Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Keywords: Chronic Obstructive Pulmonary Disease (COPD)
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 44
Healthy volunteers: no

Brief summary:
A clinical study to investigate if a single dose of an approved drug product (glycopyrrolate Inhalation Solution) reduces trapped air in the lungs of participants with chronic obstructive pulmonary disease. This study is accepting male and female participants over the age of 40. The study will be conducted at one site located in the United States.

Detailed description:
This is a single center, randomized, double-blind, placebo-controlled, single-dose, 2-way crossover study in approximately 20 adult subjects ≥ 40 years of age with COPD. The study is designed to evaluate the effect of a single dose of GIS on lung hyperinflation. The two study treatments, both administered using the Magnair device.

The study will randomize 10 subjects per treatment sequence, for a total of 20 subjects. At the Sponsor's discretion, additional subjects may be enrolled in an effort to achieve at least 20 completers, with no more than 24 subjects randomize.

The study will consist of a Screening period, a randomized 2-way cross-over treatment period during which subjects will receive two single-doses each separated by a 7-day washout period, and a follow-up 7 (± 2) days after the last study drug dose.

This study is designed to test the hypothesis that in adults with COPD subjects as characterized by the study inclusion/exclusion criteria, after 2 cross-over periods of treatment, the primary null hypothesis for this study is that the mean change of RV from baseline at 6 hours postdose for a single dose of GIS is equal to the mean change of RV from baseline at 6 hours postdose for a single dose of placebo inhalation solution (PIS). The alternative hypothesis is that these means are different.

Arms:
arm 1: Glycopyrrolate Inhalation Solution 25mcg administered by Magnair arm 2: Placebo Inhalation Solution administered by Magair

Interventions: intervention 1: Glyocopyrrolate Inhalation Solution administered by Magnair intervention 2: Placebo administered by Magnair
Intervention descriptions: intervention 1: glycopyrrolate Inhalation Solution 25mcg, single dose intervention 2: Placebo Inhalation Solution

Protocol document:
Prot_000.pdf: 
Titlpage
 
 
 
SUN-101 
LONHALA® MAGNAIR® (GLYCOPYRROLATE)  
INHALATION SOLUTION 
Clinical Study Protocol SUN101-402 
 
A Randomized, Double-blind, Placebo-controlled, 2-Way 
Crossover Study of the Effect of a Single Dose of Glycopyrrolate 
Inhalation Solution (GIS) on Lung Hyperinflation in Subjects 
with Chronic Obstructive Pulmonary Disease (COPD) 
 
IND No. 110,663 
 
Version 1.00 
 
07 August 2019 
 
 
Sunovion Respiratory Development Inc. 
84 Waterford Drive 
Marlborough, MA 01752, USA 
(508) 481-6700 


Protocol SUN101-402, Version 1.00 
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RESTRICTED DISTRIBUTION OF PROTOCOLS 
This document contains information confidential and/or of proprietary interest to Sumitomo 
Dainippon Pharma Co. Ltd. and/or Sunovion Respiratory Development Inc. (including their 
predecessors, subsidiaries or affiliates). The information cannot be disclosed to any third party or 
used for any purpose other than the purpose for which it is being submitted without the prior 
written consent of the appropriate Sumitomo Dainippon Pharma company. 
This information is being provided to you for the purpose of conducting a clinical study for 
Sunovion Respiratory Development Inc. You may disclose the contents of this protocol to the 
study personnel under your supervision and to your Institutional Review Board for the above 
purpose. You may not disclose the contents of this protocol to any other parties, unless such 
disclosure is required by government regulations or laws, without the prior written permission of 
Sunovion Respiratory Development Inc. 
Any data gathered during the conduct of this protocol and supplemental information (eg, a 
protocol amendment) that may be added to this document is also proprietary to Sunovion 
Respiratory Development Inc., and should be handled consistently with that stated above. 


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EMERGENCY CONTACTS 
Table 1: Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Responsible Physician/ 
Medical Monitor 
Telephone:  
Email:  
SAE/Pregnancy Reporting 
Hotline Number: 
Fax:  
Email:  


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1.
SYNOPSIS
Name of Sponsor: Sunovion Respiratory Development Inc. 
Name of Investigational Product: Lonhala® Magnair®; glycopyrrolate inhalation solution (GIS) 
Name of Active Ingredient: Glycopyrrolate 
Title of Study: A Randomized, Double-blind, Placebo-controlled, 2-Way, Crossover Study of the 
Effect of a Single Dose of Glycopyrrolate Inhalation Solution (GIS) on Lung Hyperinflation in 
Subjects with Chronic Obstructive Pulmonary Disease (COPD)  
Proposed Indication: COPD 
Study Centers: Single center in the United States 
Phase of Development: 4 
Study Objectives  
Primary Efficacy Objective: 
•
To compare the efficacy of GIS versus placebo inhalation solution (PIS) on lung
hyperinflation following a single dose, as measured by residual volume (RV) at 6 hours 
postdose. 
Other Efficacy Objective: 
•
To evaluate the effect of a single dose of GIS versus PIS on objective measures of lung
function. 
Exploratory Objective: 
•
To evaluate the feasibility of using the accelerateIQ System (ie, the VitalPatch® Biosensor
and accelerateIQ Platform). 
Study Design: 
This is a single center, randomized, double-blind, placebo-controlled, single-dose, 2-way crossover 
study in approximately 20 adult subjects ≥ 40 years of age with COPD. The study is designed to 
evaluate the effect of a single dose of GIS on lung hyperinflation. The two study treatments, both 
administered using the Magnair device are:  
•
GIS 25 mcg
•
PIS
The study will consist of a Screening period, a randomized 2-way cross-over treatment period during 
which subjects will receive two single-doses each separated by a 7-day washout period, and a follow-
up 7 (± 2) days after the last study drug dose. A study schematic is provided below. 


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Study Schematic 
 
GIS = Glycopyrrolate Inhalation Solution 
PIS = Placebo Inhalation Solution 
Number of Subjects (planned): The study will randomize 10 subjects per treatment sequence, for a 
total of 20 subjects. At the Sponsor’s discretion, additional subjects may be enrolled in an effort to 
achieve at least 20 completers, with no more than 24 subjects randomized. 
Diagnosis and Main Criteria for Subject Inclusion:  
Male and female subjects ≥ 40 years of age with a confirmed diagnosis of COPD and smoking history 
of ≥ 10 pack-years who provide written informed consent are eligible for study participation. Subject 
has a RV ≥ 130% predicted value at Screening (prior to reversibility testing), and a postbronchodilator 
(following inhalation of ipratropium bromide) forced expiratory volume in 1 second (FEV1) ≥ 30% 
and < 80% of predicted normal and FEV1/forced vital capacity (FVC) ratio of < 0.70 at Screening. 
Subject must also have a score of ≥ 2 on the Modified Medical Research Council Dyspnea Scale 
(mMRC). 
Complete study entry criteria are provided in Section 8. 
Investigational Product, Dosage and Mode of Administration:  
A single dose of Lonhala 25 mcg will be administered using Magnair. 
Additional details are provided in Section 9.1.1. 
Duration of Treatment:  
Subjects will receive a single dose of GIS and PIS in a crossover manner. The maximum duration of 
subject participation will be approximately 37 days (up to 17 days Screening, a randomized cross-over 
treatment period with two single-doses each separated by a 7-day washout, and 7 days post-last dose 
follow-up). 


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Reference Therapy, Dosage and Mode of Administration:  
A single dose of matching PIS will be administered using Magnair. 
Additional details are provided in Section 9.1.1.  
Concomitant Medications: 
The following concomitant medication restrictions will be employed. 
Medication Disallowed for Study Duration 
Required Withholding Interval 
Albuterol 
≥ 6 hours before each study visit, or at 
any time during study visits 
Ipratropium 
Study duration, except for reversibility 
testing at Screening (withhold ≥ 6 hours 
before reversibility testing) 
Ipratropium/albuterol combination 
≥ 2 days prior to screening assessments 
and study duration 
Inhaled Corticosteroid/LABA combination 
≥ 2 days prior to screening assessments 
and study duration 
Long-acting beta-agonist 
≥ 2 days prior to screening assessments 
and study duration 
Long-acting muscarinic antagonist 
> 7 days prior to screening assessments 
and study duration 
Leukotriene Inhibitors  
> 7 days prior to screening assessments 
and study duration 
Theophylline  
> 7 days prior to screening assessments 
and study duration 
PDE-4 inhibitors (eg, roflumilast) 
> 14 days prior to screening 
assessments and study duration 
Abbreviations: ICF = Informed Consent Form; ICS = inhaled corticosteroid(s); LABA = long-acting beta agonist; 
PDE-4 = phosphodiesterase type 4; PFT = pulmonary function test(s) 
a Subjects taking LABA/ICS or taking ICS monotherapy need to be on a stable dose for at least 4 weeks prior to Screening in 
order to be eligible for a switch to ICS monotherapy or continuation of ICS monotherapy. This switch can be made at the 
time the ICF is signed and Screening PFTs can be assessed 48 hours later to allow for the LABA washout. 
Criteria for Evaluation:  
Primary Efficacy Endpoint 
• 
Change from baseline in RV at 6 hours postdose 
Other Efficacy Endpoints 
• 
Standardized change from baseline in RV area under the curve from time 0 to 4 hours 
postdose (AUC0-4h) and RV area under the curve from time 0 to 6 hours postdose 
(AUC0-6h) 
• 
Change from baseline in inspiratory capacity (IC) at 6 hours postdose 
• 
Standardized change from baseline in IC AUC0-4h and IC AUC0-6h 
• 
Change from baseline in functional residual capacity (FRC) at 6 hours postdose 
• 
Standardized change from baseline in FRC AUC0-4h and FRC AUC0-6h 
• 
Change from baseline in total lung capacity (TLC) at 6 hours postdose 
• 
Standardized change from baseline in TLC AUC0-4h and TLC AUC0-6h 
• 
Change from baseline in specific airway resistance (sRaw) at 6 hours postdose 


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• 
Standardized change from baseline in sRaw AUC0-4h and sRaw AUC0-6h 
• 
Change from baseline in airway resistance (Raw) at 6 hours postdose 
• 
Standardized change from baseline in Raw AUC0-4h and Raw AUC0-6h 
• 
Change from baseline in RV, IC, FRC, TLC, sRaw, and Raw at 1, 2, 3, and 4 hours postdose 
• 
Change from baseline in forced expiratory volume in FEV1 at 6 hours postdose 
Safety Endpoints 
• 
Incidence of adverse events, serious adverse events, and adverse events leading to 
discontinuation 
Exploratory Endpoint 
• 
Vital sign data collected at clinic visits and data collected using the accelerateIQ System 
Statistical Methods:  
General Methodology 
The primary efficacy analysis will be based on the modified intention-to-treat (mITT) population, 
which includes all subjects who are randomized, received at least one dose of study treatment and 
have a baseline and at least one post-baseline RV measurement within the same period. Should a 
subject require a rescue medication use during the approximately 6 hours of efficacy endpoint 
collection, then any efficacy values that occur after the use of the rescue medication will be set to 
missing in the analysis. The safety population includes all subjects who are randomized and receive at 
least 1 dose of study medication. 
Primary Efficacy Analysis 
The primary efficacy estimand is defined as the difference between a single dose of GIS and PIS in 
the mean change of RV from baseline at 6 hours postdose in COPD patients as characterized by the 
study inclusion/exclusion criteria, in the hypothetical setting where the subjects were able to stay on 
study and receive their study drug during their treatment periods. 
The change from baseline in RV at 6 hours postdose will be calculated for each treatment period as 
RV at 6 hours postdose on the day of treatment minus the period baseline of each treatment period. 
Period baseline is defined as the predose RV value collected 45 minutes prior to the dosing during 
each treatment period. 
For the primary analysis of the primary efficacy endpoint, data will be analyzed using a 2-way 
crossover analysis of covariance (ANCOVA). The ANCOVA model will include terms for treatment, 
period and sequence as fixed effects, period baseline as a covariate, and subjects nested within 
sequence as a random effect. The main estimator of the primary estimand is the Least Squares (LS) 
mean difference in the change from baseline in RV at 6 hours postdose from the primary ANCOVA 
model. LS mean (and 95% Confidence Interval [CI]) for each treatment group and LS mean (and 
2-sided 95% CI), and the associated p-value for the difference between the single nebulized dose of 
GIS and PIS will be displayed. 
In general, for the primary analysis of the primary efficacy endpoint, missing observations will be 
treated as missing at random (MAR) and no data imputation will be performed. However, sensitivity 
analyses may be conducted if there is significant amount of missing data, including missing not at 
random (MNAR) assumptions. 
Supplementary analyses of the primary efficacy endpoint may be conducted as deemed appropriate 
and details will be provided in the statistical analysis plan (SAP). 
Other Efficacy Endpoint Analyses 
All other efficacy endpoints will be analyzed using the mITT population. 


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All other efficacy endpoints will be analyzed using the ANCOVA model similar to the primary 
efficacy endpoint with appropriate period baseline as a covariate. Additional covariates may be 
included in select models. 
Standardized change from baseline in RV AUC0-4h for each treatment period will be calculated using 
the trapezoid method from the changes in RV from the period baseline value within each treatment 
period and dividing by the actual length of the time interval within that treatment period. Changes in 
RV from period baseline for each time point (1, 2, 3, and 4 hours postdose) will be calculated as the 
RV values within each treatment minus the period baseline RV for each treatment period. Change in 
RV from period baseline at time=0 is equal to 0. 
Standardized change from baseline in RV AUC0-6h, IC AUC0-4h, IC AUC0-6h, FRC AUC0-4h, 
FRC AUC0-6h, TLC AUC0-4h, TLC AUC0-6h, sRaw AUC0-4h, sRaw AUC0-6h, Raw AUC0-4h, 
and Raw AUC0-6h will be calculated similarly. 
Changes from baseline in IC, FRC, TLC, sRaw, Raw and FEV1 at 6 hours postdose will be calculated 
similar to the primary analysis endpoint. All any other postdose lung volume endpoints (RV, IC, FRC, 
TLC, sRaw and Raw) at 1, 2, 3 and 4 hours postdose will be derived and analyzed similar to the 
primary endpoint. 
Safety Analyses 
Adverse events (AEs), serious adverse events (SAEs), and AEs leading to discontinuation during the 
randomized treatment period will be summarized by counts and percentages of each treatment group. 
Any AEs occurring during the screening period will only be listed. 
Exploratory Endpoint Analyses 
Vital sign data collected at clinic visits will be summarized using descriptive statistics. A separate 
SAP will be created for accelerateIQ System data. 
Multiplicity adjustment 
No multiple comparison procedures will be employed in this study. 
Sample Size: The evaluable sample size for this study was determined by a two-sample t-test (cross-
over ANOVA) using nQuery version 4.0 (nQuery + nTerim version 4.0, Statistical Solutions, Cork, 
Ireland). A sample size of 10 evaluable subjects per treatment sequence, assuming a common standard 
deviation of 0.4 L, a mean difference of -0.3 L in change from baseline in RV (single dose of GIS 
compared to PIS), with a one-sided alpha of 0.025, will give a power 88%. Discontinued subjects will 
not be replaced. At the Sponsor’s discretion, additional subjects may be enrolled in an effort to 
achieve at least 20 completers; however, no more than 24 subjects will be randomized. 
 


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Table 2: 
Schedule of Assessments 
Study Period 
 
Screeninga 
 
Treatment 
Follow-up/Early 
Terminationb 
 
 
Treatment 
Period 1 
Washout 
Treatment  
Period 2 (EOS) 
 
Study Visit 
1 
2 
 
3 
TC/In-clinic 
Study Day 
-17 to -2 
1 
2-8 
9 (+3) 
7 (± 2) after Last 
Dose 
Procedure 
 
 
 
 
 
Obtain Informed Consent  
X 
 
 
 
 
Review Inclusion and Exclusion Criteria  
X 
 
 
 
 
Review Continuation Criteriac  
 
X 
 
X 
 
Demographics  
X 
 
 
 
 
Medical History  
X 
 
 
 
 
Smoking Status  
X 
 
 
 
 
COPD Exacerbation History (With and Without Hospitalization)  
X 
 
 
 
 
Height and Weight  
X 
 
 
 
 
Modified Medical Research Council Dyspnea Scale (mMRC)d 
X 
 
 
 
 
St. Georges Respiratory Questionnaire (SGRQ) 
X 
 
 
 
 
Physical Examination 
X 
 
 
 
 
Vital Signs 
X 
Xe 
 
Xe 
 
12-lead Electrocardiogram (ECG) 
X 
 
 
 
 
Clinical Laboratory Tests  
X 
 
 
 
 
Pregnancy Testf 
X 
 
 
X 
Xg 
Begin Washout of Current/Prohibited Medications 
X 
 
 
 
 
Dispense rescue medication (if needed) 
X 
 
 
 
 
Dispense inhaled corticosteroid (if needed)h 
X 
 
 
 
 
Plethysmography  
Xi 
Xj 
 
Xj 
 
Spirometry 
Xi 
Xk 
 
Xk 
 
Observe subject administer placebo via Magnair Nebulizer Systeml 
X 
 
 
 
 
Apply VitalPatch Biosensorm 
X 
X 
 
X 
 
Randomize Subject 
 
X 
 
 
 
Administer Study Drug in clinic  
 
X 
 
Xn 
 
Prior/Concomitant Medication Review 
X 
X 
 
X 
X 
Record Pretreatment Events 
X 
X 
 
 
 
Record Adverse Events 
X 
X 
 
X 
X 
Schedule Next Visit 
X 
X 
 
X 
 


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Abbreviations: COPD = chronic obstructive pulmonary disease; EOS = End of Study; ET = Early Termination; ICS = inhaled corticosteroid; LABA = long-acting bronchodilator; 
NA = Not applicable; TC = telephone contact 
a Screening procedures will occur over multiple days. Screening assessments will be performed after informed consent and after applicable wash-out has been completed.  
b Subjects who discontinue prior to completion of Day 9 will undergo Early Termination procedures and assessments at the time of discontinuation. Female subjects of 
childbearing potential who were dosed will return to the clinic for a serum pregnancy test and final safety assessments 7 (± 2) days after their last study drug dose. All other 
dosed subjects will either be contacted by telephone or have an in-clinic visit if deemed clinically warranted by the Investigator 7 (± 2) days after their last study drug dose for a 
final safety assessment (adverse events and concomitant medication use). 
c Continuation criteria includes ensuring that the subject has not had an exacerbation of COPD, the subject has completed the 7-day washout period and continues to withhold 
disallowed medications, and in the opinion of the Investigator, the subject has not had any change that would put the safety of the subject at risk through participation. 
d The mMRC should be performed prior to any other assessments. 
 e Vital signs will be collected 45 (± 15) minutes prior to dosing and 60 (± 15) minutes postdose. Vital signs will be collected prior to plethysmography and spirometry when 
collection times coincide. 
f Serum pregnancy test will be performed for female subjects of child-bearing potential at Visit 1 and at Follow-up/Early Termination. Urine pregnancy test will be performed for 
female subjects of child-bearing potential at Visit 3. 
g Female subjects of childbearing potential will return to the clinic for a serum pregnancy test. 
h COPD subjects who washout of LABA/ICS must switch to ICS monotherapy that is equivalent to that contained in the LABA/ICS. 
i Screening plethysmography and spirometry will be performed prior to and 30-60 minutes (and no later than 2 hours) following 68 mcg ipratropium MDI (4 puffs of 17 mcg per 
actuation). Plethysmography will be performed first, followed immediately by spirometry. 
j Serial plethysmography will be performed 45 minutes predose and again at 1, 2, 3, 4, and 6 hours postdose. At each time point, plethysmography assessments will have a window 
of ± 15 minutes. Plethysmography will be performed prior to spirometry when timepoints coincide. 
k Spirometry will be performed 45 minutes predose and again 6 hours postdose after plethysmography. At each time point, spirometry assessments will have a window of 
± 15 minutes. 
l Subjects will administer placebo via the Magnair Nebulizer System for training purposes to ensure that they are able to use the device. Subjects unable to use the Magnair 
Nebulizer System will be excluded from study participation. 
m The VitalPatch Biosensor will be applied to subjects who provide additional informed consent for this assessment. If the subject meets the screening criteria, the site will apply 
the VitalPatch Biosensor, which will be worn for up to 5 consecutive days. The subject will apply a new patch to be worn for up to 5 consecutive days. The VitalPatch Biosensor 
will be worn until the safety follow-up visit. 
n Study drug administration during Treatment Period 2 will be administered between approximately 6:00 – 10:00 AM and within 1 hour of Treatment Period 1 dosing. 
 
 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
RESTRICTED DISTRIBUTION OF PROTOCOLS ......................................................................2 
EMERGENCY CONTACTS...........................................................................................................3 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............11 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF TABLES .........................................................................................................................15 
LIST OF FIGURES .......................................................................................................................15 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................16 
4. 
INTRODUCTION ......................................................................................................19 
4.1. 
Background .................................................................................................................19 
4.2. 
Study Conduct Rationale ............................................................................................19 
4.3. 
Risk-Benefit Assessment ............................................................................................20 
4.4. 
Hypothesis ..................................................................................................................20 
5. 
STUDY OBJECTIVES ..............................................................................................21 
5.1. 
Primary Objective .......................................................................................................21 
5.2. 
Other Efficacy Objective ............................................................................................21 
5.3. 
Exploratory Objective .................................................................................................21 
6. 
STUDY ENDPOINTS ................................................................................................22 
6.1. 
Primary Efficacy Endpoint .........................................................................................22 
6.2. 
Other Efficacy Endpoints ...........................................................................................22 
6.3. 
Safety Endpoints .........................................................................................................22 
6.4. 
Exploratory Endpoint ..................................................................................................22 
7. 
INVESTIGATIONAL PLAN .....................................................................................23 
7.1. 
Overall Study Design ..................................................................................................23 
7.2. 
Treatment Assignment and Blinding ..........................................................................25 
7.2.1. 
Treatment Assignment ................................................................................................25 
7.2.2. 
Blinding ......................................................................................................................25 
7.2.3. 
Emergency Unblinding Procedures ............................................................................26 
7.3. 
Rationale .....................................................................................................................26 


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7.3.1. 
Rationale for the Study Design ...................................................................................26 
7.3.2. 
Rationale for the Dosages ...........................................................................................26 
7.3.3. 
Rationale for the Study Population .............................................................................26 
7.3.4. 
Rationale for the Endpoints ........................................................................................26 
7.4. 
Prevention of Missing Data ........................................................................................26 
8. 
SELECTION OF SUBJECTS ....................................................................................28 
8.1. 
Subject Inclusion Criteria ...........................................................................................28 
8.2. 
Subject Exclusion Criteria ..........................................................................................28 
8.3. 
Continuation Criteria ..................................................................................................29 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................30 
9.1. 
Description of Study Drug ..........................................................................................30 
9.1.1. 
Glycopyrrolate and Placebo ........................................................................................30 
9.1.2. 
Albuterol .....................................................................................................................30 
9.1.3. 
Ipratropium .................................................................................................................30 
9.1.4. 
Inhaled Corticosteroid ................................................................................................30 
9.2. 
Study Drug Packaging and Labeling ..........................................................................31 
9.2.1. 
Package Description ...................................................................................................31 
9.2.2. 
Labeling Description ..................................................................................................31 
9.3. 
Study Drug Storage .....................................................................................................32 
9.4. 
Dispensing of Study Drug ..........................................................................................32 
9.5. 
Study Drug Accountability .........................................................................................32 
9.6. 
Study Drug Handling and Disposal ............................................................................32 
10. 
TREATMENT OF SUBJECTS ..................................................................................33 
10.1. 
Study Medication ........................................................................................................33 
10.2. 
Treatment Compliance ................................................................................................33 
10.3. 
Concomitant Medications and Therapies ...................................................................33 
10.4. 
Contraception Requirements ......................................................................................34 
10.5. 
Guidance for Overdose ...............................................................................................35 
11. 
STUDY ASSESSMENTS ..........................................................................................36 
11.1. 
Demographics and Baseline Characteristics ...............................................................36 
11.2. 
Modified Medical Research Council Dyspnea Scale (mMRC) ..................................36 
11.3. 
St. George’s Respiratory Questionnaire (SGRQ) .......................................................36 
11.4. 
Efficacy Assessments .................................................................................................36 


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11.4.1. 
Plethysmography ........................................................................................................36 
11.4.2. 
Spirometry ..................................................................................................................37 
11.5. 
Safety Assessments .....................................................................................................38 
11.5.1. 
Pretreatment Events and Adverse Events ...................................................................38 
11.5.2. 
12-Lead Electrocardiograms (ECG) ...........................................................................38 
11.5.3. 
Clinical Laboratory Tests ...........................................................................................38 
11.5.4. 
Physical Examination .................................................................................................39 
11.6. 
Exploratory Assessments ............................................................................................39 
11.6.1. 
AccelerateIQ System ..................................................................................................39 
11.6.2. 
Vital Signs ..................................................................................................................39 
11.7. 
Study Visits and Assessments ....................................................................................39 
11.7.1. 
Screening: Visit 1 (Day -17 to -2) ..............................................................................39 
11.7.2. 
Treatment Period ........................................................................................................41 
11.7.2.1. 
Treatment 1: Visit 2 (Day 1) .......................................................................................41 
11.7.3. 
Treatment 2/End of Study: Visit 3 (Day 9 + 3) ..........................................................41 
11.7.4. 
Follow-up/Early Termination .....................................................................................42 
12. 
SAFETY REPORTING ..............................................................................................43 
12.1. 
Definitions ..................................................................................................................43 
12.1.1. 
Adverse Events ...........................................................................................................43 
12.1.2. 
Serious Adverse Events ..............................................................................................43 
12.2. 
Objective Findings ......................................................................................................44 
12.3. 
Collection and Recording of Adverse Events .............................................................45 
12.4. 
Immediately Reportable Events ..................................................................................46 
12.4.1. 
Serious Adverse Event ................................................................................................46 
12.4.2. 
Pregnancy ...................................................................................................................47 
13. 
TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF 
STUDY DRUG ...........................................................................................................48 
14. 
STUDY TERMINATION ..........................................................................................49 
15. 
STATISTICS ..............................................................................................................50 
15.1. 
Sample Size ................................................................................................................50 
15.2. 
Analysis Populations ..................................................................................................50 
15.3. 
Data Analysis ..............................................................................................................50 
15.3.1. 
Subject Disposition .....................................................................................................51 


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15.3.2. 
Drug Exposure and Compliance .................................................................................51 
15.3.3. 
Important Protocol Deviations ....................................................................................51 
15.3.4. 
Demographic and Baseline Characteristics ................................................................51 
15.3.5. 
Efficacy Analyses .......................................................................................................51 
15.3.5.1. 
Primary Efficacy Endpoint Analysis ..........................................................................52 
15.3.5.2. 
Other Efficacy Endpoint Analysis ..............................................................................52 
15.3.5.3. 
Adjustment for Multiplicity ........................................................................................53 
15.3.6. 
Exploratory Endpoint Analyses ..................................................................................53 
15.3.7. 
Safety Analyses ..........................................................................................................53 
15.3.7.1. 
Adverse Events ...........................................................................................................53 
15.3.7.2. 
Clinical Laboratory Assessments ...............................................................................54 
15.3.7.3. 
12-Lead ECGs ............................................................................................................55 
15.3.7.4. 
Physical Examination .................................................................................................55 
15.3.7.5. 
Prior and Concomitant Medications ...........................................................................55 
15.3.8. 
Interim Analysis ..........................................................................................................55 
15.3.9. 
Treatment of Missing Data .........................................................................................55 
16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL /DATA 
COLLECTION, MANAGEMENT, AND QUALITY ASSURANCE ......................56 
16.1. 
Data Collection/Electronic Data Capture (EDC) ........................................................56 
16.2. 
Study Monitoring ........................................................................................................56 
16.3. 
Audits ..........................................................................................................................56 
16.4. 
Study Documentation .................................................................................................56 
16.5. 
Clinical Laboratory Certification and Normal Values ................................................57 
17. 
ETHICAL AND REGULATORY OBLIGATIONS..................................................58 
17.1. 
Study Conduct ............................................................................................................58 
17.2. 
Institutional Review Board .........................................................................................58 
17.3. 
Informed Consent .......................................................................................................59 
17.4. 
Subject Privacy ...........................................................................................................59 
17.5. 
Protocol Amendments and Emergency Deviations ....................................................59 
17.6. 
Records Retention .......................................................................................................60 
17.7. 
Inspection of Records .................................................................................................60 
17.8. 
Financial Disclosure ...................................................................................................60 
17.9. 
Publication Policy .......................................................................................................60 


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17.10. 
Compensation .............................................................................................................61 
18. 
REFERENCES ...........................................................................................................62 
19. 
INVESTIGATOR APPROVAL .................................................................................64 
20. 
APPENDIX I. CARDIAC SAFETY MONTIORING (ECG) ....................................65 
21. 
APPENDIX II. CLINICAL LABORATORY TESTS ...............................................66 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ..............................................................................................9 
Table 3: 
List of Abbreviations ..................................................................................................16 
Table 4: 
Definition of Key Study Terms ..................................................................................18 
Table 5: 
Investigational Product ...............................................................................................30 
Table 6: 
Current COPD Medication Withhold Intervals ..........................................................33 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................23 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The abbreviations and the definition of key study terms used in the clinical study protocol are 
shown in Table 3 and Table 4. 
Table 3: List of Abbreviations 
 
Abbreviation 
Full Form 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AUC0-x hr 
Area under the curve from time zero to x hours postdose 
CAP 
College of American Pathologists 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case report form 
CRO 
Contract research organization 
CTM 
Clinical trial material 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
ET 
Early Termination 
FDA 
U.S. Food and Drug Administration 
FEV1 
Forced expiratory volume in one second  
FRC 
Functional residual capacity 
FVC 
Forced vital capacity  
GCP 
Good Clinical Practice 
GIS 
Glycopyrrolate inhalation solution  
GOLD 
The Global Initiative for Chronic Obstructive Lung Disease 
IC 
Inspiratory capacity  
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
ICS 
Inhaled corticosteroid 
IPD 
Important protocol deviation 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
IRB 
Institutional Review Board 
LABA 
Long-acting beta2-agonists 
LABD 
Long-acting bronchodilator 
LAMA 
Long-acting muscarinic agent 
LDPE 
Low-density polyethylene 
MAR 
Missing at random 
mcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention-to-Treat 
mMRC 
Modified Medical Research Council Dyspnea Scale 
MNAR 
Missing not at random 
PFT 
Pulmonary function tests 
POC 
Point of care 
PIS 
Placebo inhalation solution 
PT 
Preferred term 
PVG 
Pharmacovigilance 
Q1 
Quartile 1 
Q3 
Quartile 3 
RV 
Residual volume 
Raw 
Airway resistance 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SAE 
Serious adverse event 
SGRQ 
St. George’s Respiratory Questionnaire 
SOC 
System organ class 
sRAW 
Specific airway resistance 
TLC 
Total lung capacity 
WBC 
White blood cells 
WHO-DD 
World Health Organization Drug Dictionary 


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Table 4: Definition of Key Study Terms 
Terms 
Definition of terms 
CRF 
A printed, optical, or electronic document 
designed to record all of the protocol required 
information to report to the Sponsor for each study 
subject. 
Screened Subject 
Any subject who signed the study specific 
informed consent and completed at least one study 
related procedure. 
Screen Failures 
Any subject who signed the study specific 
informed consent but either failed to meet study 
requirements during screening or met study 
requirements at screening but was not 
enrolled/randomized. 
Study Drug (or Study medication) Term to cover investigational drug and placebo. 
Treatment Period 
The period of the study in which the study drug is 
administered. 
Randomized Subject 
Any subject who was randomized into a treatment 
sequence of the study and was assigned a 
randomization number. 
Enrolled Subject 
Any subject who was successfully screened and 
enrolled into the pre-randomization period of the 
study. 
Randomization Failures 
Any subject who was enrolled but not randomized. 
Completed Subject 
Any subject who participated throughout the 
duration of Day 9. 
Early Termination Subject 
Any subject who was successfully screened and 
randomized to a treatment sequence, but did not 
complete both treatments during the randomized 
treatment period. 
End of Treatment 
The day that the subject receives the protocol-
defined last dose of study drug. 
End of Study 
The day that the subject completes the study per 
the study design. 


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4. 
INTRODUCTION 
4.1. 
Background 
Chronic obstructive pulmonary disease (COPD) is the major component of chronic lower 
respiratory diseases, which is the fourth leading cause of death in the United States 
(Kochanek 2016). In addition to mortality COPD also places a large economic burden in the US 
with direct and indirect cost estimated to be about $52 billion (Guarascio 2013). COPD is 
characterized by persistent respiratory symptoms and airflow limitation that is due to airway 
and/or alveolar abnormalities (GOLD 2019). The main risk factor for COPD is tobacco smoking. 
Lung hyperinflation (LH) which is defined by an abnormal increase of the volume of gas in the 
lungs and airways at the end of tidal expiration (Rossi 2015) is another important aspect of 
COPD that has major clinical consequences (Langer 2014, Thomas 2013). LH plays a central 
role in the pathophysiology of dyspnea and exercise limitation in COPD and has been shown to 
be an independent predictor of exacerbations (Chen 2016, Rossi 2015). It has also been linked to 
impairment of cardiac function by potentially causing by causing increased pressures in the 
cardiopulmonary system, right-ventricular dysfunction, impaired left-ventricular filling and 
reduced cardiac output (Hohfeld 2018, Rabe 2018). 
Long-acting antimuscarinic antagonists (LAMAs) and long-acting beta2-agonists (LABAs) are 
central to the long-term maintenance treatment of symptoms in COPD (GOLD 2019). Several 
studies have demonstrated the benefits of long-acting bronchodilators delivered via dry powder 
inhalers on lung deflation (Hohfeld 2018, Fujimoto 2017, Watz 2017, Santus 2015, Beeh 2011). 
Lonhala Magnair is the first approved nebulized LAMA (glycopyrrolate) for the treatment of 
COPD in the US (Lonhala Magnair product labeling) which allows the investigation of a 
nebulized LAMA on LH in patients with COPD. 
4.2. 
Study Conduct Rationale 
Glycopyrrolate inhalation solution (GIS; Lonhala Magnair) is a nebulized long-acting 
antimuscarinic antagonist (LAMA) indicated for the long-term maintenance treatment of airflow 
obstruction in patients with COPD, including chronic bronchitis and/or emphysema. COPD is 
characterized by expiratory flow limitation, resulting in air trapping and lung hyperinflation. 
Hyperinflation is the increased volume of air remaining in the lung at the end of spontaneous 
expirations. Lung hyperinflation is a major contributor to dyspnea in patients with COPD 
(Laveneziana 2012). Studies in COPD have shown that long-acting bronchodilators (LABD) 
administered with hand-held devices reduce hyperinflation. It has been hypothesized that distal 
penetration of LABD administered by nebulization will have a positive impact on hyperinflation 
irrespective of disease severity (Loh 2015). The Magnair device is a closed system nebulizer 
using the eFlow technology which generates a soft aerosol mist of the drug solution with a 
droplet size distribution and acceptable respirable fraction suitable for peripheral lung deposition. 
This study will provide information on the effects of a single dose of GIS on lung hyperinflation 
over 6 hours in COPD subjects with hyperinflation. 


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4.3. 
Risk-Benefit Assessment 
Lonhala Magnair is indicated for the long-term maintenance treatment of airflow obstruction in 
patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or 
emphysema. The recommended dose of LONHALA is the inhalation of the contents of one 
LONHALA vial (25 mcg) twice-daily using MAGNAIR. 
4.4. 
Hypothesis 
In adults with COPD subjects as characterized by the study inclusion/exclusion criteria, after 
2 cross-over periods of treatment, the primary null hypothesis for this study is that the mean 
change of RV from baseline at 6 hours postdose for a single dose of GIS is equal to the mean 
change of RV from baseline at 6 hours postdose for a single dose of placebo inhalation solution 
(PIS). The alternative hypothesis is that these means are different. 
 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective 
• To compare the efficacy of GIS versus PIS on lung hyperinflation following a single 
dose, as measured by residual volume (RV) at 6 hours postdose. 
5.2. 
Other Efficacy Objective 
• To evaluate the effect of a single dose of GIS versus PIS on objective measures of 
lung function. 
5.3. 
Exploratory Objective 
• To evaluate the feasibility of using the accelerateIQ System (ie, the VitalPatch® 
Biosensor and accelerateIQ Platform). 
 


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6. 
STUDY ENDPOINTS 
6.1. 
Primary Efficacy Endpoint 
• Change from baseline in RV at 6 hours postdose 
6.2. 
Other Efficacy Endpoints 
• Standardized change from baseline in RV area under the curve from time 0 to 4 hours 
postdose (AUC0-4h) and RV area under the curve from time 0 to 6 hours postdose 
(AUC0-6h) 
• Change from baseline in inspiratory capacity (IC) at 6 hours postdose 
• Standardized change from baseline in IC AUC0-4h and IC AUC0-6h 
• Change from baseline in functional residual capacity (FRC) at 6 hours postdose 
• Standardized change from baseline in FRC AUC0-4h and FRC AUC0-6h 
• Change from baseline in total lung capacity (TLC) at 6 hours postdose 
• Standardized change from baseline in TLC AUC0-4 h and TLC AUC0-6h 
• Change from baseline in specific airway resistance (sRaw) at 6 hours postdose 
• Standardized change from baseline in specific Airway Resistance (sRAW) AUC0-4h 
and sRaw AUC0-6h 
• Change from baseline in airway resistance (Raw) at 6 hours postdose 
• Standardized change from baseline in Raw AUC0-4h and Raw AUC0-6h 
• Change from baseline in RV, IC, FRC, TLC, sRaw, and Raw at 1, 2, 3, and 4 hours 
postdose 
• Change from baseline in forced expiratory volume in 1 second (FEV1) at 6 hours 
postdose 
6.3. 
Safety Endpoints 
• Incidence of adverse events, serious adverse events, and adverse events leading to 
discontinuation 
6.4. 
Exploratory Endpoint 
• Vital sign data collected at clinic visits and data collected using the accelerateIQ 
System 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a single center, randomized, double-blind, placebo-controlled, single-dose 2-way 
crossover study in approximately 20 adult subjects ≥ 40 years of age with COPD. The study is 
designed to evaluate the effect of a single dose of GIS on lung hyperinflation. The two study 
treatments, both administered using the Magnair device are:  
• GIS 25 mcg 
• PIS 
The study will consist of a Screening period, a randomized 2-way cross-over treatment period 
during which subjects will receive two single-doses each separated by a 7-day washout period, 
and a follow-up 7 (± 2) days after the last study drug dose. 
A study schematic is provided in Figure 1, and detailed descriptions and timing of assessments is 
provided in Section 11. 
Figure 1: 
Study Schematic 
 
GIS = Glycopyrrolate Inhalation Solution  
PIS = Placebo Inhalation Solution 
 
Visit 1 - Screening (Days -17 to -2) 
Written informed consent will be obtained from subjects before any study procedures are 
performed. Screening visit procedures are outlined in Table 2. Screening (Visit 1) may occur 
over more than one clinic visit and may last up to 17 days in order to determine study eligibility 
and to allow for appropriate washout of prohibited medications. 


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If needed, subjects will be dispensed albuterol as rescue medication at the Screening visit 
(Visit 1). Subjects who are required to switch from taking LABA/inhaled corticosteroid (ICS) to 
ICS monotherapy will be provided with an ICS. 
 
Visit 2 – Treatment Period 1 (Day 1) 
Subjects will return to the clinical site in the morning on Day 1. Subjects who continue to meet 
the study eligibility criteria will be randomized to 1 of 2 crossover treatment sequences with a 
1:1 allocation ratio. A single dose of study drug will be administered by the clinical staff 
between approximately 6:00 – 10:00 AM on Day 1 according to the randomization schedule. In 
order to maintain the blind during study drug administration, an unblinded clinical site staff 
member will perform the randomization and prepare and administer the study drug according to 
the randomization schedule. The unblinded study personnel will not perform any other study 
procedures. 
Lung volume measures (plethysmography) will be performed 45 minutes prior to administration 
of study drug dose on Day 1, and at 1, 2, 3, 4, and 6 hours postdose. Spirometry measures will be 
performed 45 minutes prior to administration of study drug and again 6 hours postdose. At both 
timepoints, spirometry will be performed after plethysmography. At each time point, 
plethysmography and spirometry assessments will have a window of ± 15 minutes. Additional 
study procedures identified in Table 2 will be completed at this visit. 
There will be a wash-out period of 7 (+ 2) days after dosing on Day 1. 
Visit 3 – Treatment Period 2/End of Study (EOS): (Day 9 [+3]) 
Subjects will return to the clinical site in the morning on Day 9 (+ 3) for Treatment Period 2. 
Subjects who continue to meet the study eligibility criteria will have a single dose of study drug 
administered by the clinical staff between 6:00 – 10:00 AM (and within 1 hour of Treatment 
Period 1 dosing time) according to the treatment sequence assigned.  
Lung volume measures (plethysmography) will be performed at 45 minutes prior to 
administration of study drug dose on Day 9, and at 1, 2, 3, 4, and 6 hours postdose. Spirometry 
measures will be performed 45 minutes prior to dosing and again 6 hours postdose. At both 
timepoints, spirometry will be performed after plethysmography. At each time point, 
plethysmography and spirometry assessments will have a window of ± 15 minutes. Additional 
study procedures identified in Table 2 will be completed at this visit. 
Subjects who discontinue prior to completion of Day 9 will undergo Early Termination 
procedures and assessments at the time of discontinuation.  
Follow-up 
Female subjects of childbearing potential who were dosed will return to the clinic for a serum 
pregnancy test and final safety assessments 7 (± 2) days after their last study drug dose. All other 
dosed subjects will either be contacted by telephone or have an in-clinic visit if deemed clinically 
warranted by the Investigator 7 (± 2) days after their last study drug dose for a final safety 
assessment (adverse events and concomitant medication use). 


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7.2. 
Treatment Assignment and Blinding 
After a subject provides written informed consent, a unique subject number will be assigned at 
screening, consisting of a 3-digit protocol number, 3-digit site number, and a unique 3-digit 
subject identifier (eg, the second screened subject from site 001 will be 402001002). Subjects 
will be numbered consecutively beginning with 001. No subject numbers are to be reused once 
assigned. This number will track a subject throughout their participation in the study.  
Subjects who passed study entry criteria and did not get randomized can be rescreened once to 
determine eligibility. Subjects who are rescreened must be assigned a new screening number. 
7.2.1. 
Treatment Assignment 
The randomization schedule, a sequential list consisting of the randomization numbers and their 
corresponding treatment sequence assignment, will be generated by a non-study biostatistician 
according to the process defined by the Sponsor/contract research organization (CRO)’s standard 
operating procedure (SOP). 
Once a subject is deemed eligible to be randomized at Day 1 / Visit 2 and prior to dosing, all 
eligible subjects will be given a randomization number by the unblinded clinical staff member 
that assigns them to one of the two treatment sequences. Subjects will be randomized to one of 
the two following treatment sequences in a 1:1 ratio: 
• Treatment sequence A→B (10 subjects): Single dose of GIS 25 mcg (Treatment A) to 
matching PIS (Treatment B). 
• Treatment sequence B→A (10 subjects): Matching PIS (Treatment B) to single dose 
of GIS 25 mcg (Treatment A). 
Between each treatment sequence, subjects will undergo a washout period before returning to the 
clinic for the corresponding next treatment. 
Randomization numbers will be assigned sequentially in the order the subject becomes eligible 
to participate in the study. Once a randomization number is assigned, it cannot be reused. 
7.2.2. 
Blinding 
This is a double-blind study. 
During the conduct of the study, in order to maintain the blind during the time of study drug 
administration, up until the analysis is conducted, an unblinded clinical staff member will 
perform the randomization and prepare and administer the study drug according to the 
randomization schedule. The unblinded study personnel will not perform any other blinded study 
procedures. All study drugs will be dispensed according to the randomization schedule to be 
supplied by Sponsor’s representative, using a written study drug dispensing procedure that will 
assure that subjects remain blinded to the treatment being administered. 
An unblinded clinical staff member will prepare and quality check each dose for each subject as 
instructed in the pharmacy manual according to the randomization schedule and other applicable 
local regulations as set forth in the protocol. 
Subjects, Investigator staff, persons performing the assessments, clinical operations personnel, 
data analysts, and personnel at the laboratory will remain blinded to the identity of the treatment 


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from the time of randomization until database lock and unblinding, using the following 
method:  randomization data are kept strictly confidential (eg, sealed envelopes kept in a locked 
filing cabinet or placed in a safe at the study center and the randomization schedule created by 
the randomization administrator are kept in a secure location with restricted access) until the time 
of unblinding, and will not be accessible by anyone else involved in the treatment study with the 
exception of the Sponsor’s clinical trials materials manager. 
Details of blinding will be provided in the pharmacy manual. 
7.2.3. 
Emergency Unblinding Procedures 
For emergency unblinding purposes, the Investigator will be provided with a sealed envelope for 
each subject. The cover sheet of the envelope will contain the protocol number and individual 
subject randomization number. Inside, this envelope will contain information about the 
investigational product given to the subject according to the treatment schedule. The envelope 
may only be opened in the case of emergency when knowledge of the treatment is needed to treat 
the subject. Date and reason for unblinding are to be documented on the envelope and the case 
report form (CRF). In the case of unblinding, the Investigator has to withdraw the subject from 
further study participation. These individual subject envelopes should be stored in a secure 
location and returned to the Sponsor/CRO, at the end of study. 
7.3. 
Rationale 
7.3.1. 
Rationale for the Study Design 
The study was designed to evaluate the effect of a single dose of Lonhala Magnair on lung 
hyperinflation, as measured by RV, as compared with placebo. The crossover design allows for 
subjects to serve as their own control. 
7.3.2. 
Rationale for the Dosages 
The labeled dose for Lonhala Magnair will be utilized in this study. Results of this study will 
provide information on the effect of a nebulized LAMA on lung hyperinflation following a 
single dose. 
7.3.3. 
Rationale for the Study Population 
In order to enrich the subjects with hyperinflation, a cutoff value of RV ≥ 130% predicted will be 
selected for this study. Patients with an RV ≥ 130% predicted are considered to be hyperinflated. 
7.3.4. 
Rationale for the Endpoints 
Residual volume was selected because it has been shown to demonstrate the most consistent 
physiological improvement following acute bronchodilator therapy across The Global Initiative 
for Chronic Obstructive Lung Disease (GOLD) stages. 
7.4. 
Prevention of Missing Data 
In an effort to minimize the number of subjects who are terminated from the study prior to study 
completion, the following study design and conduct elements are implemented: eg, (i) use of a 
single study center with an established history of enrolling and following eligible subjects with 


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chronic respiratory diseases, (ii) use of a study center with experience in conducting 
plethysmography and spirometry assessments, (iii) train the study center on the importance of 
continued follow-up and on the informed consent process, ensuring subjects understand the 
commitment they are making, including the intent to complete the trial, and, (iv) monitor data 
collection via on-site and/or centralized monitoring for adherence during the study, and (vi) 
rescue medication will be permitted during the study as indicated in Table 6. 
Please see Section 15.3 for statistical considerations related to missing data. 


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8. 
SELECTION OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Subjects who fulfill the following criteria will be included in the study: 
1. Subject is male or female and ≥ 40 years of age at Screening with a confirmed diagnosis 
of COPD. 
2. Subject must have the ability to comprehend the informed consent form and be willing to 
provide informed consent. 
3. Subject must possess an educational level and degree of understanding of English that 
enables them to communicate suitably with the Investigator and the study coordinator. 
4. Subject has a postbronchodilator (following inhalation of ipratropium bromide) 
FEV1 ≥ 30% and < 80% of predicted normal at Screening. 
5. Subject has a postbronchodilator (following inhalation of ipratropium bromide) 
FEV1/FVC ratio of < 0.70 at Screening. 
6. Subject has a RV ≥ 130% predicted value at Screening (prior to reversibility testing). 
7. Subject is a current or former smoker with at least 10 pack-years of cigarette smoking 
history at Screening. 
8. Subject has a score of ≥ 2 on the Modified Medical Research Council Dyspnea Scale 
(mMRC) at Screening. 
9. Subject, if female of child bearing potential, must have a negative serum pregnancy test 
at Screening. Females of childbearing potential must be instructed to and agree to avoid 
pregnancy during the study and must use an acceptable method of birth control: a) an oral 
contraceptive, an intrauterine device (IUD), implantable contraceptive, transdermal or 
injectable contraceptive for at least 30 days prior to entering the study with continued use 
throughout the study and for thirty days following participation; b) barrier method of 
contraception, eg, condom and /or diaphragm with spermicide while participating in the 
study; and/or c) abstinence. A follicle stimulating hormone (FSH) test will be used to 
confirm menopause in postmenopausal females. 
10. Subject is willing and able to attend all study visits and adhere to all study assessments 
and procedures. 
8.2. 
Subject Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from study participation: 
1. Subject is female who is pregnant or lactating or are planning on becoming pregnant 
during the study. 
2. Subject has a history of asthma. 
3. Subject has a blood eosinophil count > 5% of total white blood cell count. 
4. Subject has life-threatening/unstable respiratory status, including upper or lower 
respiratory tract infection, within the previous 30 days prior to Screening. 


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5. Recent history of COPD exacerbation requiring hospitalization or need for increased 
treatments for COPD within 12 weeks prior to Screening. 
6. Use of daily oxygen therapy > 12 hours per day. 
7. Subject is unable to perform plethysmography. 
8. Subject is unable to use the Magnair Nebulizer System. 
9. Subject has history of narrow angle glaucoma. 
10. Subject has history of or clinically significant ongoing bladder outflow obstruction or 
history of catheterization for relief of bladder outflow obstruction within the previous 
6 months prior to screening. 
11. Subject has history of long QT syndrome. 
12. Subject has a QTcF > 450 msec (males) or > 470 msec (females) at Screening, unless 
discussed with and approved by the Medical Monitor. 
13. Subject has a cardiac implanted device (internal defibrillator, pacemaker). 
14. Current severe heart failure (New York Heart Association Class IV) [New York Heart 
Association, 1994]. 
15. Subject has history of malignancies within the past 5 years, with the exception of basal 
cell carcinoma. 
16. Subject has known comorbidities including unstable cardiac, pulmonary, or psychiatric 
disease, or any other medical conditions that would, in the opinion of the Investigator, 
preclude the subject from safely completing the required tests or the study, or is likely to 
result in disease progression that would require withdrawal of the subject. 
17. Subject has participated in another investigational drug study (within 30 days prior to 
Screening). 
18. Subjects who are study site staff members or relatives of study site staff members. 
19. Subjects with a history of allergic reaction to glycopyrrolate, tiotropium, albuterol, or any 
components of the study medications. 
20. Subjects with a known allergy to hydrocolloid gel adhesive are excluded from wearing 
the VitalPatch Biosensor. 
8.3. 
Continuation Criteria 
• Subject has not had an exacerbation of COPD. 
• Subject completes the 7-day washout period and continues to withhold restricted 
medications. 
• In the opinion of the Investigator, the subject has not had any change that would put 
the safety of the subject at risk through participation. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Description of Study Drug 
9.1.1. 
Glycopyrrolate and Placebo 
Glycopyrrolate and placebo will be provided as solution for inhalation via nebulization (see 
Table 5). 
Glycopyrrolate will be provided as Glycopyrrolate inhalation solution (commercially available 
Lonhala Magnair Inhalation Solution). 
Table 5: 
Investigational Product 
Attribute 
Investigational Product 
Product name 
Glycopyrrolate 
Placebo 
Dosage form 
Inhalation solution 
Inhalation solution 
Unit dose 
25 mcg 
NA 
Route of administration 
eFlow Closed System Nebulizer 
eFlow Closed System Nebulizer 
Physical description 
Each single use vial contains l mL 
of clear, colorless, sterile, 
preservative-free aqueous 
solution 
Each single use vial contains l mL 
of clear, colorless, sterile, 
preservative-free aqueous 
solution 
 
9.1.2. 
Albuterol 
Albuterol HFA will be used as rescue medication on an as-needed basis during the study and will 
be provided by the site. 
9.1.3. 
Ipratropium  
Ipratropium bromide metered dose inhaler (MDI) will be used for reversibility testing at 
Screening and will be provided by the site. 
9.1.4. 
Inhaled Corticosteroid 
An inhaled corticosteroid will be provided by the site to subjects switching from a long-acting 
beta2 agonist (LABA)/inhaled corticosteroid (ICS) to ICS monotherapy. 
Subjects taking LABA/ICS or taking ICS monotherapy need to be on a stable dose for at least 
4 weeks prior to Screening in order to be eligible for a switch to ICS monotherapy or 
continuation of ICS monotherapy. This switch can be made at the time the informed consent 
form (ICF) is signed and Screening pulmonary function tests (PFTs) can be assessed 48 hours 
later to allow for the LABA washout. 


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9.2. 
Study Drug Packaging and Labeling 
A sponsor designee will label, package, and/or ship the appropriate clinical trial material (CTM; 
including, but not limited to Investigational Medicinal Product (IMP)/Non-Investigational 
Medicinal Product (NIMP), nebulizers, ancillary supplies, etc.) to the sites. 
9.2.1. 
Package Description 
The Glycopyrrolate (Lonhala) will be provided in its commercial packaging (refer to packaging 
insert). Each carton will include 30 pouches containing 2 unit dose vials each. There will be a 
clinical label present for accountability purposes. Secondary labeling will be performed by a 
sponsor designee and will comply with 21 Code of Federal Regulations (CFR) Part 312.6. 
Placebo (manufactured at Holopack GmbH, Germany) is supplied in a unit dose low-density 
polyethylene (LDPE) drug vial. There are 2 vials per foil laminate pouch. There will be a weekly 
carton containing 9 pouches and a monthly carton containing 30 pouches. 
Magnair nebulizer will consist of the approved commercial packaging. Each carton will be clinically 
labeled. 
9.2.2. 
Labeling Description  
All packaging for the study medications may be labeled with: 
• Protocol number 
• Sponsor’s name and address 
• Compound/Code or name of investigational drug (if needed) 
• Content (eg number of tablets, strength) 
• Caution Statement (as needed) 
• Instructions for use and storage 
• Blank space for study center number and date opened (if needed) 
• Lot number 
• Randomization number (if needed) 
• Expiration date (if needed) 
• Visit number (if needed) 
• Unique medication number (if needed) 
• Space for subject identifiers (if needed) 
• Investigator information (if needed) 
• Child proof (if needed) 


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9.3. 
Study Drug Storage 
Glycopyrrolate and its matching placebo should be stored in the protective foil pouch at 
20°-25°C (68°-77°F). After opening the foil pouch, unused unit-dose vials should be returned to, 
and stored in, the foil pouch. The Investigator or designee is required to return all unused study 
drug to the Sponsor or designee as instructed. An opened unit-dose vial should be used right 
away. Empty vials should be returned to their original pouch after dosing. Do not use any unit-
dose vial if the solution is not colorless. 
9.4. 
Dispensing of Study Drug 
Investigational product should be maintained under the strict control of qualified site staff at all 
times. Appropriate guidelines should be followed in proper dispensation to the study participant. 
Proper handling and storage should be followed. This is outlined in the Pharmacy Manual or 
Appendices supplied to the site. Sponsor-defined dispensing guidelines should be followed for 
dispensing IP to the subject, in addition to all accountability records where required.  
Proper accountability records must be maintained and up to date capturing all drug dispensing 
activities. 
9.5. 
Study Drug Accountability 
The Investigator or designee is responsible for storing the drug in a secure location and for 
maintaining adequate records of drug disposition that includes the dates, quantity, and use by 
subjects. If the study is stopped for any reason or completed, all unused supplies of drug will be 
returned to the Sponsor, unless other instructions are provided in writing by Sponsor/CRO. 
To avoid the situation where any expired study drug is dispensed and used, the Sponsor should 
retrieve all study drug before expiration date. If the study drug is not returned/retrieved from the 
site before the expiration date, the Investigator or designee should store the expired study drug 
separately. 
9.6. 
Study Drug Handling and Disposal 
A drug inventory record will be supplied from Sponsor/CRO. The Investigator or designee on an 
ongoing basis must maintain a drug inventory record of supplied, received, dispensed, and 
returned medication. The Investigator or designee is required to return all unused study drug to 
the Sponsor or designee as instructed. The Investigator or designee is required to maintain copies 
of medication shipping receipts, drug accountability records, and records of return or final 
disposal of the study drug in accordance with local regulatory requirements. 


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10. 
TREATMENT OF SUBJECTS 
10.1. 
Study Medication  
The glycopyrrolate dose will consist of 25 mcg of oral inhalation solution per vial. 
Glycopyrrolate doses will be administered via the Magnair Nebulizer System. A single dose will 
be administered by clinical staff between approximately 6:00 – 10:00 AM on Day 1 or Day 9 
according to the randomization schedule. 
The placebo dose will consist of 0 mcg of oral inhalation solution per vial. Placebo doses will be 
administered via the Magnair Nebulizer System. A single dose will be administered by clinical 
staff between approximately 6:00 – 10:00 AM on Day 1 or Day 9 according to the randomization 
schedule. 
The site will observe the subject administer a dose of placebo via Magnair Nebulizer System 
during the screening visit to ensure the subject is able to use the device. 
10.2. 
Treatment Compliance 
All single-dose treatments will be administered under supervision in the clinic. The Investigator 
will record the date of dose administration. 
10.3. 
Concomitant Medications and Therapies 
The following information on all medication administered between Visit 1 (including 
medications taken within 30 days prior to Visit 1) and Follow-up 
or at discontinuation will be recorded on the CRF: Medication name, dose, frequency, route, 
start date, stop date, and indication. 
Information regarding format and version of coding dictionary is provided in the Data 
Management Plan (DMP). All medications will be coded using World Health Organization Drug 
Dictionary (WHO-DD). 
The following restrictions will be employed. 
Table 6: 
Current COPD Medication Withhold Intervals 
Medications Disallowed for Study Duration 
Required Withholding Interval 
Albuterol 
≥ 6 hours before each study visit, or at any time 
during study visits 
Ipratropium 
Study duration, except for reversibility testing at 
Screening (withhold ≥ 6 hours before reversibility 
testing 
Ipratropium/albuterol combination 
≥ 2 days prior to screening assessments and study 
duration 
Inhaled Corticosteroid/LABA combinationa 
≥ 2 days prior to screening assessments and study 
duration 
Long-acting beta-agonist 
≥ 2 days prior to screening assessments and study 
duration 


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Table 6: 
Current COPD Medication Withhold Intervals (Continued) 
Medications Disallowed for Study Duration 
Required Withholding Interval 
Long-acting muscarinic antagonist 
> 7 days prior to screening assessments and study 
duration 
Leukotriene Inhibitors  
> 7 days prior to screening assessments and study 
duration 
Theophylline  
> 7 days prior to screening assessments and study 
duration 
PDE-4 inhibitors (eg, roflumilast) 
> 14 days prior to screening assessments and 
study duration 
Abbreviations: ICF = Informed Consent Form; ICS = inhaled corticosteroid(s); LABA = long-acting beta agonist; PDE-
4 = phosphodiesterase type 4; PFT = pulmonary function test(s) 
a Subjects taking LABA/ICS or taking ICS monotherapy need to be on a stable dose for at least 4 weeks prior to Screening in 
order to be eligible for a switch to ICS monotherapy or continuation of ICS monotherapy. This switch can be made at the time 
the ICF is signed and Screening PFTs can be assessed 48 hours later to allow for the LABA washout. 
Albuterol HFA will be provided and permitted as rescue medication for as needed use any time 
during the study. Albuterol must be withheld prior to each study visit for at least 6 hours, and for 
the duration of each study visit, unless medically necessary. If rescue albuterol is used within 
6 hours prior to plethysmography and spirometry testing at any study visit, then the visit must be 
rescheduled or delayed to allow the appropriate washout. If rescue albuterol is required post-dose 
at any study visit, plethysmography and spirometry assessments will be continued as scheduled. 
10.4. 
Contraception Requirements 
For female subjects 
1. Female subject < 65 years-old and of child-bearing potential must be using and willing to 
continue using a medically acceptable form of birth control for at least 4 weeks prior to 
study drug administration and for at least 30 days after the last study drug administration. 
Medically acceptable forms of contraception include oral or patch hormonal 
contraceptives, intrauterine device, progestin implant or injection, bilateral tubal ligation, 
or double-barrier (i.e., male condom in addition to a diaphragm or a contraceptive 
sponge). Women using hormonal contraception must use an additional form of 
contraception. 
2. A female subject is eligible to enter and participate in the study if she is of: 
a. Non-childbearing potential (ie, physiologically incapable of becoming pregnant, 
including any female who is pre-menarchal or post-menopausal); 
− Postmenopausal females defined as being amenorrheic for greater than two years 
with an appropriate clinical profile. 
− Women who have not been confirmed as postmenopausal should be advised to 
use contraception as outlined below. 
− Women who have had a hysterectomy, bilateral oophorectomy or bilateral 
salpingectomy (as determined by subject’s medical history). 


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b. Child-bearing potential (all females ≤ 65 years of age), has a negative pregnancy test 
at screening and agrees to satisfy one of the following requirements: 
− Complete abstinence from intercourse (as part of an abstinent lifestyle) a 
minimum of 4 weeks prior to administration of the first dose of study drug, 
throughout the Treatment Period, and for a minimum of 30 days following last 
study drug administration, 
− Established use of acceptable methods of contraception a minimum of 4 weeks 
prior to administration of the first dose of study drug, throughout the Treatment 
Period, and for a minimum of 30 days following last study drug administration. 
− Acceptable methods of birth control are listed below: 
− Sterilization (vasectomy) of male partner prior to commencement of female 
subject’s last normal menstrual period prior to administration of the first dose 
of study drug, and the male partner is the sole partner for that female subject; 
or 
− Implants of levonorgestrel; injectable progesterone; or hormonal contraceptive 
(combined or progestogen only) (must have been taking reliably through at 
least one full menstrual cycle period). Subjects using implants, injectable, or 
hormonal contraceptives must use additional methods of contraception for the 
duration of the study ; or 
− Documented placement of an intrauterine device (IUD) with published data 
showing that the highest expected failure rate is less than 1% per year (not all 
IUDs meet this criterion); or 
− Any other method of contraception with data documented in the product labeling 
as approved by regulatory agencies, or in the absence of approved labeling, in 
peer reviewed studies, showing that the highest expected failure rate for that 
method is less than 1% per year. 
Because of the unacceptable failure rate of barrier (chemical and/or physical) methods, the 
barrier method of contraception must only be used in combination with other acceptable 
methods. Post-coital methods of contraception are not permitted. 
*A female condom and male condom should not be used together due to friction between the 
2 barrier methods reducing efficacy. 
For Male Subjects  
Male subject with female partner(s) of childbearing potential must ensure that their partner(s) 
uses the methods of contraception as outlined for female subjects above. 
10.5. 
Guidance for Overdose 
An overdose of glycopyrrolate may lead to anticholinergic signs and symptoms such as nausea, 
vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure (causing 
pain, vision disturbances, or reddening of the eye), obstipation or difficulties in voiding (refer to 
the approved product labeling for Lonhala Magnair). 


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11. 
STUDY ASSESSMENTS 
A study schematic is presented in Figure 1. A summary of assessments to be conducted at each 
visit is presented in Table 2. 
Assessments will be conducted within the time frames specified. All times are relative to the 
time of dosing for individual subjects unless otherwise specified. 
11.1. 
Demographics and Baseline Characteristics 
Subject demographics (date of birth, sex, ethnicity, race), height and weight will be recorded in 
the CRF. 
COPD exacerbation history (with and without hospitalization) will be recorded in the CRF. 
Smoking history will be recorded in the CRF. Number of pack years is calculated as 
(number of cigarettes per day / 20) x number of years smoked. 
Other medical history (relevant/significant medical history and recurrence of any condition) will 
also be recorded in the CRF. 
11.2. 
Modified Medical Research Council Dyspnea Scale (mMRC) 
The mMRC will be used as a screening tool at Visit 1 to determine patient eligibility. The 
modified Medical Research Council (mMRC) Dyspnea Scale (Mahler 1984), is a five-item 
instrument (part of the Borg scale) to assess a patient’s degree of breathlessness in relation to 
physical activity. Subjects will be required to read a brief description of an activity and then 
select a statement that best describes their experience with dyspnea at Visit 1. The questionnaire 
should be completed before any other assessments are conducted to avoid influencing the 
responses. 
Subjects must have a score ≥ 2 to be eligible for study participation. 
11.3. 
St. George’s Respiratory Questionnaire (SGRQ) 
Each subject will complete the St. George’s Respiratory Questionnaire (SGRQ) at the clinic site 
during the screening visit (Visit 1). The SGRQ is a standardized disease-specific, 50-item 
questionnaire designed to measure impact on overall health, daily life, and perceived will-being 
in patients with obstructive airway disease. The SGRQ must be completed by the subject in the 
clinic (Jones 1991). 
11.4. 
Efficacy Assessments 
11.4.1. 
Plethysmography 
Lung plethysmography (also called body plethysmography) will be used to measure absolute 
lung volumes. Changes in pulmonary gas volume are estimated by measuring pressure changes 
in the plethysmograph. Plethysmography measurements will be conducted in accordance with 
the current ATS/ERS 2005 guidelines (Wanger 2005). 
Measurements obtained during the test include: 


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• Total Lung Capacity (TLC) – The total volume of gas in the lungs after maximal 
inspiration, or the sum of all volume compartments. 
• Functional Residual Capacity (FRC) – The volume of gas present in the lung at 
end-expiration during tidal breathing. 
• Residual Volume (RV) – The volume of gas that remains in lungs after maximal 
exhalation. 
• Inspiratory Capacity (IC) – The maximum volume of gas that can be inspired from 
FRC. 
• Airway Resistance (Raw) 
• Specific Airway Resistance (sRaw) 
Study-qualifying plethysmography during Screening (Visit 1) may only be performed after the 
subject has completed the appropriate protocol-specified washout regimen of prohibited 
medications (See Section 10.3). In order to confirm study eligibility, the subject’s RV must be 
≥130% predicted value (prior to reversibility testing). 
Plethysmography will be performed at Screening prior to and 30-60 minutes (and no later than 
2 hours) following 68 mcg ipratropium MDI (4 puffs of 17 mcg per actuation). Plethysmography 
will be performed prior to spirometry. 
Serial plethysmography (Day 1 and Day 9) will be performed 45 minutes predose and again at 1, 
2, 3, 4, and 6 hours postdose. At each timepoint, plethysmography assessments will have a 
window of ± 15 minutes. Plethysmography will be performed prior to spirometry when 
timepoints coincide. 
11.4.2. 
Spirometry 
Spirometry assessments will be performed using a standardized, PC-based pneumotach 
spirometry system. Spirometry will involve the determination of FEV1, FVC, and FEV1/FVC 
ratio. Predicted FEV1 will be obtained using the normal prediction equations obtained from 
The Third National Health and Nutrition Examination Survey (NHANES III). Spirometry 
measurements will be conducted in accordance with the current ATS/ERS 2005 guidelines 
(Miller 2005). 
Study-qualifying spirometry assessments during Screening (Visit 1) may only be performed after 
the subject has completed the appropriate protocol-specified washout regimen of prohibited 
medications (See Section 10.3). In order to confirm study eligibility, the subject’s 
post-bronchodilator FEV1 (following inhalation of 68 mcg ipratropium MDI) must be ≥ 30% and 
< 80% predicted normal value. Additionally, the FEV1/FVC ratio must be < 0.70. 
Spirometry will be performed at Screening prior to and 30-60 minutes (and no later than 2 hours) 
following 68 mcg ipratropium MDI (4 puffs of 17 mcg per actuation). Spirometry will also be 
performed during the randomized treatment period on Day 1 and Day 9 at 45 minutes predose 
and again 6 hours postdose after plethysmography. At each time point, spirometry assessments 
will have a window of ± 15 minutes. Spirometry will be performed following plethysmography. 
At least 3 “acceptable” spirometry maneuvers (up to 8 blows total per time point) will be 
obtained during each assessment. The highest and second highest FEV1 values and the highest 


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and second highest FVC values should be within 150 mL to be acceptable. The single highest 
FEV1 and the single highest FVC values from acceptable and repeatable maneuvers are reported 
even if they do not come from the same maneuver. The FEV1/FVC ratio is determined from the 
reported highest FEV1 and highest FVC values. 
Spirometry reports will be printed out after each assessment and reviewed by the clinical site 
staff to ensure subject eligibility and safety; a hard copy should be filed in the subject’s source 
documentation. 
11.5. 
Safety Assessments 
The Investigator or appropriate designee will review results of safety assessments on a regular 
basis. 
11.5.1. 
Pretreatment Events and Adverse Events 
Pretreatment events will be collected for each subject from signing informed consent at Visit 1 to 
the time of the first dose of study medication (ie, the placebo dose administered via the Magnair 
Nebulizer System at Screening for training purposes). 
Adverse events will be collected for each subject from the time of the placebo dose (for training 
purposes) administered at Visit 1 to Follow-up. Subjects should be queried in a non-leading 
manner, without specific prompting (eg, “Has there been any change in your health status since 
your last visit?”). See Section 12, Safety Reporting. 
Information regarding format and version of coding dictionary is provided in the DMP. 
AEs and serious adverse events (SAEs) will be monitored throughout the study at all visits.  
11.5.2. 
12-Lead Electrocardiograms (ECG) 
All ECGs will be obtained in the supine position, after the subject has been resting supine for at 
least 5 minutes. ECG assessments will be performed and read locally. ECGs will be 12-lead with 
a 10-second rhythm strip. The screening ECGs should be obtained prior to obtaining blood 
samples. Refer to Section 20, Appendix I for additional information. 
11.5.3. 
Clinical Laboratory Tests 
The clinical laboratory tests required by protocol are listed in Section 21, Appendix II. 
Blood and urine samples will be collected for clinical laboratory tests. All clinical laboratory 
tests will be performed locally. For detailed instructions regarding clinical laboratory procedures, 
sampling, and shipping guidelines refer to the local clinical laboratory guidelines. Samples will 
be processed at a local laboratory. All clinical laboratories will be College of American 
Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA) (or equivalent) 
certified. 
Any POC (point of care) kits that are performed on site by study personnel rather than in a lab- 
must be CLIA waived and the study center must possess a CLIA certificate of Waiver. 
 


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11.5.4. 
Physical Examination 
A complete physical examination will be performed at Screening. 
11.6. 
Exploratory Assessments 
11.6.1. 
AccelerateIQ System  
The accelerateIQ System is a wireless remote patient monitoring system intended for use by 
healthcare professionals for continuous collection of physiological data in home and healthcare 
settings. The accelerateIQ System consists of the VitalPatch Biosensor (a 510k-cleared 
disposable patch with integrated biosensors and a wireless transceiver) and the accelerateIQ 
Platform (a smartphone with a cellular plan and a mobile application for data transmission, 
cloud-based information-technology [IT] infrastructure, physiology analytics modules, and 
clinician user interface). 
The patch is worn on the torso for up to 5 days and measures and records physiological data 
including heart rate, ECG, heart rate variability, R-R interval, respiratory rate, skin temperature, 
activity (including step count), and posture. Data are transmitted wirelessly from the VitalPatch 
Biosensor to the accelerateIQ IT platform for storage and analysis and presentation within the 
clinician user interface. 
11.6.2. 
Vital Signs 
Supine systolic and diastolic blood pressures, respiratory rate, pulse rate, and oral temperature 
will be measured following 5 minutes of seated rest. Vital signs will be collected at Screening 
and during the randomized treatment period on Day 1 and Day 9 at 45 (± 15) minutes prior to 
dosing and 60 (± 15) minutes postdose. Vital signs will be collected prior to plethysmography 
and spirometry when collection times coincide. 
11.7. 
Study Visits and Assessments 
11.7.1. 
Screening: Visit 1 (Day -17 to -2) 
Subjects who provide written informed consent to participate in this study will be evaluated at 
the Screening Visit to determine eligibility. Screening may occur over more than one visit. 
Abnormal Screening clinical laboratory tests may only be repeated after discussion with the 
Medical Monitor. 
To determine subject eligibility, Screening ECG may only be repeated due to technical issues. 
The following study-related procedures will be performed in the suggested order: 
• Review inclusion and exclusion criteria. 
• Record demographics. 
• Record medical history. 
• Record smoking status. 
• Record COPD exacerbation history with and without hospitalization. 


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• Record height and weight. 
• Administer Modified Medical Research Council Dyspnea Scale (score must be ≥ 2). 
• Administer St. Georges Respiratory Questionnaire (SGRQ) 
• Perform physical examination. 
• Obtain vital signs. 
• Perform 12-lead ECG 
• Collect blood and urine samples for: 
− Clinical safety laboratory tests 
− Serum βHCG pregnancy test (female subjects of childbearing potential) 
− Urinalysis 
• Begin washout of current/prohibited medications. 
• Dispense albuterol (rescue medication) if needed. 
• Dispense inhaled corticosteroid if needed. (Note: COPD subjects who washout of 
LABA/ICS must switch to ICS monotherapy that is equivalent to that contained in the 
LABA/ICS.) 
• Perform prebronchodilator plethysmography (RV must be ≥ 130% of predicted). 
• Perform prebronchodilator spirometry. 
• Perform postbronchodilator (ipratropium bromide) plethysmography. 
• Perform postbronchodilator spirometry immediately after plethysmography (FEV1 
must be ≥ 30% and < 80% of predicted and FEV1/FVC ratio must be < 0.70). 
• Observe subject administer placebo via the Magnair Nebulizer System to ensure that 
they are able to use the device. Subjects unable to use the Magnair Nebulizer System 
will be excluded from study participation. 
• Apply VitalPatch Biosensor. (Note: The VitalPatch Biosensor will be applied to 
subjects who provide additional informed consent for this assessment.) 
• Record prior and concomitant medications. 
• Record pretreatment events (up to time of administration of placebo via Magnair 
Nebulizer System for training purposes). 
• Record adverse events (after administration of placebo via Magnair Nebulizer System 
for training purposes). 
• Schedule next visit. 


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11.7.2. 
Treatment Period 
11.7.2.1. Treatment 1: Visit 2 (Day 1) 
Subjects will return to the clinic on Day 1. The Day 1 visit is to begin in the morning to allow for 
study drug dosing between approximately 06:00 and 10:00 AM. 
The following study-related procedures will be performed: 
• Review continuation criteria to ensure: 
− The subject has not had an exacerbation of COPD. 
− The subject has not had any changes that would put subject safety at risk. 
• Record adverse events. 
• Record concomitant medications. 
• Apply VitalPatch Biosensor. 
• Obtain vital signs 45 (± 15) minutes prior to dosing. 
• Perform plethysmography 45 (± 15) minutes prior to dosing. 
• Perform spirometry 45 minutes (± 15 minutes) prior to dosing. 
• Randomize subject (Day 1). 
• Administer single dose of study drug in the clinic between approximately 6:00 and 
10:00 AM. 
• Perform plethysmography at 1, 2, 3, and 4 hours after dosing. At each timepoint, 
assessments will have a window of ± 15 minutes. 
• Perform plethysmography at 6 hours (± 15 minutes) after dosing. 
• Perform spirometry at 6 hours (± 15 minutes) dosing. 
• Record vital signs 60 (± 15) minutes after dosing. 
• Record adverse events. 
• Remind subjects to continue to withhold restricted medications during the 7-day 
washout period. 
• Schedule next visit. 
11.7.3. 
Treatment 2/End of Study: Visit 3 (Day 9 + 3) 
Subjects will return to the clinic on Day 9. The Day 9 visit is to begin in the morning to allow for 
study drug dosing between approximately 06:00 and 10:00 AM. 
The following study-related procedures will be performed: 
• Review continuation criteria to ensure: 
− The subject has not had an exacerbation of COPD. 


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− The subject completes the 7-day washout period and continues to withhold 
restricted medications. 
− The subject has not had any changes that would put subject safety at risk. 
• Record adverse events. 
• Record concomitant medications. 
• Perform urine pregnancy test. 
• Apply VitalPatch Biosensor. 
• Obtain vital signs 45 (± 15) minutes prior to dosing. 
• Perform plethysmography 45 (± 15) minutes prior to dosing. 
• Perform spirometry 45 minutes (± 15 minutes) prior to dosing. 
• Administer single dose of study drug in the clinic between approximately 6:00 and 
10:00 AM and within 1 hour of Treatment Period 1 dosing. 
• Perform plethysmography at 1, 2, 3, and 4 hours after dosing. At each timepoint, 
assessments will have a window of ± 15 minutes. 
• Record vital signs 6 hours (± 15 minutes) after dosing. 
• Perform plethysmography at 6 hours (± 15 minutes) after dosing. 
• Perform spirometry at 6 hours (± 15 minutes) dosing. 
• Record vital signs 60 (± 15) minutes after dosing. 
• Record adverse events. 
• Schedule follow-up assessment. 
11.7.4. 
Follow-up/Early Termination 
All subjects will have a follow-up 7 (± 2) days after their last dose of study drug. 
Female subjects of childbearing potential who were dosed are required to return to the clinic for 
a serum pregnancy test and final safety assessment (adverse events and concomitant medication 
use). 
All other dosed subjects will either be contacted by telephone or have an in-clinic visit if deemed 
clinically warranted by the Investigator for final safety assessment (adverse events and 
concomitant medication use). 
Subjects who discontinue prior to completion of Day 9 will undergo Early Termination 
procedures and assessments at the time of discontinuation. 


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12. 
SAFETY REPORTING 
12.1. 
Definitions 
12.1.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
Untoward medical occurrences that occur between the time of signing the ICF and first drug 
administration (ie, the placebo dose administered via the Magnair Nebulizer System at Screening 
for training purposes) are pre-treatment events. Those that occur after first administration of 
study drug (ie, the placebo dose administered via the Magnair Nebulizer System at Screening for 
training purposes) are considered AEs. 
An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease occurring after the administration of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product. AEs may 
include the onset of new illness and the exacerbation of pre-existing conditions. AEs will be 
collected from after first administration of study drug to the last study visit/EOS visit. 
New signs and symptoms of underlying disease, or signs and symptoms of emerging disease 
must be recorded as AEs. 
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE 
and not the individual signs/symptoms. 
12.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) is an AE that meets one or more of the following criteria: 
• Results in death. 
• Is life-threatening. 
• Requires hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event that may jeopardize the subject or may require a 
medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization. 
The term "severe" is often used to describe the severity of a specific event (as in mild, moderate, 
or severe myocardial infarction) (see Section 12.3); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
"serious," which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject's life or functioning as defined by the criteria above. 


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During the study, if a subject has a hospitalization or procedure (eg, elective surgery) that was 
scheduled before the study entry, ie, before informed consent for an event/condition that 
occurred before the study, the hospitalization is considered a therapeutic intervention and not the 
result of a SAE. However, if the event/condition worsens during the study, it should be reported 
as an AE (or SAE, if the event/condition results in a serious outcome such as prolongation of 
hospitalization). 
Life-threatening means that the subject was, in the view of the Investigator, at immediate risk of 
death from the event as it occurred. This definition does not include an event that had it occurred 
in a more severe form might have caused death. 
SAE criteria information will be captured on the CRF. 
12.2. 
Objective Findings 
Clinically significant abnormal objective findings (eg, clinical laboratory value, ECG value, and 
physical examination observation) will also be recorded as AEs. 
When a clear diagnosis is available that explains the objective findings, this diagnosis will be 
recorded as the AE, and not the abnormal objective finding (eg, viral hepatitis will be recorded as 
the AE, not transaminase elevation). If a definite diagnosis is not available, then record the sign 
(eg, clinically significant elevation of transaminase levels) or symptom (eg, abdominal pain) as 
the AE. 
Clinical laboratory test results will be reviewed by the Investigator. The Investigator must 
determine the clinical significance of all out of range values. Clinical laboratory test with 
possibly drug-related or clinically relevant abnormal values of uncertain causality may be 
repeated. Any abnormal values that persist should be followed at the discretion of the 
Investigator. 
Clinical Laboratory Tests Outside the Normal Range: Any value outside the normal range will be 
flagged for the attention of the Investigator or appropriate designee at the study center. The 
Investigator or appropriate designee will indicate whether or not the value is of clinical 
significance. If the result of any test (or repeat test, if done) from the samples taken during 
Screening is indicated as clinically significant and is not covered by the inclusion criteria in 
Section 8.1 , the subject will not be allowed into the study. Additional testing during the study 
may be done if medically indicated. If a clinically significant abnormality is found in the samples 
taken after dosing, during the study, and/or at the Follow-Up Visit, this should be recorded as an 
AE and the subject will be followed until the test(s) has (have) normalised or stabilised. 
All on-site ECG tracings will be reviewed by the Investigator. The Investigator must determine 
the clinical significance of all abnormal ECGs. ECG with possibly drug-related or clinically 
relevant abnormal findings of uncertain causality may be repeated. Any abnormal ECGs that 
persist should be followed at the discretion of the Investigator. ECG tracings will be initialed and 
dated on all pages by the Investigator. 


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12.3. 
Collection and Recording of Adverse Events 
All pre-treatment events and AEs must be recorded in the subject’s study records/source 
documents in accordance with the Investigator’s normal clinical practice. All pre-treatment 
events and AEs/all AEs must be recorded on the CRF. 
All AEs will be followed until resolution, stabilization of the condition, the event is otherwise 
explained, or the subject is lost to follow-up. 
Each AE is to be evaluated for duration, severity, frequency, seriousness, action taken with the 
study treatment, outcome, and causal relationship to the study treatment. Definitions for severity, 
frequency, action taken with the study treatment, outcome, and causal relationship to the study 
treatment are presented below. 
The severity of AE: 
• Mild - Ordinarily transient symptoms that do not influence performance of subject’s 
daily activities. Other treatment is not ordinarily indicated. 
• Moderate - Marked symptoms sufficient to make the subject uncomfortable. 
Moderate influence on performance of subject’s daily activities. Other treatment may 
be necessary. 
• Severe - Symptoms cause considerable discomfort. Substantial influence on subject’s 
daily activities. May be unable to continue the study, and other treatment may be 
necessary. 
The frequency of AE: 
• Once – an isolated episode. 
• Intermittent – occurs on two or more separate occasions. 
• Continuous – does not abate from date of onset to date of resolution. 
The action taken with the study treatment: 
• Drug Interrupted – Study drug stopped temporarily. 
• Drug Withdrawn – Study drug stopped permanently. 
• Not Applicable. 
• Unknown 
The outcome of the AE: 
• Recovered/Resolved 
• Recovering/Resolving 
• Not Recovered/Not Resolved 
• Recovered/Resolved with Sequelae 
• Fatal 
• Unknown 


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The causal relationship of the AE to the study treatment:  
• Not related 
o  Not related - Improbable temporal relationship and is plausibly related to 
other drugs or underlying disease. 
• Related 
o Possible - occurred in a reasonable time after study drug administration, but 
could be related to concurrent drugs or underlying disease. 
o Probable - occurred in a reasonable time after study drug administration, is 
unlikely to be attributable to concurrent drugs or underlying disease, and there 
is a plausible mechanism to implicate the study drug. 
o Definite - occurred in a reasonable time after study drug administration and 
cannot be explained by concurrent drugs or underlying disease. The adverse 
event should respond to dechallenge/rechallenge, however, this is not 
mandatory before assigning a definite causality. 
The Medical Monitor is the initial contact person for protocol related questions or discussion of 
AEs. The contact information for the Medical Monitor as well as other emergency contact 
information can be found in Table 1 of this protocol. 
12.4. 
Immediately Reportable Events 
The following medical events must be immediately reported to the Sponsor: 
• SAE 
• Pregnancy 
Emergency contact information can be found in Table 1. 
12.4.1. 
Serious Adverse Event 
If the Investigator or study center staff becomes aware of a SAE that occurs in a study subject 
after signing the informed consent through 30 days following the last dose of the study 
medication, this must be reported immediately to the Sponsor whether considered related or 
unrelated to the study drug. SAEs must be recorded on the CRF and the data recorded should 
agree with that on the SAE form. 
Following the end of subject participation in the study, the Investigator or an authorized delegate 
should report SAEs “spontaneously” to PPD-PVG if considered at least possibly related to the 
study drug. 
SAEs will be followed until resolution, loss to follow-up, stabilization of condition, or the event 
is otherwise explained. 
In addition to the initial telephone notification, an initial SAE form as applicable must be 
completed and signed and sent via fax or email (see Table 1) to PPD-PVG within 1 business day 
of the Investigator or study center staff becoming aware of the event. The SAE form must be 


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signed by the Investigator or appropriate designee. The Sponsor provides the SAE form used to 
report SAEs. 
The Sponsor or designee will promptly notify all study centers and Investigators of a SAE that is 
determined to be expedited to the Regulatory Authorities in accordance with applicable law(s) 
and regulation(s). These SAEs must be promptly reported to the Institutional Review Board 
(IRB) by the Investigator or the appropriate person at the study center if required per IRB 
guidelines. 
12.4.2. 
Pregnancy 
Pregnancies that occur from the time that informed consent is signed through 30 days following 
the last dose of the study medication will be collected and reported on the Pregnancy Event 
Form. 
If a subject becomes pregnant during the course of the study, she will be instructed to commence 
discontinuation of the study medication. Further, the subject (or female partner of male subject) 
will be instructed to return within 48 hours of the first notification of pregnancy to the study 
center and undergo a serum/urine pregnancy test, as confirmation of pregnancy. If positive, the 
female pregnant subject will no longer receive any additional study medication. All pregnancies, 
whether or not the subject received any additional study medication, will be followed until 
resolution (ie, termination [voluntary or spontaneous] or birth). 
To report a pregnancy, the Pregnancy Event Form must be completed and sent via fax to the 
PPD-PVG within 1 business day of the Investigator or study center staff becoming aware of the 
pregnancy. 
If the subject received blinded study medication, unblinding of the study medication will be 
offered to the subject when knowledge of such treatment may have an impact on further 
treatment decisions. Otherwise, information regarding to what treatment the subject was assigned 
may be provided when the study has ended. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication or other AEs were detected. 


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13. 
TERMINATION OF SUBJECT FROM 
STUDY/DISCONTINUATION OF STUDY DRUG 
Subjects may be terminated from the study/discontinued from the study drug at any time for any 
of the following reasons: 
• Adverse event 
• Lost to follow-up (specify) 
• Withdrawal by subject (specify) 
• Protocol deviation (specify) 
• Death 
• Screen failure 
• Site terminated by Sponsor 
• Study terminated by Sponsor 
• Other (specify) 
If at any time during the course of the study, in the opinion of the Investigator, the subject may 
no longer safely participate due to a change in medical status (eg, experiences an AE, becomes 
pregnant), the subject must be discontinued from the study drug. 
The reason and information on the epoch for study drug discontinuation will be recorded on the 
appropriate CRF. In case of death, the date of death should be captured on the CRF. 
Discontinued subjects will not be replaced. At the Sponsor’s discretion, additional subjects may 
be enrolled in an effort to achieve at least 20 completers, with no more than 24 subjects 
randomized. 
Subjects who discontinue prior to completion of Day 9 will undergo Early Termination 
procedures and assessments at the time of discontinuation. 


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14. 
STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study for safety or administrative reasons at 
any time while safeguarding that early termination does not compromise subjects’ safety or well-
being. In particular, a study center that does not recruit at an acceptable rate may be closed. 
Should the study be terminated and/or the study center closed for whatever reason, all 
documentation and study medications pertaining to the study must be returned to the Sponsor or 
its representative. 
If, in the opinion of the Investigator, clinical observations suggest it may be unsafe to continue, 
the Investigator may terminate part or the entire study after consultation with the Sponsor. 
In the event of study or site termination, subjects will have follow-up 7 (± 2) days after their last 
dose of study drug for a final safety assessment: 
• Female subjects of childbearing potential who were dosed are required to return to the 
clinic for a serum pregnancy test and final safety assessment (adverse events and 
concomitant medication use). 
• All other dosed subjects will either be contacted by telephone or have an in-clinic 
visit if deemed clinically warranted by the Investigator for final safety assessment 
(adverse events and concomitant medication use). 
All subjects will be provided with access to standard care. 


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15. 
STATISTICS 
A comprehensive statistical analysis plan (SAP) will be finalized for this study prior to locking 
the database. The structure and content of the SAP will provide sufficient detail to meet the 
requirements identified by the FDA and International Conference on Harmonization (ICH) of 
Technical Requirements for Registration of Pharmaceuticals for Human Use: Guidance on 
Statistical Principles in Clinical Trials to support the use of this study for registration 
applications. A separate SAP will be created for the exploratory accelerateIQ System data. Any 
deviations from the main SAP after the database lock, should be documented in the changes in 
the planned analyses form and in the Clinical Study Report (CSR). 
15.1. 
Sample Size 
The evaluable sample size for this study was determined by a two-sample t-test (cross-over 
ANOVA) using nQuery version 4.0 (nQuery + nTerim version 4.0, Statistical Solutions, Cork, 
Ireland). A sample size of 10 evaluable subjects per treatment sequence (20 subjects in total), 
assuming a common standard deviation (SD) of 0.4 L, a mean difference of -0.3 L in change 
from baseline in RV (single dose of GIS compared to PIS), with a one-sided alpha of 0.025, will 
give a power of 88%. Discontinued subjects will not be replaced. At the Sponsor’s discretion, 
additional subjects may be enrolled in an effort to achieve at least 20 completers. 
15.2. 
Analysis Populations 
Modified Intention-to-Treat Population: The modified intention-to-treat (mITT) population will 
consist of subjects who are randomized, receive at least one dose of study treatment, and have a 
baseline and at least one post-baseline RV measurement within the same period. Should a subject 
require rescue medication use during the approximately 6 hours of efficacy endpoint collection, 
then any efficacy values that occur after the use of the rescue medication will be set to missing.  
Subjects will be analyzed according to randomized treatment group. 
Safety Population: The safety population will consist of all subjects who are randomized and 
received at least one dose of study medication. Subjects will be analyzed according to treatment 
received. 
15.3. 
Data Analysis 
In general, descriptive summaries will be provided where appropriate for each of the endpoints. 
Continuous outcomes will be summarized for the number of subjects, mean, 95% Confidence 
Interval (CI) for the mean, SD, median, quartile 1 (Q1), quartile 3 (Q3), minimum, and 
maximum. For categorical outcomes, the number and percentage of subjects will be presented. 
All statistical inference analyses will be performed with 2-sided tests at a significance level of 
0.05, unless otherwise specified. No adjustments for multiplicity will be applied. 
For analyses of change from baseline, period baseline will generally be defined as the last 
measurement collected prior to dosing on Day 1 or Day 9 as scheduled. 
All data from the CRFs, as well as any derived variables, will be presented in subject data 
listings. Unscheduled measurements will be included in the listings and will not be included in 
summary tables, unless specified otherwise. 


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SAS® software Version 9.4 or higher will be used for all analyses. 
15.3.1. 
Subject Disposition 
The number and percentage of subjects screened, screen failed, enrolled, randomized, dosed, 
completing each period, and completing the study will be summarized. The number and 
percentage of subjects who terminate early will also be summarized, along with reasons of 
termination. 
15.3.2. 
Drug Exposure and Compliance 
A data listing, by subject, containing the study medication dosing and any dosing errors, if any, 
will be provided. Since dosing of subjects occurs in the clinic, treatment compliance will not be 
summarized. 
15.3.3. 
Important Protocol Deviations 
Important protocol deviations (IPDs) will be identified and documented based on a review of 
potentially IPDs. The potentially IPDs will be identified through programmatic checks of study 
data, as well as through review of selected data listings. The potentially IPDs to be reviewed 
include, but are not limited to, subjects who: 
• Did not meet inclusion/exclusion criteria. 
• Received any disallowed concomitant medication, including rescue medication use 
during the efficacy endpoint collection. 
Individual IPDs will be presented in a data listing. 
15.3.4. 
Demographic and Baseline Characteristics 
Summaries for demographic characteristics will be presented for overall using the mITT and 
Safety populations. Demographic characteristics include age (in years), age categories 
(< 65 years, and ≥ 65 years), gender, race, ethnicity, weight, height, body mass index. Baseline 
characteristics (eg, screening plethysmography and spirometry results, smoking status, COPD 
exacerbation history, mMRC dyspnea scale grades and SGRQ component and total scores) will 
also be summarized. 
The medical history of each subject will be coded by Medical Dictionary for Regulatory 
Activities (MedDRA) (see the DMP for version number) system organ class (SOC) and preferred 
term (PT). The number and percentage of subjects with medical history findings in each SOC 
and PT will be summarized by overall for the Safety and mITT populations. 
15.3.5. 
Efficacy Analyses 
All efficacy endpoints will be summarized for the mITT population using descriptive statistics. 
Should a subject require rescue medication during the approximately 6 hours of efficacy 
endpoint collection, then any efficacy values that occur after the use of the rescue medication 
will be set to missing. Continuous variables will be summarized using the number of subjects, 
mean, standard deviation, median, Q1 and Q3, minimum, and maximum. Categorical variables 
will be summarized using counts and percentages. Significance tests will be 2-sided and 
conducted at an alpha level of 0.05, unless otherwise specified. 


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15.3.5.1. Primary Efficacy Endpoint Analysis 
The primary efficacy estimand is defined as the difference between a single dose of GIS and PIS 
in the mean change of RV from baseline at 6 hours postdose in COPD patients as characterized 
by the study inclusion/exclusion criteria, in the hypothetical setting where the subjects were able 
to stay on study and receive their study drug during their treatment periods. 
The change from baseline in RV at 6 hours postdose will be calculated for each treatment period 
as RV at 6 hours postdose on the day of treatment minus the period baseline of each treatment 
period. Period baseline is defined as the predose RV value collected 45 minutes prior to the 
dosing during each treatment period. 
For the primary analysis of the primary efficacy endpoint, data will be analyzed using a 2-way 
crossover analysis of covariance (ANCOVA) using the mITT population. The ANCOVA model 
will include terms for treatment, period and sequence as fixed effects, period baseline as a 
covariate, and subjects nested within sequence as a random effect. The Kenward and Roger 
correction for the degrees of freedom will be used. No structure (i.e., unstructured) will be 
assumed for the intra-subject correlation. If convergence is not met, other variance covariance 
structures may be utilized. The main estimator of the primary estimand is the Least Squares (LS) 
mean difference in the change from baseline in RV at 6 hours postdose from the primary 
ANCOVA model. LS mean (and 95% CI) for each treatment group and LS mean (and 2-sided 
95% CI), and the associated p-value for the difference between the single dose of GIS and PIS 
will be displayed. 
Graphical displays of the LS Mean (95% CI) and the LS Mean Difference (95% CI) versus PIS 
for RV will be presented for each postdose time point (1, 2, 3, 4 and 6 hours postdose) using the 
mITT population. 
Subject profile plots for the RV efficacy endpoint at baseline and each post-baseline time point 
will be presented by subject, period and treatment sequence using the mITT population. Group 
means by period will also be plotted for each treatment sequence using the mITT population. 
15.3.5.1.1. Sensitivity Analyses 
In general, for the primary analysis of the primary efficacy endpoint, missing observations will 
be treated as missing at random (MAR) and no data imputation will be performed. However, 
sensitivity analyses may be conducted if there is significant amount of missing data, including 
missing not at random (MNAR) assumptions. 
15.3.5.1.2. Supplementary Analyses 
Supplementary analyses of the primary efficacy endpoint may be conducted as deemed 
appropriate and details will be provided in the SAP. 
15.3.5.2. Other Efficacy Endpoint Analysis 
All other efficacy endpoints will be analyzed using the mITT population. 
All other efficacy endpoints will be analyzed using the ANCOVA model similar to the primary 
efficacy endpoint with appropriate baseline as a covariate. Additional covariates may be included 
in select models. 


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Standardized change from baseline in RV AUC0-4h for each treatment will be calculated using 
the trapezoid method from the changes in RV from the period baseline value within each 
treatment and dividing by the actual length of the time interval within that treatment. Changes in 
RV from period baseline for each time point (1, 2, 3, and 4 hours postdose) will be calculated as 
the RV values within each treatment minus the period baseline RV for each treatment. Change in 
RV from period baseline at time=0 is equal to 0. 
Standardized change from baseline in RV AUC0-6h, IC AUC0-4h, IC AUC0-6h, 
FRC AUC0-4h, FRC AUC0-6h, TLC AUC0-4h, TLC AUC0-6h, sRAW AUC0-4h, sRaw 
AUC0-6h, RAW AUC0-4h, and Raw AUC0-6h will be calculated similarly. 
Changes from baseline in IC, FRC, TLC, sRaw, Raw and FEV1 at 6 hrs postdose will be 
calculated similar to the primary analysis endpoint. All any other postdose lung volume 
endpoints (RV, IC, FRC, TLC, sRaw and Raw) at 1, 2, 3 and 4 hours postdose will be derived 
and analyzed similar to the primary endpoint. 
Mean change from baseline in RV at each postdose time point will be plotted by treatment using 
the mITT population. 
Subject profile plots for the RV AUC0-6h efficacy endpoint will be presented by subject, period 
and treatment sequence using the mITT population. Group means by period will also be plotted 
for each treatment sequence using the mITT population. 
15.3.5.3. Adjustment for Multiplicity 
No multiple comparison procedures will be employed in this study. 
15.3.6. 
Exploratory Endpoint Analyses 
A separate SAP will be created for the accelerateIQ System data. 
Height and weight are collected only at Screening. They will be summarized in the demographic 
tables and will be listed.  
Summary statistics for actual values and the change from baseline for vital signs collected at the 
clinical visits will be presented by treatment for each parameter. Period baseline is defined as the 
last non-missing predose value on each treatment day. All such vital sign data will be listed. 
15.3.7. 
Safety Analyses 
15.3.7.1. Adverse Events 
All AEs will be coded using MedDRA (see the DMP for version number). AEs are untoward 
medical occurrences: 
• That occurred on or after the first dose of study medication, 
• With a missing start date and a stop date on or after the first dose of study medication, 
or 
• With both a missing start and stop date. 
AEs during the randomized treatment period starting at Day 1 will be defined as AEs: 


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• That occurred on or after the first dose of study medication given during the 
randomized treatment period, 
• With a missing start date and a stop date on or after the first dose of study medication 
given during the randomized treatment period, or  
with both a missing start and stop date. 
The following AEs during the randomized treatment period will be summarized and presented by 
treatment group and by MedDRA SOC and PT for the Safety population: 
• All AEs (including number of events and subject incidence). 
• AEs by severity (mild, moderate, severe). 
• AEs by relationship to the study treatment (related, or not related). 
Additional AE analyses may be conducted as appropriate. 
The following conventions will be followed in summarizing the AEs during the randomized 
treatment period: 
• For subject incidence summaries, each subject will be counted only once within each 
SOC and within each preferred term. 
• An AE that occurs on or after the date/time of the treatment, up through and 
excluding the date/time of the next treatment, will be assigned to the treatment group 
associated with the former treatment. An AE that occurs on or after the date/time of 
the last treatment will be assigned to the treatment group associated with the last 
treatment. 
• If the AE start date is missing, then the AE will be assigned to all treatments received 
on or prior to the known AE end date. If both the AE start date and end date are 
missing, then the AE will be assigned to all treatments the subject received. 
• If a subject reports more than one AE within a preferred term and/or a body system, 
the AE with the highest known severity within each body system and within each 
preferred term will be included in the summaries by severity. Any AE with a missing 
severity will be treated as “severe” and counted in the severe category. 
• For summaries by relationship to the study medication, AEs will be grouped as 
“related” or “not related.” AEs assessed as “possible,” “probable,” or “definite,” will 
be grouped as “related.” If a subject reports more than one AE within the same 
treatment, SOC and PT, and any are related, it will be summarized as related. 
Summaries of non-serious AEs with a 5% cutoff, SAEs, and AEs leading to study 
discontinuation may be provided. 
A listing of all AEs, as well as a listing of deaths, SAEs, AEs leading to discontinuation, and a 
listing of pre-treatment untoward medical events will be presented. 
15.3.7.2. Clinical Laboratory Assessments 
Clinical lab assessments are collected at Screening for eligibility. Any clinical lab parameter data 
(hematology, chemistry, and urinalysis) will be provided in a listing only. 


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15.3.7.3. 12-Lead ECGs 
12-lead ECGs are recorded only at Screening for eligibility. Any ECG data will be provided in a 
listing. 
15.3.7.4. Physical Examination 
Findings from the physical examination will be presented as follows: pre-existing clinically 
significant conditions recorded as medical history will be summarized, and new clinically 
significant conditions recorded as an AE. 
15.3.7.5. Prior and Concomitant Medications 
All medications will be coded using WHO-DD. All medications will be coded to indication-
specific Anatomical Therapeutic Chemical (ATC) classification and PT according to the WHO-
DD (see the DMP for version number). 
Other than the study drug, any medications that start prior to the randomized treatment period, 
but continue into the randomized treatment period, and those that start during the randomized 
treatment period, will be considered as concomitant. Medications stopped prior to the date/time 
of the first study medication during the randomized treatment period will be considered as prior 
medications. 
The number and percentage of subjects using each prior and concomitant medication will be 
summarized for each treatment by ATC class and PT. Subjects with multiple uses of a 
medication will be counted only once for a given drug class or PT. 
A detailed listing of prior and concomitant medications taken by subjects will be provided. 
15.3.8. 
Interim Analysis 
No interim analysis is planned. 
15.3.9. 
Treatment of Missing Data 
Methods to account for missing data will include the following: 
• For the calculation of an AUC, any intermittent missing measurements will be ignored, 
and the trapezoidal rule will simply span the missing time point(s). For AUC0-6h, the 
6-hour time point will be used as the end of the interval. If the 6-hour time point is 
missing, then the AUC0-6h calculation will be based on the time interval up to the last 
non-missing time point prior to hour 6. Similar rules will be applied for other AUC 
calculations. 


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16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL 
/DATA COLLECTION, MANAGEMENT, AND QUALITY 
ASSURANCE 
16.1. 
Data Collection/Electronic Data Capture (EDC) 
The results from Screening and data collected during the study (except the accelerateIQ System 
data) will be recorded in the subject’s electronic CRF. The study centers will use an EDC system 
that is compliant with relevant FDA regulatory requirements per 21 CFR Part 11 (Medidata 
Rave). Password protected access to the EDC system will be via a secure website. Data queries 
and data corrections will be handled through the same system. All transactions within the EDC 
system are fully documented within an electronic audit trail. Each set of completed CRFs must 
be reviewed and electronically signed and dated by the Investigator. 
16.2. 
Study Monitoring 
This study will be monitored using a risk-based approach from initiation to completion by the 
Sponsor or its representative. Monitoring will include centralized data monitoring, personal 
visits, and telephone or email communication to assure that the investigation is conducted 
according to protocol and in order to comply with International Council for Harmonization 
(ICH) Good Clinical Practice (GCP). Central and/or on-site review of CRF data will include a 
risk-based review of critical process compliance, critical data quality, data completeness and 
clarity, and, where required, consistency with source documents available for each subject. 
16.3. 
Audits 
The study may be subject to audit by the Sponsor/designee. If such an audit occurs, the 
Investigator must agree to allow access to required subject records. This is dependent on the 
subject granting consent by signing the ICF. By signing this protocol, the Investigator grants 
permission to personnel from the Sponsor or its representatives for on-site monitoring and 
auditing of all appropriate study documentation, as well as on-site review of the procedures 
employed in CRF generation, where clinically appropriate. 
In accordance with ICH GCP the Sponsor may select this study for audit. During the audit the 
Sponsor representative will carry out an inspection of center facilities (eg, pharmacy, drug 
storage areas, laboratory) and review study related records in order to evaluate the study 
compliance with the Sponsor/center SOPs, protocol, ICH GCP and local regulations. The PI or 
appropriate designee must also agree to inspection of all study documents by the regulatory 
authorities and the IRB. Should the PI or appropriate designee be notified of a regulatory 
inspection involving this study they should notify the Sponsor immediately. 
16.4. 
Study Documentation 
Study records are comprised of source documents, CRFs, and all other administrative 
documents, eg, IRB correspondence, clinical study materials and supplies shipment manifests, 
monitoring logs, Sponsor and CRO correspondence, etc. A study specific binder will be provided 
with instructions for the maintenance of study records. 


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Source document is defined as any hand written or computer-generated document that contains 
medical information or test results that have been collected for or are in support of the protocol 
specifications, eg, clinical laboratory reports, clinic notes, drug disbursement log, subject sign in 
sheets, subject completed questionnaires if applicable, telephone logs, ECGs, etc. All draft, 
preliminary and pre-final iterations of a final report are also considered to be source documents, 
eg, faxed laboratory reports and hard copy laboratory reports, faxed initial results and hard copy, 
final report. 
16.5. 
Clinical Laboratory Certification and Normal Values 
A local/site laboratory will be used for analysis for the clinical labs for this study. The local 
laboratory/site personnel will provide Sponsor/CRO with laboratory certification(s), a dated copy 
of normal range values for the local/site clinical laboratory selected to analyze clinical 
specimens. 


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17. 
ETHICAL AND REGULATORY OBLIGATIONS 
17.1. 
Study Conduct 
The Investigator agrees that the study will be conducted according to the protocol, ICH GCP, 
ICH guidelines and the ethical principles that have their origin in the Declaration of Helsinki. 
The Investigator will conduct all aspects of the study in accordance with applicable local law(s) 
and regulation(s). 
The Investigator will assure proper implementation and conduct of the study including those 
study-related duties delegated to other appropriately qualified individuals. The Investigator will 
assure that study staff cooperate with monitoring and audits. 
The Investigator must sign and return to Sponsor/CRO the “Investigator Approval" page. 
The Investigator must provide a copy of current curriculum vitae (including a copy of a current 
medical license, where applicable), and financial disclosure information. 
The Investigator must sign and return a completed Form FDA 1572 "Statement of Investigator" 
to Sponsor/CRO. 
17.2. 
Institutional Review Board 
Documented approval for conducting the study from appropriate Institutional Review Board 
(IRB) will be obtained for all participating study centers prior to initiation of the study, according 
to ICH GCP, applicable local law(s) and regulation(s). When necessary, an extension, 
amendment or renewal of the IRB approval must be obtained and also forwarded to the Sponsor. 
The IRB must supply the Sponsor a list of the IRB membership, and a statement to confirm that 
the IRB is organized and operates according to ICH GCP, applicable law(s) and regulation(s). 
A copy of written IRB approval or favorable opinion of the protocol, informed consent form and 
subject recruitment material (if applicable) must be provided to Sponsor/CRO prior to start of the 
study. The approval or favorable opinion letter must be signed by the IRB chairman or designee 
identify the IRB name and address, identify the clinical protocol by title and/or protocol number, 
and include the date that approval or favorable opinion was granted. The letter must also contain 
a statement that the IRB complies with the requirements in 21 CFR Part 56 for a study conducted 
under a US IND or ICH GCP, as applicable. 
The Investigator/CRO is responsible for obtaining from the IRB continued review of the clinical 
research or submitting periodic progress reports, in accordance with applicable regulations, at 
intervals not to exceed one year and (if applicable) as otherwise additionally specified by the 
IRB. The Sponsor must be supplied with written documentation of continued review of the 
clinical research. 
The Investigator must promptly inform their IRB of all SAEs reported by subjects enrolled in the 
study or other safety information reported from Sponsor/CRO in accordance with applicable 
law(s) and regulation(s). 


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17.3. 
Informed Consent 
The Sponsor/CRO will prepare the informed consent form and provide the form to the site for 
approval prior to submission to the IRB. The informed consent form will be approved by the 
Sponsor/CRO prior to submission to the IRB. The Sponsor/CRO may provide a template 
informed consent form to be qualified by each research facility to conform to local requirements. 
All informed consent forms must contain the minimum elements as mandated by ICH GCP, 
applicable local law(s) and regulations and will be subject to Sponsor/CRO approval as well as 
IRB approval. The Sponsor/CRO may submit informed consent forms to a central IRB/IEC for 
review and approval or favorable opinion contingent upon prior Investigator permission and 
review. 
Before recruitment and enrollment, each prospective subject will be given a full explanation of 
the study, allowed to read the approved informed consent form and be provided ample time and 
the opportunity to ask any questions that may arise. Once all questions have been answered and 
the Investigator is assured that the prospective subject understands the implications of 
participating in the study, the prospective subject will be asked to give consent to participate in 
the study by signing the informed consent form. As part of the consent process, each prospective 
subject must consent to direct access to his/her medical records for study-related monitoring, 
auditing, IRB review, and regulatory inspection. It should be clearly explained to each 
prospective subject that participation in each and every clinical visit and assessment is expected. 
The subject may be discontinued from study medication, but that does not necessarily negate the 
expectation that the subject will continue to participate in the study through the final 
visit/assessment. The Investigator will provide a copy of the signed informed consent form to 
each subject and will record the date of the informed consent on the CRF. 
If an amendment to the protocol changes the subject participation schedule in scope or activity, 
or if important new information becomes available that may be relevant to the subject’s consent, 
the informed consent form must be revised, submitted to the IRB for review and approval or 
favorable opinion. The revised informed consent form must be used to obtain consent from a 
subject currently enrolled in the study if he or she is affected by the amendment. The revised 
informed consent form must be used to obtain consent from any new subjects who are enrolled 
into the study after the date of the approval or favorable opinion of the protocol amendment. 
17.4. 
Subject Privacy 
The Sponsor (or Sponsor representative) or any designees affirm to uphold the subject’s 
confidentiality. The subject will be identified by unique code only; full names will be masked 
prior to transmission to the Sponsor. The confidentiality of the subject’s personal data shall be 
protected in accordance with appropriate laws and regulations. 
17.5. 
Protocol Amendments and Emergency Deviations 
All revisions and/or amendments to this protocol must be approved in writing by the Sponsor 
and the appropriate IRB. The Investigator will not make any changes to the conduct of the study 
or the protocol without first obtaining written approval from the Sponsor and the IRB, except 
where necessary to eliminate an apparent immediate hazard to a study subject. 


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Emergency deviations or modifications may be initiated without Sponsor or IRB approval or 
favorable opinion, only in cases where the deviation or modification is necessary to eliminate or 
avoid an immediate apparent hazard to subjects. Emergency deviations or modifications must be 
reported to the Sponsor/CRO and the IRB immediately, or in accordance with applicable 
regulatory requirements. 
17.6. 
Records Retention 
The Investigator/the study center must arrange for retention of study records at the study center 
for at least 15 years from time of participation in the study or longer in accordance with 
applicable regulations and Sponsor SOPs. The Investigator/site should take measures to prevent 
accidental or premature destruction of these documents. Documents cannot be destroyed without 
written Sponsor authorization. The Sponsor will inform the Investigator/the study center when 
the destruction of documents is permitted. 
17.7. 
Inspection of Records 
In the event of an inspection, the Investigator agrees to allow representatives of the Sponsor and 
its representative and, the regulatory authorities’ access to all study records. The Investigator will 
promptly notify the Sponsor/CRO of all requests to inspect a Sunovion-sponsored study by 
government agencies and will promptly forward a copy of all such inspection reports. 
17.8. 
Financial Disclosure 
By signing this protocol, the Investigator agrees to provide to the Sponsor prior to start of study 
accurate financial information to allow the Sponsor to submit complete and accurate certification 
and disclosure statements as required by the US FDA regulations (21 CFR Part 54). The 
Investigator further agrees to provide this information on a Financial Disclosure/Certification 
Form that is provided by the Sponsor. The Investigator will update this information if there are 
any relevant changes during the conduct of the study and for one year after completion of the 
study. 
The Investigator also consents to the transmission of this information to the Sponsor for these 
purposes. This may involve the transmission of information to countries that do not have laws 
protecting personal data. 
17.9. 
Publication Policy 
Any formal presentation or publication of data collected as a direct or indirect result of the study 
will be considered a joint publication by the Investigators and the appropriate personnel of the 
Sponsor. For multicenter studies, it is mandatory that the first publication is based on all data 
obtained from all analyses as stipulated in the protocol. Investigators participating in multicenter 
studies must agree not to present data gathered individually or by a subgroup of centers before 
the full, initial publication, unless this has been agreed to by all other Investigators and by the 
Sponsor. 


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17.10. 
Compensation 
If subjects have any adverse event or injury directly resulting from the study medications or 
procedures, the Sponsor will appropriately compensate in accordance with applicable regulatory 
requirements. 


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18. 
REFERENCES 
Beeh KM, Wagner F, Khindri S, Drollman AF. Effect of Indacterol on Dynamic Lung 
Hyperinflation and Breathlessness in Hyperinflated Patients with COPD. COPD: Journal of 
Chronic Obstructive Pulmonary Disease. 2011;8:340-345. 
Chen C, Jian W, Gao Y, Xie Y, Song Y, Zheng J. Early COPD patients with lung hyperinflation 
associated with poorer lung function but better bronchodilator responsiveness. International 
journal of chronic obstructive pulmonary disease. 2016;11:2519-2526. 
Fujimoto K, Yamazaki H, Ura M, Kitaguchi Y. Efficacy of tiotropium and indacaterol 
monotherapy and their combination on dynamic lung hyperinflation in COPD: a random open-
label crossover study. International Journal of COPD. 2017;12:3195-3201. 
Global Initiative for Chronic Obstructive Lung Disease [GOLD] (2019) Global strategy for the 
diagnosis, management and prevention of chronic obstructive pulmonary disease. Available from 
www.goldcopd.com. 
Guarascio AJ, Ray SM, Finch CK, Self TH. The clinical and economic burden of chronic 
obstructive pulmonary disease in the USA. Clinicoecon Outcomes Res. 2013;5:235–245.  
Hohfeld JM, Vogel-Claussen J, Biller H, Berliner D, Berschneider K, Tillman H-C, et al. Effect 
of lung deflation with indacaterol plus glycopyrronium on ventricular filling in patients with 
hyperinflation and COPD. Lancet Respir Med. 2018;6:368-378. 
Jones, PW, Quirk FH, Baveystock CM. The St George's Respiratory Questionnaire. Respir Med. 
1991;85(Suppl B):25-31. 
Kochanek KD, Murphy SL, Xu JQ, Arias E. Mortality in the United States (US), 2016. National 
Center for Health Statistics Data Brief, no 293. Centers for Disease Control and 
Prevention/National Center for Health Statistics website 
HTTPS://WWW.CDC.GOV/NCHS/PRODUCTS/DATABRIEFS/DB293.HTM Published 
December 2017. 
Laveneziana P, Guenette JA, Webb KA, O’Donnell DE. New physiological insights into dyspnea 
and exercise intolerance in chronic obstructive pulmonary disease patients. Expert Rev. Respir. 
Med. 2012;6(6):651-662. 
Langer D, Ciavaglia CE, Neder JA, Webb KA, O’Donnell DE. Lung hyperinflation in chronic 
obstructive pulmonary disease: mechanisms, clinical implications and treatment. Expert Rev 
Respir Med. 2014;8(6):731-749. 
Loh CH, Donoue JF, Ohar JA. Review of drug safety and efficacy of arformoterol in chronic 
obstructive pulmonary disease. Expert Opin. Drug Saf. 2015;14(3):463-472. 
Lonhala Magnair product labeling. Available at www.lonhalamagnair.com. June 2019. 
Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea. Contents, 
interobserver agreement, and physiologic correlates of two new clinical indexes. Chest 1984, 85: 
751-758.  
Miller MR, Hankinson J, Brusasco V, Burgos R, Casaburi R, Coates A, et al. Standardization of 
Lung Function Testing. Eur Resp J. 2005;26:153-161. 


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Rabe KF, Hurst JR, Suissa S. Cardiovascular disease and COPD: dangerous liaisons? European 
Respiratory Review. 2018;27(149):180057. 
Rossi A, Aisanov Z, Avdeev S, Di Maria G, Donner CF, Izquierdo JL, et al. Mechanisms, 
assessment and therapeutic implications of lung hyperinflation in COPD. Respir Med. 
2015;109(7):785-802. 
Santus P, Radovanovic D, Di Marco S, Valenti V. Effect of indacaterol on lung deflation 
improves cardiac performance in hyperinflated COPD patients: an interventional, randomized, 
double-blind clinical trial. International Journal of COPD. 2015;10:1917-1923. 
The Third National Health and Nutrition Examination Survey (NHANES III), 1988-94, Series 
11, No. 9A Data Release. 
Thomas M, Decramer M, ODonnell DE. No room to breathe: the importance of lung 
hyperinflation in COPD. Prim Care Respir J. 2013;22(1):101-111. 
Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, et al. Standardisation of 
the measurement of lung volumes. Eur Respir J. 2005;26:511-522. 
Watz H, Trooster T, Beeh KM, Garcia-Aymerich J, Paggiaro P, Molins E, et al. ACTIVATE: the 
effect of aclidinium/formoterol on hyperinflation, exercise capacity, and physical activity in 
patients with COPD. International Journal of COPD. 2017;12:2545-2558. 
 


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19. 
INVESTIGATOR APPROVAL 
I have read the protocol, SUN101-402, Version 1.00, A Randomized, Double-blind, Placebo-
controlled, 2-Way, Crossover Study of the Effect of a Single Dose of Glycopyrrolate Inhalation 
Solution (GIS) on Lung Hyperinflation in Subjects with Chronic Obstructive Pulmonary Disease 
(COPD)”, and agree that it contains all necessary details for conducting the study and to conduct 
the study in strict accordance with the specifications outlined herein. 
I agree that no additional procedure(s) will be added during the conduct of the study except 
through protocol amendment by Sunovion Respiratory Development Inc. and after 
documentation of IRB approval. 
Investigator Signature: ____________________________________________________ 
Print Investigator Name: __________________________________________________ 
Date: ___________________________________________ 


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20. 
APPENDIX I. CARDIAC SAFETY MONTIORING (ECG) 
1. Requirements for Testing 
ECG equipment and supplies will be provided by the clinical site and should be used for all 
in-clinic protocol ECG assessments. 
• All 12-lead ECGs will be recorded in the same manner. 
• The study center personnel must be adequately trained in performing ECGs on the 
specific ECG equipment used in this protocol. 
• To the extent possible, the same ECG machine and personnel should be used to 
acquire a subject’s ECGs throughout the period of their participation in the study. 
• ECGs will be recorded with at least one 10-second single-lead tracing recorded from 
Lead II. 
2. Subject Restrictions and Instructions 
• Prior to ECG acquisition, the subject will have rested at least 5 minutes in the supine 
position and will remain so until the ECG is obtained. 
3. Reporting 
• It is the responsibility of the Investigator to perform a safety review of the ECG data 
for changes from previous assessments and/or emergent cardiac dysfunction, and to 
determine subjects’ eligibility or continuance in the study. Abnormalities require 
comment as NCS (Not Clinically Significant) or CS (Clinically Significant). 
Typically, CS designated events will be reported as adverse events. 
• ECGs will be reviewed, signed and dated by the Investigator listed on the Form FDA 
1572 (MD or DO) after each ECG collection. The same Investigator should review all 
ECG reports for a given subject whenever possible. 
• The ECG tracing will be kept with subject’s source documentation and / or CRF 
unless it is specified otherwise. The original ECG will be retained at the study center 
and the Sponsor may collect a copy. 
 
 


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21. 
APPENDIX II. CLINICAL LABORATORY TESTS 
 
Clinical Safety Panel 
HEMATOLOGY: (Differential reported as % and absolute value) 
Hemoglobin, Hematocrit, Platelet Count, red blood cell (RBC) Count, RBC indices (MCV, MCH, 
MCHC), white blood cell (WBC) - Total Count, WBC Differential, (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils), Hemoglobin A1c (HbA1c)  
 
BLOOD CHEMISTRIES: Alanine aminotransferase (ALT), Alkaline Phosphatase (ALP), 
Aspartate aminotransferase (AST), Bicarbonate (HCO3), Bilirubin (Total, Direct, Indirect), 
Blood Urea Nitrogen (BUN), Calcium (Ca), Chloride (Cl), Creatinine (Cr), Glucose (GLU), 
Magnesium (Mg), Phosphorus (P), Potassium (K), Protein (Total), Sodium (Na), Uric Acid 
(UA), Albumin (ALB) 
 
URINALYSIS: Blood, Glucose, Ketones, Leukocyte esterase, Microscopic examination, 
Nitrites, pH, Protein, specific gravity 
 
OTHER TESTS: Serum Pregnancy (β-HcG) (female subjects < 65 years old), Urine Pregnancy 
Test (female subjects < 65 years old) 
 
Laboratory reports will be initialed and dated on all pages by the Investigator listed on the Form 
FDA 1572 (MD or DO). Laboratory test results will be reviewed by the Investigator as they 
become available. The Investigator must determine the clinical significance of all out-of-range 
lab values (except drug screens). Possibly drug-related or clinically relevant abnormal values of 
uncertain causality must be repeated. Any abnormal values that persist should be followed at the 
discretion of the Investigator. 
 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
SUN101-402 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 2-WAY CROSSOVER 
STUDY OF THE EFFECT OF A SINGLE DOSE OF GLYCOPYRROLATE INHALATION 
SOLUTION (GIS) ON LUNG HYPERINFLATION IN SUBJECTS WITH CHRONIC 
OBSTRUCTIVE PULMONARY DISEASE (COPD)
AUTHOR:
VERSION NUMBER AND DATE: FINAL, 06MAY2020 


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TABLE OF CONTENTS 
1.
LIST OF ABBREVIATIONS .............................................................................................................. 7
2.
INTRODUCTION ........................................................................................................................... 9
3.
STUDY OBJECTIVES ...................................................................................................................... 9
3.1. 
PRIMARY EFFICACY OBJECTIVE ...............................................................................................................................9 
3.2. 
OTHER EFFICACY OBJECTIVE ..................................................................................................................................9 
3.3. 
EXPLORATORY OBJECTIVES ....................................................................................................................................9 
3.4. 
STUDY ENDPOINTS ...............................................................................................................................................9 
3.4.1. 
Primary Efficacy Endpoint .......................................................................................................................9 
3.4.2. 
Other Efficacy Endpoints .......................................................................................................................10 
3.4.3. 
Safety Endpoints ...................................................................................................................................10 
3.4.4. 
Exploratory Endpoints ...........................................................................................................................10 
4.
STUDY DESIGN .......................................................................................................................... 11
4.1. 
GENERAL DESCRIPTION .......................................................................................................................................11 
4.2. 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................................................................12 
4.3. 
BLINDING .........................................................................................................................................................13 
4.4.
DETERMINATION OF SAMPLE SIZE..........................................................................................................................14
4.5. 
CHANGES IN THE CONDUCT OF THE STUDY ...............................................................................................................14 
4.6. 
SCHEDULE OF EVENTS .........................................................................................................................................14 
4.7. 
CHANGES TO ANALYSIS FROM PROTOCOL ...............................................................................................................14 
5.
PLANNED ANALYSES .................................................................................................................. 15
5.1. 
FINAL ANALYSIS .................................................................................................................................................15 
5.2. 
DATA MONITORING COMMITTEE (DMC) ANALYSIS .................................................................................................15 
5.3. 
INTERIM ANALYSIS .............................................................................................................................................15 
6.
ANALYSIS POPULATIONS ........................................................................................................... 15
6.1. 
ALL SUBJECTS SCREEND [SCR] .............................................................................................................................15 
6.2. 
ALL SUBJECTS ENROLLED [ENR] ...........................................................................................................................15 
6.3. 
ALL SUBJECTS RANDOMIZED [RND] ......................................................................................................................16 
6.4. 
EFFICACY (EFF) POPULATION ...............................................................................................................................16 
6.5. 
SAFETY [SAF] POPULATION .................................................................................................................................16 
7.
GENERAL CONSIDERATIONS ....................................................................................................... 16
7.1. 
REFERENCE START DATE AND STUDY DAY ...............................................................................................................16 
7.2. 
BASELINE .........................................................................................................................................................17 
7.3. 
UNSCHEDULED VISITS AND EARLY TERMINATION DATA .............................................................................................17 
7.4. 
WINDOWING CONVENTIONS................................................................................................................................17 
7.5. 
STATISTICAL TESTS .............................................................................................................................................17 
7.6. 
COMMON CALCULATIONS ...................................................................................................................................18 


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7.7. 
SOFTWARE VERSION ..........................................................................................................................................18 
8.
STATISTICAL CONSIDERATIONS .................................................................................................. 18
8.1. 
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN ANALYSES ...............................................................18 
8.2. 
MISSING DATA ..................................................................................................................................................18 
8.3. 
MULTIPLE COMPARISONS/ MULTIPLICITY ...............................................................................................................19 
8.4. 
EXAMINATION OF SUBGROUPS .............................................................................................................................19 
9.
OUTPUT PRESENTATIONS .......................................................................................................... 19
10.
DISPOSITION AND WITHDRAWALS ......................................................................................... 19
11.
IMPORTANT PROTOCOL DEVIATIONS ..................................................................................... 20
12.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................................................... 20
12.1. 
DERIVATIONS ................................................................................................................................................22 
13.
MEDICAL HISTORY ................................................................................................................. 23
14.
MEDICATIONS ........................................................................................................................ 23
15.
STUDY MEDICATION EXPOSURE ............................................................................................. 24
16.
STUDY MEDICATION COMPLIANCE ......................................................................................... 24
17.
EFFICACY OUTCOMES ............................................................................................................. 25
17.1. 
PRIMARY EFFICACY ........................................................................................................................................25 
17.1.1. 
Primary Efficacy Variable(s) & Derivation(s) .........................................................................................25 
17.1.2. 
Missing Data Methods for Primary Efficacy Variable(s) .......................................................................26 
17.1.3. 
Primary Analysis of Primary Efficacy Variable(s) ..................................................................................26 
17.1.4. 
Sensitivity Analysis of PRIMARY Efficacy Variable ................................................................................27 
17.1.5. 
Subgroup Analysis of Primary Efficacy Variable(s) ...............................................................................29 
17.1.6. 
Supportive Analysis of Primary Efficacy Variable(s) ..............................................................................29 
17.2. 
OTHER EFFICACY ...........................................................................................................................................29 
17.2.1. 
Other Efficacy Variables & Derivations .................................................................................................29 
17.2.1.1. 
Other Efficacy Variables - Change from baseline .......................................................................................... 29 
17.2.1.2.
Other Efficacy Variables - Standardized change from baseline .................................................................... 30
17.2.2. 
Missing Data Methods for Other Efficacy Variable(s)...........................................................................31 
17.2.3. 
Analysis of Other Efficacy Variables......................................................................................................31 
17.2.3.1. 
Analysis of Other Efficacy Variables - Change from baseline ........................................................................ 31 
17.2.3.2. 
Analysis of Other Efficacy Variables - Standardized change from baseline .................................................. 31 
17.2.4. 
Sensitivity Analysis of Other Efficacy Variables ....................................................................................31 
17.2.5. 
Subgroup Analysis of Other Efficacy Variable(s) ...................................................................................31 
17.2.6. 
Supportive Analysis of Other Efficacy Variable(s) .................................................................................32 
17.2.6.1. 
Supportive analysis of Other Efficacy Variables- Change from baseline ....................................................... 32 
17.2.6.2. 
Supportive analysis of Other Efficacy Variables - Standardized change from baseline ................................ 32 
17.3. 
EXPLORATORY ENDPOINTS ...............................................................................................................................32 
17.3.1. 
Data collected using the accelerateIQ System ......................................................................................32 


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Clinic visit Vital Signs .............................................................................................................................32 
17.3.3. 
Correlations Between Selected Efficacy Endpoints ...............................................................................33 
18.
SAFETY OUTCOMES ................................................................................................................ 33
18.1. 
ADVERSE EVENTS ...........................................................................................................................................33 
18.1.1. 
All AEs During the Randomized treatment period ................................................................................34 
18.1.1.1. 
Severity During the Randomized Treatment Period ..................................................................................... 34 
18.1.1.2. 
Relationship to Study Medication During the Randomized Treatment Period ............................................. 34 
18.1.2. 
AEs Leading to Study Discontinuation during the randomized treatment period.................................35 
18.1.3.
Serious Adverse Events during the randomized treatment period .......................................................35
18.1.4. 
Non-serious Adverse Events With a 5% Cutoff during the randomized treatment period ....................35 
18.2. 
DEATHS .......................................................................................................................................................35 
18.3. 
LABORATORY EVALUATIONS .............................................................................................................................35 
18.4. 
ECG EVALUATIONS ........................................................................................................................................36 
18.5. 
PHYSICAL EXAM EVALUATIONS .........................................................................................................................36 
APPENDIX 1. 
PROGRAMMING CONVENTIONS FOR OUTPUTS ......................................................... 37 
DATES & TIMES ............................................................................................................................................................37 
SPELLING FORMAT .........................................................................................................................................................37 
PRESENTATION OF TREATMENT GROUPS ............................................................................................................................37 
PRESENTATION OF VISITS ................................................................................................................................................37 
LISTINGS ......................................................................................................................................................................38 
APPENDIX 2. 
PARTIAL DATE CONVENTIONS FOR CONCOMITANT MEDICATIONS ............................. 39 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS: ......................................................................................................39 
APPENDIX 3. 
SGRQ QUESTIONNAIRE AND SCORING ALGORITHMS ................................................. 40 


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1. LIST OF ABBREVIATIONS
Table 1:
Abbreviations 
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2. INTRODUCTION
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3. STUDY OBJECTIVES
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CHANGES IN THE CONDUCT OF THE STUDY 
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4.7. CHANGES TO ANALYSIS FROM PROTOCOL 
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5.1. FINAL ANALYSIS
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5.2. DATA MONITORING COMMITTEE (DMC) ANALYSIS 
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5.3. INTERIM ANALYSIS
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6. ANALYSIS POPULATIONS
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6.1. ALL SUBJECTS SCREENED [SCR]
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7. GENERAL CONSIDERATIONS
7.1. REFERENCE START DATE AND STUDY DAY 
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7.2. BASELINE 
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7.3. UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
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7.5. STATISTICAL TESTS 
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8. STATISTICAL CONSIDERATIONS
8.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN
ANALYSES 
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9. OUTPUT PRESENTATIONS
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DISPOSITION AND WITHDRAWALS
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MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE(S) 
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PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
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ANALYSIS OF OTHER EFFICACY VARIABLES 
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SUBGROUP ANALYSIS OF OTHER EFFICACY VARIABLE(S) 
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17.3.1.
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18.1.1.
ALL AES DURING THE RANDOMIZED TREATMENT PERIOD 
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Severity During the Randomized Treatment Period 
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18.1.1.2.
Relationship to Study Medication During the Randomized Treatment Period 
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18.1.2.
AES LEADING TO STUDY DISCONTINUATION DURING THE RANDOMIZED TREATMENT PERIOD 
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18.1.3.
SERIOUS ADVERSE EVENTS DURING THE RANDOMIZED TREATMENT PERIOD 
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NON-SERIOUS ADVERSE EVENTS WITH A 5% CUTOFF DURING THE RANDOMIZED TREATMENT PERIOD 
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18.2.DEATHS 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
DATES & TIMES 
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SPELLING FORMAT 
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PRESENTATION OF TREATMENT GROUPS 
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APPENDIX 2. PARTIAL DATE CONVENTIONS FOR CONCOMITANT MEDICATIONS 
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ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:
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Known 
Known 
Follow algorithm in Section 14. 
Partial 
Impute stop date as latest possible date (i.e. the earlier one of the following 
two: last day of month if day unknown or 31st December if day and month 
are unknown, date of the last visit), then follow algorithm in Section 14.  
Missing 
Considered as asscociated with all treatments received on or after the 
known medication start date. 
Partial 
Known 
Impute start date as earlist possible date (i.e. 1st day of month if day 
unknown or 1st Jan if day and month are unknown), then follow algorithm 
in Section 14. 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute stop 
date as latest possible date (i.e. the earlier one of the following two: last 
day of month if day unknown or 31st December if day and month are 
unknown, date of the last visit), then follow algorithm in Section 14. 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then consider the 
medication as asscociated with all treatments received on or after the 
imputed medication start date. 
Missing 
Known 
Considered as asscociated with all treatments received on or prior to the 
known medication end date. 
Partial 
Impute stop date as latest possible date (i.e. the earlier one of the following 
two: last day of month if day unknown or 31st December if day and month 
are unknown, date of the last visit), then consider the medication as 
asscociated with all treatments received on or prior to the imputed 
medication stop date. 
Missing 
The medication will be considered as associated to all treatments received, 
including the training dose. 


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SGRQ QUESTIONNAIRE AND SCORING ALGORITHMS 
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