7 
90±21 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Confirmation of Device Set-Up 
 
X 
 
 
 
COPD Assessment Test 
X 
 
X 
X 
X 
COPD Exacerbation History 
X 
 
X 
X 
X 
Inhaler Use and Compliance  
X 
 
X 
X 
X 
Adverse Event Assessment  
 
X 
X 
X 
X 
Complete Case Report Forms (CRFs) 
X 
X 
X 
X 
X 
 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE   
The ProAir Digihaler is the first and only digital inhaler with a built-in sensor to detect inhaler use, measure 
inspiratory flow, and capture potential technique errors. This device has been studied in asthma, but little 
information is available regarding the measurement characteristics in COPD patients. This device has the 
potential to help assess SABA use as a marker of COPD control and identify inspiratory flow metrics 
representing the onset of an AECOPD. In order to inform these purposes, it is necessary to first 
characterize the normal variation in Digihaler metrics (PIF, inhalation volume, # inhalations) in a stable 
COPD population with history of AECOPD as well as assess the changes around incidental AECOPD and 
 
Figure 1.2.1: Timeline of planned study events.  

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correlations of self-reported with actual SABA use and COPD patient reported outcomes. The 
accompanying app also permits collection of a daily self-assessment asking “How are you feeling?” with 
responses provided on a Leikert scale and responses to a Digihaler metric algorithm-triggered DAQ on the 
DAQapp. The DAQ will collect yes/no responses to questions focused on change in respiratory symptoms, 
sleep disturbances, daily activity limitation, and anxiousness.. Collecting these foundational data are the 
specific objectives of this proposal. 
 
2.2 
BACKGROUND  
Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death in the United States. It is 
characterized by fluctuating respiratory symptoms punctuated by transient acute worsening termed acute 
exacerbations of COPD (AECOPD). The optimal management COPD requires accurate assessment of 
respiratory symptom burden, prevention, timely identification and early intervention on AECOPD 
(www.GOLD.org). A key component of symptom management is the use of inhaled short-acting beta-
agonists (SABA). Per treatment strategies, all individuals with spirometry-confirmed COPD (regardless of 
severity) should be prescribed SABA therapy. Accurate assessment of SABA use is essential in COPD, as it 
not only informs overall symptom control but also may also herald onset of an AECOPD event. 
Unfortunately, several studies have demonstrated that physicians are ineffective at accurately assessing 
SABA usage as a marker of disease control, as patients often misreport their actual use. Moreover, there 
are no technologies that could serve to automatically alert a patient or provider about abrupt increases 
in SABA use or decreases in inspiratory flow rate, which may both identify an impending AECOPD. Closing 
these assessment gaps through real-time electronic capture of SABA use has the potential to improve the 
assessment and care of COPD patients in the chronic setting and during acute decompensation. 
 
There are several factors that can impact successful SABA administration. These include inhalation 
technique, duration, and inspiratory effort. Dry-powder inhalers (DPIs) are breath-actuated and tend to 
be easier for patients to use than metered dose inhaler or soft mist inhalers. However, there is emerging 
evidence that delivery from DPI may be suboptimal in some patients and settings.  It has recently been 
shown that COPD patients can exhibit suboptimal peak inspiratory flow (PIF) in the stable outpatient 
setting (Ghosh, Sulaiman) and during hospital exacerbations (Loh, Sharma). Although published evidence 
regarding suboptimal delivery from DPIs in the COPD population is emerging, substantial knowledge gaps 
exist including the day to day variation in PIF in ambulatory COPD patients when clinically stable and 
during periods leading up to and recovery from AECOPD.  
 
2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS  
 
This study is considered low risk as all participants enrolled will already by using albuterol in their clinical 
care. Potential risks include albuterol side effects or loss of confidentiality.  
 
Inhaled albuterol is the most commonly used rescue medication used in the COPD population as part of 
their normal clinical care. Standard doses of inhaled albuterol can cause transient cough, mild tachycardia, 
and tremors. 
 
There is a chance of emotional distress if data from questionnaires or other home testing domains are not 
kept private. Safeguards are taken to ensure that subjects' confidentiality is maintained. General study 
measures include: 1) unique study numbers on documents containing de-identified data; 2) maintaining 
identifiers on linking file in a locked drawer in a private office; and 3)restricting access to files and 

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password protected databases to essential study personnel. All data are reported without personal 
identifiers. The study investigators, who will have access to the medical chart and personal data for study 
participants, have already received training and certification according to the institutions obligations 
under the Health Insurance Portability and Accountability Act (HIPAA). We will use unique study numbers. 
The linking form will be the only form linking study ID to personal data. This will be maintained in a locked 
drawer in a private office. We will maintain all other data linked to study ID on REDCap. All study related 
forms (regardless of identified or de-identified) will be placed in locked files and kept in a separate office 
from the linking file. Electronic data will be retained on a secure network via REDCap or password 
protected files.  
 
The DAQApp provides patients with a Privacy Notice within the App explaining Teva's policies and 
practices for handling information and the choices that patients can make about the how their 
information is collected and used.  Information that is collected and its use is described in detail in the 
Privacy Notice.  Patients must accept the privacy notice within the App and provide in-App consent to 
store their information in a cloud prior to using the App functionality.  Information stored may include 
inhalation events, inhalation metrics as well as DAQ App diagnostic data. Patients must also provide a 
separate consent to share their information with a specific healthcare provider or research study site by 
signing up to a restricted access “Healthcare Program” within the DAQ App.  A healthcare provider or 
research study personnel can view the information via a web-based application, the Digihaler® Dashboard.   
Teva has enacted commercially reasonable physical, technical, and administrative safeguards to secure 
information that is collected and stored on the Teva Digital System, which includes the App, the dashboard 
and the cloud.  To prevent unauthorized access to their personal information, the App or any portion 
thereof, to maintain information accuracy, and to ensure the correct use of information, patients are 
strongly encouraged to password protect their device and refrain from providing any third party with 
unsupervised access to their device. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
There are no known individual benefits that are expected as a result of this trial. Rather, we expect that 
the benefit will be to society as a whole if this study helps to advance the understanding of the ProAir 
Digihaler in the COPD population.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Before participating in the study, subjects will be asked about history of intolerance to albuterol. The study 
team will also confirm that the participant is using albuterol on a regular basis (defined as at least one 
puff weekly for each of the last four weeks). If the safety of albuterol use cannot be assured, the subject 
will be excluded from the study.  
 
 
3 
OBJECTIVES  
 
Primary Objective:  

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• 
To determine the variation in ProAir Digihaler metrics (PIF, inhalation volume, number of inhalation 
events) amongst COPD patients in the ambulatory setting. 
 
Secondary Objectives.  
• 
To determine the correlation of self-reported SABA use with actual SABA use collected by the ProAir 
Digihaler.  
• 
To determine the correlation of inhaler metrics (PIF, inhalation volume, number of inhalation 
events) with monthly CAT score domains.  
• 
To determine the correlation of inhaler metrics (PIF, inhalation volume, number of inhalation 
events) with the daily self-assessment asking “How are you feeling?” with responses provided on a 
Leikert scale. 
 
Exploratory Objectives.    
• 
To determine the change in inhaler metrics in patients experiencing an AECOPD during study period.  
• 
To determine the correlation of inhaler metrics (PIF, inhalation volume, number of inhalation 
events) with the Digihaler metric algorithm-triggered DAQ. 
• 
To describe COPD-related health-care resource utilization (HRU): 
o Number of COPD exacerbations-associated hospitalizations 
 
Proportion of patients with 30-day COPD-related hospital re-admission 
o Number of COPD exacerbations-associated emergency room visits 
 
Proportion of patients with 30-day COPD-related emergency room re-admission 
o SABA utilization 
• 
To describe patient treatment/device satisfaction/ease of use. 
• 
To describe patient APP satisfaction/ease of use. 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
This is a multisite, observational, 3-month pilot study of ProAir Digihaler use in 60 COPD patients at-risk 
for AECOPD. Participants will be recruited from two sites (Wake Forest University, N=30; University of 
North Carolina at Chapel Hill, N=30). All participants will have spirometry-confirmed COPD with an 
increased AECOPD risk (defined as two moderate or one severe AECOPD in the last 12 months).  
 
Participants will be recruited from existing clinical pools at both sites including COPD registries, virtual and 
in-person outpatient clinics (routine or post-hospital discharge). Although this study will not be powered 
to make meaningful assessments of inhaler metric changes at the time of an AECOPD, we are permitting 
patients recently discharged for an AECOPD event to be enrolled, which will permit assessment of changes 
during the recovery phase as well as enrich for individuals more likely to have an AECOPD event during 
study. 
 
In light of the COVID pandemic, this study is designed to be conducted entirely virtually to minimize any 
potential interruptions related to COVID. Both UNC and Wake Forest have experience conducting virtual 
studies with local IRB approval. Potentially eligible patients will be identified and screened for possible 
inclusion through existing registry review, virtual clinic visits or in-person visits.  
 

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Potentially eligible participants will be contacted, with the permission of their care providers, by study 
investigators or research coordinators and assessed for interest. Based on local IRB approval, they will 
either be mailed an informed consent (ICF) for phone review with the research coordinator or will 
complete verbal consent over the phone. After consenting, participants will be mailed the ProAir Digihaler 
(provided by Teva) The study coordinator will contact the participant to ensure set-up and correct usage.  
 
Participants will then be asked to use the ProAir Digihaler as their primary mode of SABA therapy as they 
would in usual treatment and indicated in the product package insert and Instructions for Use. They will 
be provided a COPD Action Plan to ensure they have appropriate instructions to handle a possible 
AECOPD. They will answer a daily self-assessment asking “How are you feeling?” with responses provided 
on a Leikert scale on the DAQ App, as well as Digihaler metric algorithm-triggered DAQ on the DAQ app. 
 
The participants will be contacted once per month to collect CAT score and self-reported average albuterol 
use over the preceding month. They will also be asked about any AECOPD events requiring treatment with 
antibiotics or steroids in the prior month.  If there is evidence during the calls of clinical deterioration by 
self report or an abrupt increase in CAT by > 4 units patients will be advised to contact their primary care 
or COPD provider. 
 
Participants will be enrolled for three months duration. In the event the participant has an AECOPD within 
two weeks of end of study, they will be followed for 14 days after AECOPD resolution. Total participant 
duration is three months (+21 days to account for 14 days in event of AECOPD and seven day window at 
end of study). In the event their ProAir Digihaler does not last three months, they will be prescribed 
another device (provided by Teva). Hospital admission during the course of the study will not prohibit 
continued participation.  
 
4.2 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the study 
including the last phone visit shown in the Schedule of Activities (SoA), Section 1.3. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
• 
Age >40 years old 
• 
History of cigarette smoking >=10 pack-years 
• 
Established COPD defined as physician diagnosis along with spirometry confirmation (post-BD 
FEV1/FVC<0.70) within the last two years and an FEV1 ≤80% predicted 
• 
Regular albuterol use (defined as at least one puff weekly for each of the last four weeks) 
• 
Currently non-hospitalized 
• 
Medical records confirmed history of two moderate AECOPD (defined as use of antibiotic or steroids 
to treat clinical event consistent with AECOPD) or one severe AECOPD (defined as ED/hospital visit) 
in prior 12 months  
• 
Access to smartphone, tablet or computer and internet 
• 
Willingness to switch current rescue inhaler/device to ProAir Digihaler 
 
5.2 
EXCLUSION CRITERIA 

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Subjects presenting with any of the following will not be included in the trial: 
• 
Allergy or inability/contraindication to use Albuterol Sulfate 
• 
Any condition that, in the opinion of the site investigator, would compromise the subject’s ability to 
participate in the study 
 
5.3 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently enrolled in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
The target number of study participants is 60 adult subjects (N=30 at each site). We expect that all, or 
nearly all, subjects will be recruited within 12 months. Subjects participating in other observational studies 
will not be excluded from participation, as long as they meet all other inclusion criteria, but interventional 
pulmonary drug studies will not be concurrently allowed. Participants will be recruited from existing 
clinical pools at both sites including COPD registries, virtual and in-person outpatient clinics (routine or 
post-hospital discharge). Although this study will not be powered to make meaningful assessments of 
inhaler metric changes at the time of an AECOPD, the purposeful enrollment of patients recently 
discharged for an AECOPD event will permit assessment of changes during the recovery phase as well as 
enrich for individuals more likely to have an AECOPD event during study. Given the purposeful design of 
the study through an all virtual process, we do not anticipate impediments to recruitment in light of the 
dynamic COVID pandemic. 
As this is a study of short duration that incorporates a medication already part of a patient’s routine care, 
we anticipate that there will not be significant issues with retention. Monthly phone calls will occur to 
record interval medical history. Such contacts also reinforce study participation and retention. 
Additionally, the provision of the inhaled medication by the study sponsor will further facilitate participant 
retention during the study. The use of a completion fee (described below) further facilitates study 
retention. 
 
Subjects will be reimbursed $50 for completion of each of the three calls, along with a $50 completion fee 
(Totaling $200) as a means of compensating patients for their time on calls and completing study 
questionnaires. As this is an all virtual study, there will not be any reimbursements for travel.  
  
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
Participants will be recruited from two sites (Wake Forest University, N=30; University of North Carolina 
at Chapel Hill, N=30). Participants will be recruited from existing clinical pools at both sites including COPD 
registries, virtual and in-person outpatient clinics (routine or post-hospital discharge). 

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In light of the COVID pandemic, this study is designed to be conducted entirely virtually to minimize any 
potential interruptions related to COVID. Both UNC and Wake Forest have experience conducting virtual 
studies with local IRB approval. Potentially eligible patients will be identified and screened for possible 
inclusion through existing registry review, virtual clinic visits or in-person visits.  
 
Potentially eligible participants will be contacted, with the permission of their care providers, by study 
investigators or research coordinators and assessed for interest. Based on local IRB approval, they will 
either be mailed an informed consent (ICF) for phone review with the research coordinator or will 
complete verbal consent over the phone. After consenting, participants will be mailed the ProAir Digihaler 
(provided by Teva) The study coordinator will contact the participant to ensure set-up and correct usage. 
Patients will participate in a monthly call to capture CAT score, albuterol use recall and AECOPD events 
during study period. 
 
Participants will then be asked to use the ProAir Digihaler as their primary mode of SABA therapy as they 
would in usual treatment and indicated in the product package insert and Instructions for Use. They will 
answer a daily self-assessment asking “How are you feeling?” with responses provided on a Leikert scale 
on the DAQ App, as well as Digihaler metric algorithm-triggered DAQ on the DAQ app.  The DAQ will collect 
yes/no responses to questions focused on change in respiratory symptoms, sleep disturbances, daily 
activity limitation, recent AECOPD diagnosis and treatment, and anxiousness, as well as the Leikert “How 
are you feeling?” scale. The DAQ questionnaire will be triggered in the app based on an algorithm 
incorporating data from the digihaler metrics. The DAQ will be only deployed when indicated by the 
algorithm or on an ad-hoc basis by the patient (but not necessarily daily). They will be provided a COPD 
Action Plan to ensure they have appropriate instructions to handle a possible AECOPD.  
 
The participants will be contacted once per month to collect CAT score and self-reported average albuterol 
use over the preceding month. They will also be asked about any AECOPD events requiring treatment with 
antibiotics or steroids in the prior month. 
 
Specific Data Collection Includes: 
 
Clinical Data: Enrollment characteristics including age, race, sex, smoking history, prior spirometric data 
(FEV1, FEV1% predicted, FVC, FVC % predicted, FEV1/FVC), exacerbation history, enrollment inhaler 
regimen, self-reported frequency of albuterol use, baseline CAT score 
 
Data Collection Tools: Enrollment questionnaire, CAT questionnaire, monthly AECOPD and self-reported 
albuterol use questionnaire, and Digihaler device. The Digihaler uses integrated sensors to capture 
inhalation data and stores it onto an e-module inside the device. When within range, the e-module 
transfers the stored data using Bluetooth technology to a paired app on the users’ phone. The app can 
display the data in various reports as well as export the reports in the form of pdfs which can be emailed. 
The app also shares the data to a server via a wifi connection which enables real-time data sharing to a 
provider facing dashboard. The data the provider sees is the same as what patients see and also have the 
ability to be exported into a .csv file for further analysis. For additional data points, beyond what the 
patient and provider currently see, our team has the ability to export more information in the form of 
data extracts from the back end cloud server. This can be setup to send at a predetermined interval for 
further analysis.  
 

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Patient Reported Outcomes (PROs): CAT questionnaire, self-reported monthly average albuterol use 
during study, daily self-assessment asking “How are you feeling?” with responses provided on a Leikert 
scale on the DAQ app, and Digihaler metric algorithm-triggered symptom questions using the DAQ app.  
 
6.1.2 DOSING AND ADMINISTRATION 
 
ProAir Respiclick will be dosed and administered in accordance with the package insert 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205636s000lbl.pdf). 
Specifically, 
albuterol sulfate 117 mcg will be administered 2 inhalations repeated every 4 to 6 hours as needed. 
 
6.2 
STUDY INTERVENTION COMPLIANCE 
Compliance with study interventions will be ensured by the study team during monthly.  
 
6.3 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. There will be no disallowed medications in this study.  
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
If a clinically significant finding is identified (including, but not limited to changes from baseline) after 
enrollment, the investigator or qualified designee will determine if any change in participant management 
is needed. Any new clinically relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Reason for discontinuation 
• 
Vital signs, if available 
• 
Related medical records, if available 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. An investigator 
may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 

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The reason for participant discontinuation or withdrawal from the study will be recorded in the study file. 
Subjects who sign the informed consent form but who do not receive the study intervention may be 
replaced.  Subjects who sign the informed consent form, and receive the initial study intervention, and 
subsequently withdraw, or are withdrawn or discontinued from the study, will also be replaced, to ensure 
60 complete adult data sets. 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she is not able to be contacted on phone visit 
and no-longer is transmitting data via the DAQ app.  
 
The following actions must be taken if a participant cannot be contacted: 
• 
The site will attempt to contact the participant and reschedule the missed phone contact within 
1 week and counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, three telephone calls). These contact 
attempts should be documented in the participant’s study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
No study results will be specifically distributed to the study subject.  
 
8.1 
OUTCOME ASSESSMENTS  
• 
Digihaler PIF: mean, median, standard deviation 
• 
Digihaler Inspiratory volume: mean, median, standard deviation 
• 
Digihaler Inhaler usage: count 
• 
Self-reported inhaler usage: Average use over the preceding month 
• 
COPD Assessment Test (CAT) questionnaire: Collected monthly 
• 
Self-report of COPD exacerbation events on study 
• 
       Responses to daily self-assessment asking “How are you feeling?” on Leikert scale (mean,  
median, standard deviation, variability) 
• 
Responses to DAQ on the DAQ app (cumulative score and individual domains mean, median, 
and standard deviation; variability of the responses and adherence to daily reporting) 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
Before participating in the study, subjects will be asked about history of intolerance to albuterol. The study 
team will also confirm that the participant is using albuterol on a regular basis (defined as at least one 
puff weekly for each of the last four weeks). If the safety of albuterol use cannot be assured, the subject 
will be excluded from the study. If any AE’s or SAE’s are detected, they will be followed by the investigator 
until symptoms have resolved.  
   
8.3 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS, SERIOUS ADVERSE EVENTS AND 
SERIOUS ADVERSE DEVICE EFFECTS  
 

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8.3.1 DEFINITION OF ADVERSE EVENTS (AE) AND ADVERSE DEVICE EFFECTS (ADE) 
 
An adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). Preexisting condition (i.e., a 
disorder present before the adverse event reporting period started) should not be reported as an adverse 
event unless the condition worsens or episodes increase in frequency during the adverse event reporting 
period. This is particularly relevant for subjects with COPD who may have substantial symptoms at 
baseline. 
 
An adverse device effect is an adverse event related to the use of an investigational medical device or 
combination product. This includes adverse events resulting from insufficient or inadequate instructions 
for use, deployment, implantation, installation, operation, or any malfunction of the investigational 
medical device, including any event resulting from user error or from intentional misuse of the 
investigational medical device. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of the 
investigator, it results in any of the following outcomes: death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  
 
A serious adverse device effect is an adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 
Generally, adverse events reported from clinical trials associated with hospitalization or prolongation of 
hospitalization are considered serious. Any initial admission (even if less than 24 hours) to a healthcare 
facility meets these criteria.  Admission also includes transfer within the hospital to an acute/intensive 
care unit (e.g., from the psychiatric wing to a medical floor, medical floor to a coronary care unit, 
neurological floor to a tuberculosis unit).  
 
Because of the nature of the disease population being studied, and the fact that part of the study includes 
evaluating subjects experiencing a COPD exacerbation with may require hospitalization, hospitalization 
will NOT obligatorily be considered an SAE for this study. Hospitalization will be reported as an SAE if, in 
the discretion of the investigator, it is temporally related to albuterol use. 
 
Hospitalization does not include the following: 
• 
Rehabilitation facilities; 
• 
Hospice facilities; 
• 
Respite care (e.g., caregiver relief); 
• 
Skilled nursing facilities; 
• 
Nursing homes; 
• 
Same day surgeries (as outpatient/same day/ambulatory procedures). 

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Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical adverse event 
is not in itself a Serious Adverse Event.  Examples include: 
• 
Admission for treatment of a preexisting condition not associated with the development of a new 
adverse event or with a worsening of the preexisting condition (e.g., for work-up of persistent 
pretreatment lab abnormality); 
• 
Social admission (e.g., subject has no place to sleep); 
• 
Administrative admission (e.g., for yearly physical exam); 
• 
Optional admission not associated with a precipitating clinical adverse event (e.g., for elective 
cosmetic surgery); 
• 
Preplanned treatments or surgical procedures should be noted in the baseline documentation for 
the entire protocol and/or for the individual subject. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
The following guidelines will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) and Adverse Device Effects (ADEs) must have their relationship to study 
intervention assessed by the clinician who examines and evaluates the participant based on temporal 
relationship and his/her clinical judgment. The degree of certainty about causality for adverse events will 
be graded using the categories below.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (de-challenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory re-challenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (de-challenge). Re-challenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 

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concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. As noted in 8.3.2, because of the 
nature of the disease population being studied, and the fact that that part of the study includes 
studying subjects experiencing a COPD exacerbation which may require hospitalization, 
hospitalization will NOT obligatorily be considered an SAE for this study. Hospitalization will be 
reported as an SAE if, in the discretion of the investigator, it is temporally related to albuterol use. 
 
8.3.3.3 EXPECTEDNESS  
The principal investigator or co-investigators will be responsible for determining whether an adverse 
event (AE) is expected or unexpected.  An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the study 
intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All ADEs, SAEs, and AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate CRF. Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training 
and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The study coordinator will record all reportable events with start dates occurring any time after informed 
consent is obtained until 24 hours after the last day of study participation.   Events will be followed for 
outcome information until resolution or stabilization. Given the duration of the study, these events will 
be collected during the monthly phone calls by the study coordinator, unless the information is voluntarily 
provided by the subject in between study visits or phone calls.  

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8.3.5 ADVERSE EVENT REPORTING  
In keeping with good clinical practice or good pharmacovigilance practice, and 21 C.F.R. Part 314 as the 
case may be, the external investigator will be required to report and notify the Teva Pharmaceuticals  
(Teva) of all situations mentioned below, within twenty-four (24) hours from receiving information of 
the situation.  The event will be reported to Teva by submitting the collected information to the Teva 
Local Safety Officer. The event will also be reported to the FDA, Institutional Review Boards (IRBs), and 
any other collaborators/investigators according to national, and local safety reporting requirements.  
(a) 
All related Serious Adverse Events 
(b) 
All Serious Adverse Device Effects 
(c)  
Any exposure of a pregnant study participant to the study drug within thirty (30) days of 
exposure 
(d)  
Any medical event which may reasonably be believed to impair the integrity, validity or 
ongoing viability of the study  
 
Each adverse event is to be classified by the investigator as serious or non-serious.  This classification 
determines the reporting procedures to be followed. If a serious adverse event occurs, expedited 
reporting will follow FDA and IRB regulations.  If an adverse event is both serious and unexpected, 
reporting will follow IRB reporting regulations as appropriate.  SAEs are reportable from the time that the 
subject provides informed consent, which is obtained prior to the subject’s participation in the trial (i.e., 
prior to undergoing any trial-related procedure through and including 24 hours after the final call).  Any 
serious adverse event occurring at any other time during the study must be promptly reported if a causal 
relationship to study drug is suspected. 
 
If a serious adverse event occurs, the Institutional IRB will be notified within five business days of 
awareness of the event by the investigator.  The study coordinator may initiate the IRB notification, but it 
must be filed by the study investigator or co-investigators. If the serious adverse event is fatal or life 
threatening, notification to the Institutional IRB must be made within 24 hours, irrespective of the extent 
of available adverse event information.  This timeframe also applies to additional new information (follow-
up) on previously forwarded serious adverse event reports. 
 
The MedWatch 3500A form should be utilized to report serious adverse events to the FDA.   
 
All adverse events (serious and non-serious) will be reported on the adverse event page(s) of the CRF.  
Adverse events should be reported using concise medical terminology on the CRFs. Non-serious AE’s will 
be reported annually to the IRB as appropriate.  
 
8.3.6 REPORTING EVENTS TO PARTICIPANTS  
 
Not applicable.  
 
8.3.7 ADVERSE EVENTS OF SPECIAL INTEREST  
 

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Not applicable.  
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
HYPOTHESIS 
We hypothesize that inhaler metrics (PIF, inhalation volume, rescue inhaler use) will vary among COPD 
populations. We also hypothesize that increased albuterol use will positively correlate with worse daily 
Leikert scores, declining PIF, lower inhalation volume and higher CAT scores. We hypothesize that self-
reported albuterol use will be lower than actual albuterol use captured by the DAQ app. We hypothesize 
that increased albuterol use will positively correlate with more symptomatic DAQ responses. The 
proposed study is designed to yield an initial exploration of the metrics captures by the Digihaler in a COPD 
population.   
 
9.2 
SAMPLE SIZE RATIONALE 
The primary considerations in choosing the proposed target sample size were patient availability,  fiscal 
costs,  time required to complete the study,  the proportion of subjects  expected to complete the 
protocol,  and conjectures about the precision of the estimators of interest. As such, this pilot study does 
not have pre-specified power calculations. Although this study will not be powered to make meaningful 
assessments of inhaler metric changes at the time of an AECOPD, we are permitting patients recently 
discharged for an AECOPD event to be enrolled, which will permit assessment of changes during the 
recovery phase as well as enrich for individuals more likely to have an AECOPD event during study. 
 
9.3 
MISSING DATA 
 
The primary analyses will be “per protocol” analyses.  Adult subjects must complete baseline and one 
month phone visit at minimum to be included in analysis. Subjects who complete these required visits will 
be included for analysis, and subjects who do not complete required visits will be excluded from the 
statistical analyses. Safety analyses will be included for all subjects.  Reasons for drop-out and missing 
data values will be documented in the database.  The occurrences of drop-out and missing data will be 
examined to investigate potential induction of selection biases.  Missing data (i.e., occurring during 
hospitalization) will be assumed to be missing not at random. These missing data will not be imputed.  
 
9.4 
STATISTICAL ANALYSES 
 
Below are the pre-specific outcome measures: 
 
Primary Outcome Measure: 
1. Variability in Peak Inspiratory Flow (PIF) Measured via Digihaler Device (Time Frame: Three 
months) 
b. PIF is the maximal flow occurring during an inhalation effort, expressed in Liters/minute. 
Mean, standard deviation and coefficient of variation (calculated by dividing standard 
deviation of PIF by the mean of the PIF) of daily PIF measurement collected over three 
months will be calculated.  PIF will be measured using the Digihaler device.  
 
Secondary Outcome Measures: 
1. Correlation of Self-Reported Inhaler Use with Actual Inhaler Use (Time Frame: 3 months) 

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a. Correlation between self-reported inhaler use and actual inhaler use over three months 
will be calculated with Spearman rank-order correlation coefficient. Self-reported 
inhaler use will be determined with an investigator-developed single question 
categorizing average use over the last four weeks with five groups (not at all, once a 
week or less, two or three times a week, one or two times a day, three or more times a 
day). Actual inhaler use will be directly measured via Digihaler device and categorized 
into one of the five groups described above.  
2. Variability in Inhalation Volume Measured via Digihaler (Time Frame: Three months) 
a. Inhalation volume is the volume of air inspired during an inhalation effort, expressed in 
Liters. The mean, standard deviation and coefficient of variation (calculated by dividing 
standard deviation of inhalation volume by the mean of the inhalation volume) of daily 
inhalation volume measurements collected daily over three months will be calculated. 
Inhalation volume will be measured using the Digihaler device. 
 
The primary analysis will be descriptive, with analytical plans as defined above for each primary and 
secondary outcome.  
 
The primary analysis will be descriptive, with analytical plans as defined above for each primary and 
secondary outcome.  
 
Additional exploratory analysis will include linear regression (continuous) or negative binomial 
regression (count) of the clinical and demographic factors associated with inhaler from primary and 
secondary outcomes; descriptive statistics (mean, median, variance estimate and 95% confidence 
intervals) of number of inhalation events, correlation of inhaler metrics (PIF, inhalation volume, number 
of inhalation events) with CAT score, correlation of inhaler metrics (PIF, inhalation volume, number of 
inhalation events) with daily self-assessment asking “How are you feeling?” with responses provided on 
a Leikert scale,  correlation of inhaler metrics (PIF, inhalation volume, number of inhalation events) with 
responses to metric algorithm-triggered DAQ; change in inhaler metrics (during the 7 days after and/or 
leading into hospitalized AECOPD or home treatment of a moderate AECOPD defined by a prescription 
for steroids and/or antibiotics); descriptive statistics (proportion, 95% CI) of COPD-associated 
hospitalizations and emergency room visits as well as SABA utilization; and patient satisfaction will be 
assessed with a post-study survey. The Leikert scale will be modeled using an ordinal scale with lower 
number signifying worse daily overall feeling. The DAQ will be comprised of yes/no responses to a set of 
questions (categorized as No=0; Yes=1) with higher score calculated in the analysis indicating worse 
symptoms. In exploratory analyses, individual DAQ domains and cumulative score will be evaluated as 
outcomes. Because the DAQ also includes the Leikert scale, on days where both the DAQ Leikert and 
daily Leikert are completed, the DAQ Leikert will be used for analysis. 
 
 
9.4.1 SAFETY ANALYSES 
 
As there is a small number of subjects in this study, we anticipate simple categorization of reported AEs. 
 
9.4.2 PLANNED INTERIM ANALYSES  
 
No interim analyses will be performed.  
 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms (ICF) describing in detail the study intervention, study procedures, and risks are given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.   An informed consent checklist is an SOP for our research 
group, and SOPs are followed by all study personnel engaged in the study. 
 
The following consent materials are will be prepared for the IRB submission with this protocol: adult 
participant consent form and HIPAA authorization.   
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Given the current COVID landscape, we are requesting permission for a waiver of signatures of ICF and 
HIPAA by obtaining and documenting verbal consent. Once a participant has been identified, they will be 
contacted via phone and screened using the phone screener embedded in the verbal consent form. If they 
express interest in the study, we will then proceed with obtaining verbal consent using the verbal consent 
attached to this document. The entire ICF will be read to the participant, and after completion, asking 
them to briefly describe the study (to assess comprehension). They will then be provided the chance to 
ask any questions. If they are agreeable to study, we will then document this in their record. We will follow 
a similar plan for the HIPAA form (reading the entire HIPAA to the participant verbatim and asking at the 
end if they agree and then, marking this in their chart). Recruitment conversations will occur in a private 
office with a trained study team member. We will include a copy of the consent form and HIPAA 
authorization with the study material mailing. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants (if active on the study), investigator, funding 
agency and regulatory authorities.  Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary outcome variable has been met 
• 
Determination of futility 
 

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Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the sponsor, IRB or investigators. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their interventions. Therefore, the study protocol, documentation, data, and all 
other information generated will be held in strict confidence. No information concerning the study or the 
data will be released to any unauthorized third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The representatives of the Institutional Review Board (IRB) or regulatory agencies may inspect all 
documents and records required to be maintained by the investigator, including but not limited to, 
medical records (office, clinic, or hospital) for the participants in this study. The clinical study site will 
permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the Marsico Clinical Research Center (UNC) and Wake Forest Pulmonary 
Division (Wake Forest). This will not include the participant’s contact or identifying information. Rather, 
individual participants and their research data will be identified by a unique study identification number; 
linkage files will be secured and password protected. At the end of the study, all study databases will be 
de-identified and may be archived at an off-site facility. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Not applicable  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator (UNC) 
Principal Investigator (Wake Forest) 
M. Bradley Drummond, MD 
Jill Ohar, MD 
The University of North Carolina at Chapel Hill  
Wake Forest Baptist Medical Center 
125 Mason Farm Road, CB #7248 
Pulmonary Division – Watlington Hall 2nd 
floor, Medical Center BLVD 
919-966-7054 
336-406-6733 
brad_drummond@med.unc.edu 
johar@wakehealth.edu  
 
Team Roles: 
Brad Drummond, MD, MHS – co-investigator (UNC) 
Jill Ohar, MD – co-investigator (WF) 
Caleb Hemphill and Annette Babu – study RC (UNC) 
Sharon Cornelison  – study RC (WF) 
Marc Tian, PhD – study biostatistician 

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10.1.6 SAFETY OVERSIGHT 
 
As this study is deemed low risk, using technology frequently prescribed for use by COPD patients at 
home, oversight for this feasibility study will be conducted by the PIs (Dr. Drummond and Ohar). The PIs 
will monitor data to ensure the safety of participants.  
 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory requirement(s).  
 
Given the pilot nature of the study, the study team will be responsible for regular on-site monitoring with 
100% data verification. This will primarily be conducted by the study research coordinators.  
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical site will perform internal quality management of study conduct, data collection, 
documentation and completion.  Quality control (QC) procedures will be implemented beginning with the 
data entry system and data QC checks that will be run on the database will be generated.  
 
Following written Standard Operating Procedures (SOPs), the team will verify that the clinical trial is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.  All source documents should be completed in a neat, legible manner to 
ensure accurate interpretation of data. As used in this protocol, the term case report form (CRF) should 
be understood to refer to either a paper form or an electronic data record or both.  A CRF is required and 
should be completed for each included subject.  The completed original CRFs are the sole property of UNC 
or Wake Forest and should not be made available in any form to third parties, except for authorized 
representatives of the University or appropriate regulatory authorities. Data recorded in the electronic 
case report form (eCRF) derived from source documents should be consistent with the data recorded on 
the source documents. 
 
It is the investigator’s responsibility to ensure completion and to review and approve all CRFs.  CRFs must 
be reviewed by the investigator or by an authorized staff member.  Signatures serve to attest that the 
information contained on the CRFs is true.  At all times, the investigator has final responsibility for the 
accuracy and authenticity of all clinical and laboratory data entered on the CRFs. 
 

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Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into a secure database that is password protected with 
limited access. Clinical data will be entered directly from the source documents.  
 
10.1.9.2 STUDY RECORDS RETENTION  
As required by law and to enable evaluations and/or audits from regulatory authorities, the investigator 
agrees to keep records, including the identity of all participating subjects (i.e., sufficient information to 
link records to identity), all original signed informed consent forms, and copies of all CRFs, other source 
documents, and detailed records of treatment disposition.  The records should be retained by the 
investigator according to International Conference on Harmonization (ICH), or federal and local 
regulations, whichever is longer.  
 
10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by the 
site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations 
within 14 working days of identification of the protocol deviation, or within 14 working days of the 
scheduled protocol-required activity.  All deviations must be addressed in study source documents, and if 
resulting in an AE, follow the protocols for reporting detailed in that section. Protocol deviations must be 
sent to the reviewing Institutional Review Board (IRB) per their policies. The site investigator is responsible 
for knowing and adhering to the reviewing IRB requirements.  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the publication and data sharing policies outlined in the 
clinical trials agreement. 
  
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a way 
that is appropriate to their participation in the design and conduct of this trial.  The study leadership in 
conjunction with the Institutional IRBs have established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 

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10.2 ADDITIONAL CONSIDERATIONS 
Not applicable 
 
 
 

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10.3 ABBREVIATIONS 
 
AECOPD 
Acute exacerbation of chronic obstructive pulmonary disease 
CAT 
COPD Assessment Test 
CI 
Confidence interval 
CFR 
Code of federal regulation 
CRF 
Case report form 
COPD 
Chronic obstructive pulmonary disease 
DAQ 
Digital automated questionnaire 
DPI 
Dry powder inhaler 
ED 
Emergency department 
HIPAA 
Health Insurance Portability and Accountability Act 
HRU 
Health-care resource utilization 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
ICH GCP 
International Conference on Harmonisation Good Clinical Practice 
ICF 
Informed consent form 
IRB 
Institutional review board 
PIF 
Peak inspiratory flow 
SABA 
Short acting beta-agonist 
UNC 
University of North Carolina 
WF 
Wake Forest 
 
 
 
 
10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
1.1 
01Dec2021 
Administrative staffing updates 
To update personnel on study 
1.2 
21Mar2022 
Remove exclusion criteria “Frequent 
use of nebulizer (i.e. >1 time per 
day)” 
Concominant use of nebulizers 
frequent in this population 
limiting recruitment and 
impacting generalizability 
 
 
 
 
 
 
 
 
 
 
11 REFERENCES  
 
Global Initiative for Chronic Obstructive Lung Disease Guidelines. http://goldcopd.org/wp-
content/uploads/2016/12/wms-GOLD-2017-Pocket-Guide.pdf.  
 
Ghosh S, Ohar JA, Drummond MB. Peak inspiratory flow Rate in chronic obstructive pulmonary disease: 
implications for dry powder inhalers. J Aerosol Med Pulm Drug Delivery  2017;30:1-7. 

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Loh CH, Peters SP, Lovings TM, and Ohar JA. Suboptimal inspiratory flow rates are associated with 
chronic obstructive pulmonary disease and all cause readmissions. Ann Am Thorac Soc  2017;14:1305–
1311 
 
Sharma G MD, Mayorga VM, Deering KL, Harshaw Q, and Ganapathy V. Prevalence of low peak 
inspiratory flow rate at discharge in patients hospitalized for COPD exacerbation. J COPD Found 
2017;4:217-224. 
 
Sulaiman I, Cushan B, Greeen G et al. Objective assessment of adherence to inhalers by patients with 
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2017;195:1333–1343