Clinical trial NCT03324607
Conditions: COPD
Sponsor: Bastiaan Driehuys
Start date: 2018-04-20; Completion date: 2019-11-12
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine whether the new inhaler, Bevespi improves lung function. Magnetic resonance imaging (MRI) using inhaled hyperpolarized 129Xe gas, that can provide useful images of the functioning of the lung will be used as a new measure to determine change in function. The investigator anticipate these images will provide more specific information about lung disease than standard lung function tests in response to treatment.

Detailed description:
The study will characterize ventilation and gas transfer distributions in GOLD II and III COPD patients and assess the potential for these physiological parameters as a novel phenotyping method using Magnetic resonance imaging (MRI) using inhaled hyperpolarized 129Xe gas.

The study will additionally quantify regional ventilation and gas transfer response to glycopyrrolate/formoterol in GOLD II and III COPD patients.

Arms: arm 1: glycopyrrolate/formoterol (Bevespi) 2 puffs twice a day taken for two weeks, started after completion of the study XeMRI. A follow up xeMRI occurs at the end of the two weeks of taking the Bevespi in a Pre-post study design.
Interventions: intervention 1: hyperpolarized 129Xe gas MRI intervention 2: Bevespi Aerosphere
Intervention descriptions: intervention 1: There will be MRI imaging before the treatment with Bevespi and another one 2 weeks after use Bevespi. Images obtained using 129Xe MRI will be compared with standard lung function tests that are used routinely in the clinic, 6 minute walk test that assesses walking ability and several questionnaires that assess shortness of breath and life quality. intervention 2: There will be MRI imaging before the treatment with Bevespi and another one 2 weeks after use Bevespi.

Protocol documents:
Prot_SAP_000.pdf: 
1(32) 
Drug Substance 
Glycopyrronium and Formoterol 
Fumarate 
Study Number 
ESR-17-12722/D5970L000002 
Version Number 
1 
Date 
April 20, 2017 
Effects of glycopyrrolate/formoterol (Bevespi) on ventilation and gas 
exchange abnormalities in COPD assessed by 129Xe MRI 
Sponsor: AstraZeneca/MedImmune 
 
 
NCT03324607


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
2(32) 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ....................................................................................................... 1 
TABLE OF CONTENTS ..................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................... 6 
1. 
INTRODUCTION ............................................................................................... 7 
1.1 
Background .......................................................................................................... 7 
1.2 
Research hypothesis ............................................................................................. 7 
1.3 
Rationale for conducting this study ...................................................................... 8 
1.4 
Benefit/risk and ethical assessment ...................................................................... 9 
2. 
STUDY OBJECTIVES ...................................................................................... 10 
2.1 
Primary objective ............................................................................................... 10 
2.2 
Secondary objectives .......................................................................................... 11 
2.3 
Safety objective.................................................................................................. 11 
2.4 
Exploratory objectives ....................................................................................... 11 
3. 
STUDY PLAN AND PROCEDURES ............................................................... 11 
3.1 
Overall study design and flow chart ................................................................... 11 
3.2 
Rationale for study design, doses and control groups .......................................... 11 
4. 
SUBJECT SELECTION CRITERIA.................................................................. 11 
4.1 
Inclusion criteria ................................................................................................ 12 
4.2 
Exclusion criteria ............................................................................................... 12 
5. 
STUDY CONDUCT .......................................................................................... 13 
5.1 
Restrictions during the study .............................................................................. 13 
5.2 
Subject enrollment <<and randomization>> <<and initiation of 
investigational product>> ................................................................................... 13 
5.2.1 
Procedures for randomization ............................................................................. 13 
5.3 
Procedures for handling subjects incorrectly enrolled<< or randomized>> 
<<or initiated on investigational product>> ....................................................... 13 
5.4 
Blinding and procedures for unblinding the study............................................... 13 
5.4.1 
Methods for ensuring blinding ........................................................................... 13 
5.4.2 
Methods for unblinding the study ....................................................................... 13 
5.5 
Treatments ......................................................................................................... 13 
5.5.1 
Identity of investigational product(s) .................................................................. 13 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
3(32) 
5.5.2 
Doses and treatment regimens ............................................................................ 13 
5.5.3 
Additional study drug ......................................................................................... 13 
5.5.4 
Labeling ............................................................................................................. 13 
5.5.5 
Storage ............................................................................................................... 15 
5.6 
Concomitant and post-study treatment(s) ........................................................... 16 
5.7 
Treatment compliance ........................................................................................ 16 
5.7.1 
Accountability.................................................................................................... 16 
5.8 
Discontinuation of investigational product ......................................................... 16 
5.8.1 
Procedures for discontinuation of a subject from investigational product ............ 16 
5.9 
Withdrawal from study....................................................................................... 16 
6. 
COLLECTION OF STUDY VARIABLES ........................................................ 17 
6.1 
Recording of data ............................................................................................... 17 
6.2 
Data collection at enrolment and follow-up ........................................................ 17 
6.2.1 
Enrollment procedures ....................................................................................... 18 
6.2.2 
Follow-up procedures......................................................................................... 18 
6.3 
Efficacy ............................................................................................................. 18 
6.3.1 
<<Efficacy variable>> ....................................................................................... 18 
6.4 
Safety................................................................................................................. 20 
6.4.1 
Definition of adverse events ............................................................................... 20 
6.4.2 
Definitions of serious adverse event ................................................................... 20 
6.4.3 
Recording of adverse events ............................................................................... 20 
6.4.4 
Reporting of serious adverse events ................................................................... 23 
6.4.5 
Laboratory safety assessment ............................................................................. 24 
6.4.6 
Physical examination ......................................................................................... 24 
6.4.7 
ECG ................................................................................................................... 24 
6.4.7.1 
Resting 12-lead ECG ......................................................................................... 24 
6.4.7.2 
Real time display (telemetry) ............................................................................. 25 
6.4.8 
Vital signs .......................................................................................................... 25 
6.4.8.1 
Pulse and blood pressure .................................................................................... 25 
6.4.8.2 
Body temperature ............................................................................................... 25 
6.4.9 
Other safety assessments .................................................................................... 25 
6.5 
Patient reported outcomes (PRO) ....................................................................... 25 
6.5.1.1 
<<Name of PRO method or questionnaire>> ........ Error! Bookmark not defined. 
6.6 
Pharmacokinetics ............................................................................................... 25 
6.6.1 
Collection of samples ......................................................................................... 25 
6.6.2 
Determination of drug concentration .................................................................. 25 
6.7 
Pharmacodynamics ............................................................................................ 25 
6.7.1 
Collection of pharmacodynamic markers ........................................................... 25 
6.8 
Pharmacogenetics .............................................................................................. 25 
6.8.1 
Collection of pharmacogenetic samples .............................................................. 25 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
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6.9 
Health economics ............................................................................................... 25 
7. 
BIOLOGICAL SAMPLING PROCEDURES .................................................... 26 
7.1 
Volume of blood ................................................................................................ 26 
7.2 
Handling, storage and destruction of biological samples ..................................... 26 
7.2.1 
Pharmacokinetic and/or pharmacodynamic samples ........................................... 26 
7.2.2 
Pharmacogenetic samples................................................................................... 26 
7.3 
Labeling and shipment of biohazard samples...................................................... 26 
7.4 
Chain of custody of biological samples .............................................................. 26 
7.5 
Withdrawal of informed consent for donated biological samples ........................ 26 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 26 
8.1 
Ethical conduct of the study ............................................................................... 26 
8.2 
Ethics and regulatory review .............................................................................. 26 
8.3 
Informed consent ............................................................................................... 26 
8.4 
Changes to the protocol and informed consent form ........................................... 26 
8.5 
Audits and inspections ....................................................................................... 27 
9. 
STUDY MANAGEMENT ................................................................................. 27 
9.1 
Training of study site personnel ......................................................................... 27 
9.2 
Monitoring of the study ...................................................................................... 27 
9.2.1 
Source data ........................................................................................................ 27 
9.3 
Study timetable and end of study ........................................................................ 27 
10. 
DATA MANAGEMENT ................................................................................... 27 
11. 
EVALUATION AND CALCULATION OF VARIABLES ............................... 27 
11.1 
Calculation or derivation of efficacy variable(s) ................................................. 27 
11.2 
Calculation or derivation of safety variable(s) .................................................... 28 
11.2.1 
Other significant adverse events (OAE).............................................................. 28 
11.3 
Calculation or derivation of patient reported outcome variables.......................... 28 
11.4 
Calculation or derivation of pharmacokinetic variables ...................................... 28 
11.5 
Calculation or derivation of pharmacodynamic variable(s) ................................. 28 
11.5.1 
Calculation or derivation of the relationship between pharmacokinetic and 
pharmacodynamic variables ............................................................................... 28 
11.5.2 
Population analysis of pharmacokinetic/pharmacodynamic variables ................. 28 
11.6 
Calculation or derivation of pharmacogenetic variables ...................................... 28 
11.7 
Calculation or derivation of health economic variables ....................................... 28 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ........... 28 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
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12.1 
Description of analysis sets ................................................................................ 28 
12.1.1 
Efficacy analysis set ........................................................................................... 28 
12.1.2 
Safety analysis set .............................................................................................. 28 
12.2 
Methods of statistical analyses ........................................................................... 29 
12.2.1 
Interim analyses ................................................................................................. 29 
12.3 
Determination of sample size ............................................................................. 29 
12.4 
Data monitoring committee ................................................................................ 29 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR .............................................................................................. 30 
13.1 
Overdose ............................................................................................................ 30 
13.2 
Pregnancy .......................................................................................................... 30 
13.2.1 
Maternal exposure .............................................................................................. 30 
13.2.2 
Paternal exposure ............................................................................................... 30 
14. 
LIST OF REFERENCES ................................................................................... 30 
 
LIST OF TABLES 
None 
LIST OF FIGURES 
None 
LIST OF APPENDICES 
None 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
6(32) 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this Clinical Study Protocol. 
Abbreviation or 
special term 
COPD 
LAMA 
LABA 
SABA 
ADC 
VDP 
TEAE 
GFF 
6MWT 
SGRQ 
DLCO 
Explanation 
 
Chronic obstructive pulmonary disease 
Long-acting muscarinic receptor antagonist 
Long-acting beta-receptor agonist 
Short-acting beta-receptor agonist 
Apparent diffusion coefficient 
Ventilation defect percentage 
Treatment-emergent adverse event 
Glycopyrronium-formoterol fumarate 
6-minute walk test 
St. George’s respiratory questionnaire 
Carbon monoxide diffusing capacity of the lung 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
7(32) 
1. 
INTRODUCTION 
The Centers for Disease Control (CDC) updated projections that chronic obstructive 
pulmonary disease (COPD) is now the 3rd leading cause of death in the US (1, 2). Although 
there have been significant advances in care, the COPD epidemic persists, leading to greater 
than 130,000 deaths/yr in the US alone (2). COPD represents the only disease in the top ten 
causes of death that has consistently increased in frequency over the past 4 decades only 
showing a slight decrease (~4%) in the preliminary data for deaths in 2011 recently released 
(2). The economic burden of COPD in the US in 2005 was estimated at 38.8 billion dollars in 
total costs (direct plus indirect) (3). Population based studies have suggested that as many as 
24 million people in the US have airflow limitation consistent with COPD (4, 5). In addition, 
in the U.S., there are approximately 90 million current or former smokers who are at risk of 
developing COPD.  
1.1 
Background 
Glycopyrronium (the active moiety of glycopyrronium bromide, also referred to as 
glycopyrrolate) is a LAMA which exerts its bronchodilatory effect via muscarinic receptors 
located on smooth muscle cells within the trachea and bronchi. Glycopyrronium is approved 
in many countries in multiple formulations for different indications, including COPD. There is 
also a large body of published data evaluating the safety and efficacy of inhaled 
glycopyrronium in healthy volunteers, patients with COPD and patients with asthma. 
Glycopyrronium is also approved in many countries worldwide as an 
intravenous/intramuscular injection or as an oral tablet and is indicated for systemic 
administration in adults for use as a preoperative antimuscarinic to reduce salivary, 
tracheobronchial, and pharyngeal secretions; to reduce the volume and free acidity of gastric 
secretions; and to block cardiac vagal inhibitory reflexes during induction of anesthesia and 
intubation. Glycopyrronium is also approved in the United States (US) as an oral solution 
which is indicated to reduce chronic severe drooling in patients aged 3-16 with neurologic 
conditions associated with problem drooling (e.g., cerebral palsy). 
Formoterol fumarate is a potent and selective LABA approved in the US and worldwide for 
use in asthma and COPD. Formoterol fumarate is also approved in the US and worldwide in 
combination with budesonide for use in patients with asthma and COPD. When inhaled, 
formoterol fumarate acts locally in the lung as a bronchodilator. Formoterol fumarate 
stimulates β2 adrenoreceptors in the airways, inducing airway smooth muscle relaxation and 
reducing or preventing bronchoconstriction. 
Although formoterol fumarate is classified as a LABA, it has a rapid onset of action similar to 
short-acting β2-agonists (SABAs). Formoterol fumarate is highly potent, displays high 
intrinsic activity, and can result in greater than 80% relaxation even under induced tone. 
Studies in patients with COPD have demonstrated that the onset of action with formoterol 
fumarate is faster than with anticholinergic agents or salmeterol and similar to that of SABAs, 
such as albuterol, and that the duration of action is ≥12 hours. Large, placebo-controlled 
clinical studies of up to 12 months in duration in nearly 2,500 patients demonstrated that 
formoterol fumarate is effective and well tolerated in patients with COPD. 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
8(32) 
1.2 
Research hypothesis 
Glycopyrrolate/formoterol improves regional ventilation and gas transfer assessed by 129Xe 
MRI in GOLD II or III COPD patients. 
1.3  
Rationale for conducting this study 
COPD like most common chronic diseases has a complex etiology involving interactions 
between environmental exposures and genetic risk factors. While airflow obstruction is the 
defining phenotype of COPD, the abnormality is not uniform in all parts of the lung. The 
current literature and clinical experience clearly indicate non-homogeneity for this disease, 
even in patients who are within the same GOLD category. The non-homogeneity (i.e. clinical 
phenotype) includes the substantial variability in an individual’s susceptibility to smoking and 
other insults, in disease progression and tempo (e.g. exacerbation frequency), and clinical 
manifestations, and in response to bronchodilator and anti-inflammatory therapies. These 
clinical phenotypes in large part are related to the insults that cause variable structural 
damages to different lung units resulting in an array of impairment in ventilation and gas 
exchange. Currently there is no single assessment modality that provides a comprehensive 
evaluation of regional lung function. The most recent revision of the GOLD criteria (Global 
Initiative for Chronic Obstructive Lung Disease) has expanded beyond spirometric measures 
to include the patient level of symptoms, risk of exacerbations, and evaluation of 
comorbidities (6), but no regional lung function parameters were included.  A recent CT based 
study in the COPDGene project suggests that imaging parameters (% emphysema and mean 
segmental wall thickness) may be used to model progression/prognosis of exacerbations in 
COPD (7), but the CT imaging is static and cannot reflect dynamic lung function. Other 
currently available imaging techniques such as scintigraphy, single photon computed 
tomography (SPECT) or positron emission tomography (PET), don’t provide enough 
resolution for the lung. Recent work with stable Krypton gas as a contrast agent with dual 
energy CT adds another possible strategy (8). All of these above imaging modalities, however, 
deliver ionizing radiation, and thus serial use in patients is dose limited and they are largely 
unsuitable for use in clinical trials beyond inclusion criteria.   
This gap is well addressed by MR imaging that allows regional ventilation to be directly 
“visualized” and quantified. These techniques employ inhalation of gases, such as oxygen (9-
11), perfluorinated gases (12, 13), and hyperpolarized (HP) 3He (14-16). Ventilation defects 
visualized by hyperpolarized 3He have been shown to correlate with airway tone (16-19) and 
quantitatively and spatially correlated to abnormal airways on CT scan (20).  Hyperpolarized 
3He imaging has shown in patients with COPD.  showed multiple ventilation defects, with 
irregular and delayed patterns of redistribution and air trapping (21). The apparent diffusion 
coefficient (ADC) correlates with the severity of emphysema (22-24). In many patients with 
asthma whose spirometric indices were normal, there was an increased number of ventilation 
defects (15). In asymptomatic active and passive smokers, the 3He MRI technology was able 
to shown a higher ADC compared with never-smokers, indicating the presence of emphysema 
(25). In COPD patients, treatment with inhaled beta-agonist (albutamol), there was significant 
decrease in ADC in the most anterior and most posterior image slices, suggesting a reduction 
in regional gas trapping (26). These changes in regional lung function occurred despite 
minimal improvement in FEV1 (26). In a COPD ex-smoker who underwent pulmonary 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
9(32) 
function tests and hyperpolarized 3He MRI serially over 4 years, ventilation defect percent 
(VDP) and ADC were worse without worsening FEV1 six months prior to acute exacerbation. 
After hospitalization and AE treatment, VDP decreased, whereas FEV1 did not improve (27). 
The above results support the importance of measuring regional lung function in patients with 
obstructive lung diseases.  Unfortunately, the limited supply of the 3He isotope makes the  3He 
MRI technology unsustainable (see report to Congress) (28).   
More recently, 129Xe has emerged as the most prominent alternative to 3He (29-31). 129Xe 
MRI appears to more readily detect ventilation defects than 3He MRI, perhaps due to its 
higher density and lower diffusivity in the distal airways (19, 32). 129Xe MRI has been shown 
by Svenningsen et al to readily visualize the elimination of ventilation defects after 
bronchodilator administration (33). Our group has shown different ventilation histograms in 
COPD patients with similar airway obstruction by spirometry (30). In addition to ventilation, 
129Xe also has a unique property that, during the transfer of 129Xe from the alveolar space to 
RBC, it generates barrier and RBC signals distinct from the gas phase signals. These 
additional signals correspond to diffusion across the lung parenchyma and plasma and 
perfusion respectively.  The capability of 129Xe MRI to evaluate both ventilation and gas 
transfer functions of the lung non-invasively and the high sensitivity to detect abnormalities 
make this technique ideal for assessment of mild changes in the disease lung and small 
improvement after treatment.  
Pharmacologic therapy in COPD is used to reduce symptoms, reduce the frequency and 
severity of exacerbations and improve health status and exercise tolerance (34). 
Bronchodilator medications are central to the symptomatic management of COPD. The 
principal bronchodilator treatments are β2-agonists, anticholinergics, and methylxanthines 
used as monotherapy or in combination. Treatment with long-acting bronchodilators is more 
convenient and more effective at producing symptom relief than treatment with short-acting 
bronchodilators. Combining bronchodilators from different pharmacological classes may 
improve efficacy and decrease the risk of side effects compared to increasing the dose of a 
single bronchodilator (34). LAMAs and LABAs reduce bronchoconstriction through different 
mechanisms, and there is a long history of combination therapy for COPD with short-acting 
agents in these classes. 
In clinical trials, LAMAs and LABAs have been shown to improve FEV1 in patients with 
COPD (35). The increment in FEV1, however, was relatively small and is insufficient to 
explain clinical improvement in exercise tolerance and reduction in acute exacerbations. In 
addition, the individual response to LAMAs/LABAs is variable and it is possible that the 
degree of ventilation heterogeneity at baseline could determine the magnitude of the 
improvement. 129Xe MRI is a unique tool that may be used to address these questions and 
provide a mechanistic link between physiological improvement and the patient-centered 
outcome measures.  
1.3 
Benefit/risk and ethical assessment 
In the three clinical trials conducted by Pearl Therapeutics (PT003006, PT003007, 
PT003008), 1,329 patients with moderate to severe COPD were treated with glycopyrronium-


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
10(32) 
formoterol fumarate (GFF). GFF consistently produced a maximal 150-175 ml increase in 
FEV1 at 2 weeks better than placebo, LAMA or LABA alone across the studies. The 
benefitial effects on FEV1 persisted for up to 52 weeks (PT003008).  
The most commonly reported TEAEs in patients taking GFF that occurred at higher 
incidences (at least 1 percentage point higher) than the Placebo group were urinary tract 
infection (3.3% versus 2.2%, respectively), cough (3.3% versus 2.2%, respectively), and 
oropharyngeal pain (1.6% versus 0%, respectively), although the differences in incidence 
were small (<2%) across treatment groups (Study PT003007). Serious TEAEs were most 
frequently reported in the SOCs of Respiratory, thoracic, and mediastinal disorders, and 
Infections and infestations. The most frequently reported serious TEAEs by preferred term 
were COPD and pneumonia. In general, most other serious TEAEs were reported for fewer 
than 2 subjects (Study 003006). The incidence of drug-related serious TEAEs was low and 
similar between GFF group (0.6%) and Placebo (0.5%). None of the drug-related serious 
TEAEs were reported by >1 subject in any treatment group. (Study 003006). A total of 4 
treatment-emergent deaths in the GFF group were reported in Study PT003006; 1 of the 
subject deaths in the GFF group occurred within 14 days post-treatment. Two subjects (0.4%) 
in the GFF group died of acute myocardial infarction and cardiac arrest respectively. Two 
subjects (0.4%) died due to a cause other than a probable cardiovascular or respiratory cause: 
metastatic neoplasm and gunshot wound. There were no treatment-emergent deaths due to a 
probable respiratory cause. In Study 003006, the only TEAE leading to permanent 
discontinuation of study drug in the GFF group that had a higher incidence (at least 1 
percentage point higher) than the Placebo group was pneumonia (1.0% versus 0%, 
respectively). The incidences of the other TEAEs leading to permanent discontinuation of 
study drug in the GFF group were similar to those in the individual component groups. 
Overall, the benefit-risk ratio is quite favorable for GFF in the management of moderate to 
severe COPD patients. In this study, a 2-week treatment protocol will be used. GFF achieved 
the maximal improvement on FEV1 at 2 weeks, the first time point after the treatment was 
started in all three studies (PT003006, PT003007, PT003008). The shorter protocol decreases 
the probability of adverse events, and further increases the benefit-risk ratio. 
2. 
STUDY OBJECTIVES    
2.1 
Primary objective 
1) Characterize ventilation and gas transfer distributions in GOLD II and III COPD 
patients and assess the potential for these physiological parameters as a novel 
phenotyping method.  
2) Quantify regional ventilation and gas transfer response to 
glycopyrrolate/formoterol in GOLD II and III COPD patients. 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
11(32) 
2.2 
Secondary objectives 
• Correlate changes in ventilation and gas transfer parameters with other endpoints, 
including spirometry, lung volumes, DLCO, 6MWD, dyspnea, and SGRQ.  
2.3 
Safety objective 
N/A 
2.4 
Exploratory objectives 
N/A 
3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall study design and flow chart 
The study uses a pre-post treatment design.  
Visit 1
Visit 2
Visit 3
7-14 days run-in
Screening
Informed consent
Begin a 7-14 day run-
in period
Data collection
•
Demographics
•
Medical History
•
Vital Signs
•
Physical Exam
•
Concomitant Medication 
Assessment
•
Lab 
•
Complete PFT
•
6-min walk test
•
St. Georges’s questionnaire
•
Borg dyspnea scale
MRI (Hyperpolarized 129Xe)
Start glycopyrrolate/formoterol 
aerosphere (Bevespi)
Inhaler teaching
Data collection
•
Medical History
•
Vital Signs
•
Physical Exam
•
Concomitant Medication 
Assessment
•
Assessment of adverse 
events
•
Complete PFT
•
6-min walk test
•
St. Georges’s questionnaire
•
Borg dyspnea scale
MRI (Hyperpolarized 129Xe)
2-week treatment with BEVESPI AEROSPHERE
Phone call
Assessment of adverse 
events
2-week follow-up for AEs 
 
3.2 
Rationale for study design, doses and control groups 
The study uses a pre-post design. The pre-post design is preferred for several reasons. 1) Since 
each patient will have a difference ventilation and gas exchange distribution pattern before the 
treatment, the paired design increases the sensitivity to detect regional changes using each 
patient as his or her own control. This eliminates the need for a separate control with no or 
placebo treatment. 2) The pre-post design decreases the number of patients needed to detect 
changes produced by the treatment.  
Subject Selection Criteria 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
12(32) 
3.3 
Inclusion criteria 
For inclusion in the study subjects should fulfill the following criteria: 
• Outpatients of either gender, age ≥ 40. 
• Clinical diagnosis of COPD confirmed by post-bronchodilator spirometry 
demonstrating FEV1/FVC < 0.70 and FEV1 in GOLD 2 or 3 stage (30%≤ FEV1 < 
80%) (http://www.goldcopd.org/). 
• Willing and able to give informed consent and adhere to visit/protocol schedules. 
(Consent must be given before any study procedures are performed.) 
• Women of childbearing potential must have a negative serum pregnancy test. This will 
be confirmed before participation in this investigational protocol. 
3.4 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
• Upper respiratory tract infection within 6 weeks (in this case, we will rescreen the 
patient after 6 weeks) 
• Chronic systemic corticosteroid use > 10 mg/day of prednisone 
• Chronic oxygen use (intermittent or continuous) 
• Previous lung resection surgery or decortication 
• Previous history of pneumothorax 
• Evidence of interstitial, occupational or chronic infectious lung disease by imaging 
studies 
• History of exposure to occupational or environmental hazards that are known to cause 
lung diseases 
• For women of child bearing potential, positive pregnancy test 
• Major chronic illnesses which in the judgement of the study physician would interfere 
with participation in the study 
• Patients who are not willing to withhold COPD inhalers for the run-in period. 
• For MRI: 
o MRI is contraindicated based on responses to MRI screening questionnaire 
o Subject is pregnant or lactating 
o Respiratory illness of a bacterial or viral etiology within 30 days of MRI 
o Subject has any form of known cardiac arrhythmia 
o Subject does not fit into 129Xe vest coil used for MRI 
o Subject cannot hold his/her breath for 15 seconds 
o Subject deemed unlikely to be able to comply with instructions during imaging 
 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
13(32) 
4. 
STUDY CONDUCT 
4.1 
Restrictions during the study 
• Do not use albuterol HFA or nebulization treatment for at least 6 hours before 
Visit 2 and Visit 3 
4.2 
Subject enrollment <<and randomization>> <<and initiation of 
investigational product>> 
4.2.1 
Procedures for randomization 
N/A 
4.3 
Procedures for handling subjects incorrectly enrolled<< or 
randomized>> <<or initiated on investigational product>> 
N/A 
4.4 
Blinding and procedures for unblinding the study 
4.4.1 
Methods for ensuring blinding 
N/A 
4.4.2 
Methods for unblinding the study 
N/A 
4.5 
Treatments 
4.5.1 
Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
Manufacturer 
glycopyrrolate/formoterol 
(Bevespi) 
7.2 μg glycopyrronium and 
4.8 μg of formoterol fumarate 
ex-actuator/per actuation. 
AstraZeneca 
Bevespi will be provided to the patient with a voucher BEVESPI AEROSPHERE that can be 
filled at a pharmacy. 
4.5.2 
Doses and treatment regimens 
2 puffs BID 
4.5.3 
Additional study drug 
N/A 
4.5.4 
Labeling 
The label will include the following information: 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
14(32) 
INDICATIONS AND USAGE 
BEVESPI AEROSPHERE is a combination of glycopyrrolate, an anticholinergic, and 
formoterol fumarate, a long-acting beta2-adrenergic agonist (LABA) indicated for the long-
term, maintenance treatment of airflow obstruction in patients with chronic obstructive 
ulmonary disease (COPD).   
Limitation of Use: Not indicated for the relief of acute bronchospasm or for the treatment of 
asthma.  
DOSAGE AND ADMINISTRATION 
• For oral inhalation only. 
• Maintenance treatment of COPD: 2 inhalations of BEVESPI AEROSPHERE twice 
daily. 
DOSAGE FORMS AND STRENGTHS 
Inhalation aerosol: Pressurized metered dose inhaler containing a combination of 
glycopyrrolate (9 mcg) and formoterol fumarate (4.8 mcg) as an inhalation aerosol. Two 
inhalations equal one dose.   
CONTRAINDICATIONS 
• All LABAs are contraindicated in patients with asthma without use of a long-term 
asthma controller medication. BEVESPI AEROSPHERE is not indicated for the 
treatment of asthma. 
• Hypersensitivity to glycopyrrolate, formoterol fumarate, or to any component of this 
product. 
WARNINGS AND PRECAUTIONS 
• Do not initiate in acutely deteriorating COPD or to treat acute symptoms.  
• Do not use in combination with an additional medicine containing a LABA because of 
risk of overdose. 
• If paradoxical bronchospasm occurs, discontinue BEVESPI AEROSPHERE and 
institute alternative therapy. 
• Use with caution in patients with cardiovascular disorders.  
• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes 
mellitus, and koacidosis. 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
15(32) 
• Be alert to hypokalemia and hyperglycemia.  
• Worsening of narrow-angle glaucoma may occur. Use with caution in patients with 
narrow-angle glaucoma and instruct patients to contact a physician immediately if 
symptoms occur. 
• Worsening urinary retention may occur. Use with caution in patients with prostatic 
hyperplasia or bladder-neck obstruction and instruct patients to contact a physician 
immediately if symptoms occur.  
ADVERSE REACTIONS 
Most common adverse reactions (incidence ≥2 % and more common than with placebo) 
include: urinary tract infection and cough 
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or 
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 
DRUG INTERACTIONS 
Other adrenergic drugs may potentiate effect: Use with caution  
Xanthine derivatives, steroids, diuretics or non-potassium sparing diuretics may potentiate 
hypokalemia or ECG changes. Use with caution.  
Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated 
with non-potassium sparing diuretics may worsen with concomitant beta 2-agonists.  
Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May 
potentiate effect of formoterol fumarate on cardiovascular system.  
Beta-blockers: Use with caution and only when medically necessary. 
Anticholinergics: May interact additively with concomitantly used anticholinergic 
medications. Avoid administrations of BEVESPI AEROSPHERE with other anticholinergic-
containing drugs.  
4.5.5 
Storage 
Each canister of glycopyrrolate/formoterol aerosphere (Bevespi) is foil overwrapped with 
desicant and is formulated with sufficient suspension to ensure delivery of 120 inhalations 
from the nominal 50 μL valve over the product shelf life. Glycopyrrolate/formoterol 
aerosphere (Bevespi) should be stored below 25°C (77°F). Do not freeze. Excursions 
permitted up to 30°C (86°F). 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
16(32) 
4.6 
Concomitant and post-study treatment(s) 
All medications that the patient is taking prior to the enrollment will continue, except for long-
acting inhalers that the patient takes for COPD, including LABA, LAMA and inhaled steroids. 
These medications will be held for 7-14 days of the run-in period. BEVESPI AEROSPHERE 
will be given at the end of the run-in period and continue for the study period (2 weeks). At 
the end of the study period, the patient can go back to their original COPD medications, or 
continue BEVESPI AEROSPHERE, depending on the patient’s insurance coverage. The 
patient can continuealbuterol HFA and nebulization treatments, but will be asked not use it at 
least 6 hours before Visit 2 and Visit 3. 
4.7 
Treatment compliance 
4.7.1 
Accountability 
Each subject will be provided with a voucher of BEVESPI AEROSPHERE that can 
be filled at a pharmacy. We will monitor treatment compliance by checking the 
dose indicator on the inhaler, which moves after tenth actuation.  
4.8 
Discontinuation of investigational product 
If the patient calls complaining of any new symptoms after the use of BEVESPI 
AEROSPHERE, including but not limited to adverse events described above, he or 
she will enter the following procedures for discontinuation from investigational 
product. 
4.8.1 
Procedures for discontinuation of a subject from investigational product  
1. The patient will be asked to stop taking BEVESPI AEROSPHERE 
2. A visit with PI or co-PI will be scheduled. During the visit, PI will evaluate the 
patient and restart the patient’s COPD medications that were taken by the 
patients before the study. The patient will also return the unused BEVESPI 
AEROSPHERE 
3. If the patient was considered having an acute exacerbation or infection, 
appropriate treatments, including prednisone taper and antibiotics, will be 
prescribed. A follow-up appointment with the patient’s primary pulmonary 
physician will be scheduled. 
4.9 
Withdrawal from study 
The patient can withdraw from the study at any time for any reason.  


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
17(32) 
5. 
COLLECTION OF STUDY VARIABLES 
5.1 
Recording of data 
Data will be recorded in Excel spreadsheets stored in a specific folder (e.g. Bevespi MRI 
COPD) of a common drive of the Duke Network. 
5.2 
Data collection at enrollment and follow-up 
Visit 1 (Screening Visit) 
• Outpatients of either gender, age ≥ 40. 
• Clinical diagnosis of COPD confirmed by post bronchodilator spirometry 
demonstrating FEV1/FVC < 0.70 and FEV1 in GOLD 2 or 3 stage (30%≤ FEV1 < 
80% of predicted normal value) (http://www.goldcopd.org/). The PFT should be 
within 6 months of the screening visit. 
• Current or former cigarette smokers with 10 or more pack-years cigarette smoking 
history 
• Begin a run-in period (7-14 days) for eligible patients 
• Sign informed consent 
• MRI suitability using MRI questionnaire 
Visit 2 (7-14 days after Visit 1) 
• Demographics 
• Medical History (including AEs) 
• Vital Signs 
• Physical Exam 
• Concomitant Medication Assessment 
• Lab (including existing lab in medical records and serum pregnancy test, if needed) 
• MRI (Hyperpolarized 129Xe) 
• Complete pulmonary function test (including DLCO) 
• 6-min walk test (6MWT) 
• St. Georges’s respiratory questionnaire (SGRQ) 
• Borg’s dyspnea scale 
• COPD assessment test (CAT) 
• Start glycopyrrolate/formoterol aerosphere (Bevespi) 
• Teaching the subject how to use the inhalers (glycopyrrolate/formoterol aerosphere 
and albuterol) 
Visit 3 (2 weeks after Visit 2) 
• Medical History (including AEs) 
• Vital Signs 
• Physical Exam 
• Concomitant Medication Assessment 
• Assessment of Adverse Events 
• MRI (Hyperpolarized 129Xe) 
• Complete pulmonary function test (including DLCO) 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
18(32) 
• 6MWT 
• SGRQ 
• Borg’s dyspnea scale 
• CAT 
Follow-up telephone call (2 weeks after Visit 3) 
• Assessment of Adverse Events 
5.2.1 
Enrollment procedures 
The study coordinator will screen and recruit patients from Duke Asthma, Allergy and Airway 
Center (AAAC). All clinical data, including PFT, 6MWT, SGRQ and Borg’s dyspnea scale, 
will be collected at AAAC. After clinical data collection is finished, the patient will be 
referred for 129Xe MRI scanning, which is located at Duke North Hospital. We expect that 
the clinical assessment and data collection can be finished in the morning of the visit. 129MRI 
scan can be performed in the afternoon.  
5.2.2 
Follow-up procedures 
A telephone call will be placed at the end of the first week to discuss with the subject 
regarding his or her COPD status and Bevespi use. It also serves to remind the subject of the 
follow-up visit (Visit 3) of th study.  
5.3 
Efficacy 
5.3.1 
Efficacy variables: the following variables will be measured and compared 
before and 2 weeks after glycopyrrolate/formoterol aerosphere (Bevespi) 
treatment. We will allow a 1-week window for all visits. 
• MRI (Hyperpolarized 129Xe)  
• Assessment of ventilation distribution (Figure 1A) 
o Bin 1 (red): ventilation defect region (VDR, 0 to mean-2SD) 
o Bin 2 (orange): low ventilation region (LVR, mean-2SD to mean-1SD]) 
o Bins 3 and 4 (greens): regions with normal ventilation (mean-1SD to 
mean+1SD) 
o Bins 5 and 6 (blues): high ventilation region (HVR, > mean+1SD).   
• Assessment of dissuion distribution (Figure 1B) 
o Bins 1 and 2 (red and orange)(BarrierLow): high diffusion regions (0 to mean-
1SD) 
o Bins 3 and 4 (greens)(BarrierNormal): normal diffusion regions (mean-1SD to 
mean+1SD) 
o Bins 5 to 8 (pinks)(BarrierHigh): low diffusion regions (> mean +1SD). 
• Assessment of perfusion distribution (Figure 1C) 
o Bins 1 and 2 (red and orange) (RBCLow): low perfusion regions (0 to mean-
1SD) 
o Bins 3 and 4 (greens) (RBCNormal): regions with normal perfusion (mean-1SD 
to mean+1SD) 
o Bins 5 and 6 (blues) (RBCHigh): high perfusion regions (> mean+1SD).  


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
19(32) 
Figure 1.  The nearly Gaussian distributions of ventilation (A), Barrier:gas (B) and RBC:gas 
(C) in the reference population of 10 healthy subjects (n=10, age 29±8 yrs). Their mean and 
standard deviations were used to define the thresholds of intensity bins used to display the 
maps, with colors depicted above the histogram. The color coding for ventilation and RBC 
maps used the same scheme as previously introduced (36): red for defects; orange for low 
intensity; greens for the two bins around either side of the mean of the reference population; 
and blues for higher intensities. For the barrier maps, the first 4 colors were the same as for 
ventilation and RBC. However, to allow for better differentiation of the high barrier signals 
anticipated in patients with severe interstitial lung diseases, the highest bins were assigned 
pink and purple colors. 
A 
 
B 
 
C 
RBCHigh
 
o   
• Complete pulmonary function test (including DLCO) 
• 6-min walk test 
• St. Georges’s questionnaire 
• Borg dyspnea scale 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
20(32) 
• CAT 
 
5.4 
Safety 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
5.4.1 
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 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. 
5.4.2 
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. 
5.4.3 
Recording of adverse events 
To the ISSROT: 
The Patient Safety CDP Technical Planning Document (TPD), or other appropriate project document, 
provides recommendation on recording of adverse events.  The text in this guideline should be 
modified to comply with the Patient Safety TPD/ other appropriate project/TA documents if not 
otherwise agreed with Patient Safety. 
Insert un numbered subheadings as appropriate. 
Consider: 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
21(32) 
• 
How AEs related to specific study procedures (eg, biopsy, endoscopy) will be handled 
• 
How AEs related to abnormal ECGs will be handled  
• 
How symptoms of the Disease Under Study and/or symptoms of expected disease progression 
and/or lack of effect would be handled. There may be circumstances when it is justifiable not 
to record these symptoms as adverse events. Refer to the Technical Planning Document for 
how symptoms of the disease under study/disease progression and/or adverse event variables 
should be collected and analyzed. 
• 
How SAEs that are also efficacy endpoints should be handled/whether there are waivers for 
endpoints 
Time period for collection of adverse events 
During the 2-week study period and 2 weeks after the study ends. 
Follow-up of unresolved adverse events 
The PI will follow up with the patients who develop adverse events. These patients will be 
scheduled to be seen in the clinic if needed. 
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the Investigational Product (yes or no) 
• 
Action taken with regard to investigational product 
• 
AE caused subject’s withdrawal from study (yes or no) 
• 
Outcome 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
Causes for serious AE 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to Study procedure(s) 
• 
Causality assessment in relation to Other medication 
• 
Description of AE. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 5.4.2.  An AE of severe 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
22(32) 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. 
Adverse Events based on signs and symptoms 
When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms.  However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the 
diagnosis and each sign or symptom will be recorded separately. 
Adverse Events based on examinations and tests 
Deterioration as compared to baseline in physical exams and lab tests will 
therefore only be reported as AEs if they fulfill any of the SAE criteria or are the 
reason for discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated 
laboratory result/vital sign will be considered as additional information.  
Wherever possible the reporting investigator uses the clinical, rather than the 
laboratory term (eg, anemia versus low hemoglobin value). In the absence of 
clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s s). 
Deterioration of a laboratory value, which is unequivocally due to disease 
progression, should not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 
There are currently no adequate data of on the use of this study medication, or its individual 
components in pregnant women.  Animal reproduction studies in rats and rabbits showed no 
teratogenic effects of glycopyrrolate individually, when dosed at approximately 18000 and 
270 times the maximum recommended human daily inhalation dose in adults.  However, 
single-dose studies in humans have found that very small amounts of glycopyrrolate pass 
through the placental barrier.  Formoterol fumarate individually has been shown to have 
teratogenic effects, embryocidal effects, lead to increased pup loss at birth and during 
lactation, and lead to decreased pup weight in rats and rabbits when dosed at approximately 
1500 and 61000 times, respectively, the maximum recommended human daily inhalation dose 
in adults.  Additional complications such as umbilical hernia, prolonged pregnancy, and fetal 
brachygnathia were observed in rats as well when dosed at 1500 and 7600 times the maximum 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
23(32) 
recommended human daily inhalation dose.  No teratogenic effects were seen when dosed at 
approximately 600 times the maximum recommended dose, however (BEVESPI Aerosphere® 
PACKAGE INSERT 2016). 
Therefore the study medication and its individual components, glycopyrrolate and formoterol 
fumarate, should only be used during pregnancy if the expected benefits outweigh the 
potential risks. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study medication 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as SAEs.  The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
patient was discontinued from the study. 
If any pregnancy occurs, the Investigator or other site personnel will inform AstraZeneca the 
appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 24 
hours of when he or she becomes aware of it. 
The designated AstraZeneca (?? should it not read Quintiles??) representative will work with 
tThe Investigator should to ensure that all relevant information is provided to the AstraZeneca 
Patient Safety data entry site within 1 or 5 calendar days for SAEs (see Section 6.4 please 
check if this is the right section) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
Disease progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  In this 
proposal, the development of progressive dyspnea on exertion would be considered as disease 
progression and not an AE.  Events, which are unequivocally due to disease progression, 
should not be reported as an AE during the study. 
5.4.4 
Reporting of serious adverse events  
Investigators and other site personnel must inform the FDA, via a MedWatch/AdEERs form, 
of any serious or unexpected adverse events that occur in accordance with the reporting 
obligations of 21 CFR 312.32, and will concurrently forward all such reports to AZ.  A copy 
of the MedWatch/AdEERs report must be faxed to AstraZeneca at the time the event is 
reported to the FDA.  It is the responsibility of the investigator to compile all necessary 
information and ensure that the FDA receives a report according to the FDA reporting 
requirement timelines and to ensure that these reports are also submitted to AstraZeneca at the 
same time. 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
24(32) 
When reporting to AstraZeneca, a cover page should accompany the MedWatch/AdEERs 
form indicating the following: 
• 
Investigator Sponsored Study (ISS) 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number 
Investigative site must also indicate, either in the SAE report or the cover page, the causality 
of events in relation to all study medications and if the SAE is related to disease progression, 
as determined by the principal investigator. 
Send SAE report and accompanying cover page by way of fax to AstraZeneca’s designated 
fax line: 1-866-984-7229 
Serious adverse events that do not require expedited reporting to the FDA need to be reported 
to AstraZeneca preferably using the MedDRA coding language for serious adverse events.   
In the case of blinded trials, AstraZeneca will request that the Sponsor either provide a copy of 
the randomization code/ code break information or unblind those SAEs which require 
expedited reporting. 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to 
the investigational product.  All SAEs will be documented.  The investigator is responsible for 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. 
5.4.5 
Laboratory safety assessment 
Minimum. No blood samples are obtained, except for pregnancy test for females of 
child bearing age. 
For blood volume see Section 6.1. 
5.4.6 
Physical examination 
Minimum risk 
5.4.7 
ECG 
N/A 
5.4.7.1 
Resting 12-lead ECG 
N/A 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
25(32) 
5.4.7.2 
Real time display (telemetry) 
N/A 
5.4.8 
Vital signs 
Minimum risk 
5.4.8.1 
Pulse and blood pressure 
Minimum risk 
5.4.8.2 
Body temperature 
Minimum risk 
5.4.9 
Other safety assessments 
N/A  
5.5 
Patient reported outcomes (PRO) 
• St. Georges’s questionnaire -- minimumrisk 
• Borg dyspnea scale – minimum risk 
5.6 
Pharmacokinetics 
N/A 
5.6.1 
Collection of samples 
N/A 
5.6.2 
Determination of drug concentration 
N/A 
5.7 
Pharmacodynamics 
N/A 
5.7.1 
Collection of pharmacodynamic markers  
N/A 
5.8 
Pharmacogenetics 
N/A 
5.8.1 
Collection of pharmacogenetic samples 
5.9 
Health economics 
N/A 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
26(32) 
6. 
BIOLOGICAL SAMPLING PROCEDURES 
6.1 
Volume of blood 
N/A 
6.2 
Handling, storage and destruction of biological samples 
6.2.1 
Pharmacokinetic and/or pharmacodynamic samples 
N/A 
6.2.2 
Pharmacogenetic samples 
6.3 
Labeling and shipment of biohazard samples 
N/A 
6.4 
Chain of custody of biological samples 
N/A 
6.5 
Withdrawal of informed consent for donated biological samples 
N/A 
7. 
ETHICAL AND REGULATORY REQUIREMENTS 
7.1 
Ethical conduct of the study 
LABA/LAMA combination is the mainstay therapy for COPD patients. 
Glycopyrrolate/formoterol aerosphere belongs to this medication category. The 7-14 day run-
in period has been used routinely in all randomized controlled trials that compared the 
efficacy of a specific inhaler with placebo or another inhaler in GOLD 2 and 3 COPD patients. 
The risk for worsening symptoms during the short run-in period should be minimum.  
7.2 
Ethics and regulatory review 
The protocol will be submitted to Duke IRB for approval prior to the start of the study. IRB 
will be informed of all AEs and SAEs. 
7.3 
Informed consent 
Eligible patient will sign the informed consent during Visit 1 
7.4 
Changes to the protocol and informed consent form 
Any changes in the prototol and informed consent will be submited to IRB for approval.  


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
27(32) 
7.5 
Audits and inspections 
AstraZeneca does not conduct ESR onsite audits, however, the AstraZeneca ESR ESSROs 
portal containing study information and site updates are internally audited 
8. 
STUDY MANAGEMENT 
8.1 
Training of study site personnel 
All study personnel will keep human study training up to date. The CRC will all be trained to 
be familiar with the protocol and procedures involved in the study. These procedures include 
pulmonary function test, 6 minute walk test, St. George’s questionnaire and Borg’s dyspnea 
scale. 129Xe MRI is a core facility at Duke and all personnel in this core has been well trained 
to perform the scan. 
8.2 
Monitoring of the study 
8.2.1 
Source data 
The raw data will be entered into Excel. Each patient will have a spreadsheet. This will be the 
source data. 
8.3 
Study timetable and end of study 
After the protocol approval by AstraZeneca, the study will be submitted to Duke IRB. It 
usually takes 6-8 months for approval. Once the protocol is approved by IRB, the study is 
expected to be completed in 18-24 months. 
9. 
DATA MANAGEMENT 
All data will be entered into Excel spreadsheets via a Duke computer and stored in a specific 
folder (e.g., Bevespi MRI COPD) in a common drive. The drive can be accessed by the study 
team. The spreadsheets will be passwork protected. Only the study team can access the data. 
The data can be shared with AstraZeneca upon request. When sharing data with AstraZeneca, 
the study team will follow the Duke IT security guidelines. These guidelines discourage 
sending data outside of Duke network by E-mail. A more secure mechanism to share the data 
will be used, including face-to-face meetings,  
10. 
EVALUATION AND CALCULATION OF VARIABLES 
10.1 
Calculation or derivation of efficacy variable(s) 
• 129Xe MRI ventilation and gas exchange parameters, described above. 
• Pulmonary function test 
• 6 minute walk test 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
28(32) 
10.2 
Calculation or derivation of safety variable(s) 
N/A 
10.2.1 
Other significant adverse events (OAE) 
N/A 
10.3 
Calculation or derivation of patient reported outcome variables 
• St. Georg’s questionnaire 
• Borg’s dyspnea scale 
10.4 
Calculation or derivation of pharmacokinetic variables 
N/A 
10.5 
Calculation or derivation of pharmacodynamic variable(s) 
N/A 
10.5.1 
Calculation or derivation of the relationship between pharmacokinetic and 
pharmacodynamic variables  
N/A 
10.5.2 
Population analysis of pharmacokinetic/pharmacodynamic variables  
N/A 
10.6 
Calculation or derivation of pharmacogenetic variables 
N/A 
10.7 
Calculation or derivation of health economic variables 
N/A 
11. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
11.1 
Description of analysis sets 
11.1.1 
Efficacy analysis set 
• 129Xe MRI parameters 
• Complete pulmonary function test (including FVC, FEV1, FEF25-75, TLC, RV, 
RV/TLC and DLCO) 
• 6-min walk test 
• St. Georges’s questionnaire 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
29(32) 
• Borg dyspnea scale 
11.1.2 
Safety analysis set 
Descriptive analysis. Patients who only have visit 2 will be included (for Aim 1).  
11.2 
Methods of statistical analyses 
Paired t-test. Only patients who have both visits 2 and 3 will be included (for Aim 
2). Significance level is at 0.05 for a 2-taliled test. We plan to use line graph or box 
plots to show pre- an dpost-changes. 
MRI endpints will be correlated with other parameters using linear regression 
analyses. We plan to use scattered plots to demonstrate the correlation. 
11.2.1 
Interim analyses 
None 
11.3 
Determination of sample size 
In this study, the sample size was estimated using the paired t-test based on the following 
parameters: alpha 0.05, beta 0.20, effect size of 20% (based on ventilation defect percentage) 
and standard deviation of 30% (based on MRI ventilation distribution). At least 18 patients 
will be needed. The effect size of 20% was derived from the preliminary data in asthma 
patients before and after albuterol. The ventilation defect percentage in older asthma patients 
decreased by approximately 40% after albuterol treatment. If we assume 40% as the upper 
limit of airway reversibility in older asthma patients, we could take half of that size (i.e. 20%) 
for COPD patients since airway obstruction in COPD patients is only partially reversible. The 
standard deviation of 30% is derived from previous studies that assessed ventilation 
distribution in pulmonary patients.   
11.4 
Data monitoring committee  
N/A 


Clinical Study Protocol 
Drug Substance Glycopyrronium and Formoterol Fumarate 
Study Number ESR-17-12722/D5970L000002 
Edition Number 1 
Date April 20, 2017 
30(32) 
12. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
N/A 
12.1 
Overdose  
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel inform appropriate AstraZeneca representatives within 
one day, ie, immediately but no later than the end of the next business day of when he or she 
becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
The reporting process will be the same as that described in section 5.4.4 above. 
12.2 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca. 
12.2.1 
Maternal exposure 
N/A 
12.2.2 
Paternal exposure 
N/A 
13. 
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