An Investigator Initiated, Randomized, Double Blind, Placebo Controlled Study to Assess the Effect of Glycopyrrolate/Formoterol on Exercise Tolerance and Dynamic Hyperinflation in Patients With Chronic Obstructive Pulmonary Disease.
Phase: PHASE4
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: William Stringer, md

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 1 of 42 
Template Revision: October 15, 2023 
 
1) Protocol Title 
An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, Two 
Period, Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® 
Therapy (Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic 
Hyperinflation in Patients with Chronic Obstructive Pulmonary Disease.    
 
2) HSC Review History 
N/A 
 
3) Investigators 
William Stringer, M.D. Principal Investigator 
Richard Casaburi, Ph.D., M.D. Co-Investigator 
Harry B. Rossiter, Ph.D. Co-Investigator 
Janos Porszasz, M.D., Ph.D., Co-Investigator 
 
4) Objectives* 
 
Patients with chronic obstructive pulmonary disease (COPD) have obstruction to 
expiratory airflow, marked breathlessness, high dyspnea scores, and reduced exercise 
tolerance relative to age and gender matched non-smoking controls (Casaburi, 2009; 
Casaburi et al., 2014; Puente-Maestu et al., 2016). A prominent mechanism for exercise 
intolerance is thought to be dynamic hyperinflation during exercise (an increase in the end-
expiratory lung volume) that contributes to the sensation of breathlessness, and ultimately 
results in early cessation of exercise. A co-maladaptive mechanism of exercise limitation in 
COPD is related to wasted or excessive ventilation at all work intensities from increased dead 
space ventilation relative to total ventilation (increased VD/VT).  This requirement for 
additional ventilation limits exercise capacity and contributes to dynamic hyperinflation and 
ventilatory limitation (O'Donnell et al., 2004). 
 
Treatment with individual bronchodilators, including short acting beta agonists (SABA), 
long acting beta agonists (LABA), short acting muscarinic antagonists (SAMA) and long 
acting muscarinic antagonists (LAMA) is effective in partially reversing the expiratory 
airflow obstruction at rest and during exercise resulting in reduced dynamic hyperinflation.  
Because beta-agonists and anticholinergics broncho-dilate synergistically, they are often used 
in combination products (SABA+SAMA or LABA/LAMA). The optimal sustained 
bronchodilation effect in COPD appears to be achieved by fixed dose, long acting 
combination medications (LABA/LAMA).  (Bateman et al., 2014; Casaburi, 2009; Casaburi 
et al., 2014; Cope et al., 2013; Huisman et al., 2015).  As dynamic hyperinflation appears to 
also be a limiting factor in exercise tolerance, and LABA/LAMA preparations improve 
airflow during exercise, it appears likely that use of a fixed-dose combination bronchodilator, 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
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Template Revision: October 15, 2023 
BEVESPI AEROSPHERE ® (Glycopyrrolate/Formeterol) will increase exercise tolerance 
and reduce hyperinflation in COPD patients.   
 
We hypothesize that exercise tolerance in a constant work rate, high intensity 
cardiopulmonary exercise test will be increased with BEVESPI AEROSPHERE ® 
(Glycopyrrolate/Formeterol), and that the increase in exercise tolerance will be mediated by 
a combination of: 1) reduced dynamic hyperinflation, and 2) decreased dead space 
ventilation (VD/VT) during exercise.   
 
Primary objective: To determine the magnitude of exercise time improvement (seconds) with 
BEVESPI AEROSPHERE ® (Glycopyrrolate/Formeterol) relative to placebo during high 
intensity, constant work rate exercise in COPD patients.   
 
Secondary objective: To determine if the VD/VT can be reliably assessed during constant 
work rate exercise using transcutaneous CO2 measurement (tcpCO2) and, if so, if  BEVESPI 
AEROSPHERE ® (Glycopyrrolate/Formeterol) results in a  reduction in VD/VT relative to 
placebo at isotime during high intensity constant work rate exercise in COPD patients. 
 
Tertiary objective: To determine if computerized assessment of the spontaneous expiratory 
flow-volume loop during exercise can provide additional information about both dynamic 
hyperinflation and the effects of BEVESPI AEROSPHERE ® (Glycopyrrolate/Formeterol) 
during high intensity, constant work rate exercise in COPD patients. 
 
5) Background* 
 
Chronic obstructive pulmonary disease (COPD) is a major worldwide cause of disability 
and death, with an estimated prevalence of 210 million and with more than 80 million of 
these having severe disease (World Health Organization). Recent data suggest that COPD is 
now the third leading cause of death in the USA (Miniño, 2010).  In addition, COPD is 
among the top five causes of adult disability, of which exercise intolerance consequent to 
dynamic hyperinflation is the main feature (Eisner et al., 2011), (Casaburi and ZuWallack, 
2009).  
 
In COPD patients, exertional dyspnea causes the avoidance of physical activity (Casaburi 
et al., 1999). Relief of hyperinflation, as well as reduction in wasted ventilation and reduction 
in VD/VT should result in improved exercise capacity. 
 
The purpose of the proposed study is to determine if exercise tolerance in COPD patients 
is improved with the use of FDA approved  
(https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Drug
Details) BEVESPI AEROSPHERE ® (Glycopyrrolate/Formeterol) relative to placebo during 
a high intensity, constant work rate cardio-pulmonary exercise test.   

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
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We hypothesize that this LABA/LAMA preparation, BEVESPI AEROSPHERE ® 
(Glycopyrrolate/Formeterol) relative to placebo will demonstrate improved pulmonary 
function and reduce dynamic hyperinflation in COPD patients in a stable phase of their 
disease.  
 
 
An advantage of BEVESPI AEROSPHERE ® (Glycopyrrolate/Formeterol) is related to 
the pressurized metered dose inhaler delivery system.  All other LABA/LAMA formulations 
(either once or twice a day) are dry powder or soft mist inhalers, which may be more difficult 
for patients to utilize on a regular basis and to self-administer the appropriate dosage each 
time. 
 
Use of Constant Work Rate (Endurance) Tests to evaluate exercise capacity in COPD 
 
 
Puente-Maestu, et al. have recently reviewed the literature on the use of exercise testing 
in the evaluation of the efficacy of interventions for the European Respiratory Society (ERS).  
(Puente-Maestu et al., 2016)  This official Task Force Statement concludes that “Exercise 
tests are reliable and consistently responsive to rehabilitative and pharmacological 
interventions.” and that “While bronchodilators do not always show clinically relevant 
effects in chronic obstructive pulmonary disease, high-intensity constant work rate 
(endurance) tests (CWRET) are considerably more responsive than incremental exercise tests 
and 6 minute walk test (6MWTs).”  These authors document that, in their exhaustive review 
of the literature, a minimally important clinical difference (MCID) in the CWRET in COPD 
was 105 seconds (page 434, Table 3).    Further, for single long acting bronchodilator 
interventions in COPD, 14/26 studies (54%) showed an average improvement in exercise 
duration of > 105 seconds or a relative percentage increase in time of 33% (page 435, Table 
4).  For non-pharmacologic interventions (e.g. rehabilitation, Heliox, Oxygen, Non-Invasive 
Ventilation (NIV), etc.) a change in endurance time of 105 seconds or a percentage increase 
in time of 33% was suggested as the MCID (page 437, Figure 1).   
 
 
We have therefore selected constant work rate (endurance) tests on a cycle ergometer to 
evaluate the exercise capacity improvements in COPD with the BEVESPI AEROSPHERE ® 
(Glycopyrrolate/Formeterol) combination.    Patients will perform an initial incremental test 
to exhaustion (Wasserman et al., 2005), and this will be followed (in about 2 hours) with a 
constant work rate exercise test (CWRET) at 80 % of the peak work rate targeting an 
exercise duration between 4 and 8 minutes (van der Vaart et al., 2014) . 
 
 
VD/VT Measurement using Transcutaneous CO2 during Exercise 
 
Measurement of physiologic dead space to tidal volume ratio (VD/VT) is an important 
measure of gas exchange efficiency. VD/VT  is the fraction of the expired tidal volume that 
does not participate in gas exchange (specifically, in CO2 elimination). In health, VD/VT is 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
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Template Revision: October 15, 2023 
~0.3 at rest and decreases during exercise. VD/VT  is immediately reduced on initiation of 
exercise and at low exercise intensity, and then remains approximately constant as exercise 
intensity increases (Jones et al., 1966; Wasserman et al., 1967; Hansen et al., 1984; Lewis et 
al., 1994; Sun et al., 2002; Wasserman et al., 2012). In diseases affecting the lungs or blood 
flow through the lungs (in particular) VD/VT can be high at rest (>0.3), but most notably 
VD/VT fails to fall substantially during exercise, thereby contributing to functional limitations 
in these patients – limits that reduce the quality of life, and increases morbidity and mortality. 
Therefore, exercise unmasks clinically meaningful abnormalities in VD/VT. The normal 
exercise-induced decrease VD/VT is the result of processes that influence both VD and VT 
independently. Early in exercise, alveolar dead space decreases as pulmonary arterial 
pressure increases and apical lung units become perfused. Anatomic dead space volume 
increases mildly during exercise as volume of the conducting airways increase due to 
exercise-induced bronchodilation and increased radial traction on airways at higher lung 
volumes. At high exercise intensities, an increase in the ratio of ventilation to perfusion 
(VA/Q) may also occur (Wagner et al., 1986). Each of these processes contribute to 
increasing VD during exercise. However, these effects are relatively small compared to the 
large increase in tidal volume, resulting an overall VD/VT reduction in healthy individuals as 
exercise intensity is increased (ATS/ACCP, 2003). Patients with chronic diseases of the 
lungs or cardiovascular system often have an elevated VD/VT at rest and an abnormal 
exercise response where VD/VT fails to fall, or even increases. Examples of diseases where 
this pattern of exercise response is seen includes: emphysema, COPD, asthma, pulmonary 
fibrosis, pulmonary vascular disease, right or left ventricular dysfunction, and ischemic heart 
disease (Wasserman et al., 2012). This may occur because of a high alveolar dead space i.e. 
alveoli that are not perfused, a worsening of VA/Q mismatch on exercise or a small (limited) 
exercise-induced increase in VT. As such, knowledge of VD/VT during exercise provides 
valuable insight into the etiology of a patient’s pathophysiology.  
VD/VT is calculated from the equation: VD/VT = (PaCO2 – PECO2) /(PaCO2) (1) where 
PaCO2 is the partial pressure of carbon dioxide (CO2) in the arterial blood and PECO2 is the 
mixed expired PCO2. Since, by definition, PECO2 is the inverse of the ratio of the expired 
ventilation (VE) to the CO2 output (VCO2), VD/VT can be calculated from the relation: 
VE/VCO2 = 863 / [PaCO2 · (1 - VD/VT)] (2) where a high value for VE/VCO2 is considered as 
a possible indication of a high VD/VT. This approach is commonly used in clinical exercise 
testing because standard metabolic cart equipment measures directly both VE and VCO2 on a 
breath-by-breath basis. 
 
However, elevated VE/VCO2 may be attributed to: (1) an increased VD/VT; (2) a decrease 
in PaCO2; or (3) both, such that the relationship between VE/VCO2 and VD/VT is not simple 
(Figure 1). Factors related to altered respiratory control, such as hyper- or hypo-ventilation 
due to anxiety, hypoxemia, chronic respiratory alkalosis, metabolic acidosis, or altered 
respiratory mechanics may cause changes in PaCO2 that alter VE/VCO2 independently of 
VD/VT. These assumptions become especially pertinent in pulmonary pathologies where gas 
exchange and CO2 elimination are impaired.  

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
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Template Revision: October 15, 2023 
 
Figure 1. The relationship between deadspace fraction of tidal volume (VD/VT) and the 
ventilatory equivalent for CO2 (VE/VCO2) across a range of different arterial PCO2 (PaCO2) 
values. The equation in the insert is a rearranged form of Eq (2) above. 
 
In line with this, we have recently shown (Roman et al., 2013), in the largest collection 
(n=691) of cardiopulmonary exercise tests with serial arterial blood gas measurements, that 
VE/VCO2 (using the VE/VCO2 value at the lactate threshold (LT) during exercise) is 
inadequately discriminatory of abnormalities in the VD/VT response. In this population of 
patients with a wide range of diagnoses, while very high (>39) or very low (<28) VE/VCO2 
values were indicative of abnormal or normal VD/VT respectively.  In 58% of these exercise 
tests the VE/VCO2 value was between these limits and provided no reliable information on 
VD/VT. Again, this emphasizes that accurate diagnosis of VD/VT pathology in a large 
majority of patients requires direct measurement of PaCO2. Recently, in a preliminary study 
we have shown that using tcpCO2 as a surrogate of PaCO2 in the above equation gives a 
better estimate of dead-space ventilation. (Cao et al.) 
 
In the ideal lung, ventilation is evenly matched to perfusion and gas exchange is highly 
efficient. Patients with COPD have abnormal VD/VT responses to exercise in that they 
demonstrate an increase in VD/VT due to non-uniform emptying of the airways, with the 
longest time-constant low VA/Q lung units contributing to end tidal gas (Hansen et al., 
2007).  There is opportunity, therefore, to dramatically improve the assessment of a 
pathological VD/VT response to exercise using non-invasive transcutaneous PCO2 
measurement (tcPCO2), as an accurate and precise surrogate for PaCO2. This method 
determines the PCO2 of skin capillaries under a heated, Severinghaus-type electrode. The 
sensor is clipped to the earlobe and mildly heats the skin and dilates the underlying 
𝑉𝑉𝑉𝑉
𝑉𝑉𝑉𝑉= 1 −
863
PaCO2 ∗
VE
𝑉𝑉𝑉𝑉𝑉𝑉2
 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
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capillaries; this increases the gas diffusion through the lipid structure of the skin, allowing 
carbon dioxide diffuse to the electrode for measurement. Because the metabolic rate in the 
ear is low, the resulting increase in blood flow causes capillary PCO2 to approach PaCO2. 
Were tcPCO2 to approximate PaCO2 change during an exercise test in patients with COPD, it 
could provide a considerable advance in the diagnostic capability of cardiopulmonary 
exercise testing.  
 
We have identified 20 published articles where tcPCO2 has been used during 
cardiopulmonary exercise testing (Table 1). Of the 20 articles, 3 are noteworthy (Carter and 
Banham, 2000; Sridhar et al., 1993; Stege et al., 2009) in that they made paired arterial and 
transcutaneous PCO2 measurements during clinical exercise assessments in patients. Sridhar 
et al. (1993) found good limits of agreement between PaCO2 and tcPCO2 during cycling 
ergometry (mean bias 0.2 mm Hg; CI -1.2 to +1.9 mm Hg) in 24 patients with chronic 
obstructive pulmonary disease (COPD), ischemic heart disease (IHD) and other pulmonary 
disorders.  
 
Carter and Bahnam (2000) were the first to perform rapid arterial blood sampling (every 
2 minutes) during a standard clinical cardiopulmonary exercise test in 14 
patients with COPD, IHD and other cardiac and respiratory disorders. They found very good 
limits of agreement between arterial and transcutaneous measurements (mean bias 0 mm Hg; 
CI -0.2 to +0.2 mmHg). However, they used an “in vivo‟ calibration method where the 
tcPCO2 values were corrected using a resting arterial blood PaCO2 measurement prior to the 
exercise test. A major potential benefit of non-invasive tcPCO2 measurement is to avoid the 
requirement for arterial blood sampling. Therefore, the in vivo calibration approach used by 
Carter and Bahnam (2000) would be an undesirable recommendation for standard use. 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
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Stege et al. (2009) performed the most detailed investigation to date in 21 patients with 
COPD, asthma, sarcoidosis and other respiratory disorders. They showed that  
tcPCO2 provided a superior PaCO2 estimate (mean bias -0.2 mm Hg; CI -5.7 to 5.2 mm Hg) 
compared with end-tidal PCO2 (mean bias 7.7 mm Hg; -0.67 to 16.2 mm Hg).   
  
We have recently performed a study in our laboratory (which is in manuscript preparation) of 
10 COPD patients using the Radiometer (TOSCA 500) Transcutaneous pCO2 device and 
compared the non-invasive results to multiple simultaneous arterial blood gas pCO2 values from 
an arterial line during ramp pattern exercise. We have found that across a wide range of PaCO2 
from < 30 torr to > 50 torr, the transcutaneous pCO2 was accurate and precise relative to the 
arterial pCO2 value (See Figure 2, Bland Altman analysis, below).  Specifically, the bias was 
very nearly zero and the standard deviation was about 2 torr.  We believe that this device will 
allow us to accurately and precisely assess repetitive VD/VT measurements during exercise to 
assess the effect of the BEVESPI AEROSPHERE ® (Glycopyrrolate/Formeterol) on airflow 
and hyperinflation as well as the effect on deadspace ventilation (VD/VT). 
 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
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Figure 2. Bland – Altman analysis of arterial CO2 (PaCO2) versus transcutaneous CO2 
(tcPCO2) during exercise in 10 COPD patients.   
 
 
 
The effect of bronchodilators on exercise gas exchange efficiency, as quantitated by 
VD/VT, has not received adequate study in COPD patients (Díaz et al., 2001; Elbehairy et al., 
2015; Marvin et al., 1983; O'Donnell et al., 2016).  Physiologic considerations would predict 
that bronchodilators would have three distinct effects on VD/VT.  First, bronchodilation of 
airways increases dead space in the conducting zone of the lung. Second, bronchodilation of 
airways serving poorly perfused regions of the lung has potential to increase physiologic 
dead space, leading to VD/VT increase.  Third, bronchodilation tends to reduce dynamic 
hyperinflation, which allows a slower deeper breathing pattern, allowing a greater tidal 
volume and/or an attenuated constraint of tidal volume increase during exercise.  Better 
maintenance, or increase, in tidal volume without change in dead space volume would 
translate into a lesser VD/VT.  In fact, mildly greater isotime inspiratory capacity and 
pulmonary ventilation has been observed in COPD during exercise following bronchodilator 
therapy (O'Donnell et al., 2004). It is not possible to determine whether this stems from an 
increase in VD/VT or a decrease in PaCO2.  This study will provide this information, yielding 
better understanding of the beneficial effects of bronchodilator therapy on the exercise 
responses of COPD patients.       
 
 
We therefore feel that transcutaneous pCO2 measurement will be an effective, non-invasive 
way to repetitively determine the effects of BEVESPI AEROSPHERE ® 
(Glycopyrrolate/Formeterol) on VD/VT during exercise. 
 
 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
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Flow-Volume Measurement During Exercise 
 
Breath-by-breath quantification of progressive airflow limitation during exercise in COPD is 
an area in which this laboratory has substantial experience.  We have published that the 
progressive fall in intrabreath flow, manifested by concavity in the spontaneous expiratory 
flow volume (SEFV) curve, can be analyzed electronically from the digitized expiratory flow 
signal (100 Hz).  Each breath’s SEFV curve, point of highest flow (V max) and end-expiratory 
flow (VEE) can be identified using a ‘rectangle diagonal area’ or (RAR) strategy.  See Figure 
3; RAR < 0.5 identifies concavity of the SEFV curve and identifies patients with progressive 
airflow limitation during exercise. (Ma et al., 2010)  We have recently had a paper accepted 
for publication demonstrating a close correlation between the onset of concavity in the SEVF 
curve and dynamic hyperinflation.(Varga et al., 2016)  
 
 
 
Figure 3:  Progression of the spontaneous flow volume (SEFV) curve configuration during 
incremental exercise in a healthy subject (top panels) compared to a patient with COPD 
(lower panels). 
 
Recently, Porszasz {Porszasz, 2013, Effect of tiotropium on spontaneous expiratory flow-
volume curves during exercise in GOLD 1&2 COPD} has shown that tiotropium 
significantly increased RAR during exercise while improving dynamic hyperinflation and 
resting FEV1. (Porszasz et al., 2013) We therefore feel exercise flow-volume analysis to 
determine the change in RAR during exercise will add additional information regarding 
airflow improvements leading to less hyperinflation in patients treated with BEVESPI 
AEROSPHERE ® Therapy (Glycopyrrolate/Formeterol).  We hypothesize that, in COPD 
patients, at an identical work rate and exercise time, RAR will be higher after treatment with 
this combination bronchodilator.  
 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
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6) Setting of the Human Research 
 
Patient recruitment and testing will take place at Los Angeles Biomedical Institute 
(LABioMed) in Torrance, California.  Our research group is located in the Chronic Disease 
Clinical Research Center (CDCRC) building.  There is adequate free parking and a large 
reception area for our research subjects.  Our Pulmonary group consists of 4 principal 
investigators (Casaburi, Porszasz, Rossiter and Stringer), 5 study coordinators, several 
postdoctoral researchers, a full time exercise physiologist, and other technical research staff.  
The research space available to us in the CDCRC includes 5 separate rooms that house an 
exercise-training center, a complete exercise physiology laboratory with state of the art 
cardiopulmonary exercise testing equipment (including the ability to perform inspiratory 
capacity maneuvers during exercise), a Radiometer transcutaneous CO2 monitor (TOSCA 
500), the equipment to perform either cycle and treadmill exercise, a 6 minute walk course, 
and a complete pulmonary function laboratory with spirometry, body box and DLCO.  We 
also have 3 well-equipped examination rooms and offices suitable for obtaining informed 
consent, interviewing subjects, performing physical examinations, and discussing study 
specifics in a quiet, private, and protected environment.  
 
7) Resources Available to Conduct the Human Research 
 
This study is financially supported by AstraZeneca as part of their Investigator Initiated 
Studies program.  The study design was initiated by the LA BioMed investigators. 
 
The Pulmonary Division in the Chronic Disease Clinical Research Center (CDCRC) at 
LA BioMed has a > 20-year history in recruiting large numbers of COPD patients and 
healthy controls for multiple NIH, DOD, and industry sponsored clinical trials, including a 
large number of exercise studies. We commonly conduct large-scale COPD-related clinical 
trials, and as such there is potential access to several hundred subjects per year.   
 
Fifty COPD subject/patient volunteers are needed for this study over an approximate 1-
1.5 year period, which is a small fraction of our recruitment pool. We regularly enroll 
subjects into COPD exercise research studies, therefore, we do not anticipate any problems 
with patient recruitment.  All of our investigators (Casaburi, Porszasz, Rossiter and Stringer) 
and research staff will contribute to the study. Because Dr. Casaburi has received consulting 
and speaking fees from Astra Zeneca a management plan for his potential conflict of interest 
(COI) is in place.  He will disclose this COI to study staff and research participants.  He will 
not engage in participant recruitment or the consent process, among other restrictions. All 
members of the research team have extensive experience in working with COPD patients in 
physiologic exercise studies. The methods used in this study were developed at LABioMed 
and the PI and all Co-Is are world leaders in the field, and contribute to setting the guidelines 
for clinical and research exercise testing in patient populations.  
 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 11 of 42 
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All the equipment required for the study is in standard use in our lab. The PI (Stringer) 
will devote 10% FTE to the study, with Co-PIs (Casaburi and Rossiter) will contribute 3% 
FTE. Co-I (Porszasz) will contribute 10% FTE. All investigators have MD or PhD degrees or 
both.  
 
Recruitment and regulatory compliance will be supported by contributions from study 
coordinators (Cavanaugh, Diaz). Physiological testing will be supported by post-doctoral 
scientists, and an exercise physiologist lab (Calmelat). Staff members have been involved in 
previous studies using similar measurements and are well trained in their application. Our 
laboratory has weekly staff meetings where the experimental protocols and recruitment goals 
are continually reviewed and the current activities of each staff member reviewed. 
 
No adverse events are anticipated. However, in the event of an adverse event, our lab is 
equipped with a crash cart and a California licensed physician will be available in the 
Exercise Laboratory during initial exercise tests for each subject. In case of medical 
emergency, the lab is located in the CDCRC Building on the Harbor-UCLA Medical Center 
(HUMC) campus, with excellent access to the emergency facilities. HUMC is a full service, 
academic medical center, a level 1 trauma center, and an STEMI receiving center for our 
region. All of the physician investigators are Harbor-UCLA physicians with full and 
unrestricted California medical licenses.  
 
The principal investigator or our study coordinators will be providing complete 
information about the study and obtaining informed consent prior to initiation of the 
study.  The principal investigator will be available for any subject questions through 
and after the study.    
 
8) Prior Approvals 
The approval and contracting process is underway between LABioMed 
with AstraZeneca (AZ).  A detailed investigator initiated proposal has been 
submitted via the AZ website and has obtained tentative approval from the world 
research team.  Final contracts are scheduled to be signed by late September 2016. 
 
9) Study Design 
a) Recruitment Methods 
 
Potential subjects for the study will be drawn from people known to our 
Pulmonary Research Group in the Chronic Disease Clinical Research Building 
(CDCRC) who have previously participated in our studies, attended clinics of Harbor-
UCLA Medical Center, have completed a local Pulmonary Rehabilitation Program, are a 
member of a local patient support group, or have their clinical care performed in the 
network of area pulmonologists (including Kaiser and Health Care Partners).  Subjects 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 12 of 42 
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who have given prior consent for contact will be contacted by phone to determine their 
willingness to participate, and if agreeable, will be invited to the study site for a 
complete in-person explanation of the protocol and consent. 
 
Advertising (paper, internet, and radio) is not currently planned, however 
advertising may be utilized if the recruitment goals are not optimal 4 months after study 
initiation.  If advertising is pursued, all advertising copy, media, and text will be 
approved by the LABioMed Institutional Review Board. 
 
Subjects are reimbursed for their time and inconvenience in participating in this 
study. They will be informed of the following:  
 
“For your time and inconvenience related to your taking part in this study, you 
will be paid a total of $1,250 if you complete this study. If you do not complete the 
study, for any reason, you will be paid for the study visits you do complete according to 
the following schedule: $300 for visit 1; $200 for visit 2; $150 for visits 3, 4, 5, 6, and 
7.” 
 
b) Inclusion and Exclusion Criteria* 
 
Inclusion criteria 
1) All patients must have a clinical diagnosis of chronic obstructive pulmonary disease 
(COPD) and must meet the following criteria:  
(a) Stable state of their disease with no exacerbation (antibiotics, oral steroids, ER 
visit, or hospitalization for COPD) within the previous 4 weeks; and  
(b) At visit 1 Spirometric Values must demonstrate a post-bronchodilator FEV1 
between 35% and 80% of predicted normal and a post-bronchodilator FEV1/FVC 
<70%.  [The rationale for the lower limit is to exclude patients unlikely to tolerate 
withholding of long acting bronchodilators.  The rationale for the upper limit is to 
exclude patients unlikely to be limited in their exercise tolerance by 
hyperinflation and air trapping.] 
2) Male or female patients, between 40 and 80 years (inclusive) of age.  
3) Patients must be current or ex-smokers with a smoking history of more than 10 pack-
years.  
4) Patients must be able to perform technically acceptable pulmonary function tests and a 
symptom-limited cardiopulmonary cycle ergometry test.  
5) Patients must be able to inhale medication in an acceptable manner from the metered 
dose inhalers used in this study.  
 
 
Exclusion criteria 
1) Patients with a significant disease other than COPD; a significant disease is defined as a 
disease which, in the opinion of the investigator, may 
(i) put the patient at risk because of participation in the study,  

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 13 of 42 
Template Revision: October 15, 2023 
(ii) influence the results of the study, or  
(iii) cause concern regarding the patient’s ability to participate in the study. 
2) Patients with a documented personal history of childhood asthma, a clinical presentation 
consistent with asthma, and a family history of asthma. For patients with allergic rhinitis, 
atopy, or prior allergy treatment, medical records will be obtained to verify that the 
patient does not have asthma.  The final determination on the possibility of an overlap 
condition [Asthma-COPD Overlap Syndrome, (Postma and Rabe, 2015)], and thus, 
appropriateness for entry into the study, will be the principal investigator’s decision. 
3) Patients with any of the following conditions: 
a) A history of myocardial infarction within 1 year of screening visit. 
b) Unstable or life-threatening cardiac arrhythmia. 
c) Hospitalized for heart failure within the past year.  
d) Known active tuberculosis. 
e) A malignancy for which patient has undergone resection, radiation therapy or 
chemotherapy within the past 6 months (patients with treated local skin tumors are 
allowed). 
f) A history of life-threatening COPD exacerbation requiring intubation.   
g) A history of cystic fibrosis. 
h) Clinically significant and active bronchiectasis.  
i) A history of alcohol or drug abuse within the past year. 
j) Any contraindications for exercise testing as outlined below (see contraindications to 
exercise). 
k) Patients who have undergone thoracotomy with pulmonary resection in the past year. 
4) Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than 
six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone 
per day or 20 mg every other day. 
5) Patients who regularly use daytime oxygen therapy for more than 6 hours per day and in 
the investigator’s opinion will be unable to abstain from the use of oxygen therapy during 
clinic visits and exercise testing. 
6) Patients who desaturate to SpO2 <80% on screening incremental exercise testing. 
7) Patients who have completed a pulmonary rehabilitation program in the six weeks prior 
to the screening visit or patients who are currently in a pulmonary rehabilitation program. 
8) Patients who have a limitation of exercise performance as a result of factors other than 
fatigue or exertional dyspnea, such as arthritis in the leg, angina pectoris or claudication 
or morbid obesity. 
9) Patients with a constant power cycle ergometry endurance time less than 4 or greater than 
8 minutes after work rate adjustment procedures (described below).  
10) Patients who have taken an investigational drug within one month or six half-lives 
(whichever is greater) prior to screening visit (Visit 1). 
11) Pregnant or nursing women. 
12) Women of childbearing potential who are not using a highly effective method of birth 
control. Female patients will be considered to be of childbearing potential unless 
surgically sterilized by hysterectomy or bilateral tubal ligation, or post-menopausal for at 
least two years.  Pregnancy testing will be performed in women of childbearing potential 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 14 of 42 
Template Revision: October 15, 2023 
and repeated during the study if questioning of the participant suggests a change of status.  
13) Patients who are currently participating in another interventional study.  
14) Patients who are unable to comply with pulmonary medication restrictions (washout of 
any LABA/LAMA) prior to randomization. 
 
All subjects will be screened for eligibility during visit 1.  Eligibility will be determined 
by medical history, physical examination, spirometry (visit 1) and exercise testing (visit 
1).  Women with the potential for pregnancy will be tested using a urine-based testing kit. 
Eligibility will be determined according to the study inclusion and exclusion criteria 
 
c) Local Number of Subjects 
 
Fifty patients are required to complete the research procedures. LA BioMed is the only 
study site.  Based on our experience we anticipate an approximate 15% screen failure rate 
from spirometry and a 15% screen failure rate following the screening ramp exercise test and 
subsequent constant work rate exercise test. Therefore, we anticipate screening 
approximately 70 patients to complete the research in 50 subjects. 
 
d) Study-Wide Number of Subjects* 
 
Not applicable. 
 
e) Study Timelines* 
 
Each patient will be enrolled for approximately 12 weeks. This is a randomized, 
crossover, placebo controlled, two-period, double-blind study that includes 7 laboratory visits 
and two, 2 week washout periods from drug or placebo.  
 
The timeline for each patient visit is shown in Figure 4. Visit 1 will be approximately 1 
hour duration. Visit 2 will be approximately 4 hours duration. Visits 3, 4, 5, and 6 will each 
be approximately 2 hours duration.  Visit 7 will take < 1 hour. 
 
Completion of study of the patient population (n=50) is anticipated to take 12 - 18 
months. Depending on protocol, IRB and contract approval a tentative target for starting 
patient recruitment is December 2016. Completion of primary analysis is anticipated within 
three months of the last patient completing the protocol. 
 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 15 of 42 
Template Revision: October 15, 2023 
 
 
Figure 4. Study Timeline for weeks -4 to 8. Screening, Washout, Randomization, 2 week Drug or 
Placebo periods, Ramp Pattern and Square Wave Exercise Testing, and Safety Visit at day # 56.  
Drug refers to BEVESPI AEROSPHERE ® Therapy (Glycopyrrolate / Formeterol).   The 
administration of these drugs (drug or placebo) will be double-blinded.  
Our group anticipates that the performance of the entire study from first 
enrollment (subject # 1) to completion (subject # 50) will require between 12 and 
18 months. 
f) Study Endpoints* 
 
The study endpoint is completion of Visit # 7. Patient safety will be monitored 
throughout, and the procedures stopped if a problem arises. There are no clinical or 
therapeutic endpoints. 
 
Safety endpoints include the ability to complete a ramp and constant work rate  exercise 
test safely, as judged by the investigator. Exercise tests will be stopped if clinically 
significant changes in the ECG occur, such as ST-segment depression, marked desaturation 
(< 80%), or a dangerous/complex/progressively increasing arrhythmias. 
 
Definition of adverse events  
 
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.  An 
undesirable medical condition can be symptoms (eg, nausea, chest pain), signs (eg, 
tachycardia, enlarged liver) or the abnormal results of an investigation (eg, laboratory 
findings, electrocardiogram).  In clinical studies, an AE can include an undesirable medical 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 16 of 42 
Template Revision: October 15, 2023 
condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
 
Definitions of serious adverse event 
 
A serious adverse event is an AE occurring during any study phase (ie, run-in, 
treatment, washout, follow-up), that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity or substantial disruption of the 
     ability to conduct normal life functions 
• 
Is a congenital abnormality or birth defect. 
• 
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
 
The causality of SAEs (their relationship to all study treatment/procedures) will be 
assessed by the investigator(s) and communicated to AstraZeneca. 
 
Causality assessment 
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 
For SAEs a causal relationship will also be assessed for other concomitant medications, study 
procedures, and comparator study drugs.  Note that for SAEs that could be associated with 
any study procedure the causal relationship is implied as ‘yes’. 
 
Adverse events (AE) and serious adverse events (SAE) are safety endpoints of the study. 
Medical judgment will be used to determine the relationship between study drug or 
procedures and an (S)AE, 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. 
 
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE, if they are judged clinically relevant by the investigator. Vital signs, 
ECG, and physiological test results are recorded as part of cardiopulmonary exercise testing 
at each visit. These may cause exclusion of the patient from the study at any time, should 
they meet the exclusion criteria listed. 
 
 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 17 of 42 
Template Revision: October 15, 2023 
g) Procedures Involved in the Human Research* 
 
All study procedures are done solely for the purposes of research. 
 
Study design 
 
This will be a randomized, placebo controlled, double-blind study investigating the 
effects of the FDA approved fixed combination long acting beta agonist and long acting 
muscarinic antagonist (LABA/LAMA) inhaler BEVESPI AEROSPHERE ® 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease. 
The study is a crossover, within-patient, two period design comparing the effect 
BEVESPI AEROSPHERE ® Therapy (Glycopyrrolate/Formeterol)  to placebo on endurance 
time (exercise capacity/time during a constant work rate exercise test), dynamic 
hyperinflation, and dead space to tidal volume (VDVT).  Fifty (50) patients with moderate to 
severe COPD (post-bronchodilator FEV1 between 35% and 70% of predicted normal and a 
post-bronchodilator FEV1/FVC <70%) will be recruited into this study.  
 
Initially pulmonary function, chest computerize tomography (CT) imaging, and 
cardiopulmonary exercise variables will be used to characterize recruited patients. 
Subsequently, a constant power exercise test (calculated from the initial incremental exercise 
test to bring the patient to intolerance to between 4 and 8 minutes on a constant work rate 
exercise test) will be designed and administered at the same work rate for the entire study.  
Patients will perform two tests, each to the limit of tolerance, while being treated with either 
BEVESPI AEROSPHERE ® (Glycopyrrolate/Formeterol) bronchodilator and placebo. A two 
week wash out period will precede randomization and after the first treatment period.  The 
patient will return to their usual medications at day 42 and will have a final exit/safety visit at 
study completion (day 56).  
 
An independent statistician will randomize the order of these two tests, and both patients 
and investigators blinded to the condition. A pharmacist, who will otherwise not participate 
in the study, will facilitate drug and placebo distribution to the subject.   Unblinding 
information will be kept in sealed envelopes by the pharmacist in case of (S)AE.  The PI will 
be available by beeper (24 x 7) to the subject and health care providers if unblinding would 
be necessary to facilitate their acute care (e.g. ER visit or hospitalization). 
 
The endurance times at the start and completion of each treatment period (with an 
appropriate washout period between them) will be analyzed as the primary study outcome 
variable.  Secondary outcome variables will be the change (fall) in inspiratory capacity at 
isotime during the constant work rate studies of treatment period one and two.  Finally, 
transcutaneous CO2 will be used to assess the changes in dead space to tidal volume (VD/VT) 
at iso-time for the two treatment periods.  
 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 18 of 42 
Template Revision: October 15, 2023 
 
10) Visit schedule 
 
Written informed consent will be administered in the study center. All consenting 
subjects will discontinue long-acting bronchodilators (LABA and LAMA) for the entire 
duration of the study, and will utilize short acting beta agonists (SABA), a  short acting 
muscarinic antagonist (SAMA), or a combination product SABA + SAMA (e.g. albuterol 
and ipratropium, Combivent).  If the patient is on an inhaled corticosteroid in addition to his 
LABA (LABA+ICS), the patient will be transitioned to an inhaled corticosteroid that will be 
individually formulated.  
 
The study drug (BEVESPI AEROSPHERE ® - Glycopyrrolate/Formeterol) or placebo) 
will be administered twice daily during two 2 week periods in the protocol. Each time, the 
study drug will be taken for two weeks before testing is performed with a washout between 
periods. The study timeline is shown in Figure 4. The study will require a total 7 visits by 
each patient to complete the study.   
 
Visit 1: Informed Consent, Demographics, Physical Exam, BMI, Vital Signs, 12 lead EKG, 
Pulse Oximeter, Review of Inclusion and Exclusion Criteria, Urine Pregnancy Test (if female 
of childbearing age), BODE index with 6 minute walk, Spirometry, Lung Volumes/DLCO, 
SGRQ and CAT Questionnaires, and Chest CT with Inspiratory / Expiratory phases.  
 
Washout of any LABA or LAMA that the patient is currently taking for 14 days.  The 
patient will use a short acting bronchodilator (albuterol or albuterol + ipratropium).  The 
patient will also be transitioned off of any combination inhaled corticosteroids (ICS) and 
onto beclomethasone or another equivalent inhaled steroid for the duration of the study. 
 
Visit 2: Vital Signs, Spirometry (No Bronchodilator), Vital Signs, Ramp Pattern 
cardiopulmonary exercise test (CPET), followed in 2 hours with a Constant Work Rate 
(CWR) or “Square Wave” exercise test designed from the initial ramp pattern CPET.  Both 
tests will have inspiratory capacity maneuvers, flow volume loop analysis and transcutaneous 
CO2 measurements.  The CWR test should be high intensity (80% of peak VO2) and targeted 
to last between 4 and 8 minutes.   
 
Visit 2.5 (If Necessary): ** If the first CWR exercise test is not between 4 and 8 minutes in 
duration, a second test will be performed prior to washout.  This test will be high intensity 
but the work rate will be adjusted from the first test by an increase or decrease of 5% (as 
appropriate) and targeted to last between 4 and 8 minutes.  In case this test is also not within 
4 and 8 minutes in duration, a third test will be performed with appropriate 5% work rate 
change after one hour of rest; if this test is not within 4-8 minutes in duration the patient will 
be considered a screen fail.   
 
Visit 3:  The patient will be randomized on visit 3 and have vital signs, weight, pulse 
oximetry, spirometry (no bronchodilator), SGRQ and CAT questionnaires.  The patient will 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 19 of 42 
Template Revision: October 15, 2023 
begin treatment period # 1 of 14 days duration (either placebo or drug, randomized with 
respect to sequence of administration).  Spirometery will be performed 30-45 minutes after 
administration of medication. 
 
Visit 4:  At the end of treatment period #1 (14 days), the subject will have vital signs, weight, 
and pulse oximetry, spirometry (no bronchodilator), SGRQ and CAT questionnaires and 
CWR exercise test with inspiratory capacity, flow-volume loop, and transcutaneous CO2 
measurements.  The subject will administer the final dose of medication (placebo or 
medication) in the laboratory 45 minutes before spirometry and constant work rate testing.  
At this visit the patient will have the study medications stopped for another 14 day washout. 
 
Visit #5:  At the end of the washout from treatment period # 1, the subject will have  
vital signs, weight, and pulse oximetry, spirometry (no bronchodilator), SGRQ and CAT 
questionnaires and CWR exercise test with inspiratory capacity, flow-volume loop, and 
transcutaneous CO2 measurements.  Spirometery will be performed 30-45 minutes after 
administration of the new medication during the visit.   
 
[The patient will receive the new study medications for a 14 day treatment period (treatment 
period # 2) of either placebo or drug; the subject will receive the alternate study drug (active 
medication or placebo) from what the subject received during treatment period # 1. The order 
will be randomized.] 
 
Visit # 6:  At the end of treatment period #2 (14 days), the subject will have  
vital signs, weight, and pulse oximetry, spirometry (no bronchodilator), SGRQ and CAT 
questionnaires and CWR exercise test with inspiratory capacity, flow-volume loop, and 
transcutaneous CO2 measurements.  The subject will administer the final dose of medication 
in the laboratory 45 minutes before spirometry and the CWR testing.   At this visit the patient 
will have all study medications stopped and the subject will return to his/her normally 
prescribed medications. 
 
Visit # 7:  Exit and Safety Visit; vital signs, weight and pulse oximeter.  Assess for adverse 
events and record.   
 
 
11) Medications 
 
Subjects will take their daily dose of the study medication in the laboratory 90 minutes 
before undergoing spirometry and constant work rate testing. 
 
BEVESPI AEROSPHERE ® (Glycopyrrolate/Formeterol):  
 
BEVESPI AEROSPHERE ® (Glycopyrrolate (GLY)/ Formeterol (FOR)) is an FDA 
approved (April 2016) twice daily fixed dose combination bronchodilator for maintenance 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 20 of 42 
Template Revision: October 15, 2023 
treatment of patient with COPD.  The Glycopyrrolate/Formeterol is delivered by pressurized 
metered dose inhaler; two inhalations result in 18 micrograms of glycopyrrolate and 9.6 
micrograms (µg) of formoterol.  These drugs in this combination and delivery device have 
been studied in two randomized, double-blind, placebo-controlled, parallel group, 24 week, 
phase 3 studies in which patient with moderate to very severe COPD were randomized to 
treatment with twice daily Gly/For (19/9/6 µg), GLY (18 µg), FOR (9.6 µg), or placebo 
(Rabe, 2015).  The primary endpoint of these studies was the change from baseline in trough 
FEV1 at 24 weeks.  A total of 3699 patients were randomized in the two studies. 
 
Lung Function Treatment with GLY/FOR (18/9.6 µg) resulted in significant improvement in 
trough FEV1 at 24 weeks compared with mono-components and placebo (Figure 5). 
 
 
Figure 5: Twice Daily Glycopyrrolate/Formoterol (18/9.6 µg) FDC: Lung Function 
(PINNACLE-1 and PINNACLE-2, Pooled Analysis).  Change in FEV1 Trough at 24 weeks 
for GLY/For vs Placebo, GLY/FOR vs FOR, and GLY/FOR vs GLY.  The change in trough 
FEV1 is roughly double for the combination of GLY/FOR relative to either FOR or GLY 
alone relative to placebo. 
 
HRQL and Rescue Medication: Treatment with twice daily GLY/FOR (18/9.6 µg) 
FDC was associated with improvement in St. George’s Respiratory Questionnaire (SGRQ) 
total score at 24 weeks and rescue medication use compared with placebo and GLY (18 µg) 
monotherapy, but not with FOR (9.6 µg) monotherapy (Table 2). 
 
 
 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 21 of 42 
Template Revision: October 15, 2023 
Table 2: Glycopyrrolate/Formoterol FDC: Pooled Analysis PINNACLE-1 and PINNACLE-
2 
Endpoint 
GLY/FOR 
(18/9.6 µg)  
vs Placebo 
GLY/FOR 
(18/9.6 µg)  
vs FOR (9.6 µg) 
GLY/FOR 
(18/9.6 µg)  
vs GLY (18 µg) 
SGRQ Total Score  
(treatment 
difference, change 
from baseline at 24 
weeks) 
-2.13 
P = 0.005 
-0.64 
P = 0.283 
-1.56 
P = 0.009 
Daily Rescue 
Medication 
(treatment 
difference, puffs/day 
over 24 weeks) 
-1.06 
puffs/day 
P < 0.0001 
-0.15 puffs/day 
P = 0.124 
-0.42 puffs/day 
P < 0.0001 
 
Safety and Tolerability: The safety profile of twice daily GLY/FOR (18/9.6 µg) FDC 
in the PINNACLE-1 and PINNACLE-2 studies was similar to the monocomponents, open-
label TIO, and placebo, with 60% of patients in the GLY/FOR treatment group with at least 
one AE compared with 56%, 57%, 58%, and 63% in the GLY, FOR, placebo and TIO 
groups, respectively.  Over a total of 52 weeks, incidence of AEs was similar across 
treatment groups, with nasopharyngitis and cough the most frequently reported events, 
ranging from 4.3% to 6.8% and 3.4% to 4.7% of patients respectively. In patients treated 
with twice daily GLY/FOR (18/9.6 µg), 7.8% of patients discontinued due to AEs compared 
with 7.2% for GLY (18 µg), 6.0% in the FOR (9.6 µg) treatment group, and 6.2% of patients 
who received TIO (18 µg).  
  
Glycopyrrolate is a non-chiral, long-acting, inhaled anticholinergic bronchodilator 
initially developed for the long-term, once-daily, maintenance treatment of bronchospasm 
and dyspnea associated with chronic obstructive pulmonary disease (COPD), including 
chronic bronchitis and emphysema. It has had FDA approval in aerosolized form since 2014. 
 
Formoterol is a long-acting beta2-adrenergic agonist bronchodilator indicated for the 
long-term, twice-daily maintenance bronchodilator treatment of airflow obstruction in 
patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis 
and/or emphysema.  It has had FDA approval for use in COPD since 2007. 
 
The drug product, BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) was recently approved by the FDA (April 2016).  It is 
delivered by ta metered dose inhaler in a fixed combination of 2 puffs equaling 18 mcg of 
glycopyrrolate and 9.6 mcg of formoterol.   
 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 22 of 42 
Template Revision: October 15, 2023 
Common side effects (more common than placebo) include: 
 
Table 3 : Common Adverse Reactions with Bevespi Aerosphere ® 
(Glycopyrrolate/Formoterol FDC)  (>- 2%) relative to Placebo in patients with COPD:  
Pooled Analysis PINNACLE-1 and PINNACLE-2 
 
 The drug package insert is attached to this application. 
 
Placebo BEVESPI AEROSPHERE ® Therapy (Glycopyrrolate/Formeterol):  The placebo 
STIOLTO™ RESPIMAT® inhaler will be prepared by AstraZeneca and contains no active 
therapeutic agent. 
 
Albuterol: Albuterol is an FDA approved medication for pulmonary function testing. It may 
be used in this study as a short-acting medication during the entire study, including washout 
periods. The drug package insert is attached to this application. 
 
Combivent: Combivent contains ipratropium bromide and albuterol. Ipratropium bromide is a 
marketed drug approved for use in the United States. It is a bronchodilator for maintenance 
treatment of bronchospasm (tightening of the airways) associated with COPD, including 
chronic bronchitis and emphysema. It may be used in this study as a maintenance therapy 
during the washout periods, but not the study periods. The drug package insert is attached to 
this application. 
 
Inhaled corticosteroids (ICS): Some COPD patients take combination therapies that contain 
an inhaled corticosteroid and a long-acting bronchodilator in one dose. In these cases, 
patients will be transitioned to inhaled corticosteroid monotherapy for the duration of the 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 23 of 42 
Template Revision: October 15, 2023 
study. The drug package insert for a typical inhaled corticosteroid is attached to this 
application. 
 
12) Procedures 
An assessment schedule for the procedures in the study is shown in Table 4. 
 
Pulmonary function: Visit 1 will include spirometry with bronchodilator albuterol, lung 
volume by body plethysmography, and single-breath carbon monoxide diffusing capacity 
tests. Each will be made according to ATS/ERS guidelines, at least 10 min after 200 µg of 
albuterol (Millar et al., 2005). Visits 2-7 will include spirometry measurements without 
albuterol. 
 
Resting ECG: Visit 1 will include a resting 12 lead ECG to document that the 
electrocardiogram has no safety concerns prior to any exercise testing as reviewed by the 
principal investigator.  
 
Medical history and questionnaires: During visit 1 a medical history will be collected, 
including respiratory and heart history, smoking history, and medication history. Patients will 
also complete the SGRQ and the COPD Assessment Tool (CAT) to assess COPD symptoms. 
 
 
 
 
 
Table 4. Assessment Schedule for the Study (see attached full page version) 
 
 
Incremental exercise test: All patients will perform one ramp-incremental cycle exercise on 
an electromagnetically-braked cycle ergometer (Excalibur Sport PFM, Lode NL) to the limit 
of tolerance after an overnight washout of short-acting bronchodilator and a two-week 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 24 of 42 
Template Revision: October 15, 2023 
washout of long-acting bronchodilators (visit 2). Patients will breathe through a mouthpiece 
with nose clip in place for measurement of respired gases and volumes for breath-by-breath 
gas exchange and ventilatory measurements (Vmax Spectra, CareFusion USA). Tests will be 
administered with 3 minutes of rest and at least 3 minutes of unloaded cycling (until a steady-
state is achieved), followed by an increase in power output at 5 W/min (for patients with 
FEV1 ≤ 1 L) or 8 – 20 W/min (for patients with FEV1 > 1 L) and continued to the limit of 
tolerance. The limit of tolerance will be determined as the point at which the patient 
experiences intolerable dyspnea or is unable to maintain pedaling rate above 50 rpm despite 
verbal encouragement.  At specified times during the exercise test, inspiratory capacity (IC) 
measurements will be made using a maximum inhalation. These will be made at rest, every 2 
min during exercise, and at end-exercise. 
 
Constant work rate (CWR) exercise tests: From an unloaded pedaling baseline (~3 min), the 
power output will be abruptly increased to approximately 80% WRpeak (this is the peak 
work rate achieved during the incremental exercise test). The specific work rate chosen will 
be chosen to elicit intolerance between 4 and 8 minutes after the first washout period (van der 
Vaart et al., 2014). Patients will breathe through a mouthpiece with nose clip in place for 
measurement of respired gases and volumes for breath-by-breath gas exchange and 
ventilatory measurements (Vmax Spectra, CareFusion USA). A familiarization CWR test 
will be performed at visit 2, at least 1 hour after the incremental test. At specified times 
during the exercise test, inspiratory capacity (IC) measurements will be made using a 
maximum inhalation. These will be made at rest, every 2 min during exercise, and at end-
exercise. 
 
The constant power test will be performed on at least 4 occasions. The initial constant 
power test will be made at least 2 hours after the incremental test and will be used to identify 
the ~6 min endurance time in untreated conditions (visit 2). If the endurance time is not in the 
range 4-8 minutes, then an additional visit (visit 2.5) (with the potential for one more after 
this, if necessary) will be made to identify required power output. After this, constant power 
tests will be performed to intolerance with either BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) or placebo (visits 4, 5, 6 and 7). The condition (active drug vs 
placebo) of visits 4-7 will remain blinded to the participants and the experimenters until the 
end of the study.  
 
13) Measurements 
 
Ramp Pattern CardioPulmonary Exercise Testing (CPET):  Ventilation, gas exchange, heart 
rate, and perceived exertion during exercise will be recorded during incremental and CWR 
exercise.  Patients will breathe through a mouthpiece for breath-by-breath pulmonary gas 
exchange and ventilation measurement (Vmax Encore, CareFusion USA). Heart rate, arterial 
oxygen saturation, and transcutaneous CO2 partial pressure will be measured. Patients will be 
asked to rate their perceived exertion (“rate your leg fatigue” and “rate your difficulty of 
breathing”) every 2 minutes during exercise and recovery. All methods are well established 
in our laboratory.  

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 25 of 42 
Template Revision: October 15, 2023 
From these measurements the following variables will be determined in the incremental 
test:  Peak oxygen uptake, lactate threshold (LT), ventilatory equivalent for CO2 at LT (as an 
index of ventilatory efficiency), peak ventilation (also expressed relative to maximum 
voluntary ventilation calculated from pulmonary function tests).  
 
Constant work rate testing:  From the results of the Ramp pattern CPET, a constant work rate 
test will be designed to last between 4 and eight minutes at baseline.  This work rate will not 
change throughout the study, and endurance time in seconds will be recorded for each test.   
 
Dynamic hyperinflation (DH): DH will be evaluated from inspiratory capacity (IC) 
measurements at rest, every 2 min during exercise, and at end-exercise. (Somfay et al., 2001). 
This reproducible method allows dynamic changes in the operational lung volume to be 
determined.  
 
 Transcutaneous CO2 Measurements (tcPCO2):  tcPCO2 and oxygen saturation (Radiometer 
Transcutaneous CO2 Monitor (TOSCA 500) will be recorded on a breath-by-breath basis at 
rest and during exercise.  
 
  Breath by Breath Flow Volume Loop Analysis (FVA):  Airflow will be recorded every 100 
msec throughout the exercise tests using a digitized signal. This will be analyzed for breath-
by-breath configuration of the expired flow-volume loop using special software off line.   
 
The entire laboratory will focus on subject safety throughout the study.  This includes 
investigator involvement with all screening, medical history, physical examinations, 
laboratories, EKG, PFTs, and CPET results.  This also includes real time assessment of all 
physiologic variables (heart rate, blood pressure, oxygen uptake, carbon dioxide output, 
ventilation, oxygen saturation, transcutaneous CO2, and EKG tracings at all times during 
exercise testing.   
 
 
 
a) Data and Specimen Banking* 
 
N/A 
 
b) Data Management * 
1) Training on Data Management 
a. All individuals involved with the project, including data analysis and 
management will complete the LA BioMed training requirement regarding 
human research, data security and protection of personal information 
(Collaborative Institutional Training Initiative (CITI)).  
 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 26 of 42 
Template Revision: October 15, 2023 
 
2) Electronic Data 
Referencing the Los Angeles Biomedical Research Institute at Harbor-UCLA 
Medical Center (LA BioMed) Computer Security and Privacy Policy (from Dr. Kevin 
Dawson, Vice President of Information Services at LA BioMed): 
 
 
LA BioMed has implemented a comprehensive security/privacy framework to 
safeguard protected health information, personally identifiable data, and other 
confidential or classified data on storage media, in computers, and in transit. 
LABIOMED and the CDCRC have administrative, physical, and technical safeguards 
enforced and in place.  
 
a) Administrative Safeguards: 
• 
An Information Security Policy has been published and is 
enforced. It controls access to information resources, anti-malware management, 
vulnerability testing, password rules, privileged access, network infrastructure 
management, encryption of laptops and portable devices, compliant hardware, 
software, and services, and the annual review of the policy. An Accessible Use 
Policy of Computer Equipment is included in the Employee Handbook. 
• 
All LA BioMed employees are hired after passing a background 
investigation. Employees working with electronic data need to take HIPAA 
training and pass a test. An Employee Onboarding, Transfer, and Offboarding 
Policy controls granting and revoking access to information resources when 
employment status is changing.  
 
b) Physical Safeguards: 
• 
Our data center is protected by a key card entry system. The 
building itself is also protected by a key card entry system. Key cards are 
assigned to authorized personnel only and an entry log is maintained for future 
audits. Switch cabinets are protected by combination locks and/or metal keys. 
Key wiring closets and IS storage areas are protected by individual numeric 
keypad locks.  Entry codes are assigned on an individual basis. Entry logs can 
be downloaded from the locks onto a computer for future audits. 
 
c) Technical Safeguards: 
• 
Access to all computers containing business data are password 
protected. A strong password policy and 90 days renewal policy is enforced. 
Access to our wireless network is encrypted and password protected. Remote 
access to computer resources is granted through Secure Socket Layer-encrypted 
Virtual Private Network (SSL VPN). Access to individual enterprise applications 
are also password-protected. Access to individual computers, SSL VPN, emails, 
wireless network, and most enterprise applications is managed through Active 
Directory (AD) single sign-on. This gives us the ability to revoke all access if 
necessary by a single action. 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 27 of 42 
Template Revision: October 15, 2023 
 
 
All computers attached to our network must comply with minimal acceptable security 
safeguards. This includes a malware detection software be installed, running, and regularly 
updated and an updated and patched operating system. The policy is enforced by a network 
scanning application. Our network is protected by hardware firewall and intrusion prevention 
and detection systems (IPS/IDS). Hardware decommissioning includes the step of physically 
destroying or wiping all storage media with a Department of Defense (DoD)-compliant wipe 
application. 
 
3)  Physical and Identifiable / Confidential Data 
 
Physical Data will be stored in secure, locked filing cabinets in the LABIOMED 
CDCRC Building.  In order to minimize the risk of inappropriate use of medical 
information, no data will be labeled in a way that they can be readily identified to an 
individual. Participants’ data will de-identified using a number code system and the key 
will be kept in a locked cabinet in the PI’s office or records room. Access to identifiable 
data will be limited to members of the study team (PI and Study Coordinators).  No 
protected health information (PHI) will be transmitted via email or on portable devices. 
 
4)  Data Analysis Plan for the Study 
 
Power calculation 
 
In making the sample size calculation, we have selected a two-sided test.   
 
We will also assert that the study should powered to at least 80%. 
      
 
The two remaining variables necessary for the sample size calculation are the 
posited test duration effect size associated with the intervention and the posited standard 
deviation of the change in test duration among subjects associated with the intervention.   
We deal with these separately: 
 
• 
Standard deviation of change.  This has been estimated in placebo-controlled 
COPD studies in which the standard deviation of constant work rate (CWR) exercise 
duration has been assessed between tests done at baseline and post-placebo 
administration.  Values in the range of 180 seconds were seen (Casaburi, 2005).    A more 
recent study tended to confirm this.  In a study of 111 COPD patients, the change in 
CWR duration in response to placebo had a standard error of 17 seconds (SD of 179 
seconds) (Casaburi et al., 2014).  However, a key determinant of the magnitude of change 
of CWR duration is the baseline test duration (longer baseline duration predicts larger 
change in CWR duration for a given intervention).  Previous studies generally did not 
carefully control baseline CWR duration between 4 and 8 minutes (as we propose here, 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 28 of 42 
Template Revision: October 15, 2023 
and as proposed in a recent ERS guideline (Puente-Maestu et al., 2016)). Baseline 
durations outside this range predictably increase the SD of the change in duration 
following intervention.  Furthermore, these studies were generally multicenter trials, 
which can be argued to add to variability, in itself.  We therefore feel that an estimate of 
180 seconds is conservative.     
 
• 
Effect size.  This can be chosen considering 1) changes in CWR duration 
considered clinically significant (MCID) and 2) improvements in CWR duration seen in 
other combination bronchodilator trials or extrapolation of improvements seen in single 
bronchodilator trials.   
 
o 
As to the MCID, the best figure available is approximately 105 seconds (Puente-
Maestu et al., 2016).  From the most recent ERS statement:   “In COPD, 100-s (95% CI 
60–140 s) or 33% (95% CI 18–48%) change from baseline using cycle ergometry related 
well with positive patient-reported outcomes after pulmonary rehabilitation.” 
 
o 
As to the effect size to be expected from dual bronchodilator therapy, 4 studies 
are included in the recent ERS statement referred to above.  Increases in CWR duration 
average 60, 95, 410 and 310 seconds.  The same analysis shows that single 
bronchodilators are associated with increases (though variable) averaging about 90 
seconds.  A recent report of umeclidinium + vilanterol showed a ~50 second 
improvement vs. placebo ((Maltais et al., 2014)) and a poster at ATS in 2015 showed a 
68 second increase with tiotropium + olodaterol vs placebo (O’Donnell et al.) 
 
We have chosen 60 seconds for an effect size; this corresponds to the lowest 
range of observed effect sizes and is well below the MCID.  This choice can be seen to be 
highly conservative.  
 
Table 5. Sample size for a range of effect size and standard deviation of change in CWR 
duration for combination bronchodilator therapy  
 
 
Effect size 
 
 
60 s 
80 s 
90 s 
SD of 
change 
in 
duration 
100 s 
24 
15 
12 
120 s 
34 
20 
16 
150 s 
52 
30 
24 
180 s 
73 
42 
34 
 
      As can be seen, the suggested sample size of 40 will be inadequate only if both the 
most conservative estimates of effect size and standard deviation are chosen (in red).  We 
therefore propose 50 subjects as a good balance between these issues.   
       
Analysis Plan 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 29 of 42 
Template Revision: October 15, 2023 
     It is hypothesized that BEVESPI AEROSPHERE ®  (Glycopyrrolate/Formeterol) will 
improve exercise endurance time relative to placebo. We also believe this medication 
combination relative to placebo will reduce dynamic hyperinflation as measured by 
inspiratory capacity, VD/VT measurements from the non-invasive transcutaneous 
CO2 measurements, and show less evidence of coving in the expiratory limb of the flow-
volume loops during exercise. 
Differences in endurance time (seconds) between BEVESPI AEROSPHERE 
®(Glycopyrrolate/Formeterol) and placebo on the constant work rate high intensity test 
will be assessed using a mixed model with covariate adjustment for baseline endurance 
time and period and by treating subject as a random effect to account for within subject 
correlation.  Statistical significance will be declared if two-sided p is less than or equal to 
0.05. 
We will analyze the difference in isotimes between BEVESPI 
AEROSPHERE® (Glycopyrrolate/Formeterol) and placebo for inspiratory capacity, 
VD/VT and RAR. These will also be assessed in a similar manner to exercise endurance 
time. 
  
 
 
 
 
c) Confidentiality 
 
Source Documents:  These will include all data with patient demographics, history, 
questionnaires, pulmonary function, and exercise testing results. The documents will be filed 
in the subject’s source document binder. This binder will also contain the properly executed 
consent form, the HIPAA (PHI) form as well as demographic data.  
 
The patient identifiers will be kept in this folder, but under a separate section from the 
study source data. This section will be marked as ‘confidential’ and the binders will be kept 
in a locked cabinet in a locked room. Access to the patient identifiers will be permitted only 
for the study coordinator, the investigators and person(s) with direct contact with the patient. 
 
Source Documents / CF / Identifying Information / Electronic Data 
• Physical Data (paper based) will be stored locally in locked cabinets in the 
LABIOMED CDCRC building for 3 years after the study is completed.   
• Only the PIs and Study Coordinators will have access to PHI.  All others 
involved with data analysis and presentation, including AZ will have de-
identified data. 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 30 of 42 
Template Revision: October 15, 2023 
• A unique ID will be created along with a log that connects the ID to the 
subject’s PHI.  The document that connects the unique ID to the subject’s 
PHI  will be kept in a locked cabinet along with the consent forms.  
• The subjects name and other identifiers will be stored separately from both 
paper and electronic data.  The identifier log will be destroyed 3 years 
after the study is completed. 
• Electronic data will be stored on password protected personal computers 
in the LABIOMED CDCRC building, per LABIOMED Computer 
Security and Privacy Policy.   
• No identifiable data will be transferred via either email or portable disk. 
 
• Only de-identified data will be available for the sponsoring company to 
review, unless a compelling reason is presented to the local IRB for 
approval. 
 
 
d) Provisions to Monitor the Data to Ensure the Safety of Subjects* 
 
 
The PI will be responsible for reporting any adverse events to the local IRB 
utilizing the adverse event reporting policy established by the local IRB. All serious 
adverse events and non-serious adverse events which are relevant for a reported serious 
adverse event and Adverse Events of Special Interest (AESI) shall be reported to 
AstraZeneca, Inc.  Data monitoring will be made on a per-procedure basis by the PI or 
co-investigators.  
 
Per its policy, periodic audit for study conduct in compliance with regulations, 
Good Clinical Practice, etc will be undertaken for this study by a member of the 
Compliance Office at Los Angeles Biomedical Research Institute at Harbor-UCLA 
Medical Center. 
 
The assigned Astra Zeneca Medical Study Leader will maintain direct 
communications with the site, and will set up quarterly visits with the PI to provide AZ 
support by managing any study or contractual questions or concerns the site have. 
However, the medical study leader will not review nor perform source documentation 
validation of any kind. 
 
e) Withdrawal of Subjects* 
 
Participants will be free to withdraw from the study at any time. Participants may 
choose to stop study treatment or leave the study at any time without it affecting their 
future care. Subjects are asked to discuss the decision to leave the study with the study 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 31 of 42 
Template Revision: October 15, 2023 
doctor. Subjects will be asked to return to the clinic for a follow-up visit and to return any 
unused study medication, but do not have to do this.  
 
Participants are told that the study doctor may decide to withdraw them from this study at 
any time even without their consent. Participants will be withdrawn for any of the 
following reasons:   
• Consent is withdrawn 
• The subject is unwilling or unable to follow the rules of the protocol 
• The subject becomes pregnant 
• The subject experiences a medical emergency that makes it necessary to stop 
taking study treatment or that requires treatment assignment to be revealed to the 
study doctor and/or staff 
• At the decision of the PI of one of the participating physicians 
f)  
Publication Policy 
The investigators are dedicated to support process of free exchange of relevant 
scientific information.  The rights of the investigators and of the sponsor with 
regard to publication of the results of this trial are described in the investigator 
contract. As a general rule, no trial results should be published prior to 
finalization of the Clinical Trial Report. 
 
14) 
Risks to Subjects*  
 
Identification of risk and protections to minimize risk 
 
Exercise 
Our primary concern is the safety of the participant during exercise testing. Participants 
will perform high-intensity exercise that may lead to physical discomforts (e.g. fatigue, 
delayed onset muscle soreness), but especially dyspnea in this patient population. The risks 
associated with participating in this study may include, although unlikely: muscle cramps, 
muscle strain and/or joint injury, delayed muscle soreness, dyspnea, syncope, and fatigue.  
They may feel delayed muscle soreness (24-48 hours) after exercise. There is a risk of a 
cardiac event, such as cardiac ischemia, cardiac arrest, dangerous arrhythmia, or acute 
cardiac collapse. This risk is approximately 1-2 occurrences in 10,000 tests of ‘high risk’ 
subjects with cardiovascular disease (American College of Sports Medicine). Similarly, an 
assessment of risk during high-intensity interval exercise testing and training of patients with 
coronary heart disease revealed approximately 1 event in over 23,000 hours of exercise, such 
as arrhythmia or myocardial infarction (Rognmo et al., 2012). 
 
A person trained in basic cardiac life support (ACLS) CPR will be present during testing 
and a defibrillator is located within the laboratory in case of a cardiac event. A licensed 
physician will be available within the CDCRC for all exercise testing study visits and will be 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 32 of 42 
Template Revision: October 15, 2023 
in the room during each subject’s initial incremental exercise test. Participants will be 
coached and queried during testing to identify for the investigators any unexpected symptoms 
and the exercise stopped immediately to mitigate risk during exercise testing. All tests are 
done with a 12-lead ECG and the test is stopped should arrhythmic or ischemic patterns 
develop. All tests are done with pulse oximetry and the exercise will be stopped should 
oxygen saturation fall below 85%. 
Medications 
 
All medications have the potential to cause side effects.  The drugs involved in this study 
may involve risks that are already known, as well as risks that are currently unknown. 
Serious allergic reactions that can be life threatening may occur with any medication. 
However, we will take precautions to reduce these risks. Patients will be instructed to 
immediately report any allergic reactions to the PI, such as: 
• rash  
•  difficulty breathing 
• wheezing 
• sudden dizziness, especially when standing 
• swelling around the mouth, throat, or eyes 
• fast pulse 
• sweating 
 
Short Acting Bronchodilator Medications 
 
The study utilizes a crossover design. Prior to beginning each new treatment period, a 2 
week washout from the study drug, usual medications, or placebo is required. This means 
that the COPD patients in the study will be asked not to take long-acting beta agonists 
(LABA) or long acting anticholinergic (LAMA) for two, 2 week periods during the study. In 
addition, during both of the two, 2 week treatment periods, the patient will be using a short 
acting bronchodilator medication (albuterol) as their rescue medication. 
During the washout and placebo time windows, subjects will be provided with a short-
acting brochodilator replacement medication (albuterol, or in some cases, Combivent) and be 
given instructions how to use it. In addition, any patients on combination therapies that 
include a long-acting bronchodilator will be required to discontinue its use prior to the study. 
This may include combination inhaled corticosteroid medications. The patient can continue 
on inhaled corticosteroids, as long as it is an isolated preparation (not associated with a 
LAMA or LABA). 
The transition from longer acting medications to shorter acting medications of the same 
class during the two wash out periods (2 weeks each) can result in side effects, including 
increased dyspnea, particularly on exertion, and a need for increased rescue inhaler use.  In 
addition, there is a risk that the subject will have an exacerbation (or COPD exacerbation) 
that may require additional medications, such as inhaled or oral corticosteroids, antibiotics, a 
doctor’s office visit, an emergency room visit, or even hospitalization.   
These risks are felt to be low and mitigated by the following interventions: 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 33 of 42 
Template Revision: October 15, 2023 
1) subjects will continue with their short acting medications. 
2) The subject can continue inhaled corticosteroids if they were present prior to 
enrollment, 
3) the selected enrollment criteria excludes the most severe COPD patients (must be > = 
35% of their predicted FEV1),  
4) the investigators will be following the patients very closely during the washout period 
with instructions to call if any difficulty breathing or reduced exercise tolerance. 
 
Although the risk is low, it is certainly possible that some subjects will not tolerate 
changing the long acting medications to shorter acting ones of the same categories, and 
may have to be dis-enrolled and restarted on their usual medications. It is also possible 
that participation in the study could cause a doctor’s office visit, emergency room visit, or 
potentially a hospitalization. 
 
Albuterol 
Four puffs of albuterol will be given at visit 1 during the lung function tests, and will be 
provided as a short-acting bronchodilator medication. Albuterol is an FDA approved 
bronchodilator with mild side effects. Reported risks include:        
• Very common (greater than 10%): Pharyngitis (sore throat). 
• Common (3% - 7%): Headache, rapid heart rate, muscle and joint pain, dizziness, stuffy 
and runny nose, and unpleasant awareness of palpitations (strong heart beat).   
• Uncommon (less than 3%): Chest pain, infection, diarrhea, inflammation of the tongue, 
accidental injury, anxiety, shortness of breath, ear disorder, ear pain and urinary tract 
infection. 
 
Combivent 
Combivent is an FDA approved short-acting bronchodilator containing albuterol and 
ipratropium bromide.  
• Common side effects (greater than 2%) associated with Combivent include: Cough, 
shortness of breath, headache, bronchitis, sore throat, respiratory infection 
• Uncommon side effects (less than 2%) include: High blood pressure, dizziness, tremor, 
muscle spasms or muscle pain, diarrhea, nausea, dry mouth, constipation, vomiting, 
weakness, flu-like illness, chest discomfort, eye pain, low blood potassium, palpitations 
(strong heat beat), fast heartbeat, skin itching or rash, pain in nose or throat, wheezing 
 
Patients taking an inhaled corticosteroid (combined therapy) will transition to an FDA 
approved monotherapy corticosteroid at the beginning of the study. Risks of corticosteroids 
include:  
• Common side effects (greater than 3%) associated with inhaled corticosteroids include: 
upper respiratory infections, throat irritation, upper respiratory inflammation, sinus infection, 
hoarseness, mouth or throat infection, cough, bronchitis, headache 
• Uncommon side effects (less than 3%) include: runny nose or post-nasal drip, nasal sinus 
disorders, laryngitis, diarrhea, viral gastrointestinal infections, dyspeptic symptoms, 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 34 of 42 
Template Revision: October 15, 2023 
gastrointestinal discomfort and pain, dry mouth, joint pain, muscle pain, muscle 
stiffness/tightness/rigidity, dizziness, migraines, fever, viral infections, pain, chest symptoms, 
viral skin infections, muscle injuries, soft tissue injuries, urinary infections 
 
 
Study Medications 
 
Placebo BEVESPI AEROSPHERE® 
There are no known risks associated with using the placebo BEVESPI AEROSPHERE®  
 
BEVESPI AEROSPHERE® 
Combination treatment with glycopyrrolate and formeterol (BEVESPI AEROSPHERE® ) has 
been studied in 12 completed clinical trials.   It is delivered by a metered dose inhaler in a 
fixed combination of 2 puffs equaling 18 mcg of glycopyrrolate and 9.6 mcg of formoterol.   
 
 
The two studies for Bevespi Aerosphere® included 4,911 subjects with COPD in two 24 
week lung function trials, one long term safety extension study of 28 weeks, and 10 other 
trials of shorter duration.  A total of 1,302 subjects have received at least one dose of Bevespi 
Aerosphere ®.  The safety data described below is based upon the two 24 week trials and the 
one 28 week long term safety extension trial.  Adverse reactions observed in the other trials 
were similar to those observed in these confirmatory trials.   
 
Common side effects (> 2 % and more common than placebo) in COPD patients relative 
to placebo include: 
 
 
 
The drug package insert is attached to this application. 
 
Specifically:   
The following side effects occurred in more than 3% of subjects: 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 35 of 42 
Template Revision: October 15, 2023 
• cough (4.0% vs 2.7%) 
• urinary tract infection (2.6% vs 2.3% placebo)  
 
Other side effects that occurred in > 1%, but less than 2% of patients are: 
• arthralgia 
• chest pain 
• tooth abscess 
• muscle spasms  
• headache 
• oropharyngeal pain 
• vomiting 
• pain in extremity 
• dizziness 
• anxiety 
• dry mouth 
• fall 
• influenza 
• fatigue 
• acute sinusitis 
• contusion 
 
Pulmonary Function Testing  
Pulmonary function tests represent minimal risk and are done routinely. In the past fifteen 
years there has been no adverse event precipitated by pulmonary function tests in our 
laboratory. Some people find the breathing tests tiring and occasionally patients experience a 
sense of dizziness, headache or shortness of breath that usually resolves quickly (common, 
mild seriousness). A few may experience a feeling of claustrophobia while in the body 
plethysmograph. This usually passes as soon as the door is opened (uncommon, mild 
seriousness). The carbon monoxide content of the gas mixture used to measure lung diffusion 
capacity is low (0.3%) and the duplicate tests are done five minutes apart; therefore this test 
does not significantly increase blood carboxy-hemoglobin concentration. 
 
Questionairres 
The risks associated with reading and filling out questionnaires are, rarely, some 
psychological discomfort and anxiety. 
 
Chest CAT Scans 
The risks associated with the Chest CAT scans are related to ionizing radiation.  For this 
study, the subjects will be exposed to radiation during the two chest CT scans (inspiratory 
and expiratory).  The maximum amount of radiation exposure during these 2 chest CT scans 
is about 900 millirads (mrads).  A millirad is a measurement of radiation.  The average 
amount of background radiation (present in our daily environment) that most people are 
exposed to in the United States is about 300 mrads per year.  That means that the radiation 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 36 of 42 
Template Revision: October 15, 2023 
received during this chest CT scan is equal to the amount received through our normal 
environment on a daily basis spread over a 3 year period. For the sake of comparison, other 
estimated doses of medical radiation are:  chest x-ray (25 mrads), set of dental x-rays (750 
mrads) and barium enema x-ray (2000 mrads).  The more radiation received over the course 
of a person’s life, the greater the risk of developing cancerous tumors or of causing changes 
in the genes.   Women who are pregnant will not be given a chest CT scan because of 
possible risks to an unborn child.  
 
Personal Information Risk 
Only personal information essential to the research will be recorded, including age, 
anthropometric data such as height and weight, and physiologic data gathered during the 
experiments. These variables are important to describe the patients enrolled for future 
publications. Personal health information is protected by conducting all data collection, 
storage, or transfer according to HIPAA Privacy regulations.  None of the data are considered 
to be sensitive or place the subject at legal risk. Personally identifiable data will not be 
disclosed to anyone other than the research team without the written consent of the subjects 
or their legal representative.  PHI linking the data to the subject will be destroyed 3 years 
after study completion. 
 
15) 
Potential Benefits to Subjects* 
 
There are no direct benefits to the subjects from their participation in the study. 
 
16) 
Provisions to Protect the Privacy Interests of Subjects 
 
The collection of data will be within the confines of the LABIOMED CDCRC building.  
The CDCRC Building has private offices and examination rooms that ensure subject privacy 
away from other ongoing activities and personnel. Only investigators and the necessary 
support staff will interact with the subjects during historical and experimental data collection. 
 
The investigators and the support personnel involved are highly experienced with 
appropriate interaction with research subjects. This expertise and the physical means of 
providing privacy (see above) are the main methods in place in order to maximize the 
subjects’ sense of ease during the study-related activities.  
 
The patients’ historical and experimental data will be secured. Only the investigators and 
the necessary support personnel with a need to know will have access to the files. 
 
Subjects are informed in the consent form: 
 
“We will do our best to make sure that the personal information in your medical record is kept 
private.  However, we cannot guarantee total privacy. We may have to give out your personal 
information if required by law.  If information from this study is published or presented at 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 37 of 42 
Template Revision: October 15, 2023 
scientific meetings, we will not use your name or other personal information that can identify 
you. 
 
Organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis include: 
• The maker of the study medication, AstraZeneca Inc., and its representatives 
• The Office of Human Research Protection and other government agencies, like 
the Food and Drug Administration (FDA), involved in keeping research safe for 
people 
• The Institutional Review Board at the Los Angeles Biomedical Research Institute 
or its staff 
The ways your study doctor will use your study-related health information and the people 
who may receive it are identified in a separate form entitled Authorization For Release of 
Protected Health Information (PHI).”  
 
17) 
Compensation for Research-Related Injury 
 
Participants are informed: 
 
“If you are injured because of your taking part in this research study medical care will be 
available. This care will not necessarily be free of charge. If you are injured as a direct 
result of taking the drugs used in this study or as a result of a procedure that would not 
have been performed on you if you were not in the study, you will be provided with 
appropriate medical care including treatment and hospitalization if necessary. The care 
will not necessarily be free of charge. Financial compensation for any injury from this 
research is not available. The study sponsor Los Angeles Biomedical Research Institute 
will not pay for the normal progress of your disease, or any injury or complication due to 
the medical condition you already have. Financial compensation for such things as lost 
wages, disability or discomfort due to an injury is not available.” 
 
18) 
Economic Burden to Subjects 
 
Participants are informed: 
“You do not have to pay for study drugs, study visits, supplemental medications or tests 
that are part of the study. 
 
The study drug/placebo, supplemental (rescue) medications and all tests and procedures 
required for this study at no cost and will be paid for by the study grant. 
  
 
19) Consent Process 
 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 38 of 42 
Template Revision: October 15, 2023 
Informed consent will be obtained at the CDCRC Building in a private office before any 
study-related procedures are performed. Subjects will be told that they have as much 
time as they need to consider the consent information, and will be given the opportunity 
to discuss the study with friends, family and their health care provider. At each visit, 
subjects will be reminded that participation in the study is voluntary and their questions, 
if any, will be answered. We will follow the SOP: Informed Consent Process for 
Research (HRP-090). 
 
Non-English Speaking Subjects 
Since our area has a significant Spanish-speaking population, this ethno-linguistic 
population will also be considered for recruitment. An IRB-approved Spanish Language 
Consent form will be officially produced if needed. Several of the study associates are 
natively fluent in Spanish and will assist with communication during the actual 
experiments.  
 
Waiver or Alteration of the Consent Process (consent will not be obtained, required 
information will not be disclosed, or the research involves deception) 
Not Applicable. 
 
Subjects who are not yet adults (infants, children, teenagers) 
Subjects who are not yet adults are excluded from this research. 
 
Cognitively Impaired Adults  
Subjects who are cognitively impaired are excluded from this research. 
 
Adults Unable to Consent 
Adults who are unable to consent are excluded from this research. 
 
 
20) 
Process to Document Consent in Writing 
 
We will follow the standard operating procedure (Written Documentation of Consent; 
HRP-091) for written documentation of consent. 
 
21) 
Vulnerable Populations 
Vulnerable populations such as, pregnant women, adults unable to give consent, 
individuals who are not yet adults and prisoners are excluded from this research. 
 
22) 
Drugs or Devices 
 
The study drug, BEVESPI AEROSPHERE ® (Glycopyrrolate/Formeterol) and 
matching placebo, will be prepared by the manufacturer who is experienced in placebo 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
Page 39 of 42 
Template Revision: October 15, 2023 
controlled trials. Medication will be packaged with a coded label and shipped to each 
study site. The LA BioMed Research Pharmacy will prepare blinded study medication, 
utilizing randomization codes supplied by an independent statistician who is otherwise 
not involved in the study.  Blinded drug supply for each patient will be kept in 
temperature and humidity controlled cabinets in the Research Pharmacy. 
 
The study drug and matching placebo will be provided by AstraZeneca Inc. 
Supplemental medication (albuterol, Combivent, and ICS) will be obtained 
commercially by the research team. These drugs will be stored in a locked cabinet in the 
Drug Supply Room in the CDCRC and supplied to study participants as needed in 
unblinded containers. 
 
 
23) 
Multi-Site Human Research* 
Not applicable. 
 
24) 
Community-Based Participatory Research 
Not applicable. 
 
25) 
Sharing of Results with Subjects 
 
The results of this study will not be shared directly with the participants. As part 
of the consent process it will be explained to the participants that they can contact the 
Principal Investigator should they wish to find out about the results of the study, or for 
any other information about the study.  
 
The results of the pulmonary function tests, CT scans, and cardiopulmonary 
exercise tests may be shared with the patient on request. Patients are likely to have 
performed these tests previously, and the results of this test may provide information on 
the progression of their disease. Patients will be provided with a copy of their 
incremental exercise test results on request. Information on pulmonary function or 
clinical exercise testing will be provided by the PI or participating physician. Other 
results will be explained on request by the PI or his staff, but these are experimental 
procedures and have no specific diagnostic or clinical benefit to the individual patient. 
 
 
 
References: 
 
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Care Med, v. 167, p. 211-77. 

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
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COPD:  A New Method.: Respiratory Medicine v. 104, p. 389-396 
  

PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
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PROTOCOL TITLE: An Investigator Initiated, Randomized, Double Blind, Placebo Controlled, 
Two Period Crossover Study to Assess the Effect of BEVESPI AEROSPHERE ® Therapy 
(Glycopyrrolate/Formeterol) on Exercise Tolerance and Dynamic Hyperinflation in Patients 
with Chronic Obstructive Pulmonary Disease.                                  Revised: 12/28/2016 
 
 
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