A Single Center, Open Label, Prospective Study Measuring Proportion of Patients With Suboptimal Peak Inspiratory Flow Rate (sPIFR) Over 24 Weeks in an Ambulatory Setting Among Moderate to Very Severe COPD Patients
Phase: NA
Conditions: COPD
Sponsor: University of North Carolina, Chapel Hill

STUDY PROTOCOL 
 
A Single Center, Open Label, Prospective, Observational Study 
Measuring Proportion of Patients with Suboptimal Peak Inspiratory 
Flow Rate (sPIFR) over 24 Weeks in an Ambulatory Setting among 
Moderate to Very Severe COPD Patients 
 
 
NCT number NCT04168775 
Document Date 02/18/2021 
 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
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Complete Title: A single center, open label, prospective, observational study measuring proportion of 
patients with suboptimal Peak Inspiratory Flow Rate (sPIFR) over 24 weeks in an ambulatory setting 
among moderate to very severe COPD patients  
 
 
Short Title: PIFR in COPD  
Drug or Device Name(s): N/A  
Protocol Date: February 18, 2021  
Revision #1 Date: August 16, 2019 
SUMMARY OF REVISIONS (AUGUST 16, 2019) 
• 
ADD WIXELA® INHUB® AS LOW-MEDIUM RESISTANCE INHALER 
• 
REMOVE TWO YEAR WINDOW ON PRIOR CONFIRMATORY SPIROMETRY TESTING FOR INCLUSION 
• 
REQUEST TO ADD DR. ROBERT BURKES, MD AS CO-INVESTIGATOR 
Revision #2 Date: May 21, 2020 
SUMMARY OF REVISIONS (MAY 21, 2020) 
• 
REMOVE PERFORMANCE OF PRE AND POST-BRONCHODILATOR SPIROMETRY TESTING  
• 
CHANGE SPIROMETRY CRITERIA TO THREE YEAR WINDOW WITH ABSTRACTION OF PREVIOUSLY COMPLETED 
SPIROMETRY DATA FOR ENROLLMENT DATA 
• 
MOVE ALL IN-PERSON PROCEDURES (POSITIONAL PIFR, PRE AND POST-BRONCHODILATOR PIFR 
MEASUREMENTS TO V1 ENROLLMENT 
• 
MODIFY V6 TO PHONE VISIT 
Revision #3 Date: February 18, 2021 
SUMMARY OF REVISIONS (FEBRUARY 18, 2021) 
• 
REMOVE DR. ROBERT BURKES, MD (CO-INVESTIGATOR) AS HE HAS LEFT UNC 
• 
CHANGE SPIROMETRY CRITERIA TO ANY HISTORY OF SPIROMETRY CONFIRMING COPD WITH ABSTRACTION OF 
ANY PREVIOUSLY COMPLETED SPIROMETRY DATA FOR ENROLLMENT DATA 
• 
CHANGE EXACERBATION CRITERIA TO ONE OR MORE EXACERBATIONS OF COPD REQUIRING SYSTEMIC 
CORTICOSTEROIDS WITHIN LAST 3 YEARS (CHANGING FROM 2 YEARS) 
 
 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
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Study Principal Investigator: M. Bradley Drummond, MD, MHS 
CB 7207 Marsico Hall 
Chapel Hill, NC 27599 
Phone 919-966-7054 Fax 919-966-5178 
email:  brad_drummond@med.unc.edu 
   
 
 
 
A single center, open label, prospective, observational study measuring proportion of patients with 
suboptimal Peak Inspiratory Flow Rate (sPIFR) over 24 weeks in an ambulatory setting among 
moderate to very severe COPD patients  
  
 
 
(Short Title: PIFR in COPD) 
 
Lead Investigator: 
 M. Bradley Drummond, MD, MHS 
 University of North Carolina at Chapel Hill 
Protocol Version: REVISION 3 
Version Date: February 18, 2021 
 
I confirm that I have read this protocol and understand it.    
Principal Investigator Name:  
 
 
M. Bradley Drummond, MD, MHS 
 
Principal Investigator Signature:  
 
 
 
 
 
 
 
Date:   
 
 
 
 
 
 
  
 
 
 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
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Table of Contents 
 
Table of Contents .............................................................................................................................................. 3 
Abbreviations and Definitions of Terms ............................................................................................................ 4 
Protocol Synopsis .............................................................................................................................................. 5 
1 
BACKGROUND AND RATIONALE ............................................................................................................... 9 
2 
STUDY OBJECTIVES .................................................................................................................................. 13 
3 
INVESTIGATIONAL PLAN .......................................................................................................................... 13 
5 
STUDY EVALUATIONS AND MEASUREMENTS ......................................................................................... 18 
6 
STATISTICAL CONSIDERATION ................................................................................................................. 21 
7 
STUDY PROCEDURES ............................................................................................................................... 24 
8 
DATA COLLECTION AND MANAGEMENT ................................................................................................ 24 
9 
CONSENT PROCESS...................................................................................... Error! Bookmark not defined. 
10 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS ..................................... 26 
11 
REFERENCES ............................................................................................................................................ 28 
16 
APPENDIX ................................................................................................................................................ 31 
 
 
 
 
 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
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Abbreviations and Definitions of Terms 
 
Abbreviation 
Definition 
AE 
Adverse Event 
CAT 
COPD Assessment Test 
COPD 
Chronic obstructive pulmonary disease 
DPI 
Dry Powdered Inhaler 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
MDI 
Metered dose Inhaler  
mMRC 
modified Medical Research Council 
mBorg 
modified Borg dyspnea scale 
PIFR 
Peak inspiratory flow rate 
PRO 
 
Patient reported outcome 
RV 
Residual Volume  
sPIFR 
Suboptimal peak inspiratory flow rate 
 
 
 
 
 
 
 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
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Protocol Synopsis 
Study Title 
Peak Inspiratory Flow Rate in COPD Patients  
Study 
Rationale 
Recent studies have reported that some COPD patients may have a 
suboptimal ability to generate a sufficient inspiratory effort to achieve 
adequate lung delivery of inhaled medications through dry powder 
inhalers. Sparse data is available about the inspiratory capacity of these 
patients in the home setting, whether clinically stable or when 
experiencing worsened respiratory symptoms outside the acute care 
setting.  Thus, we are undertaking this study to better understand the 
proportion of patients with suboptimal peak inspiratory flow rate 
(sPIFR) measurements amongst COPD patients receiving dry powder 
inhaler(s) (DPI) in the ambulatory setting. Further, we seek to 
characterize PIFR over time, the variability of PIFR measurements, and 
the associations with potential predictors (demographics, clinical, PRO, 
body position, and device) as well as exacerbations frequency and 
change in PIFR around period of exacerbation. 
Study 
Endpoint(s) 
Primary Endpoint 
For each patient, the occurrence of suboptimal Peak Inspiratory Flow 
Rate (sPIFR) over 24 weeks. sPIFR will be defined as any two consecutive 
measurements on different days below the optimal threshold for any 
prescribed DPI (e.g.,<30 L/min for Handihaler® (High resistance DPI), 
<60 L/min for Ellipta® (Medium resistance DPI)) 
Exploratory Endpoints   
•  PIFR Endpoints 
 
Time to first occurrence of sPIFR (in days) 
 
Number and proportion of sPIFR  
 
Rate of sPIFR, defined as the number of sPIFR / number of 
days in the study, multiplied by 30 as sPIFR/month.  
• 
Exacerbation Endpoints 
Occurrence (yes/no), number, severity (mild, moderate, severe) 
and rate of COPD exacerbations over 24 weeks. Mild, moderate and 
severe exacerbations will be defined as: 
 
Mild – doubling use of inhaled rescue medication > 48 hours 
and not meeting definition of moderate or severe 
 
Moderate – increased rescue medication and either oral 
corticosteroid or antibiotics, not requiring hospitalization;  
 
Severe – hospitalization for exacerbation 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
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Test Article(s) 
(If Applicable) 
Measurement of PIFR using the InCheck Dial® device and quantification 
of respiratory symptoms and COPD exacerbations using standardized 
questionnaires in the patient’s home setting and during research visits 
in the clinic setting.   
Funding Source 
Boehringer Ingelheim Pharmaceuticals Inc. 
Study Design 
 
 
 
Prospective, monocenter, observational study in 120 COPD patients 
over a 24 week period with six study visits. 
Subject 
Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria:   
• Age > 50 years-old 
• Spirometry-confirmed diagnosis of COPD (FEV1/FVC <0.70)  
• GOLD II-IV based on existing spirometry results 
• CAT score > 10 
• For high resistance DPI, baseline PIFR < 90 L/min (InCheck DIAL®) and 
>=30 L/min; for medium resistance DPI, PIFR ≤ 90 L/min (InCheck 
DIAL®) and >=60 L/min. Handihaler is a high resistance DPI. Examples 
of medium resistance DPI: Anoro, Incruse, Breo Ellipta®, Advair® 
Diskus® DP or Wixela® Inhub® 
• History of smoking tobacco products > 10 pack years 
• Prescribed at least one daily maintenance DPI with no change in 
prescription within the four weeks prior to the Enrollment Visit  
• One or more exacerbations of COPD requiring systemic 
corticosteroids within last 3 years 
• Patients will be enrolled with regards to the below pre-specified 
characteristics based on gender and  the prescribed maintenance 
inhaler(s) as follows (note that patients are commonly prescribed 
multiple inhalers): 
 
Male:Female ratio  1:1 (+ 10%) 
 
Target recruitment stratified to two treatment arms: 
 
N=60 patients receiving medium resistance DPI (Anoro, 
Incruse, Breo Ellipta®, Advair® Diskus® or Wixela® Inhub® 
DPI) with planned recruitment to include 50% of participants 
on Diskus®/ Inhub® and 50% on Ellipta® 
 
N= 60 patients receiving high resistance DPI (Spiriva 
Handihaler® DPI) 

 
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Study participants may also receive another MDI, Respimat® inhaler, or 
DPI (e.g. Breo Ellipta® + Spiriva Respimat®, Symbicort MDI® + Spiriva 
Handihaler®, Advair Diskus® + Spiriva Handihaler®, Wixela® Inhub® + 
Spiriva Handihaler®) Subjects will be placed into one of the two cohorts 
based on the DPI, if on more than one DPI, they will be placed into the 
cohort 
for 
the 
DPI 
with 
the 
highest 
resistance 
(Handihaler>Ellipta=Diskus=Inhub). These strata are for recruitment 
only, and PIFR measurement for both DPIs will be recorded and used in 
analyses. 
Exclusion Criteria:  
• Inability to demonstrate proper technique for the InCheck DIAL® 
device  
• Inability to achieve minimum PIFR for prescribed DPI(s) at 
screening/enrollment visit (< 30 L/min for e.g., Handihaler® (High 
resistance DPI), < 60 L/min for Ellipta® (Medium resistance DPI))  
• Neuromuscular disease associated with weakness  
• Any condition that, in the opinion of the site investigator, would 
compromise the subject’s ability to participate in the study. 
• Pneumothorax within the past 4 weeks  
 
Number Of 
Subjects  
N=120  
Study Duration 
Each participant’s duration of involvement will last 24 weeks.  
Study Phases 
Screening 
Study 
Enrollment 
Follow-Up    
 
  
Visit 1- Screening Visit 
Visit 2- Enrollment Visit  
Home monitoring of PIFR and PRO over 24 weeks 
Visits 3, 4, 5, 6: Telephone Visits  
Efficacy 
Evaluations 
Changes in PIFR and dyspnea (modified Borg) that occur in the COPD 
population in the home setting during periods of stable respiratory 
symptoms and periods of worsening will be measured and recorded by 
participating subjects. PIFR measurements, PRO (mMRC, modified 
Borg, CAT) will also be undertaken in the research clinic setting. PRO 
will also be completed with each telephone-based study visit. This study 
will not be powered to definitely test for efficacy of different inhalers. 

 
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Safety 
Evaluations 
Minimal risk 
 
Statistical And 
Analytical Plan 
Primary analysis will be descriptive. The primary endpoint will be 
described as the proportion of patients with suboptimal PIFR and 
reported with 95% confidence intervals. Suboptimal PIFR will be 
defined as any two consecutive measurements on different days below 
the optimal threshold for any prescribed DPI (<30 L/min for High 
resistance, <60 L/min for Medium resistance). Descriptive analysis of 
PIFR measurements, including mean (SD), median (IQR), range over 
time per patient per device, and in different body positions, will be 
conducted. The time of first occurrence of sPIFR will be reported in days 
and will be plotted with a Kaplan-Meier curve. We will explore, for each 
device, with logistic regression (binary) or negative binomial (count) the 
clinical and demographic factors associated with sPIFR measurements. 
Correlation of PIFR with CAT score, mBORG and mMRC score will be 
conducted. The associations between exacerbations and PIFR will be 
explored in different ways, for all exacerbation, stratified by severity of 
exacerbations, and stratified by device. See section 6.1 to 6.3 for 
detailed statistical plan. 
Data and Safety 
Monitoring Plan 
Data will be managed on REDCap, developed by PI of study. The PI and study 
staff will review data collection forms on an ongoing basis for data 
completeness and accuracy as well as protocol compliance. The PI will be 
responsible for data quality management and ongoing assessment of safety.  
 
 
 
 

 
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1 
BACKGROUND AND RATIONALE 
1.1 
Introduction 
The optimal management of chronic obstructive pulmonary disease (COPD) is important at 
population and health system levels due to substantial costs, morbidity and mortality.  At the 
individual patient level, experiencing shortness of breath, often on a daily basis, with periods of 
worsening symptoms, can have a big impact on quality of life, productivity, and outcomes.  Inhaled 
medications are the most effective therapies for symptom relief and available for COPD patients– 
particularly when given in combination. (GOLD 2017)  Inhaled therapies are available as metered 
dose inhalers (MDI), soft-mist inhalers (SMI), dry powder inhalers (DPI), and by nebulization.   
Although DPI’s are breath-actuated and tend to be easier for patients to use than the MDI or SMI, 
there is emerging evidence that delivery from DPI and drug stability of the powder is suboptimal 
in some patients and settings.  It has recently been shown that COPD patients can exhibit 
suboptimal inspiratory rates during exacerbations in the hospital (Loh, Sharma) as well as in the 
outpatient setting (Sulaiman 2017a, Jansenns); it is unclear what impact this this may have on the 
efficacy and safety of DPIs.   Several population-based studies from the United Kingdom report 
that a DPI (Diskus® inhaler),  with relatively low respirable mass (portion delivered into target 
airways) and larger particle size  is associated with greater COPD exacerbation frequency and 
oropharyngeal side-effects compared to inhalers with a higher respirable mass in both COPD and 
asthma patients. (Price, Jones, Dekhuijzen)   Although published evidence regarding suboptimal 
delivery from DPIs in the COPD population is emerging, substantial knowledge gaps exist, including 
peak inspiratory flow in ambulatory COPD patients when clinically stable and during periods of 
worsened respiratory symptoms.   This specific knowledge gap is the principal basis of our 
investigation. 
1.2 
Name and Description of Procedures  
This is an observational study but certain study procedures and PROs will be measured in the study. 
The proposed procedure is measurement of peak inspiratory flow rate (PIFR), using a device called 
In-Check DIAL® (Alliance Tech, Granbury, TX), and recording of respiratory symptoms in COPD 
patients in the home setting.  This device has been used in the clinical and research settings for 
more than a decade. 
 
 

 
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1.3 
Relevant Literature and Data 
 
Factors that can influence optimal delivery of inhaled drug therapy in the obstructive lung disease 
population include the inhalational device as well as the drug and formulation and patient 
characteristics such as cognition, disease severity, and clinical status of the patient. Important 
device characteristics include overall ease of use, aerosol particle size, fine particle fraction or 
dose, and in the case of DPIs, the inspiratory resistance inherent to the inhaler.  Of the three types 
of multi-dose inhalers, the MDI is the most difficult device to use correctly, particularly in the 
elderly COPD patient, whereas DPI breath-activated devices tend to be easier to use.  The fine 
particle fraction, the portion of the emitted dose in the respirable range of 1-5 microns that is 
most likely to reach target airways, varies widely among different multi-dose inhalers:  12-35% for 
DPIs, 10-50% for MDI, and ~ 30% for SMI.  It has been shown that a higher fine particle fraction 
can result in greater lung delivery into the peripheral airways (Pitcairn) - COPD is a disease that 
also affects the small airways.  For the SMI and MDI, a slow, deep inspiration delivers the most 
respirable particles, whereas for the DPI, a rapid deep breath is required to de-agglomerate the 
powder.   As noted previously, some COPD patients are not able to generate an adequate 
inspiratory effort with the DPI in order to achieve adequate lung drug delivery.  
 
Depending on the DPI, the minimum peak inspiratory flow rate (PIFR) ranges from 30 L/min for the 
Handihaler® to 60 L/min for the Diskus® and Ellipta® DPI’s. (Ghosh 2017, Mahler 2017).   The 
Handihaler® is a high-resistance DPI, whereas the Ellipta® and Diskus® are classified as medium-
resistance inhalers.  In vitro studies indicate that the fine particle dose from Diskus®, and Ellipta® 
DPIs can be reduced when inspiratory flow rate decreases below 60 L/min (Buttini, Feddah, 
Yokohama, Grant, Prime), whereas other studies showed little effect. (Hamilton)    Recent studies 
in humans are finding that inhaled drug delivery with the Diskus® is suboptimal when the PIFR 
decreases below 60 L/min.  In a study of healthy volunteers using the Diskus® inhaler, a decrease 
in the PIFR from 60 to 30 L/min resulted in 30% decrease in blood levels of albuterol and fluticasone 
(Sulaiman 2017b), indicative of decreased lung delivery. (Lipworth)   A recent study evaluated 
errors made by COPD patients using the Diskus® over a one month period in the ambulatory setting 
post-hospitalization.  For this study, an audio monitoring device (INCA) was attached to the inhaler 
to measure the inspiratory flow rate and monitor adherence.  Subjects were educated on the 
proper use of the inhaler prior to discharge from the hospital.  The most frequent error made by 
patients was an inadequate inspiratory effort in nearly one-half of the COPD patients. (Sulaiman 
2017b)   It is possible that PIFR may have been lower as a consequence of the recent exacerbation. 
In a study conducted in an outpatient research setting, using an instrumented Ellipta® inhaler, it 
was found that severe to very severe COPD patients had shorter inspiratory times and tended to 
have impaired inspiratory flow (< 60 L/min) through the device. (Prime)   It appears that lung 

 
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delivery with the Diskus® and Ellipta® may be suboptimal between 30 L/min and 60 L/min.  The 
aforementioned data is the basis for the use of target PIFR values for Handihaler®, Diskus®, and 
Ellipta® devices (30 L/min, 60L/min, and 60 L/min, respectively) for the current study.  We have 
also chosen to only enroll patients with a PIFR < 90 L/min at a medium resistance PIFR setting 
(Ellipta®) in order to select a cohort that has a reasonable probability that their PIFR may approach 
the minimally acceptable value for their prescribed DPI(s) with worsened symptoms. 
 
Patient-related impediments to achieving this minimum inspiratory flow in the COPD population 
include age, gender, and stature (Seheult, Mahler 2013).  Mahler reported that persons most likely 
to have an impaired PIFR are the elderly and females, (Mahler 2013), thus the rationale for having 
an equivalent number of males and females participate in the present study.  Another factor that 
could affect inspiratory flow in the COPD patient is the physical position of the patient when using 
their DPI (standing, sitting, supine).  It has been shown that peak expiratory flow rate (Wade) and 
other pulmonary function test measures (Wallace) including forced residual capacity  are lower in 
a supine position than in a standing position.  Therefore it is possible that a hospitalized COPD 
patient in a supine position, particularly with worsened respiratory status, could have decreased 
lung deposition from a DPI because of impaired inspiratory ability.   Another scenario that a COPD 
patient could have impaired inspiratory capability is a morbidly obese subject using their DPI in a 
sitting position, where the diaphragm is displaced upwards and thus the lungs are less capable to 
generate a strong inspiratory effort.   To our knowledge, the effect of physical position of the COPD 
patient on PIFR has not been investigated.  
 
Disease related factors that could affect a patient’s inspiratory ability include diaphragmatic 
dysfunction, air trapping, narrowing of the airways, and worsening respiratory symptoms such as 
during an exacerbation. (Broeder, Jansenns, Malmberg, Taube, Loh, Sharma).   In COPD patients 
with air trapping, it was shown that in addition to a reduced forced residual capacity and decreased 
inspiratory capacity, the inspiratory flow was also reduced. (Taube)   Decreased inspiratory flow 
has been shown when COPD patients are clinically stable (Ghosh, Janssen, Mahler, Seheult) and 
during exacerbations requiring hospitalization. (Broeder, Loh, Sharma)  Studies by Loh and Sharma 
found that impaired PIFR, below minimums for DPIs, occurred in a third or more of COPD patients 
with acute exacerbations requiring hospitalization.  The study by Loh indicated patients with 
impaired PIFR were at a greater risk of all cause 90-day re-hospitalization, whereas this was not 
found in the study by Sharma.  In the study by Loh, the PIFR was performed in patients while in a 
sitting position. (personal communication)   The decrease in inspiratory flow and capacity 
apparently persists for some time after exacerbations.      Broeder reported that PIFR, using the 
InCheck DIAL®, increased between 17% and 22% between hospital admission and 5 weeks later 
when patients were clinically stable in the outpatient setting.  There are no published studies that 

 
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have measured longitudinal changes in PIFR in ambulatory COPD patients when clinically stable 
and during periods of worsened respiratory symptoms and recovery.  
 
The In-Check DIAL® has been used for both clinical and research purposes for over 15 years to 
mimic the resistance to inspiration through DPIs.  The In-Check G16 DIAL® (Alliance Tech Medical, 
Granbury TX) is a simple hand-held device that measures PIFR via a brief inspiratory maneuver. 
Measurement consists of a simple, 1-2 second inhalation requiring less user effort than an 
incentive spirometer. The best of three efforts are recorded.  The InCheck DIAL® is designed to 
simulate the internal resistance of different inhalers and measure the PIFR against a specific level 
of resistance, either to assess a patient’s ability to achieve a minimum effort recommended for DPI 
or to train patients on the proper inspiratory effort needed for a specific inhaler.  The InCheck 
DIAL® measures PIFR between 15 and 120 L/min with a +/- 10% accuracy and has a repeatability 
of 5 L/min.  Calibration of the device was shown to meet American Thoracic Society (ATS) standards 
through testing with an ATS waveform generator.  The device includes a one-way disposable 
mouthpiece, measurement diaphragm, and a directly visualized PIFR scale.  Importantly, the device 
also includes an adaptor with adjustable resistances to mimic nine resistance groups encompassing 
the popular MDIs and DPIs currently commercially available. These have been used repeatedly for 
both research and clinical purposes since 1991 (Broeder).  Using these measurements against a set 
resistance, one can assess the frequency and degree of suboptimal PIFR in COPD patients with 
moderate to very severe obstruction in the home setting. 
 
To inform this application, Dr Drummond and Ghosh have previously obtained IRB approval for a 
study to measure PIFR using the In-Check DIAL® in a clinic-based, stable COPD patient population 
prescribed maintenance inhalers and free of recent exacerbation, as well as a group of healthy 
controls (UNC IRB 16-3343; PI Ghosh; data presented by Ghosh et al ATS 2017).  Over a four month 
period, 27 COPD patients and 19 healthy controls were recruited (Ghosh 2018).  Among COPD 
patients, 20/27 (74%) were able to generate PIFR >120 L/min when no internal resistance was 
applied.   However, PIFR (mean±SD) was 61±13 L/min with Diskus® resistance and 36±10 L/min 
with Handihaler® resistance.  In the COPD patients, 11 used a medium resistance DPI alone, 25 a 
high resistance DPI alone, and 14 were receiving both a medium and high-resistance DPI.   
Among the healthy controls, 19/19 (100%) were able to generate PIFR >120 L/min when no internal 
resistance was applied.  PIFR was 97±13 L/min with Diskus® resistance and 55±7 L/min with 
Handihaler® resistance.  Overall, 15 (55%) of COPD patients were not able to generate optimal PIFR 
(defined as >45L/min for this study) on at least one prescribed DPI.  Compared to COPD patients 
able to generate optimal PIFR, discordant COPD participants had a greater prevalence of 
uncontrolled COPD (defined as COPD Assessment Test≥10): 93% versus 83%.  Among nine 

 
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participants with repeated measures over two weeks, there were no statistical differences 
between intersession measurements for any inhaler resistance setting.  These preliminary data 
demonstrate that suboptimal PIFR is common in stable COPD and may correlate with symptom 
burden.   
Preliminary data has also demonstrated stability in PIFR over 2-4 weeks, suggesting this is 
inadequate duration to capture full spectrum of variability. Specifically, preliminary data from 15 
COPD participants who underwent repeated measures at two to four weeks showed that 
participants using low-medium resistance inhalers did not have a difference in PIFR measurements 
at baseline versus follow-up (65 L/min on visit 1 and 64 L/min on visit 2; p=0.69). Of the 14 
participants on a high resistance inhaler, there was no difference in baseline and repeated PIFR 
measurement (38 L/min on visit 1 and 38 L/min on visit 2; p=0.46). A study duration of 24 weeks 
has been selected to ensure adequate duration to capture normal variability of PIFR as well as need 
for adequate duration to capture COPD exacerbation events (an important exploratory outcome). 
2 STUDY OBJECTIVES  
 
2.1 
Objectives:   
• 
The primary objective of the study is to determine the proportion of patients with suboptimal 
peak inspiratory flow rate (sPIFR) measurements amongst COPD patients receiving dry powder 
inhaler(s) (DPI) in the ambulatory setting. 
• 
The exploratory objectives are to characterize PIFR over time, the variability of PIFR 
measurements, and the associations with potential predictors (demographics, clinical, PRO, 
body position, device)  
• 
Additionally, we will explore the exacerbations frequency and change in PIFR around period of 
exacerbation. 
 
3  INVESTIGATIONAL PLAN  
3.1 
Study Design 
This prospective, monocenter, observational study will be conducted over 24 weeks. The Study 
Procedures and Assessments (Appendix 1) are shown in the table and are also described further 
 

 
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3.2 
Allocation to Treatment Groups and Blinding  
All enrolled subjects will undergo the same procedures.  There will be no blinding of subjects or 
study personnel to any aspect of the study. 
3.3 
Study Duration, Enrollment and Number of Subjects 
Study duration and timeline:  The duration of study is 24 weeks.   
 
Enrollment:  Participants will be recruited from UNC Clinics.  
 
Number of subjects:  One hundred twenty patients will be enrolled into this study.  
 
Enrollment to ensure balance of seasonal effects across all arms: Enrollment such that the 24 
week study period for each subject includes >2 months during the ‘exacerbation season’ of 
October – March (this translates into April and May being the only months to not enroll patients). 
Screening visits can be undertaken during these two months (April and May). 
3.4 
Study Population 
Our study population will be outpatients with moderate, severe, or very severe COPD.  
Participants will be recruited from multiple sources as described above. 
 
Inclusion Criteria:   
• 
Age > 50 years-old 
• 
Spirometry-confirmed diagnosis of COPD (FEV1/FVC <0.70)  
• 
GOLD II-IV based on existing spirometry results 
• 
CAT score > 10 
• 
For high resistance DPI, baseline PIFR < 90 L/min (InCheck DIAL®) and >=30 L/min; for medium 
resistance DPI, PIFR ≤ 90 L/min (InCheck DIAL®) and >=60 L/min. Handihaler is a high resistance 
DPI. Examples of medium resistance DPI: Anoro, Incruse, Breo Ellipta® ,Advair® Diskus®, or  Wixela® 
Inhub® DPI 
• 
History of smoking tobacco products > 10 pack years 
• 
Prescribed at least one daily maintenance DPI with no change in prescription within the four weeks 
prior to the Enrollment Visit 
• 
One or more exacerbations of COPD requiring systemic corticosteroids within last 3 years 
• 
Patients will be enrolled with regards to the below pre-specified characteristics based on gender 
and  the prescribed maintenance inhaler(s) as follows (note that patients are commonly prescribed 
multiple inhalers): 
 Male : Female ratio  1:1 (+ 10%) 
 Target recruitment stratified to two treatment arms: 

 
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 N=60 patients receiving medium resistance DPI (Anoro, Incruse, Breo Ellipta®, Advair® Diskus®, 
or Wixela® Inhub® DPI) with planned recruitment to include 50% of participants on Diskus® and 
50% on Ellipta® 
 N= 60 patients receiving high resistance DPI (Spiriva Handihaler® DPI) 
 
For all study participants, participants may also receive another MDI, Respimat® inhaler, or DPI 
(e.g. Breo Ellipta® + Spiriva Respimat®, Symbicort MDI® + Spiriva Handihaler®, Advair Diskus® + 
Spiriva Handihaler®,  Wixela® Inhub® + Spiriva Handihaler®) Subjects will be placed into one of the 
two cohorts based on the DPI, if on more than one DPI, they will be placed into the cohort for the 
DPI with the highest resistance (Handihaler>Ellipta=Diskus=Inhub). These strata are for 
recruitment only, and PIFR measurement for both DPIs will be recorded and used in analyses. 
 
Exclusion Criteria:  
• 
Inability to demonstrate proper technique for the InCheck DIAL® device  
• 
Inability to achieve minimum PIFR for prescribed DPI(s) at screening/enrollment visit (< 30 L/min 
for e.g., Handihaler® (High resistance DPI), < 60 L/min for Ellipta® (Medium resistance DPI))  
• 
Neuromuscular disease associated with weakness  
• 
Any condition that, in the opinion of the site investigator, would compromise the subject’s ability 
to participate in the study. 
• 
Pneumothorax within the past 4 weeks  
4 STUDY PROCEDURES  
4.1 
Home Monitoring 
 
Subjects will record their PIFR using the InCheck DIAL®and modified Borg dyspnea score three 
times weekly (MWF) when clinically stable and daily while respiratory symptoms worsen per 
patient self-assessment.    At each session, the participant will repeat efforts three times, with the 
highest of the three repeated efforts being recorded by the participant. They will be asked to 
perform the PIFR for the DPI(s) they are receiving at home (Ellipta®, Inhub®, Diskus®or 
Handihaler®)   using the InCheck DIAL®.  If on more than one DPI, patient will record PIFR for each 
device.  PIFR will be recorded with best approximation to nearest 1 L/min. 
 
4.2 
Study Visits  
 
There will be six study visits/encounters over a 22-26 week period as shown in the Study 
Procedures and Assessments Table.  Two study visits will occur at the UNC Clinics (Visits 1 and 2) 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
16 
 
 
 
 
and four visits will only involve a telephone interview of subjects by study personnel (Visits 3, 4, 5, 
and 6). 
 
  
Visit 1- Screening Visit 
 
At Visit 1, after obtaining written informed consent, a clinical history will be obtained from the 
patient and if the subject meets all inclusion and exclusion criteria, a CAT score will be determined. 
The patient will be undergo PIFR assessment based on prescribed DPI. PIFR will be recorded with 
best approximation to nearest 1 L/min. Subjects will be excluded if PIFR > 90 L/min based on 
Ellipta® and Diskus® setting or inability to achieve minimum PIFR for prescribed DPI setting (< 30 
L/min for Handihaler®, < 60 L/min for Ellipta® , Diskus® , or Inhub®). The PIFR will be performed in 
triplicate by the patient at the recommended device setting (based on patient’s DPI specific 
internal resistance) in the physical position (e.g. sitting) that the patient normally uses to self-
administer their inhaler(s).  Further, they will be instructed to perform the PIFR consistent based 
on the manufacturer instructions for proper DPI inhalation technique (e.g. Ellipta®, Diskus® DPI, , 
Inhub®) “Breathe out gently and breathe in steadily and deep”). For the Handihaler®, subjects will 
be instructed as follows – “Breathe out completely in one breath. Empty your lungs of air. Breathe 
in deeply until your lungs are full.” If the patient meets the inclusion and exclusion criteria including 
a PIFR < 90 L/min, they can proceed to Visit 2 (Enrollment) either during the same encounter or 
scheduled within 30 days.  If there is greater than 30 days between Visit 1 and 2, another informed 
consent will be reviewed and signed. 
 
For inclusion, historical spirometry is required to be documented to ensure patients meet the 
GOLD definition of COPD using airflow obstruction. Most recent spirometry data will be used for 
characterization of the enrolled cohort. No spirometry testing will be performed as part of this 
study. 
 
 
 
Visit 2- Enrollment Visit 
 
• 
A physical examination including measurement of waist circumference (measured in inches 
horizontally through the narrowest part of the torso, between the lowest rib and the iliac crest) 
• 
Medical history (includes exacerbations history) 
• 
COPD medication use (maintenance and reliever) 
• 
Patient-reported outcomes (PROs)  
o 
CAT score (COPD Assessment test) 
o 
mMRC score (modified Medical Research Council) 
o 
mBorg score (modified Borg dyspnea score)  

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
17 
 
 
 
 
• 
PIFR measurement in three different physical positions – sitting, standing, and lying tilted at 45o with 
head forward.  (repeated using PIFR setting for each DPI patient is receiving) 
• 
Pre- and post-bronchodilator PIFR measurement in sitting position   
• 
Subject instructed on proper use of PIFR device and recording of PIFR measurement and modified Borg 
dyspnea score using the provided Study Notebook  
• 
Subject instructed to mail PIFR and modified Borg dyspnea score on a monthly basis to the research 
team using supplied self-addressed, stamped envelopes 
 
 
 
Visits 3, 4, 5, and 6 - Telephone Visits 
 
At Visits 3, 4, 5, and 6 (at 4, 8, 12 , and 24 weeks after Visit 2 -permissible +2 week window for each 
visit), study personnel will contact the participant by telephone to obtain PIFR and symptom 
questionnaires recordings  during the preceding 2 weeks.  A time period less than 2 weeks is 
acceptable if the subject had mailed in their monthly log recently. PIFR measurements and 
respiratory symptom questionnaires (modified Borg dyspnea score only) will have been recorded 
by study participants using a Study Notebook.  PIFR will be recorded for each DPI the patient is 
receiving. A CAT score, mBorg, and mMRC will also be determined by study personnel as part of 
each visit. Ascertainment of exacerbations, medication adherence, and change in inhaler regimens 
will be completed. In part, the telephone visit will be undertaken to increase subject’s compliance 
to study procedures.      
   
4.3 
Unscheduled visits 
No unscheduled visits will be incorporated into this protocol.  
 
4.4 
Concomitant Medication documentation 
All COPD medications within 30 days of study enrollment and during the 24 week study period will 
be recorded. 
  
4.5 
Rescue medication administration (if applicable) 
Inhaled albuterol 2 puffs by metered dose inhaler will be administered as part of pre- and post-
PIFR measurement at Visit 2  
   

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
18 
 
 
 
 
4.6 
Subject Completion/ Withdrawal procedures 
If a patient decides to withdraw for any reason our contact information will be provided and they 
can email any member of the research team. If participants have a change in their prescribed DPI 
during study, study procedures will continue using previously prescribed DPIs and noting 
prescription changes.  
 
4.7 
Screen failure procedures 
All consented participants will receive a study ID number. Those who fail initial screening will be 
excluded and no information will be collected. If a participant failed initial screening due to 
temporary exclusion criteria (e.g., failed due to recent exacerbation, recent change in meds), the 
participant will be offered a re-screening visit for a future date outside of the exclusion window.   
Last name and partial MRN for participant failing screening will be retained during study 
recruitment on a secured document to prevent re-screening.  
 
       5 STUDY EVALUATIONS AND MEASUREMENTS  
5.1 
Data collection  
 
5.1.1 
Data abstracted from electronic medical charts 
• Historical spirometry  
• Evidence of any COPD exacerbation requiring systemic corticosteroids within the last 
three years 
• Concurrent diseases 
• Prescribed COPD medications 
• Demographics: age, height, weight, gender 
 
5.1.2. Questionnaires 
 
The questionnaires administered will be the modified Borg dyspnea scale, modified Medical 
research Council, and the COPD Assessment Test.  Additional questionnaires will capture 
exacerbations, medication adherence, and inhaler regimens. The questionnaires will be self-
administered by study subjects or conducted by study personnel with the subjects when 
appropriate.  For the mMRC (APPENDIX 2), mBorg (APPENDIX 3), and CAT (APPENDIX 4), the time 
period for subjects to self-assess symptoms is not specified.  The modified Borg dyspnea scale will 
be used for home monitoring of respiratory status, whereas modified Medical Research Council 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
19 
 
 
 
 
score, modified Borg scale, and CAT will be used for clinic visits (2, 6) as well  the 4 telephone visits 
(3, 4, 5). In addition, CAT will be determined at the enrollment visit (Visit 1). 
             
When questionnaires are administered by study personnel, they will be completed using a polite, 
professional, and non-judgmental tone.  Pacing of the interview will be adjusted to each 
participant. Interviewers will be familiar with the forms and questionnaires they are administering. 
Familiarity allows the coordinator to maintain eye contact with the participant, which helps build 
rapport. The interviewer must be careful not to inadvertently change the wording of questions or 
instructions because he or she has partially memorized the interview. If a participant appears to 
not understand the question or provides an incomplete answer, the interviewer may employ 
several techniques to improve participant response. In the case of misunderstood questions, the 
interviewer may re-read the question with a different emphasis, stressing the part of the question 
the subject appears to have misunderstood. The interviewer should not modify the question 
wording. For incomplete answers, interviewers may use probing to further clarify a participant’s 
answer. The most commonly used probing technique is silence. In this situation the interviewer 
waits for the participant to provide an answer. Participants may require time to recall events or 
consider how to respond. If the participant seems uneasy with the length of time he or she is taking 
to answer a question, the coordinator may reassure the participant, i.e., “Take your time” or “There 
is no rush.” 
 
5.1.3. Spirometry:  
 
Historical spirometry will be abstracted from medical charts. If multiple spirometry records are 
available, the most contemporaneous will be abstracted. This will also include the age, height and 
weight at the time of spirometry.  
 
5.1.4. PIFR Measurements 
 
Study visits PIFR: PIFR measurements will be collected using the In-Check G16 DIAL® which is a 
simple, hand-held low range inspiratory flow device that measures PIFR via a brief inspiratory 
maneuver (APPENDIX 5). The device includes a one-way disposable mouthpiece, measurement 
diaphragm, and a directly visualized PIFR scale. The device also includes an adaptor with adjustable 
resistance to mimic nine resistance groups encompassing the popular MDIs and DPIs currently 
available.  After each inspiratory maneuver to a set resistance, the PIFR score will be visualized on 
the scale and recorded. Subjects will perform the PIFR in the following manner:  
Patients receiving Handihaler® and/or Ellipta® and/or Diskus® and/or Inhub®  

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
20 
 
 
 
 
• 
For testing during study visits, perform PIFR in the physical position they most commonly use when self-
administering their maintenance inhaler(s) 
• 
Perform PIFR using the inspiratory effort described by the manufacturer (Ellipta®,Diskus®, and  Inhub®)- 
breathe out fully, then take a long, steady deep breath’; ‘breathe out all the way, then breathe in slowly 
and deeply’) For the Handihaler®, subjects will be instructed as follows – “Empty your lungs of air. 
Breathe in deeply until your lungs are full.” 
• 
Measurements will be collected on each prescribed DPI resistance setting. PIFR will be recorded with 
best approximation to nearest 1 L/min. Ample time will be given to any patients who may be feeling 
short of breath or fatigued.  
Home measurement of PIFR: Using the In-Check G16 DIAL®  
• 
Perform PIFR in physical position most commonly used when self-administering maintenance inhaler(s) 
• 
Perform PIFR (proper setting) for each maintenance DPI patient is receiving 
• 
Use maximum inspiratory effort, by first breathing out fully, and breathing in as hard and fast as 
possible, and as above, repeat the maneuver two more times, recording the highest value. 
 
5.1.4.1 
Efficacy Evaluation (if applicable) 
 
Changes in PIFR and dyspnea (modified Borg) that occur in the COPD population in the home 
setting during periods of stable respiratory symptoms and periods of worsening will be 
measured and recorded by participating subjects. PIFR measurements, PRO (mMRC, modified 
Borg, CAT) will also be undertaken in the research clinic setting. PRO will also be completed with 
each telephone-based study visit. 
 
5.1.4.2 
Safety Evaluations 
 
Measurement of PIFR will be deferred or not performed for those with chest, abdominal, oral or 
facial pain; stress incontinence; dementia; recent myocardial infarction (6 weeks), chest or 
abdominal or ocular surgery (6 weeks), those with prior significant difficulties with spirometry or 
participant refusal. 
 
 
 
 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
21 
 
 
 
 
6 
STATISTICAL CONSIDERATION    
 
6.1 
Primary Endpoint 
For each patient the occurrence of suboptimal Peak Inspiratory Flow Rate (sPIFR) over 24 weeks. sPIFR will be 
defined as any two consecutive measurements on different days below the optimal threshold for any prescribed 
DPI (e.g.,<30 L/min for Handihaler® (High resistance DPI), <60 L/min for Ellipta® (Medium resistance DPI)) 
 
 
6.2  Exploratory Endpoints   
PIFR Endpoints: 
1. Time to first occurrence of sPIFR (in days) 
2. Number and proportion of sPIFR  
3. Rate of sPIFR, defined as the number of sPIFR / number of days in the study, multiplied by 30 as 
sPIFR/month.  
 
 
Exacerbation Endpoints:  
Occurrence (yes/no), number, severity (mild, moderate, severe) and rate of COPD exacerbations over 24 
weeks. Mild, moderate and severe exacerbations will be defined as: 
 
1. Mild – doubling use of inhaled rescue medication > 48 hours and not meeting definition of moderate 
or severe  
2. Moderate – increased rescue medication and either oral corticosteroid or antibiotics, not requiring 
hospitalization  
3. Severe – hospitalization for exacerbation 
 
6.3 
Statistical Methods 
 
Analysis populations 
Full analysis set (FAS): all screened patients with informed consent and at least two consecutive PIFR 
measurements on different days. 
 
Descriptive Statistics 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
22 
 
 
 
 
Using the FAS, the following variables will be described using descriptive statistics (mean and standard 
deviation, min, max, median) and graphical displays (boxplots, histograms).  Data transformation will be used if 
applicable, and extreme values will be verified and their effect on analysis results will be reported.  
 
demographics and clinical variables 
 
patient reported outcomes (CAT, mBORG and mMRC) 
 
concomitant diseases and medications 
 
Primary analysis 
The primary endpoint will be described as the proportion of patients with suboptimal PIFR and reported with 
95% confidence intervals, on the FAS. The proportion of sPIFR will be computed from the Kaplan-Meier curve. 
 
Subgroup analyses of the primary endpoint: 
 
per DPI device type (moderate vs. high resistance) 
 
per gender 
 
per GOLD stage based on spirometry results. 
 
Analysis of exploratory endpoints: on FAS. 
 
We will analyze the PIFR measurements over time, specifically: 
• 
Descriptive analysis of PIFR measurements, including mean (SD), median (IQR), range over time per 
patient per device, and in different body positions (standing, sitting, supine at 45 degrees). PIFR curves 
per patient/device can be explored. Descriptive analysis for different time’s period (week, month) may be 
explored.  
• 
The time of first occurrence of sPIFR will be reported in days and will be plotted with a Kaplan-Meier 
curve. A patient will be considered censored for sPIFR at the time of the latest documented visit or PIFR 
measurements, the end of the study, the switching of device (between medium and high resistance DPI) 
or death (whichever occurs earlier), if they did not experience a sPIFR before. Associations with possible 
demographics and clinical variables will be explored using a Cox regression analysis.  
• 
The proportion of suboptimal PIFR measurements will be reported with 95% CI, and also the rates. This 
analysis will also be performed per device in patients that used two devices with different resistances 
(e.g. Advair + Spiriva HH). 
• 
We will explore, for each device, with logistic regression (binary) or negative binomial (count) the clinical 
and demographic factors associated with sPIFR measurements.  
• 
We will use mixed models to explore associations of monthly PFIR averages over time and clinical and 
demographic factors. Subjects will be considered as random factor, other variables will be considered 
fixed effects. 
• 
Association of PIFR with CAT score, mBORG score and mMRC  
 
Association of PIFR and CAT scores at V1, V3, V4, V5,V6 (for PIFR, use the measurement in the week 
of each telephone follow-up, or the month average) 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
23 
 
 
 
 
 
Correlation of change in CAT scores with change in PIFR from baseline after 24 weeks 
 
Association of PIFR and mBORG score at V2, V3, V4, V5, V6 
 
Association of PIFR and mMRC scores at V1, V3, V4, V5,V6 (for PIFR, use the measurement in the 
week of each telephone follow-up, or the month average) 
 
For COPD exacerbation analyses, the proportion of patients with COPD exacerbations (from Kaplan Meier curve) 
and the rate of exacerbations occurring during follow-up will be reported along with 95% CI. A patient will be 
considered censored for exacerbations  at the time of the last documented visit, the end of the study, the 
switching of device (between medium and high resistance DPI) or death (whichever occurs earlier), if they did 
not experience an exacerbation before.  The exacerbations will be reported overall and stratified by severity.  
The associations between exacerbations and PIFR will be explored in different ways, for all exacerbation, 
stratified by severity of exacerbations, and stratified by device.  
 
The rate of exacerbations and sPFIR will be analyzed with negative binomial models (or another 
model if more appropriate). 
 
For patients with exacerbations, the mean of PIFR in the week before, of, and after each 
exacerbation will be calculated and reported.  
 
All tests with p value < 0.05 will be interpreted nominally as statistically significant.  
 
Missing data 
 
No imputation for PIFR  
 
No imputation for COPD exacerbations 
 
No imputation for CAT, mBORG and mMRC 
 
Sample Size and Power 
In this application, we propose to recruit 120 COPD participants for study enrollment. There are several 
rationales for this sample size selection. 
 
The primary outcome focuses on characterizing the proportion of participants with suboptimal PIFR. There 
are no available data on prevalence of sPIFR from home measurements in COPD, highlighting the novelty 
of this proposal. While there is no established clinical threshold of variability of proportion with suboptimal 
PIFR, it is felt that a precision of <10% (95% CI range <20%) is desirable for clinical interpretation of sPIFR 
prevalence. From pilot study data, we observed that 40% of patients had sPIFR. We have generated three 
scenarios with different ranges of proportion of sPIFR (30%, 40%, and 50%) along with the required sample 
sizes to obtain a range of precisions (see table). Given that clinical expertise and judgement suggests that 
a precision of <10% is acceptable for this study, one can see that sample size range of N=105 to 125 will 
achieve this precision across a range of possible sPIFR proportions (highlighted column). 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
24 
 
 
 
 
 
Precision (half of Confidence Interval) 
sPIFR proportion 
5% 
8.8% 
10% 
15% 
20% 
30% 
323 
105 
81 
36 
21 
40% 
369 
120 
93 
41 
24 
50% 
385 
125 
97 
43 
25 
 
Interim Analysis 
None planned 
 
7 
STUDY PROCEDURES  
This is an observational study but certain study procedures and PROs will be measured in the study. 
Procedures includes performing pre- and post-bronchodilator PIFR as well as completion of PROs during 
clinic visits.  In the home setting, subjects will be expected to record PIFR and modified Borg score three 
times weekly (MWF), or more often with worsened symptoms.  
 
8 
DATA COLLECTION AND MANAGEMENT  
Each participant will be given a unique identifier which will be assigned serially with study 
enrollment starting with P001. The linking form will be the only form linking study ID to name or 
medical record number. All study related forms (regardless of identified or de-identified) will be 
placed in locked drawers. Hard copies of questionnaires marked with unique study numbers will 
not contain identifying information. The linking form will be kept on a secure password protected 
document on REDCap. This de-identified data will be entered and retained on a secure network via 
REDCap which has been developed to provide a mechanism for retaining a confidential, secure 
database with valid and accurate records. The system is comprehensive, thorough and constantly 
monitored on many levels. Protection against loss of data is provided through scheduled backup 
of data files by a central REDCap support center. The PI and study staff will review data collection 
forms on an ongoing basis for data completeness and accuracy as well as protocol compliance. 
Data managers write programs for data verification of all data collected, including field range limits 
and logical checks to help identify and eliminate data-entry errors. Hard copies of questionnaires 
will be saved should data entry questions arise, and will again be kept in a locked drawer. Follow 
up scheduling will be maintained on the REDCap Database and events will be recorded using only 
Study ID.  

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
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9 
CONSENT PROCESS 
HIPPA authorization will allow us to screen patients’ medical record after permission from primary 
pulmonologist. This will allow us to screen for inclusion criteria prior to approaching the patients 
and minimize the likelihood of approaching patients who would not qualify. Informed consent is 
the first data collection form administered during the research encounter. A signed informed 
consent means the patient fully understands the requirements of the procedures and assessments 
included in the study as well as the risks of those procedures/assessments. It is important that the 
patient fully comprehends the time commitment required for participation, as well as the potential 
implications of specimen storage and dissemination of study findings.  
 
 
● Reception 
Upon arrival at the clinical center the study coordinator should greet the patient and confirm 
patient’s identity. No data can be collected until the full informed consent has been obtained. 
 
● Administration 
The study coordinator and/or investigator should take the patient to a quiet, private area to review 
the informed consent. The coordinator should provide a copy of the consent to the participant, and 
ask the participant whether he or she would like to read the consent form or have it read to them 
by the staff person. If the participant is visually handicapped, the coordinator should read the form 
to him or her. If the participant chooses to read the form, the coordinator should still review, 
although not read, the consent form with the participant to ensure he or she is fully informed. This 
should be handled sensitively, so as not to imply poor comprehension on the part of the patient. 
The coordinator should encourage the participant to ask for clarification or any questions he or she 
may have. The original signed copy of the informed consent should be kept with the participant’s 
study information. A copy of the consent form should be provided to the participant. 
 
● Training and Certification 
All study personnel interacting with participants must have received appropriate training and 
certification in confidentiality, privacy, and informed consent prior to having any contact with 
participants. 
 
● Data and Collection 
Informed consents are collected on paper. 
 
● Ability to Comprehend the Informed Consent 
The ability to provide informed consent is a requirement for participation in the study. In order to 
remain in compliance with ethical and regulatory standards, study coordinators should make every 
effort to ensure the patients understand their rights and risks when participating in this study. It can 
be difficult to determine whether a participant understands the informed consent. Behaviors and 
patterns to look for that might indicate poor comprehension include repetitive behaviors and 
speech patterns and looking to spouses and companions for assistance answering questions. If the 
coordinator doubts the patient’s comprehension, he or she can ask the patient to explain the rights 

 
BI Protocol Number: CTMS# 0352-2137 
 
 
 
 
26 
 
 
 
 
and risks detailed in the consent form in his or her own words. If the coordinator continues to 
question the ability of the patient to consent, he or she should speak with the PI. 
10. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS 
 
10.1 
DEFINITIONS OF ADVERSE EVENTS 
 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product.  
 
Adverse reaction (ADR) 
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility. Adverse reactions may arise from use of 
the product within or outside the terms of the marketing authorization or from occupational 
exposure. Conditions of use outside the marketing authorization include off-label use, overdose, 
misuse, abuse and medication errors. 
 
Serious adverse event 
A serious adverse event is defined as any AE which 
 
Results in death,  
 
Is life-threatening  
 
requires in-patient hospitalization, or 
 
Prolongation of existing hospitalization,  
 
Results in persistent or significant disability or incapacity, or  
 
Is a congenital anomaly/birth defect  
 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at the 
time of the reaction; it does not refer to a reaction that hypothetically might have caused death if 
more severe. 
 
Medical and scientific judgement should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 

 
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27 
 
 
 
 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse. Any suspected transmission via a medicinal product of an infectious agent is also considered 
a serious adverse reaction. 
 
Adverse Event of Special Interest (AESI) 
The term AESI relates to any specific AE that has been identified at the project level as being of 
particular concern for prospective safety monitoring and safety assessment within this study, e.g. 
the potential for AEs based on knowledge from other compounds in the same class.  
 
No AESIs have been defined for this study. 
 
10.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND REPORTING 
 
The investigator shall maintain and keep detailed records of all AEs in their patient files.  
 
INSTITUTION/Investigator will be responsible for reporting AEs which occur during the conduct of 
the Study, (i.e. from signing of informed consent to end of data collection), to the competent 
regulatory authorities, accredited Institutional Review Boards and/or Independent Ethics 
Committee(s) (“IRB/IEC(s)”) in accordance with the applicable laws and regulations.  
 
10.3  ADVERSE EVENT REPORTING TO BOEHRINGER-INGELHEIM (BI) 
 
 INSTITUTION shall report  
(i) 
All ADRs (serious and non-serious)  
(ii) 
All AEs with fatal outcome  
(iii) 
Pregnancies in female subjects and partners of male subjects 
 
which are associated with the BI Drug (Spiriva, Combivent, Stiolto, Striverdi, Atrovent),  
administered for the disease (COPD) in scope of the study by fax to the BI Unique Entry Point  as 
specified in Safety Data Exchange Agreement  using BI NIS SAE report form in following timelines. 
  
< BI Unique Entry Point> 
Boehringer Ingelheim Pharmaceuticals, Inc.  
900 Ridgebury Road  
Ridgefield, CT  
Fax: 1-203-837-4329  
Email:  PVIRTGlobalCaseManagement.ING@boehringer-ingelheim.com 
 
All Serious ADRs and AEs with fatal outcome shall be forwarded immediately (within twenty four 
(24) hours or next business day whichever is shorter). All non-serious ADRs and Pregnancy 
Monitoring Forms shall be forwarded within seven (7) calendar days. The investigator carefully 
assesses whether an AE constitutes an ADR using the information below.  

 
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28 
 
 
 
 
 
Causal relationship of adverse event: The definition of an adverse reaction implies at least a 
reasonable possibility of a causal relationship between a suspected medicinal product and an 
adverse event. An adverse reaction, in contrast to an adverse event, is characterized by the fact that 
a causal relationship between a medicinal product and an occurrence is suspected.   
 
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history.  
 
Causality should be assessed for each event as either “yes” or “no”. No other variation should be 
reported.  
 
Intensity of adverse event: The intensity of the AE should be judged based on the following: 
Mild: 
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe: Incapacitating or causing inability to work or to perform usual activities 
 
Pregnancy: 
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the study, 
after having taken BI Drug administered for the disease in scope of the study, the investigator must 
report any drug exposure during pregnancy, which occurred in a female subject or in a partner to a 
male subject to the Sponsor by means of BI Pregnancy Monitoring Form provided. 
 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective timelines.  
 
Reporting of related Adverse Events associated with any other BI drug 
The investigator is encouraged to report all adverse events related to any BI drug other than the BI 
drug taken for the disease in scope of the study according to the local regulatory requirements for 
spontaneous AE reporting at the investigator’s discretion by using the locally established routes and 
AE report forms.  The term AE includes drug exposure during pregnancy, and, regardless of whether 
an AE occurred or not, any abuse, off-label use, misuse, medication error, occupational exposure, 
lack of effect, and unexpected benefit. 
 
 
11 
REFERENCES  
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Broeders ME, Molema J, Hop WC, Vermue NA, and Folgering HT. The course of inhalation profiles during 
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APPENDIX 1. STUDY PROCEDURES AND ASSESSMENTS 
Visit number 
V1 a 
V2 
V 3,4,5,6 
Procedures and assessments 
Screening Visit 
Enrollment Visit 
Telephone Follow-up Visits 
Target time(s) and allowable time 
frames 
  
At same time  as or within 1 
month of Screening Visit 
At 4, 8, 12, 24 weeks after V2 (± 
2 weeks) 
Informed consent 
X 
 
 
Clinical history 
X 
X  
 
Prior medication history 
X 
X 
 
Inclusion and exclusion criteria 
X 
 X 
  
Physical examination including waist 
circumference 
  
X 
 
Vital signs measurement 
  
X 
  
Peak Inspiratory Flow Rate 
(Performed in triplicate at resistance 
of all DPIs the patient is receiving) 
X 
Pre- and post-bronchodilator 
(albuterol) 
Perform PIFR  in three positions 
(sitting, standing, and lying at 
45o angle with head tilted 
forward)#     
Done 3x/wk. (each session in 
triplicate with highest value 
recorded) at home by patient 
after enrollment#  
(Daily during worsened 
symptoms) 
COPD Assessment Test score (CAT) 
questionnaire 
X 
X 
X 
Modified Borg Dyspnea Score (mBorg) 
 
X 
X 
Done 3x/wk at home by 
patient after enrollment 
Modified Medical Research 
Council questionnaire (mMRC) 
 
X 
X 
COPD exacerbation history* 
X 
X 
X 
COPD medication use and adherence 
X 
X 
X 
*Mild, moderate and severe exacerbations will be defined as: 
Mild – doubling use of inhaled rescue medication > 48 hours and not meeting definition of moderate or severe; Moderate – increased rescue 
medication and oral corticosteroid, not requiring hospitalization; Severe – hospitalization for exacerbation 
# PIFR will be performed before performing spirometry (if spirometry is performed at that visits) using InCheck Dial settings for each DPI patient is receiving 
APPENDIX 2.  Modified Medical Research Council questionnaire (mMRC) 
 

 
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APPENDIX 3.  mBORG 
 

 
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APPENDIX 4.  COPD ASSESSMENT TEST 
 

 
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APPENDIX 5.  In-Check G16 DIAL® 
 
 

 
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