A Randomized, Double-Blind, Chronic Dosing (24 Weeks), Placebo-Controlled, Parallel Group, Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects With Moderate to Very Severe COPD, Compared With Placebo
Phase: PHASE3
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Pearl Therapeutics, Inc.

 
 
Revised Clinical Study Protocol 
Study Code 
PT003014 
NCT #  
NCT02343458 
Date 
20 January 2017 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Double-Blind, Chronic Dosing (24 Weeks), 
Placebo-Controlled, Parallel Group, Multi-Center Study to Assess 
the Efficacy and Safety of PT003, PT005, and PT001 in Subjects 
with Moderate to Very Severe COPD, Compared with Placebo 
 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
The following Amendment(s) are included in this revised protocol: 
  
Amendment No.        
Date of Amendment                
Version 1 
17 July 2014 
Version 2,  Amendment 1 
18 December 2014 
Version 3,  Amendment 2  
08 April 2015 
Version 4,  Amendment 3 
20 April 2015 
Version 5,  Amendment 4 
01 May 2015 
Version 6,  Amendment 5 
20 January 2017 
 
 
 

 
 
Revised Clinical Study Protocol 
Study Code 
PT003014 
NCT #  
NCT02343458 
Edition Number 
Ver. 6 Amendment 5 
Date 
20 January 2017 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Double-Blind, Chronic Dosing (24 Weeks), 
Placebo-Controlled, Parallel Group, Multi-Center Study to Assess 
the Efficacy and Safety of PT003, PT005, and PT001 in Subjects 
with Moderate to Very Severe COPD, Compared with Placebo 
 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
The following Amendment(s) are included in this revised protocol: 
  
Amendment No.        
Date of Amendment                
Version 1 
17 July 2014 
Version 2,  Amendment 1 
18 December 2014 
Version 3,  Amendment 2  
08 April 2015 
Version 4,  Amendment 3 
20 April 2015 
Version 5,  Amendment 4 
01 May 2015 
Version 6,  Amendment 5 
20 January 2017 
 
 
 

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Page 1 of 169
Clinical Trial Protocol: PT003014-05 
Title:
A Randomized, Double-Blind, Chronic Dosing (24 Weeks), 
Placebo-Controlled, Parallel Group, Multi-Center Study to Assess 
the Efficacy and Safety of PT003, PT005, and PT001 in Subjects 
with Moderate to Very Severe COPD, Compared with Placebo
Study Number:
PT003014-05 
Study Phase:
III
Product Name:
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; 
PT003 
Formoterol Fumarate Inhalation Aerosol; PT005 
Glycopyrronium Inhalation Aerosol; PT001
IND Number 
107739
EudraCT 
Number
2014-004712-10 
Indication:
COPD
Investigators: 
Multicenter
Sponsor:
Pearl Therapeutics, Inc.
Sponsor Contact 
  
Version Number 
Date
Original Protocol: 
Version 1.0 
Amended Protocol #1
Version 2.0 
Amended Protocol #2
Version 3.0 
Amended Protocol #3
Version 4.0 
Amended Protocol #4
Version 5.0 
Amended Protocol #5 
Version 6.0 
Confidentiality Statement
Property of Pearl Therapeutics
This document is confidential and may not be used, divulged, published or 
otherwise disclosed without consent of Pearl Therapeutics Inc.

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SUMMARY OF CHANGES TO PROTOCOL PT003014-04 
(AMENDMENT 4, VERSION 5.0), DATED 
The amended study protocol, PT003014-05 (Version 6.0), includes the following edits: 
No.
Description of Change
Rationale
1
Updated Sponsor Address 
Revised Sponsor Contact name  
Title Page
Appendix 11, Sponsor Signatory (updated 
name only)
Sponsor address changed 
Sponsor Contact name changed to 
reflect the Global Clinical Leader for the  
GFF MDI program
2
Deleted Hybrid approach  
Synopsis: Efficacy Assessments; Primary 
Endpoint; Secondary Efficacy Endpoints 
Section 3, Study Endpoints; Section 3.1, 
Primary Objective(s)/Endpoint(s); Section 
3.2, Secondary Endpoints; Section 9.2.1, 
Efficacy Endpoints; Section 9.2.1.1, 
Primary Efficacy Endpoint; Section 
9.2.1.2, Secondary Efficacy Endpoints; 
Section 9.3.2.1, TDI (formerly Section 
9.3.1.2, TDI [Co Primary Endpoint for 
EU/Hybrid Approaches]); Section 9.3.2, 
Analysis of Secondary Endpoints; Section 
9.3.4, Control of Type I Error; and Section 
9.3.4.3, European Union/South 
Korea/Taiwan Endpoints
The Hybrid approach is no longer 
needed to support GFF MDI registration 
in any market.   
3
Clarified use of the ITT Population vs. the 
Symptomatic and Rescue Ventolin User 
Populations  
Synopsis: Efficacy Assessments; Section 3, 
Study Endpoints; Section 9.2.1, Efficacy 
Endpoints; Section 9.9, Study Populations
Analyses of symptomatic endpoints 
(TDI and SGRQ) will be conducted in 
the Symptomatic Population in addition 
to the ITT Population. Rescue Ventolin 
usage will be analyzed in the Rescue 
Ventolin User Population. 
4
Clarified the language for TDI as a 
secondary endpoint for all registration 
approaches.
Synopsis: Secondary Efficacy Endpoints; 
Section 3.2, Secondary Efficacy Endpoints; 
Original language for TDI in the 
US/China approach had potential for 
misinterpretation.
For the US/China and EU/South 
Korea/Taiwan approaches, TDI will be 

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Section 9.2.1.2, Secondary Efficacy 
Endpoints; Section 9.3.2, Analysis of 
Secondary Endpoints; Section 9.3.4 
Control of Type 1 Error 
classified as a secondary endpoint for 
consistency with the study objectives 
and to better reflect the requirement that 
success with morning pre-dose trough 
FEV1 must be achieved first.
5
Deleted “peak expiratory flow rate (PEFR), 
and forced expiratory flow from 25% to 
75% of FVC (FEF 25-75)” from the 
following endpoint:  
Change from baseline at each post-dose 
time point in FEV1, forced vital capacity 
(FVC), peak expiratory flow rate (PEFR), 
and forced expiratory flow from 25% to 
75% of FVC (FEF 25-75) as well as FEV1 
AUC0-2 
Synopsis: Other Efficacy Endpoints (Day 1 
Assessments); Section 3.3.1, Day 1 
Assessments; Section 9.2.1.3.1 Day 1 
Assessments 
Deleted “PEFR and (FEF 25-75)” from the 
following endpoints:   
•
Change from baseline in morning pre-
dose trough for FVC, PEFR and (FEF 
25-75), as well as FEV1 AUC0-2 at each 
post-randomization 
visit, 
over 
24 
weeks, and over Weeks 12-24  
•
Peak change from baseline in FEV1,
FVC, PEFR, and (FEF 25-75) through 
2 hours post-dose over 24 weeks, over 
Weeks 12-24, and at each post-
randomization visit 
Synopsis: Assessments Over 24 Weeks 
(Unless Otherwise Stated); Section 
3.3.2, Assessments Over 24 Weeks 
(Unless Otherwise Stated); Section 
9.2.1.3.2, Assessments Over 24 Weeks 
(Unless Otherwise Stated)
Deleted “FEF(25-75) and PEFR” from the 
following sentence: 
These spirometry parameters will be 
collected but no longer analyzed. 

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Spirometry will be conducted 60 minutes
and 30 minutes prior to study drug 
administration at Visit 4 through Visit 11.  
The mean of the -60 minutes and -30 
minutes pre-dose spirometry assessments 
conducted at Visit 4 will be used to 
establish baseline FEV1, FVC, FEF(25-75) 
and PEFR. 
Section 7.1 Pulmonary Function Tests 
Deleted “and PEFR” from the following 
sentences: 
Forced expiratory spirometry maneuvers 
for derivation of FEV1, FVC and PEFR 
will be assessed using a spirometer that 
meets or exceeds minimum performance 
recommendations of the ATS (Refer to 
Appendix 1).
All pulmonary function tests including 
FEV1, FVC, and PEFR as defined in 
ATS/ERS guidelines will be performed in 
accordance with ATS criteria (Miller ,
2005). 
Section 7.1 Pulmonary Function Tests 
Deleted “PEFR and FEF(25-75) from the 
following sentence: 
The analysis of the other comparisons of 
changes in morning pre-dose trough FEV1 
over 24 weeks has already been described 
in Section 9.3.1.  Treatment differences in 
the change from baseline in FEV1 AUC0-2,
morning pre-dose trough FVC, PEFR and 
FEF(25-75) will be evaluated in a similar 
manner to the primary endpoint. 
Section 9.3.3.1 Other Spirometry 
Endpoints  
6
Added the following endpoints: 
Time to first clinically important 
Time to first CID is a composite 
endpoint that assesses deterioration in 
COPD using clinically relevant 

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deterioration (CID)
Time to sustained CID
Synopsis: Other Efficacy Endpoints 
(Assessments Over 24 Weeks [Unless 
Otherwise Stated]), Section 3.3.2, 
(Assessments Over 24 Weeks [Unless 
Otherwise Stated]);  Section 9.2.1.3.2, 
(Assessments Over 24 Weeks [Unless 
Otherwise Stated])
decreases in lung function, health status, 
and/or exacerbations. Thus, the time to 
CID endpoints assess stability in COPD 
and may provide additional insights on 
treatment benefits.
7
Deleted the following endpoints: 
•
Percentage of days with ‘no night-time 
awakenings’
•
Percentage of nights with ‘fewer than 
three night-time awakenings
•
Percentage of days with ‘no daytime 
symptoms’
Synopsis: Other Efficacy Endpoints 
(Assessments Over 24 Weeks [Unless 
Otherwise Stated]); Section 3.3.2, 
(Assessments Over 24 Weeks [Unless 
Otherwise Stated]); Section 9.2.1.3.2, 
Assessments Over 24 Weeks [Unless 
Otherwise Stated])
Deleted as these endpoints will be 
collected but not analyzed. 
8
$GGHGP/DVDWKUHVKROGIRUWKH
proportion of subjects achieving an 
improvement from baseline in FEV1 
Synopsis, Other Efficacy Endpoints Day 1 
Assessments; Section 3.3.1, Day 1 
Assessments; Section 9.2.1.3.1, Day 1 
Assessments; Section 9.3.3.1, Other 
Spirometry Endpoints
Added because 100 mL is the MCID for 
trough FEV1 and deemed to add value to 
the evaluation of improvement in FEV1.
9
For the SGRQ endpoints, changed that the 
analysis for the EU/South Korea/Taiwan 
approach will be over Weeks 12-24 instead 
of over 24 weeks 
Synopsis, Secondary Efficacy Endpoints; 
Section 3.2, Secondary Efficacy Endpoints; 
Updated as the SGRQ instrument post-
randomization is not administered until 
Week 12. 

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Section 9.2.1.2, Secondary Efficacy 
Endpoints; Section 9.3.2, Analysis of 
Secondary Endpoints; and Section 9.3.4.3, 
European Union/South Korea/Taiwan 
Endpoints
10
For the endpoints of change in individual 
domain scores of the SGRQ, deleted over 
24 Weeks timepoint and for the SGRQ 
endpoint of percentage of subjects 
achLHYLQJDQ0&,'WKUHVKROGRIXQLWV
on average in SGRQ total score, deleted 
over 24 Weeks and  revised to “Over 
Weeks 12 to 24 and separately at Week 
24”. 
Synopsis: Other Efficacy Endpoints 
(Assessments Over 24 Weeks [Unless 
Otherwise Stated]), Section 3.3.2,
(Assessments Over 24 Weeks [Unless 
Otherwise Stated]);  Section 9.2.1.3.2, 
(Assessments Over 24 Weeks [Unless 
Otherwise Stated]); Section 9.3.2.3, St. 
George’s Respiratory Questionnaire
Changed to clarify timepoints
11
Deleted “smoking status at baseline, and 
inhaled corticosteroid (ICS) use at 
baseline”, clarified the language 
surrounding the unstructured covariance 
matrix, deleted the AR(1) structure, and 
added that the heterogeneous Toeplitz 
(TOEPH) structure will be fit if the 
unstructured matrix model fails to 
converge in the following paragraph:  
The change from baseline in pre-dose 
trough FEV1 will be analyzed using a 
repeated measures (RM) linear model.  The 
model will include baseline FEV1 and 
reversibility to Ventolin (albuterol sulfate) 
HFA as continuous covariates and visit, 
treatment, treatment by visit, smoking 
status at baseline, and inhaled 
corticosteroid (ICS) use at baseline as  
categorical covariates. Baseline is defined 
as the average of the non-missing -60 min 
and -30 min values obtained prior to dosing 
Deleted the covariates as these 
covariates have not been shown in 
previous studies to be predictive of 
treatment response. 
The unstructured matrix models not only 
correlation but also the variance 
structure within a subject, allowing for 
changes in variance over time.
The AR(1) structure assumes a 
correlation structure that is too 
restrictive and will likely have problems 
with convergence. 

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at Visit 4.  An unstructured matrix will be 
used to model the variance-covariance 
structure within subject.  If this model fit 
fails to converge, the heterogeneous 
Toeplitz (TOEPH) structure will be fit.
Synopsis: Statistical Methods (Primary 
Efficacy Analysis)
Section 9.3.1.1 Change from Baseline in 
Morning Pre-dose Trough FEV1
12
Removed ICS use and smoking status as 
covariates
Section 9.3.2.1, TDI; Section 9.3.2.3, St. 
George’s Respiratory Questionnaire; 
Section 9.3.3.1, Other Spirometry 
Endpoints
These covariates have not been shown to 
be predictive of treatment response.
13
Deleted “and the analysis of weighted 
average (WAVE).  WAVE will be 
calculated as the weighted average change 
from baseline over 24 weeks and over 
Weeks 12-24 using the exposure time 
represented by each clinic visit as the 
weights.  It will be analyzed using an 
analysis of covariance (ANCOVA).  
The ANCOVA will evaluate treatment 
differences and include baseline and 
reversibility to Ventolin (albuterol sulfate) 
HFA as continuous covariates and, 
smoking status at baseline and ICS use at 
baseline as categorical covariates.” 
Synopsis: Statistical Methods (Primary 
Efficacy Analysis); Section 9.3.1.1, 
Change from Baseline in Morning Pre-dose 
Trough FEV1
The WAVE analysis results from 
previous studies were very similar to the 
results over 24 weeks and do not add 
any interpretive value.
14
Deleted the following paragraph: 
Removed TDI sample size calculation
Synopsis: Statistical Methods (Sample 
Size); Section 9.6, Sample Size 
For the EU/South Korea/Taiwan 
approach, TDI will be classified as a 
secondary endpoint for consistency with 
the study objectives and to better reflect 
the requirement that success with 
morning pre-dose trough FEV1 must be 
achieved first. Therefore, sample size 
justification is not required for TDI.

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19
Clarified text concerning subgroup 
analyses.
Section 9.3.1.1 Change from Baseline in 
Morning Pre-dose Trough FEV1; Section 
9.3.2 Analysis of Secondary Endpoints 
Important subgroup analyses will 
include by-country and regional 
evaluations for trough FEV1 and 
secondary endpoints. Additionally, 
subpopulation analyses based on CAT 
score thresholds will be conducted for 
TDI and SGRQ.
20
Deleted the following text:
Supportive analysis of the TDI will use the 
Symptomatic Population, a population 
possessing sufficient levels of dyspnea at 
the time of randomization to allow for a 
treatment benefit.  Refer to Section 9.9 for 
further details. Analyses in the PP 
Population will also be conducted as 
supportive.  
Section 9.3.2.1, TDI (formerly Section 
9.3.1.2, TDI [Co-Primary Endpoint for 
EU/Hybrid Approaches])
Analysis of TDI using the Symptomatic 
Population is a secondary endpoint 
rather than a supportive analysis. 
21
Deleted the following text:
Supportive analysis of the SGRQ will use 
the Symptomatic Population, a population 
possessing sufficiently diminished levels of 
quality of life at the time of randomization 
to allow for a treatment benefit.  Refer to 
Section 9.9 for further details. 
Section 9.3.2.3, St. George’s Respiratory 
Questionnaire (formerly Section 9.3.2.2, 
St. George Respiratory Questionnaire)
Analysis of SGRQ using the 
Symptomatic Population is a secondary 
endpoint rather than a supportive 
analysis.
22
Added text concerning the ANCOVA 
model for time to onset of action. 
Section 9.3.2.5 Onset of Action 
Previous text concerning the analysis 
referred to the same model specification 
for WAVE. Since WAVE has been 
removed, the model specification must 
be included for time to onset of action. 
23
Deleted “season at baseline (winter, spring, 
summer or fall)” from the following 
paragraphs:  
The rate of all COPD exacerbations of any 
Adjusting for these variables has not 
been shown in previous studies to be 
predictive of treatment response. 

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severity will be analyzed using negative 
binomial regression.  COPD exacerbations 
will be considered separate events provided 
that 7 or more days are between the 
recorded stop date of the earlier event and 
start date of the later. Exposure to 
randomized medication will be used as an 
offset variable. Time during an 
exacerbation or in the 7 days following an 
exacerbation will not be included in the 
calculation of exposure.  Treatments will 
be compared adjusting for baseline percent 
predicted FEV1, baseline CAT score, 
baseline COPD exacerbation history, 
smoking status at baseline, season at 
baseline (winter, spring, summer, or fall) 
and ICS use at baseline. 
The time to first COPD exacerbation of 
any severity will be analyzed using Cox 
regression model for the ITT population.  
The model will include treatment, baseline 
percent predicted FEV1, baseline COPD 
exacerbation history, baseline CAT score,
smoking status at baseline, season at 
baseline (winter, spring, summer, or fall) 
and ICS use at baseline. Estimated adjusted 
hazard ratios relative to the comparator 
will be displayed along with the associated 
Wald two-sided 95% confidence interval 
and p-values.  Time to first moderate or 
severe COPD exacerbation as well as the 
time to first COPD exacerbation will be 
displayed graphically for each treatment 
group using a Kaplan-Meier curve.  
Subjects who did not experience a COPD 
exacerbation will be censored at the Week 
24 visit. Subjects who withdrew from the 
study without experiencing a COPD 
exacerbation will be censored at the date of 
withdrawal.
Section 9.3.3.3, COPD Exacerbations 
Deleted “season at baseline (winter, spring, 
summer or fall” from the following 
paragraph: 

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Treatment failure will be defined as a 
moderate or severe COPD exacerbation or 
discontinuation from the study for any 
reason. The time to treatment failure will 
be analyzed using a Cox regression model 
for the ITT Population.  The model will 
include treatment, baseline percent 
predicted FEV1, baseline COPD 
exacerbation history, baseline CAT score, 
smoking status at baseline, season at 
baseline (winter, spring, summer or fall) 
and ICS use at baseline. Estimated adjusted 
hazard ratios will be displayed along with 
associated 95% confidence interval and p-
values.  Time to treatment failure will be 
displayed graphically for each treatment 
group using a Kaplan-Meier curve.  
Subjects who did not experience a 
treatment failure will be censored at 
Week 24. 
Section 9.3.3.4, Time to Treatment Failure
24
Added section to indicate how CID will be 
analyzed
Add new Section 9.3.3.5, Time to First and 
Sustained Clinically Important 
Deterioration (formerly Section 9.3.3.5, 
Symptom Scores [Daily, Morning and 
Evening Symptom Scores])
Added because time to first CID and 
time to sustained CID have been added 
as endpoints for this study 
25
Deleted previous Section 9.3.3.5.1 
Percentage of Nights with ‘No Nighttime 
Awakenings’ over 24 weeks; Section
9.3.3.5.2, Percentage of Nights with 
‘Fewer than Three Nighttime Awakenings’ 
Over 24 Weeks; and Section 9.3.3.5.3, 
Percentage of Days with ‘No Daytime 
Symptoms’ Over 24 weeks
Deleted description of analyses of these 
endpoints as these will be collected but 
not analyzed
26
Added secondary endpoints for TDI and 
SGRQ tested using the Symptomatic 
Population.  
Clarified that rescue Ventolin usage will be 
analyzed in the Rescue Ventolin User 
Analyses of symptomatic endpoints 
(TDI and SGRQ) will be conducted in 
the Symptomatic Population and are 
considered clinically important; thus, 
they are designated secondary endpoints. 

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Population.
Additional edits were made for clarity.
Section 9.3.4.1, United States/China 
Endpoints; 9.3.4.2, Japan Endpoints; 
Section 9.3.4.3 European Union/South 
Korea/Taiwan Endpoints
27
Updated the Type I error control procedure 
across secondary endpoints within a 
treatment comparison to a purely 
simultaneous testing approach. 
Section 9.3.4.1 United States/China 
Endpoints; 9.3.4.2 Japan Endpoints; 
Section 9.3.4.3, European Union/South 
Korea/Taiwan Endpoints
The prior specification of sequential 
then simultaneous testing of secondary 
endpoints to control Type I error may 
have caused the order of importance of 
the secondary endpoints to be 
misinterpreted.
28
Clarified that the Symptomatic Population 
ZLOOEHGHILQHGDV&$7UDWKHUWKDQ
&$7
Added the following text: 
Regional differences in rescue Ventolin 
HFA usage are expected, with some 
regions using virtually no rescue 
medication at study entry. Therefore, 
the Rescue Ventolin User Population is 
defined as all subjects in the ITT 
Population with average baseline Rescue 
9HQWROLQXVHRISXIIGD\
Section 9.9, Study Populations
7KHSRSXODWLRQRIVXEMHFWVZLWK&$7
15 in previous studies has shown 
sufficient symptomatic burden at 
baseline to derive a greater treatment 
benefit on symptomatic endpoints.  In 
addition across various studies, values of 
CAT between 15 and 20 inclusive have 
been shown to correspond to an MMRC 
value of 2. 
Rescue Ventolin usage may differ 
among countries; therefore, the criterion 
for rescue Ventolin population for 
analysis was defined.
29
Minor typographical errors were addressed 
but not captured as individual items in the 
summary of changes
To improve readability 

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SYNOPSIS 
Sponsor:
Pearl Therapeutics, Inc.
Names of Finished Products:
Glycopyrronium and Formoterol Fumarate Inhalation Aerosol; PT003, Glycopyrronium 
and Formoterol Fumarate Metered Dose Inhaler (GFF MDI) 
Formoterol Fumarate Inhalation Aerosol; PT005, Formoterol Fumarate Metered Dose 
Inhaler (FF MDI)
Glycopyrronium Inhalation Aerosol; PT001, Glycopyrronium Metered Dose Inhaler 
(GP MDI)
Placebo (matching) for GFF MDI, FF MDI, and GP MDI 
Name of Active Ingredients:
Glycopyrronium and Formoterol Fumarate 
Glycopyrronium 
Formoterol Fumarate
Study Title:
A Randomized, Double-Blind, Chronic Dosing (24 Weeks), Placebo-Controlled, Parallel 
Group, Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and 
PT001 in Subjects with Moderate to Very Severe COPD, Compared with Placebo
Study Number:  PT003014-05
Study Phase: III
Study Objective(s):
The overall objective of this study is to assess the efficacy and safety of treatment with 
*O\FRS\UURQLXPDQG)RUPRWHURO)XPDUDWH0',*))0',ȝJH[-actuator, 
BID), )RUPRWHURO)XPDUDWH0',))0',ȝJH[-actuator, BID), and
*O\FRS\UURQLXP0',*30',ȝJH[-actuator, BID) compared with each other and 
with Placebo MDI over 24 weeks in subjects with moderate to very severe COPD.
Primary Objectives:
The primary objective of this study is to compare the efficacy of treatment with GFF 
MDI, FF MDI, and GP MDI to Placebo MDI and to compare the efficacy of GFF MDI to 
its components on lung function using trough forced expiratory volume in 1 second 
(FEV1) in subjects with moderate to very severe COPD.
Secondary Objectives:

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•
To compare the effects of GFF MDI, FF MDI, GP MDI, and Placebo MDI on dyspnea 
using the Transition Dyspnea Index (TDI) focal score.
•
To compare the effects of GFF MDI, FF MDI, GP MDI and Placebo MDI on quality 
of life using the change in St. George Respiratory Questionnaire (SGRQ) score.  
•
To compare the effects of GFF MDI, FF MDI, GP MDI, and Placebo MDI on 
symptoms using the change in rescue Ventolin (albuterol sulfate) HFA use as an 
indirect measure of COPD symptom control.  
•
To determine the time to onset of action on Visit 4 (Day 1).
Other Efficacy Objectives:
•
To evaluate the effects of GFF MDI, FF MDI, GP MDI, and Placebo MDI on 
pulmonary function test (PFT) parameters. 
•
To assess the effects of GFF MDI, FF MDI, GP MDI, and Placebo MDI on COPD 
exacerbations.
•
To evaluate the effect of treatments on nighttime awakenings, morning and evening 
rescue Ventolin (albuterol sulfate) HFA use, breathlessness, cough, and sputum 
production as assessed by subjects’ electronic diary entries.
Safety Objective:
To assess the safety of GFF MDI, FF MDI, and GP MDI relative to Placebo MDI based 
on adverse events (AEs), vital sign measurements, ECGs, and clinical laboratory 
evaluations.

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MDI compared to Placebo MDI.
Primary Endpoint (US/China) 
•
For the US/China approach, the primary endpoint will be the change from baseline in 
morning pre-dose trough FEV1 at Week 24 of treatment.
Primary Endpoint (Japan) 
•
For the Japan approach, the primary endpoint will be the change from baseline in 
morning pre-dose trough FEV1 over Weeks 12 to 24 of treatment. 
Primary Endpoint (EU/ South Korea/Taiwan) 
x
For the EU/South Korea/Taiwan approach, the primary endpoint will be the change 
from baseline in morning pre-dose trough FEV1 over 24 weeks of treatment. 
Secondary Efficacy Endpoints:  
•
TDI score over 24 weeks (US/China and EU/South Korea/Taiwan approaches) and 
over Weeks 12 to 24 (Japan approach) 
•
TDI score over 24 weeks (US/China and EU/South Korea/Taiwan approaches) and 
over Weeks 12 to 24 (Japan approach) in the Symptomatic Population 
•
Change from baseline in morning pre-dose trough FEV1 over 24 weeks (US/China 
approach)
•
Peak change from baseline in FEV1 within 2 hours post-dosing at Week 24 
(US/China approach), over 24 weeks (EU/South Korea/Taiwan approach), and over 
Weeks 12 to 24 (Japan approach)  
•
Change from baseline in SGRQ total score at Week 24 (US/China approach) and 
over Weeks 12-24 (EU/South Korea/Taiwan and Japan approaches)  
•
Change from baseline in SGRQ total score at Week 24 (US/China approach) 
and over Weeks 12-24 (EU/South Korea/Taiwan and Japan approaches) in the 
Symptomatic Population 
•
Change from baseline in average daily rescue Ventolin (albuterol sulfate) HFA use 
over 24 weeks (all approaches) in the Rescue Ventolin User Population
•
Time to onset of action on Day 1 (all approaches) 
Other Efficacy Endpoints:
Day 1 Assessments 
•
Change from baseline at each post-dose time point in FEV1 and forced vital capacity 
(FVC), as well as FEV1 AUC0-2

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•
Proportion of subjects achieving an improvement from baseline in FEV1  using 
different thresholds (ie,  P/P/DQGDQG mL)
Assessments Over 24 Weeks (Unless Otherwise Stated) 
•
Rate of moderate to severe COPD exacerbations  
•
Time to the first moderate or severe COPD exacerbation
•
Rate of all COPD exacerbations 
•
Time to the first COPD exacerbation of any severity
•
Time to treatment failure
•
Time to first clinically important deterioration (CID)
•
Time to sustained CID
•
Change from baseline in morning pre-dose trough for FVC as well as FEV1 AUC0-2 at 
each post-randomization visit, over 24 weeks, and over Weeks 12-24  
•
Peak change from baseline in FEV1 and FVC through 2 hours post-dose over 24 
weeks, over Weeks 12-24, and at each post-randomization visit
•
Percentage of days with ‘no rescue Ventolin (albuterol sulfate) HFA use’ 
•
Change from baseline in mean daily total symptom score as well as each individual 
symptom (cough, shortness of breath, sputum volume, nighttime awakenings, and 
rescue Ventolin HFA use), the mean morning total and individual symptom scores, 
and the mean evening total and individual symptom scores over 24 weeks, over 
Weeks 12-24, and over each 4-week interval of the 24 week Treatment Period
•
TDI focal score at each post-randomization visit 
•
Individual components of the TDI: functional impairment, magnitude of task, and 
magnitude of effort over 24 weeks, over Weeks 12 to 24, and at each post-
randomization visit 
•
Percentage of subjects achieving a minimal clinically important difference (MCID) 
WKUHVKROGRIXQLWRQDYHUDJHLQ7',IRFDOVFRUHRYHUZHHNVDQGVHSDUDWHO\RYHU
Weeks 12 to 24 
•
Changes from baseline at each post-randomization visit for SGRQ total score
•
Change in individual domain scores of SGRQ: Symptoms, Activity, and Impacts over
Weeks 12 to 24 and at each post-randomization visit 
•
3HUFHQWDJHRIVXEMHFWVDFKLHYLQJDQ0&,'WKUHVKROGRIXQLWVRQDYHUDJHLQ6*54
total score over Weeks 12 to 24 and separately at Week 24 

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Safety Endpoints:
The safety endpoints for this study include the following: 
•
AEs
•
12-Lead ECG: Change from baseline in heart rate, PR interval, QRS axis, QRS 
interval, QT interval, and QTcF (Fridericia Corrected QT) interval
•
Clinical Laboratory Testing
•
Vital Sign Measurements
Health Care Resource Utilization Endpoints:
The number of days missed from work, and COPD-related and non-COPD related 
telephone calls and visits to healthcare providers, Emergency Room (ER) visits, and 
hospitalizations including days in hospital, days in Intensive Care Units (ICU), days in 
Coronary Care Units (CCU), and subject intubation events will be captured and 
compared between treatment groups.
Statistical Methods: 
Primary Efficacy Analysis:
The change from baseline in morning pre-dose trough FEV1 will be analyzed using a 
repeated measures (RM) linear model. The model will include baseline FEV1 and 
reversibility to Ventolin (albuterol sulfate) HFA as continuous covariates and visit, 
treatment, and treatment by visit as categorical covariates. Baseline is defined as the 
average of the non-missing -60 min and -30 min values obtained prior to dosing at Visit 
4. An unstructured matrix will be used to model the variance-covariance structure within 
subject. If this model fails to converge, a heterogeneous Toeplitz (TOEPH) structure will 
be fit. Contrasts will be used to obtain estimates of the treatment differences at Week 24, 
over Weeks 12 to 24, and over the entire 24-week Treatment Period. Two-sided p-values 
and point estimates with two-sided 95% confidence intervals (CIs) will be produced for 
each treatment difference. For all approaches, the primary analysis will be conducted 
using the ITT Population.  
Additional supportive analyses of morning pre-dose trough FEV1 will include the change 
from baseline at Week 24, over Weeks 12 to 24, and over the entire 24-week treatment 
period in the per protocol (PP) Population and the treatment differences at individual 
timepoints estimated by the RM model.  
Sensitivity analyses will also be conducted to evaluate the robustness of the primary 
analyses to the nature of the missing data. 
Sample Size:
It is estimated that a sample size of 1614 subjects (514 subjects in the GFF MDI arm, 
440 subjects in the FF MDI and GP MDI arms, and 220 subjects in the Placebo MDI 
arm) will provide approximately 91% power with Type I error controlled at a two-sided 

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alpha level of 0.05 to detect differences for all five primary comparisons if the true 
differences from Placebo MDI are 90 mL for FF MDI, 100 mL for GP MDI, and 150 mL 
for GFF MDI resulting in corresponding differences between GFF MDI and FF MDI and 
GP MDI of 60 mL and 50 mL, respectively, in morning pre-dose trough FEV1 at 
Week 24, approximately 99% power for morning pre-dose trough FEV1 over 24 weeks 
and approximately 99% power for morning pre-dose trough FEV1 over Weeks 12 to 24.  
Assumptions regarding variability for the primary endpoint are based on the experience 
of Pearl Therapeutics with Phase IIb clinical studies and on published data for within 
patient variation (D’Urzo, 2001, van Noord , 2005; Maesen, 1995) and between patient 
variation (Dahl, 2001, Calverley, 2003).  A composite value standard deviation (SD) of 
200 mL has been assumed.  A within subject correlation structure has been assumed 
combining a block diagonal structure induced by using subject as a random effect with 
DQ$5VWUXFWXUHZLWKȡ 'LIIHUHQWLDOGURSRXWUDWHVKDYHEHHQDVVXPHGZLWK
increased dropout due to lack of efficacy ranging up to 25% in the Placebo MDI arm.  
Under these assumptions, based on this sample size, the study will have approximately 
99% power to detect differences between FF MDI and Placebo MDI and between GP 
MDI and Placebo MDI in morning pre-dose trough FEV1 at Week 24, over 24 weeks or 
over Weeks 12-24 using a two-sided alpha level of 0.05. 
Data Monitoring Committees:  
An independent, external Data Monitoring Committee (DMC) will be set up to review all 
serious adverse events (including deaths and all hospitalizations) and cardiovascular 
events.  Members of the DMC will review summaries of these safety data generated 
externally and independently of Pearl Therapeutics in a semi-blinded and unblinded 
manner at predetermined intervals.  If significant safety issues arise in between scheduled 
meetings, ad hoc meetings will be scheduled to review the data.  Based on the safety 
implications of the data, the DMC may recommend modification or termination of the 
study.
Adjudication Committees: 
Two external adjudication committees will be established for this study. The committees 
will consist of independent experts outside of Pearl who are not involved in the study 
conduct.  Committee members will be blinded with respect to the subject’s study 
medication. At regular intervals, the Committee will review narratives, discharge 
summaries, and medical records, as available
•
Cardio- and Cerebro-vascular (CCV) Adjudication Committee will review and 
assess non-fatal serious CCV events as major cardiovascular events (MACE). 
•
Mortality Adjudication Committee will assess the cause of deaths for 
cardiovascular and respiratory related events.

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Date of Original Approved Protocol: 
Date of Protocol Amendment 1 (Version 2.0): 
Date of Protocol Amendment 2: 
Date of Protocol Amendment 3:
Date of Protocol Amendment 4: 
Date of Protocol Amendment 5: 

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TABLE OF CONTENTS
SUMMARY OF CHANGES TO PROTOCOL PT003014-04 (AMENDMENT 4, 
VERSION 5.0), DATED 
 ...........................................................................2
SYNOPSIS ...............................................................................................................................13
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................28
TRADEMARK INFORMATION ...........................................................................................32
1
INTRODUCTION AND STUDY RATIONALE ...........................................................33
1.1
Study Rationale ......................................................................................................36
2
STUDY OBJECTIVES ....................................................................................................37
2.1
Primary Objective: .................................................................................................37
2.2
Secondary Objectives: ...........................................................................................37
2.3
Other Efficacy Objectives: .....................................................................................37
2.4
Safety Objectives ...................................................................................................37
2.5
Healthcare Resource Utilization (HCRU) Objective: ............................................38
3
STUDY ENDPOINTS .....................................................................................................39
3.1
Primary Objective(s)/Endpoint(s) ..........................................................................39
3.2
Secondary Efficacy Endpoints ...............................................................................40
3.3
Other Efficacy Endpoints .......................................................................................40
3.3.1
Day 1 Assessments ......................................................................................40
3.3.2
Assessments Over 24 Weeks (Unless Otherwise Stated) ............................40
3.4
Safety Endpoints ....................................................................................................41
3.5
Health Care Resource Utilization Endpoints .........................................................41
4
INVESTIGATIONAL STUDY DESIGN .......................................................................43
4.1
General Considerations for Treatment Visits 4 through Visit 11: .........................45
4.2
Rationale of Study Design .....................................................................................49
4.3
Rationale of Dose/Regimen, Duration of Treatment, and Placebo Arm ...............49
5
STUDY POPULATION SELECTION AND WITHDRAWAL CRITERIA .................51
5.1
Inclusion Criteria....................................................................................................51
5.2
Exclusion Criteria ..................................................................................................53
5.3
Subject Identification .............................................................................................57
5.4
Prior, Concomitant, and Prohibited Medications ...................................................57
5.4.1
Prohibited COPD Medications ....................................................................57
5.4.2
Other Prohibited Medications ......................................................................60
5.5
Other Restrictions, Illicit Drugs or Drugs of Abuse ..............................................62
5.5.1
Illicit Drugs ..................................................................................................62
5.5.2
Dietary Restrictions .....................................................................................62
5.6
Smoking Status ......................................................................................................62

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5.7
Reasons and Procedures for Early Termination.....................................................62
6
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
CLINICAL SUPPLIES ....................................................................................................65
6.1
Subject Information ...............................................................................................65
6.2
Product Descriptions and Primary Packaging and Labeling Information .............65
6.3
Secondary Packaging and Labeling Information (Box) .........................................67
6.4
Emergency Unblinding of Treatment Assignment ................................................67
6.5
Storage Requirements ............................................................................................68
6.6
Instructions for Preparation of Treatments for Administration and Dispensing....68
6.6.1
GFF MDI, GP MDI, FF MDI, and Placebo MDI ........................................68
6.6.2
Atrovent (Ipratropium Bromide) HFA .........................................................69
6.6.3
Ventolin (Albuterol Sulfate) HFA ...............................................................69
6.7
Drug Accountability/Return of Clinical Supplies ..................................................70
7
STUDY ASSESSMENTS ...............................................................................................71
7.1
Pulmonary Function Tests .....................................................................................71
7.1.1
Characterization of Reversibility .................................................................72
7.1.2
FEV1 Baseline Stability Criteria ..................................................................73
7.1.3
Subject Electronic Diary Data Collection ....................................................73
7.1.4
Rescue Product Use .....................................................................................74
7.1.5
Medication Compliance ...............................................................................74
7.1.6
Recording of Dose Indicator Reading..........................................................74
7.1.7
Subject Questionnaires.................................................................................75
7.1.7.1
COPD Assessment Test .....................................................................75
7.1.7.2
Modified Medical Research Council Dyspnea Scale .........................75
7.1.7.3
Baseline (BDI) and Transition (TDI) Dyspnea Indices (BDI/TDI) ...76
7.1.7.4
St. George’s Respiratory Questionnaire (SGRQ) ..............................77
7.1.8
COPD Exacerbations ...................................................................................77
7.2
Safety Assessments ................................................................................................78
7.2.1
Medical/Surgical History and Physical Examination ..................................78
7.2.2
Vital Sign Measurements .............................................................................78
7.2.3
12-Lead Electrocardiogram .........................................................................79
7.2.4
Clinical Laboratory Tests .............................................................................80
7.2.4.1
Hematology ........................................................................................80
7.2.4.2
Clinical Chemistry .............................................................................80
7.2.4.3
Urinalysis ...........................................................................................81
7.2.4.4
Pregnancy Test ...................................................................................82
7.2.5
Adverse Events ............................................................................................82
7.2.5.1
Performing Adverse Events Assessments ..........................................82
7.2.5.2
Adverse Event Definitions .................................................................82
7.2.5.3
Pre-Randomization Adverse Events ..................................................83

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7.2.5.4
Severity ..............................................................................................83
7.2.5.5
Relationship .......................................................................................83
7.2.5.6
Chronic Obstructive Pulmonary Disease Exacerbations ...................84
7.2.5.7
Clinical Laboratory Adverse Events ..................................................84
7.2.5.8
Serious Adverse Events .....................................................................85
7.2.5.9
Supplemental Investigations of SAEs ................................................86
7.2.5.10
Post-Study Follow-Up of Adverse Events .........................................86
7.2.5.11
Notification of Post-Study Serious Adverse Events ..........................86
7.2.5.12
Investigational Research Board/Independent Ethics Committee 
Notification of Serious Adverse Events .............................................86
7.2.5.13
Health Authority Safety Reports ........................................................87
7.2.6
Overdose ......................................................................................................87
7.2.7
Pregnancy .....................................................................................................87
7.2.8
Use of Steroids during the Trial ...................................................................87
7.2.9
Adjudication Committee ..............................................................................88
7.2.10
Data Monitoring Committee ........................................................................88
7.3
Health Care Resource Utilization ..........................................................................88
7.4
Termination of the Study .......................................................................................88
8
STUDY ACTIVITIES .....................................................................................................90
8.1
Visit 1 .....................................................................................................................96
8.2
Visit 2 .....................................................................................................................97
8.3
Visit 3 .....................................................................................................................98
8.4
Visit 4 (Randomization) .........................................................................................98
8.5
Visit 5 to Visit 10 ...................................................................................................99
8.6
Final Visit (Visit 11) ............................................................................................101
8.7
Unscheduled Visit/Premature Discontinuation Visit ...........................................102
8.8
Follow-Up Telephone Call ..................................................................................103
8.9
Completion of the Study ......................................................................................104
9
PLANNED STATISTICAL METHODS ......................................................................105
9.1
Introduction ..........................................................................................................105
9.2
Protocol Variables ................................................................................................105
9.2.1
Efficacy Endpoints .....................................................................................105
9.2.1.1
Primary Efficacy Endpoint ..............................................................106
9.2.1.2
Secondary Efficacy Endpoints .........................................................106
9.2.1.3
Other Efficacy Endpoints .................................................................107
9.2.2
Safety Endpoints ........................................................................................108
9.2.3
Health Care Resource Utilization ..............................................................108
9.3
Analysis................................................................................................................109
9.3.1
Primary Efficacy Analysis .........................................................................109
9.3.1.1
Change from Baseline in Morning Pre-dose Trough FEV1 .............109
9.3.2
Analysis of Secondary Endpoints ..............................................................110

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9.3.2.1
TDI ...................................................................................................110
9.3.2.2
Peak FEV1 ........................................................................................111
9.3.2.3
St. George’s Respiratory Questionnaire ..........................................111
9.3.2.4
Rescue Ventolin (albuterol sulfate) HFA Use .................................111
9.3.2.5
Time to Onset of Action ..................................................................112
9.3.3
Analysis of Exploratory Endpoints ............................................................112
9.3.3.1
Other Spirometry Endpoints ............................................................112
9.3.3.2
Percentage of Days With “No Rescue Use” ....................................112
9.3.3.3
COPD Exacerbations .......................................................................112
9.3.3.4
Time to Treatment Failure ...............................................................113
9.3.3.5
Time to First and Sustained Clinically Important Deterioration .....114
9.3.3.6
Symptom Scores (Daily, Morning and Evening Symptom Scores) 114
9.3.4
Control of Type I Error ..............................................................................114
9.3.4.1
United States/China Endpoints ........................................................114
9.3.4.2
Japan Endpoints ...............................................................................115
9.3.4.3
European Union/South Korea/Taiwan Endpoints ............................117
9.3.5
Safety Analysis ..........................................................................................118
9.3.5.1
Adverse Events ................................................................................118
9.3.5.2
Cardio- and Cerebrovascular and Mortality Events Determined by 
Adjudication Committee ..................................................................118
9.3.6
Clinical Laboratory Measurements ............................................................118
9.3.7
Vital Signs ..................................................................................................119
9.3.8
ECGs ..........................................................................................................119
9.3.9
Health Care Resource Utilization ..............................................................119
9.4
Randomization .....................................................................................................119
9.5
Experimental Design ............................................................................................119
9.6
Sample Size ..........................................................................................................120
9.7
Data Validation and Transformation ...................................................................120
9.8
Analysis Plan .......................................................................................................120
9.9
Study Populations ................................................................................................120
9.10
Handling of Missing Data ....................................................................................121
9.11
Statistical Software ..............................................................................................122
10 ADMINISTRATIVE CONSIDERATIONS ..................................................................123
10.1
Regulatory Authority Approval ...........................................................................123
10.2
Ethical Conduct of the Study and Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) Approval ..................................................123
10.3
Subject Information and Consent.........................................................................124
10.4
Laboratory Accreditation .....................................................................................124
10.5
Confidentiality .....................................................................................................124
10.5.1
Confidentiality of Data ..............................................................................124
10.5.2
Confidentiality of Subject/Patient Records ................................................124

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10.6
Quality Control and Assurance ............................................................................125
10.7
Data Management ................................................................................................125
10.8
Study Monitoring .................................................................................................125
10.9
Retention of Data .................................................................................................126
10.10 Financial Disclosure.............................................................................................126
10.11 Investigator's Final Report ...................................................................................126
10.12 Publication Policy ................................................................................................126
11 REFERENCE LIST .......................................................................................................129

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LIST OF IN-TEXT TABLES
Table 1.
COPD Medications: Required Washout Periods, Pre Visit 2 ......................57
Table 2.
Other Respiratory/Nasal Medications: Required Washout Periods .............59
Table 3.
Non-COPD Medications Allowed Under Certain Condition ......................60
Table 4.
Prohibited Medications ................................................................................60
Table 5.
Study Product Packaging Descriptions ........................................................66
Table 6.
Description of Boxes....................................................................................67
Table 7.
MMRC Dyspnea Scale ................................................................................75
Table 8
Laboratory Parameters .................................................................................81
Table 9.
Schedule of Events .......................................................................................91
Table 10.
Timed Assessments during Treatment Period (Visits 4-11) ........................94
LIST OF IN-TEXT FIGURES
Figure 1.
Study Flow Diagram ....................................................................................48
Figure 2.
Indicator at Top of Canister .......................................................................142
Figure 3.
Wash Actuator through Top of Actuator ...................................................143
Figure 4.
Wash Actuator through Mouthpiece ..........................................................144
Figure 5.
Metered Dose Inhaler Parts ........................................................................145
LIST OF APPENDICES
Appendix 1
Spirometry Performance Recommendations ...................................133
Appendix 2
Spirometry Assessment Criteria ......................................................139
Appendix 3
Classification of Severity - GOLD Guidelines (2014) ....................141
Appendix 4
Subject Instructions for Use of GFF,GP, FF and Placebo MDI ......142
Appendix 5
Instructions for Use of Atrovent HFA Inhalation Aerosol Device ..146
Appendix 6
Instructions for Use of Ventolin HFA Inhaler .................................149
Appendix 7
COPD Assessment Test ...................................................................154
Appendix 8
St. George Respiratory Questionnaire (SGRQ) ...............................155
Appendix 9
BDI/TDI Questionnaire ...................................................................161
Appendix 10
Dose Indicator Display Reading Instructions ..................................167
Appendix 11
Sponsor Signatory ............................................................................168
Appendix 12
Investigator’s Agreement and Signature Page .................................169

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AR (1)
First order autoregressive  
AST
Aspartate aminotransferase
ATS
American Thoracic Society
AUC
Area under the curve
AV
Atrioventricular block 
BDI
Baseline Dyspnea Index
BID
bis in di.e., Twice Daily
BiPAP
Bilevel Positive Airway Pressure
BMP
Basic Metabolic Panel
BP
Blood Pressure 
BPM
Beats per minute
BTPS
Body Temperature and Pressure Saturated
CAT 
COPD Assessment Test
CCU
Coronary Care Unit 
CCV
Cardio- and Cerebro-vascular
CID
Clinically Important Deterioration
CFR
Code of Federal Regulations
CHF
Congestive Heart Failure
CHMP
Committee for Medicinal Products for Human Use 
CI
Confidence Interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
COPD
Chronic Obstructive Pulmonary Disease 
CPAP
Continuous Positive Airway Pressure 
CRT
Cardiac Resynchronisation Therapy
CRT_D
Cardiac Resynchronization Therapy-Defibrillator
CT
Computed Tomography 

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CTCAE
Common Terminology Criteria for Adverse Events  
DMC
Data Monitoring Committee
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDiary
Electronic Diary
eg
Exempli gratia, for example
ER
Emergency Room 
ERS
European Respiratory Society 
EU
European Union 
EV
Back Extrapolation Volume 
ex-actuator
Dose Delivered From The Actuator (i.e., mouthpiece) Of The MDI  
FDA
Food and Drug Administration 
FEV1
Forced Expiratory Volume In 1 Second 
FF MDI
Formoterol Fumarate MDI
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GFF MDI
Glycopyrronium and Formoterol Fumarate MDI 
GP MDI
Glycopyrronium MDI 
HCG
Human Chorionic Gonadotropin 
HCRU
Healthcare Resource Utilization
HFA
Hydrofluroalkane 
HR
Heart Rate
HRQoL
Health-related Quality of Life
IB
Investigator’s Brochure
ICD
Implantable Cardioverter-Defibrillator
ICF
Informed Consent Form 
ICH
International Conference on Harmonization 
ICMJE
International Committee of Medical Journal Editors
ICS
Inhaled Corticosteroid

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ICU
Intensive Care Unit
ie
Id est, that is
IEC
Independent Ethics Committee 
IPF
Interstitial Pulmonary Fibrosis
IRB
Institutional Review Board
ITT
Intention-to-treat
IUD
Intrauterine device
IWRS
Interactive Web Response System
L 
Liter
LABA
Long-acting Beta Agonist
LAMA
Long-acting Muscarinic Antagonist
LTOT
Long Term Oxygen Therapy
MAR
Missing At Random 
MCAR
Missing Completely At Random 
MCH
Mean Corpuscular Hemoglobin 
MCHC
Mean Corpuscular Hemoglobin Concentration 
MCID
Minimal clinically important difference
MCV
Mean Corpuscular Volume 
MDI
Metered Dose Inhaler
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
MMRC
Modified Medical Research Council
MMRM
Mixed Model Repeated Measures
Msec (ms)
Millisecond
NHANES III
Third National Health and Nutrition Examination Survey 
NIPPV
Non-invasive Positive Pressure Ventilation Device
NMAR
Not Missing At Random 
OTC
Over the counter 
PFT
Pulmonary Function Test 
PIN
Personal identification number 

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PMDA
Pharmaceuticals and Medical Devices Agency
PP
Per Protocol 
PRN
pro re nata, As Needed
QD
quaque di.e., Once Daily
QID
quater in die; Four Times Daily
QTcF
QT corrected using Fridericia’s formula (QT/(RR 1/3))
SABA
Short-acting Beta Agonist
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure 
SGRQ
St. George Respiratory Questionnaire 
SOP
Standard Operating Procedure 
SSRI
Selective Serotonin Reuptake Inhibitors 
TDI
Transition Dyspnea Index 
71)Į
Anti-WXPRU1HFURVLV)DFWRUĮ
TURP
Trans-urethral Resection Of Prostate
US
United States
VT
Ventricular Tachycardia

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TRADEMARK INFORMATION 
Trademarks Not Owned By Pearl Therapeutics
Aerolizer
Handihaler
Anoro 
Seebri
Atrovent 
Spiriva 
Breezhaler
Tudorza 
Combivent  
Ventolin
Eklira 
Ellipta
Foradil 
Genuair

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1
INTRODUCTION AND STUDY RATIONALE
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality
at a global level and recent statistics suggest it will become more prevalent as smoking 
frequencies rise and the population ages (Calverley, 2003; Feenstra, 2001; Ferrer ,1997; 
Murray, 1997; Sullivan, 2000).  In a systematic review and meta-analysis by Halbert and 
colleagues, the prevalence of physiologically defined COPD in adults aged  years was 
observed to be 9-10% (Halbert 2003 and Halbert 2006).  The causes behind COPD are 
multi-factorial, where various risk factors and environmental stimuli have been identified and 
include smoking, air pollution, and occupational hazards.  Hence, COPD is not only a
smoker’s disease with familial origins, but one that worsens with age. 
COPD is a disease of the lungs characterized by airflow limitation that is not fully reversible. 
The chronic airflow limitation characteristic of COPD is caused by a mixture of small 
airways disease (obstructive bronchiolitis) and parenchymal destruction (emphysema) the 
relative contributions of which vary from person to person.  The airflow limitation is 
progressive in nature and associated with abnormal inflammatory response of the lung to 
noxious particles or gases.  This disease is characterized by premature loss of ventilatory 
function as determined by a decline in forced expiratory volume in the first second of 
exhalation (FEV1).  Pathological inflammatory changes are characterized by elevations in 
activated macrophages, neutrophils, elastases, and CD8 lymphocytes.  These molecular and 
cellular changes cause the destruction of small airways and surrounding alveoli.  As 
expiratory airflow (FEV1 or forced vital capacity [FVC]) is a function of pressure against 
resistance, airflow in COPD is diminished due to a loss of elastic recoil and airway 
constriction. 
Pharmacologic therapy for COPD is used to reduce symptoms, reduce the frequency and 
severity of exacerbations, and improve health status and exercise tolerance.  Bronchodilators 
are the mainstay of pharmacologic treatment of COPD.  The principal bronchodilator 
treatments are short-acting beta agonists (SABAs), long-acting beta agonists (LABAs), short
acting muscarinic antagonists, long-acting muscarinic antagonists (LAMAs) and 
methylxanthines used as monotherapy or in combination.  In subjects with significant 
symptoms but low risk of exacerbations regular treatment with LABAs is more effective in 
the management of COPD than SABAs.  In subjects with a high risk of exacerbations 
regardless of the number of symptoms, a fixed combination of an inhaled 
corticosteroid/LABA or a LAMA is recommended (GOLD, 2014).
Currently, one fixed-dose combination of a LABA and a LAMA is commercially available 
(Anoro™Ellipta® [umeclidinium and vilanterol] from GlaxoSmithKline.  Combivent® 
[salbutamol sulfate and ipratropium bromide] is a short-acting fixed dose combination of a 
SABA and short acting muscarinic antagonist indicated for the treatment of COPD and is 
administered as two inhalations four times daily.  Published studies (van Noord , 2005; van
Noord , 2006;Vogelmeier, 2006) have shown that the complementary mechanisms of action 
of a LABA (formoterol fumarate) and a LAMA (tiotropium bromide) significantly improved 
bronchodilation in COPD subjects compared to the individual agents. 

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Pearl Therapeutics is developing a combination product, Glycopyrronium and Formoterol 
Fumarate Inhalation Aerosol (hereafter referred to as GFF MDI), as a maintenance
bronchodilator treatment in patients with COPD.  Pearl Therapeutics is also developing the 
individual products, Glycopyrronium Inhalation Aerosol (hereafter referred to as GP MDI) 
and Formoterol Fumarate Inhalation Aerosol (hereafter referred to as FF MDI) as 
maintenance bronchodilator treatments in patients with COPD.
Pearl Therapeutics has recently changed the naming convention for GFF MDI and GP MDI 
to make reference to the active moiety – glycopyrronium – instead of the bromide salt form 
previously used (glycopyrronium bromide, also known as glycopyrrolate).  There have been 
no changes made to formulation of GFF MDI or GP MDI, just a change in how the 
strength/dose is expressed.  All references to strengths/doses of GFF MDI and GP MDI in 
this protocol are based on the mass of glycopyrronium.  In all prior clinical studies, Pearl 
Therapeutics expressed the strengths/doses of GFF MDI and GP MDI based on the mass of 
glycopyrrolate (glycopyrronium bromide), which is the bromide salt form of the active 
material.  In this study, GFF MDI 14.4/9.6 μg contains 14.4 μg of glycopyrronium and 
9.6 μg of formoterol fumarate and GP MDI 14.4 μg contains 14.4 μg of glycopyrronium. 
Both GFF MDI and GP MDI are administered twice daily (BID).  The dose of 
glycopyrronium (14.4 μg) in GFF MDI and GP MDI is equivalent to 18 μg of glycopyrrolate 
(glycopyrronium bromide). 
Glycopyrronium is a LAMA which exerts its bronchodilatory effect via muscarinic receptors 
located on smooth muscle cells within the trachea and bronchi.  Glycopyrronium is approved 
in many countries in multiple formulations for different indications, including COPD. 
An inhaled formulation of glycopyrronium (Seebri® Breezhaler® Inhalation Powder, 
glycopyrronium bromide [Novartis, AG]) was recently approved throughout the European 
Union (EU) Australia, Canada, and Japan for the management of adult patients with COPD.  
The recommended dose is 44 μg (delivered dose of 55 μg of glycopyrronium bromide 
equivalent to 44 μg of glycopyrronium) administered once daily (QD) using the Seebri 
Breezhaler inhaler.  The clinical development program for Seebri Breezhaler included 
12 clinical studies, five Phase I studies, four Phase II clinical studies and three Phase III 
clinical studies.  Overall, the clinical development program included a total of 1361 patients 
with COPD exposed to Seebri Breezhaler 44 μg QD with a total of 842 and 428 patients with 
COPD exposed to Seebri Breezhaler 44 J4'IRUZHHNVDQG weeks, respectively 
[CHMPAssessment Report for Seebri Breezhaler, 2012].  In addition to the published data 
with Seebri Breezehaler (also referred to as NVA 237), there is also large body of published 
data evaluating the safety and efficacy of inhaled glycopyrronium in healthy volunteers, 
patients with COPD, and patients with asthma.
Ten clinical studies have been conducted to support the dose selection of GFF MDI, 
GP MDI, and FF MDI.  Efficacy and safety data are available from three studies conducted 
with GP MDI, and two studies with FF MDI.  In addition, four studies conducted in subjects 
with COPD and one study conducted in healthy volunteers has been completed with 
GFF MDI, GP MDI, and FF MDI across a wide range of doses.  Please note that the doses of 

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GFF MDI and GP MDI are expressed in terms of glycopyrronium bromide (glycopyrrolate) 
for the previously completed studies described below. 
GP MDI has been evaluated in eight studies conducted by Pearl Therapeutics, including a 
single dose, single center, healthy volunteer study in Australia and seven multi-center studies 
in subjects with COPD conducted in the United States (US), Australia, and New Zealand.  
This program has assessed the safety and efficacy of GP MDI across a wide range of doses 
from 144 μg down to 0.6 μg.  Across these eight studies, approximately 350 subjects with 
moderate to severe COPD were exposed to one or more doses of GP MDI.  The lower end of 
the dose-response curve has been adequately characterized in two chronic-dose, dose-ranging 
studies (Studies PT001002 and PT001003), and the findings from these two studies and the 
previous Phase II studies support GP MDI 18 μg BID as the most appropriate dose to be 
evaluated in Phase III clinical studies.
Formoterol fumarate is a potent and selective LABA approved in many countries worldwide 
for use in asthma and COPD.  When inhaled, formoterol fumarate acts locally in the lung as a 
EURQFKRGLODWRU)RUPRWHUROIXPDUDWHVWLPXODWHVȕ2 adrenoreceptors in the airways, inducing 
airway smooth muscle relaxation and reducing or preventing bronchoconstriction. 
In patients with COPD, formoterol fumarate is typically administered at an orally inhaled 
dose of 12 μg twice daily with doses up to 24 μg twice daily approved in some countries.  
Although formoterol fumarate is classified as a LABA, it has a rapid onset of action similar 
to SABAs.  Formoterol fumarate is highly potent, displays high intrinsic activity, and can 
result in greater than 80% relaxation even under induced tone (Anderson, 1993).  Five large 
placebo-controlled clinical studies of up to 12 months in duration in nearly 2500 subjects 
demonstrated that formoterol fumarate is effective and well tolerated in patients with COPD 
(Dahl, 2001; Rossi, 2002; Albers, 2002; Campbell, 2005; Campbell, 2007). 
Pearl Therapeutics conducted three studies to confirm dose selection and safety for FF MDI.  
These include studies: PT0050801, PT0031002, and PT003005.  Results demonstrated dose 
proportionality of FF MDI 9.6 μg and bioequivalence to Foradil. In terms of safety, results 
showed no substantial differences between the FF MDI treatment groups to placebo or to 
Foradil 12 ȝJDnd there were no important trends noted for FF MDI at any dose. 
Pearl Therapeutics is developing its combination product GFF MDI in parallel with the 
individual agents.  Eight different doses of GFF MDI have been evaluated in five studies 
conducted by Pearl Therapeutics, including a single dose, single center, healthy volunteer 
study in Australia, and four multicenter studies in subjects with COPD conducted in the US, 
Australia, and New Zealand.  The studies in subjects with COPD included three Phase IIb 
studies of 1-week duration and one cardiovascular safety study of 2-week duration.  
The GFF MDI doses that have been studied include the following dosing combinations: 
72/9.6 ȝJ ȝJ ȝJ ȝJ ȝJ ȝJ ȝJDQG ȝJ
Throughout this Phase IIb program, over 300 subjects with COPD have been exposed to one 
or more doses of GFF MDI.  A brief summary of the data supporting dose selection is 
presented, as follows: 

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In Study PT0031002, GFF MDI 72/9.6 μg was comparable to GFF MDI 36/9.6 μg and Pearl 
Therapeutics determined that GFF MDI 36/9.6 μg would be the highest dose for further 
evaluation.  Study PT003003 evaluated the overall cardiovascular safety of GFF MDI 
36/9.6 μg compared to its components and open-label Foradil.  In this study, 24-hour Holter 
monitoring data obtained on Day 1 and Day 14 of dosing were comparable across all 
treatments and comparable to 24-hour Holter monitoring data obtained during the screening 
period on Atrovent HFA MDI.  Study PT003004 evaluated the safety and efficacy of GFF 
MDI 36/9.6 ȝJ*))0', ȝJ*))0', ȝJDQG*))0', μg compared 
to GP MDI 36 μg and FF MDI 9.6 μg.  In this study, all GFF MDI doses provided roughly 
comparable bronchodilation as assessed by FEV1 AUC0-12 on Day 7 with a similar safety 
profile.  These results are aligned with those of the earlier GP MDI dose ranging study 
(Study PT001002) and supported a relatively flat dose response to glycopyrrolate whether 
administered alone or as a fixed combination with formoterol fumarate.  Based on these 
results, even lower doses of GFF MDI were evaluated in Study PT003005.  Study PT003005 
was a randomized, double-blind, chronic-dosing (7 days), four-period, eight-treatment, 
incomplete block, crossover, multi-center study to assess efficacy and safety of five doses of 
GFF MDI (18/9.6, 9/9.6, 4.6/9.6, 2.4/9.6, and 1.2/9.6 μg administered BID) compared with 
FF MDI (9.6 μg administered BID), GP MDI (18 μg administered BID), and Spiriva 
Handihaler (Spiriva, 18 μg open-label, QD) in subjects with moderate to severe COPD.  All 
doses of GFF MDI demonstrated statistically significant improvements compared to FF MDI 
9.6 μg and GP MDI 18 μg in FEV1 AUC0-12 with the exception of GFF MDI 1.2/9.6 μg 
relative to FF MDI 9.6 μg, which just missed a statistically significant difference.  In 
addition, all doses of GFF MDI from 2.4/9.6 μg to 18/9.6 μg demonstrated statistically 
significant improvements compared to Spiriva in FEV1 AUC0-12.  Based on this data the 
incremental value of GP MDI 18 μg when added to FF MDI 9.6 μg provides a reasonable 
benefit across all parameters.  GFF MDI 18/9.6 μg was safe and well tolerated with an AE 
profile similar to its components and approved products for the management of COPD 
(i.e., Spiriva, Atrovent, and Foradil Aerolizer).  A more detailed description of the studies 
design and results can be obtained in the Investigator Brochure (IB). 
1.1 Study Rationale 
The purpose of this study is to provide pivotal efficacy and safety data for GP MDI, FF MDI, 
and GFF MDI in subjects with moderate to very severe COPD.  Data obtained from this 
study, together with two similarly designed 6-month pivotal studies (Study PT003006 and 
Study PT003007) and a 28-week safety extension (Study PT003008) are intended to be used 
to support the registration of GFF MDI, GP MDI, and FF MDI worldwide.  As described 
above, the doses selected for evaluation in this study are based primarily on the findings from
three previous clinical studies with GP MDI (Studies PT0010801, PT001002, and 
PT001003), two clinical studies with FF MDI (Studies PT0050801 and PT005003), and four 
studies with GFF MDI (Studies PT0031002, PT003003, PT003004, and PT003005). 

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2
STUDY OBJECTIVES
Overall Study Objective:
The overall objective of this study is to assess the efficacy and safety of treatment with 
Glycopyrronium and Formoterol Fumarate MDI (GFF MDI, 14.4/9.6 ȝJH[-actuator, BID),
Formoterol Fumarate MDI (FF MDI, 9.6 ȝJH[-actuator, BID), and Glycopyrronium MDI 
(GP MDI, 14.4 ȝJH[-actuator, BID) compared with each other and with Placebo MDI over 
24 weeks in subjects with moderate to very severe COPD.
2.1
Primary Objective:
The primary objective of this study is to compare the efficacy of treatment with GFF MDI, 
FF MDI, and GP MDI to Placebo MDI and to compare the efficacy of GFF MDI to its 
components on lung function using trough forced expiratory volume in 1 second (FEV1) in 
subjects with moderate to very severe COPD.
2.2
Secondary Objectives:
•
To compare the effects of GFF MDI, FF MDI, GP MDI, and Placebo MDI on dyspnea 
using the Transition Dyspnea Index (TDI) focal score. 
•
To compare the effects of GFF MDI, FF MDI, GP MDI and Placebo MDI on quality of 
life using the change in St. George Respiratory Questionnaire (SGRQ) score. 
•
To compare the effects of GFF MDI, FF MDI, GP MDI, and Placebo MDI on symptoms 
using the change in rescue Ventolin (albuterol sulfate) HFA use as an indirect measure of 
COPD symptom control.  
•
To determine the time to onset of action on Visit 4 (Day 1).
2.3 Other Efficacy Objectives: 
•
To evaluate the effects of GFF MDI, FF MDI, GP MDI, and Placebo MDI on pulmonary 
function test (PFT) parameters.
•
To assess the effects of GFF MDI, FF MDI, GP MDI, and Placebo MDI on COPD 
exacerbations.
•
To evaluate the effect of treatments on nighttime awakenings, morning and evening 
rescue Ventolin (albuterol sulfate) HFA use, breathlessness, cough, and sputum 
production as assessed by subjects’ electronic diary entries.
2.4
Safety Objectives
•
To assess the safety of GFF MDI, FF MDI, and GP MDI relative to Placebo MDI based 
on adverse events (AEs), vital sign measurements, ECGs, and clinical laboratory 
evaluations. 

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2.5 Healthcare Resource Utilization (HCRU) Objective: 
•
To assess overall and COPD-specific HCRU between treatment groups.

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3
STUDY ENDPOINTS
All efficacy assessments are relative to pre-dose baseline obtained at Visit 4.  Lung function 
measurements and symptom-based endpoints will be evaluated.  The primary endpoint 
differs by approach but is always based on morning pre-dose trough FEV1.
The three different registration approaches will be called: 1) US/China, 2) Japan, and 3) 
EU/South Korea/Taiwan.  The primary endpoint is identical for the US and China. 
The Japan approach is for registration purposes based on the agreement with the Japan 
Health Authority for which endpoints assessed over weeks 12 to 24 are required. 
The EU/South Korea/Taiwan approach is for endpoints assessed over 24 weeks. 
The delineation of multiplicity controls for the primary and secondary measures are separated 
by approach.
All inferential results will be based on analyses using the Intent-to-Treat (ITT) Population 
unless otherwise noted. In addition to the ITT analysis, symptomatic endpoints will also be 
analyzed using the Symptomatic Population. The primary analyses of rescue Ventolin usage 
will be conducted in the Rescue Ventolin User Population (refer to Section 9.9).
3.1
Primary Objective(s)/Endpoint(s) 
The primary objective of this study is to confirm the efficacy of GFF MDI compared to its 
individual components and Placebo MDI as well as the efficacy of FF MDI and GP MDI 
compared to Placebo MDI. 
Primary Endpoint (US/China)
•
For the US/China approach, the primary endpoint will be the change from baseline in 
morning pre-dose trough FEV1 at Week 24 of treatment. 
Primary Endpoint (Japan) 
•
For the Japan approach, the primary endpoint will be the change from baseline in 
morning pre-dose trough FEV1 over Weeks 12 to 24 of treatment. 
Primary Endpoint (EU/South Korea/Taiwan)  
•
For the EU/South Korea/Taiwan approach, the primary endpoint will be the change from 
baseline in morning pre-dose trough FEV1 over 24 weeks of treatment.

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3.2  Secondary Efficacy Endpoints 
•
TDI score over 24 weeks (US/China and EU/South Korea/Taiwan approaches) and over 
Weeks 12 to 24 (Japan approach) 
•
TDI score over 24 weeks (US/China and EU/South Korea/Taiwan approaches) and over 
Weeks 12 to 24 (Japan approach) in the Symptomatic Population 
•
Change from baseline in morning pre-dose trough FEV1 over 24 weeks (US/China 
approach)
•
Peak change from baseline in FEV1 within 2 hours post-dosing at Week 24 (US/China 
approach), over 24 weeks (EU/South Korea/Taiwan approach), and over Weeks 12 to 24 
(Japan approach)
•
Change from baseline in SGRQ total score at Week 24 (US/China approach) and over 
Weeks 12-24 (EU/South Korea/Taiwan and Japan approaches)
•
Change from baseline in SGRQ total score at Week 24 (US/China approach) and over 
Weeks 12-24 (EU/South Korea/Taiwan and Japan approaches) in the Symptomatic 
Population 
•
Change from baseline in average daily rescue Ventolin (albuterol sulfate) HFA use over 
24 weeks (all approaches) in the Rescue Ventolin User Population 
•
Time to onset of action on Day 1 (all approaches) 
3.3 Other Efficacy Endpoints  
3.3.1 Day 1 Assessments 
•
Change from baseline at each post-dose time point in FEV1 and forced vital capacity 
(FVC), as well as FEV1 AUC0-2
•
Proportion of subjects achieving an improvement from baseline in FEV1 using different 
thresholds (ie,  P/ P/DQGDQG mL)
3.3.2 Assessments Over 24 Weeks (Unless Otherwise Stated)
•
Rate of moderate to severe COPD exacerbations 
•
Time to the first moderate or severe COPD exacerbation
•
Rate of all COPD exacerbations 
•
Time to the first COPD exacerbation of any severity
•
Time to treatment failure
•
Time to first CID
•
Time to sustained CID

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•
Change from baseline in morning pre-dose trough for FVC as well as FEV1 AUC0-2 at 
each post-randomization visit, over 24 weeks, and over Weeks 12-24  
•
Peak change from baseline in FEV1 and FVC through 2 hours post-dose over 24 weeks, 
over Weeks 12-24, and at each post-randomization visit 
•
Percentage of days with ‘no rescue Ventolin (albuterol sulfate) HFA use’ 
•
Change from baseline in mean daily total symptom score as well as each individual 
symptom (cough, shortness of breath, sputum volume, nighttime awakenings, and rescue 
Ventolin HFA use), the mean morning total and individual symptom scores, and the 
mean evening total and individual symptom scores over 24 weeks, over Weeks 12-24, 
and over each 4-week interval of the 24 week Treatment Period
•
TDI focal score at each post-randomization visit 
•
Individual components of the TDI: functional impairment, magnitude of task, and 
magnitude of effort over 24 weeks, over Weeks 12 to 24, and at each post-randomization 
visit
•
Percentage of subjects achieving a minimal clinically important difference (MCID) 
WKUHVKROGRIXQLWRQDYHUDJHLQ7',IRFDOVFRUHRYHUZHHNVDQGVHSDUDWHO\RYHU
Weeks 12 to 24 
•
Changes from baseline at each post-randomization visit for SGRQ total score 
•
Change in individual domain scores of SGRQ: Symptoms, Activity, and Impacts over 
Weeks 12 to 24 and at each post-randomization visit 
•
3HUFHQWDJH RI VXEMHFWV DFKLHYLQJDQ0&,'WKUHVKROGRI units on average in SGRQ 
total score over Weeks 12 to 24 and separately at Week 24
3.4
Safety Endpoints 
The safety endpoints for this study include the following: 
•
AEs
•
12-Lead ECG: Change from baseline heart rate, PR interval, QRS axis, QRS interval, QT 
interval and QTcF (Fridericia Corrected QT) interval
•
Clinical Laboratory Testing
•
Vital Sign Measurements
3.5 Health Care Resource Utilization Endpoints 
The number of days missed from work, and COPD-related and non-COPD related telephone 
calls and visits to healthcare providers, Emergency Room (ER) visits, and hospitalizations 
including days in hospital, days in Intensive Care Units (ICU), days in Coronary Care Units 

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(CCU), and subject intubation events will be captured and compared between treatment 
groups.

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4
INVESTIGATIONAL STUDY DESIGN
This is a multicenter, randomized, double-blind, parallel group, chronic dosing (24 weeks), 
placebo-controlled study to assess the efficacy and safety of GFF MDI (14.4/9.6 μg
ex-actuator, BID), FF MDI (9.6 μg ex-actuator, BID), and GP MDI (14.4 μg ex-actuator, 
BID) compared with Placebo MDI in subjects with moderate to very severe COPD.
This multicenter study will be conducted at approximately 180 sites, contributing 
approximately 10 to 20 subjects per site.  Across these sites, it is planned that approximately 
1614 subjects with moderate to very severe COPD will be randomized into the study to 
provide approximately 1300 subjects to complete the study. 
Subjects will be randomized in a 7:6:6:3 scheme (GFF MDI, FF MDI, GP MDI, and Placebo 
MDI).  Approximately 514 subjects will be enrolled into the GFF MDI treatment group, 
440 subjects each into the FF MDI and GP MDI treatment groups and approximately 
220 subjects will be enrolled in the Placebo MDI treatment group.  Randomization will be 
stratified by reversibility to Ventolin (albuterol sulfate) HFA and by disease severity.
At Visit 1 (Screening), all subjects are to sign an informed consent form prior to the conduct
of any screening assessments.  The Investigator will obtain a medical history including 
specific cardiovascular history, COPD exacerbations within the last year, clinical laboratory 
tests, physical examination, and any required documentation in order to determine eligibility 
for participation (i.e., inclusion/exclusion criteria). Subjects must meet spirometry criteria for 
COPD (FEV1 < 80% predicted and FEV1/FVC ratio < 0.7) at Visit 1 to qualify for study 
enrollment.  Re-screening is not allowed for subjects who do not meet the spirometry criteria 
at Visit 1.  Providing the subject meets the eligibility criteria, the Investigator or designee 
will review current COPD medications and, if necessary, will make arrangements to adjust 
the prohibited COPD therapy to protocol-allowable COPD therapy as described below.
Subjects who meet all entry criteria but are using certain prohibited COPD medications 
(eg, oraOȕ2 agonists, LABAs), cromoglycate or nedocromil inhalers, leukotriene antagonists 
(eg, zafirlukast, montelukast, zileuton), glycopyrronium bromide (eg, Seebri® Breezhaler® , 
[Novartis AG]), aclidinium (eg, Tudorza®Pressair™[Forest Research Institute], 
Eklira®Genuair [Almirall Limited]) or tiotropium (Spiriva® Handihaler®[Boehringer 
Ingelheim]) will discontinue these medications for the duration of the trial.  During the 
screening period, subjects will be switched to sponsor-provided Atrovent® (ipratropium 
bromide inhalation aerosol) HFA (Boehringer Ingelheim) administered four time daily (QID) 
and sponsor-provided rescue Ventolin® (albuterol sulfate ihalation aerosol) HFA 
(GlaxoSmithKline), as needed, to control symptoms. 
Subjects taking a fixed-dose combination treatment with an inhaled corticosteroid plus a 
LABA must discontinue the combined medication and instead be prescribed an inhaled 
corticosteroid monotherapy at an equivalent dose and regimen for the duration of the study, 
and be switched to sponsor-provided Atrovent (ipratropium bromide) HFA administered QID 
and sponsor-provided rescue Ventolin (albuterol sulfate) HFA, as needed, to control 
symptoms (Refer to Section 5.4).

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Subjects will be issued and trained on an electronic diary (eDiary) use at Visit 1 (Screening)
and will be instructed to collect practice data during the screening period (between Visit 1 
and Visit 4). 
During the screening period (Between Visit 1 and Visit 4), subjects will use 
sponsor-provided Atrovent (ipratropium bromide) HFA QID and use sponsor-provided 
rescue Ventolin (albuterol sulfate) HFA, as needed, to control symptoms.  Subjects 
previously on an inhaled corticosteroids (ICS) and/or phosphodiesterase inhibitor may 
continue using these medications at the same dose as described above.
In order to allow for an adequate washout of previous maintenance medications, subjects will 
undergo a washout period of at least one week (at least two weeks, if taking Spiriva or other 
LAMA), but not greater than 26 days in duration prior to returning to the clinic for Visit 2. 
Reversibility of FEV1 to a SABA and to a short-acting anticholinergic will be tested on two 
separate test days.
At Visit 2, reversibility to Ventolin (albuterol sulfate) HFA will be evaluated (Refer to 
Section 7.1.1).  The spirometry data obtained at Visit 2 will be used as an inclusion criterion 
(Section 5.1).  In addition, at Visit 2, dyspnea will be evaluated through the Modified 
Medical Research Council (MMRC) questionnaire, and the burden of disease will be 
assessed through the COPD Assessment Test (CAT).  Subject eDiary compliance will be 
reviewed, and the subject will be retrained, if appropriate (Refer to Section 7.1.3).
At Visit 3, reversibility to Atrovent (ipratropium bromide) HFA will be evaluated (Refer to 
Section 7.1.1).  The spirometry data obtained at this visit will not be used as an entry 
criterion, but will be used to characterize the population.  Subject eDiary compliance will be 
reviewed, and the subject will be retrained, if appropriate.  
At Visit 4 (Randomization Visit; Treatment Day 1), subjects will return to the clinic before 
10:00 am.  Subject eDiary compliance will be reviewed, and subjects who are unable to meet 
the compliance requirHPHQWVXEMHFWFRPSOHWLRQRIGLDU\DVVHVVPHQWVLQWKHODVW days 
preceding the Randomization Visit or who are unable to meet the FEV1 Baseline Stability 
criteria will be considered a screen failure (Refer to Section 7.1.3).  Subjects who continue to 
meet entry inclusion/exclusion criteria, including the FEV1 Baseline Stability criteria (the 
baseline FEV1 at Visit 4 must be within ±20% or 200 mL of mean of the pre-dose FEV1
values obtained at the two preceding visits (Refer to Section 7.1.2) and that remain eligible
for participation in the study will be randomized into one of the treatment arms.  At Visit 4, 
all sponsor-provided Atrovent (ipratropium bromide) HFA and Ventolin (albuterol sulfate) 
HFA provided during the screening period will be discontinued and collected by site 
personnel for accountability. 
If a subject is assigned to GFF MDI, GP MDI, FF MDI or Placebo MDI, it will not be
possible to differentiate between these treatments since they will appear to be identical in all 
aspects.
Randomization will be centralized through the use of an Interactive Web Response System 
(IWRS).  The randomization will be stratified by disease severity (moderate vs. severe or

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very severe) and to reversibility (yes or no) to ensure even distribution of treatment arms 
within each stratum.
Subjects will be trained on how to read the dose indicator.  Refer to Appendix 10 for 
instructions on how to read the dose indicator. 
After the randomization visit, subjects will be examined at Visit 5 (Week 2), Visit 6 
(Week 4), Visit 7 (Week 8), Visit 8 (Week 12), Visit 9 (Week 16), Visit 10 (Week 20) and 
Visit 11 (Week 24).  In total, each completed subject will attend 11 scheduled visits in this 
study.  For the assessments scheduled at each of these visits, refer to the assessment schedule 
in Table 9.
Subjects will be required to take their study medication twice a day.  Subjects will inhale 
2 puffs from their MDI in the morning between 06:00 and 10:00 AM (Breakfast time) and in 
the evening between 06:00 and 10:00 PM (Dinner time).  
Mean pre-dose morning PFTs will be assessed at every visit.  Post-dose PFTs will be 
assessed at all visits except Visit 6 and Visit 9 (Refer to Section 7 for details).  
SGRQ will be assessed in all subjects at Visit 4 (Day 1), Visit 8 (Week 12), Visit 9 
(Week 16), Visit 10 (Week 20), and Visit 11 (Week 24).  BDI will be assessed in all subjects 
at Visit 4 (Day 1) and TDI at Visit 6 (Week 4), Visit 7 (Week 8), Visit 8 (Week 12), Visit 9 
(Week 16), Visit 10 (Week 20) and Visit 11 (Week 24).  When BDI/TDI and SGRQ are 
obtained at the same visit, it is recommended that the BDI/TDI be collected first, followed 
immediately by the SGRQ.  Whenever possible, the BDI/TDI and SGRQ should be 
completed by the subject prior to any other visit procedures.
4.1 General Considerations for Treatment Visits 4 through Visit 11: 
•
At the start of each study visit, prior to any study procedures being performed, site 
personnel must confirm the subject withheld all COPD medications, including study 
medication, rescue Ventolin (albuterol sulfate) HFA, and maintenance medications (ICS, 
theophylline, phosphodiesterase-4 inhibitors or other comparable products) for at least 
6 hours, by confirming the last time of dosing for all COPD medication(s).  Note:
Subjects who inadvertently took COPD medication(s) within 6 hours of the start of study 
procedures must be rescheduled as soon as is practical but within the specified visit 
window.  In addition, before the in-clinic dose is administered, the site must confirm the 
subject met all other protocol specified requirements (eg, FEV1 Baseline Stability and 
eDiary compliance).
•
Subjects must not ingest xanthine and/or xanthine analogue (caffeine)-containing foods 
and beverages for at least 6 hours prior to each study visit and for the duration of each 
study visit.
•
Subjects will be required to refrain from smoking (nicotine gums or patches are allowed) 
for at least 4 hours prior to each study visit and throughout the duration of each study 
visit.

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•
In order to minimize diurnal variance, sites should make every effort to assess subjects at 
the same time throughout the study and to discuss the importance of dosing in a timely 
manner, every 12 hours. 
•
Subjects will be required to return to the clinic at approximately the same time as 
Visit 2 for all treatment visits (± 2 hours) but no later than 10:00 AM and will be
required to remain at the clinic until completion of all protocol-defined assessments. 
•
Sites should make every effort to ensure that the in-clinic dosing time is before 
10:00 AM and within 12±2 hours of the prior at home evening dosing time.
•
To ensure standardization of dosing times, it is recommended that sites encourage 
subjects to maintain adosing schedule consistent with their in-clinic dosing time and 
that sites call the subject on the day before a scheduled visit to remind the subject of 
the following: 
ƕ
Subjects should be reminded to take their last dose the evening before the 
scheduled visit. 
ƕ
To bring their study medications with them to the clinic and to withhold all 
COPD medications (including ICS and phosphodiesterase-4 inhibitors) prior to 
the study visit. Short acting bronchodilators should be withheld for at least 
6 hours prior to PFTs. 
ƕ
Refrain from ingesting xanthine and/or xanthine analogue (caffeine)-containing 
foods and beverages for at least 6 hours prior to each study visit and for the 
duration of each study visit. 
ƕ
Refrain from smoking for at least 4 hours prior to the study visit and throughout 
the duration of each study visit 
•
The in-clinic dosing time for study drug (GFF MDI, GP MDI, FF MDI or Placebo MDI)
will be recorded as the time of administration of the second puff. 
•
Site personnel will instruct subjects not to take any COPD medications, without site 
personnel permission, during a visit until all study procedures have been completed, 
and the subject is discharged.  Site personnel should take every precaution to prevent 
subject use of COPD medications during test day.  Site personnel may request the subject 
to surrender all COPD medications prior to the start of the visit before performing any 
study procedures and return the COPD medications to the subject at the end of the visit 
when all study procedures are completed.  Subjects will be asked to abstain wherever 
possible from using rescue Ventolin (albuterol sulfate) HFA during study visits.  If a 
subject is experiencing severe symptoms and requires Ventolin (albuterol sulfate) HFA 
for relief of COPD symptoms at any time during a test day, site personnel must note the 
time and justification of use in the subject’s chart and all subsequent spirometry 
assessments should be stopped.  However, safety assessments should be continued at the 
discretion of the Investigator. 
•
Protocol-adjusted ICS therapy as defined at Visit 1 (Screening) if any, should be
continued and remain stable for the duration of the trial (refer to Section 5.4).

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•
Post-randomization, all visits will be scheduled relative to Visit 4 (Day 1). Thus Visits 5, 
6, 7, 8, 9, 10 and 11 will be scheduled 2, 4, 8, 12, 16, 20 and 24 Weeks ± 2 days of 
Visit 4 respectively. Sites should make every effort to maintain subjects within the 
scheduled visit window.  If a visit falls outside the expected visit window the subsequent 
visit should still be scheduled as planned relative to Visit 4.  
Subjects will complete all Visit 11 (Final Study Visit) assessments and will be scheduled for 
a post-study follow-up telephone call at least 14 days from Visit 11.   
A Study Flow Diagram is displayed in Figure 1.

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Figure 1. Study Flow Diagram

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4.2 Rationale of Study Design 
This study will assess the long-term (24 weeks) bronchodilator efficacy, safety and 
tolerability of GFF MDI 14.4/9.6 μg, GP MDI 14.4 μg, and FF MDI 9.6 μg administered 
twice daily compared to Placebo MDI.  This study will also allow for comparison of the 
efficacy and safety of GFF MDI 14.4/9.6 μg to its components (GP MDI 14.4 μg and 
FF MDI 9.6 μg) to assess the relative contribution of each component to the combination and 
to confirm that the combination is safe and effective for patients with moderate to very 
severe COPD.
Due to the duration of the trial, a randomized, double-blind, parallel-group design was 
adopted in order to minimize bias in treatment allocation and to allow unbiased comparisons 
of treatment groups.
4.3 Rationale of Dose/Regimen, Duration of Treatment, and Placebo 
Arm
The selection of the GFF MDI (14.4/9.6 ȝJ%,'GRVHLQWKLVVWXG\ZDVEDVHGRQGDWDIURP
the findings of three previous dose-ranging studies with GP MDI (Studies PT0010801, 
PT001002, and PT001003), two dose-ranging clinical studies with FF MDI 
(Studies PT0050801 and PT005003), and four studies with GFF MDI (Studies PT0031002, 
PT003003, PT003004, and PT003005).   
These programs identified the optimal doses as 9.6 ȝJ%,'IRU))0',DQG ȝJ%,'IRU
GP MDI.  The aforementioned studies also showed that GP 14.4 μg when added to FF 9.6 μg 
provides a reasonable benefit across all parameters.  GFF MDI 14.4/9.6 μg was safe and well 
tolerated with an AE profile similar to its components and other approved products for the 
management of COPD (i.e., Spiriva, Atrovent, and Foradil® Aerolizer®. 
The study will evaluate the effect of GFF MDI, GP MDI, FF MDI, and Placebo MDI on lung 
function; subject reported outcomes such as symptoms, and health status over 24 weeks.  
While studies of shorter duration (eg, 8-12 weeks) may be sufficient for the assessment of 
bronchodilators, Pearl Therapeutics has decided to characterize efficacy and safety of the 
aforementioned drugs for at least 24 weeks to allow for global registration of GFF MDI, GP 
MDI, and FF MDI. 
In order to place the efficacy and safety of GFF MDI (14.4/9.6 ȝJLQWRFRQWH[W))0',
(9.6 ȝJDQG*30', ȝJDUHLQFOXGHGLQWKHVWXG\,WLVLPSRUWDQWWRQRWHWKDW
subjects will receive the treatment assigned by randomization in addition to the subject’s 
established maintenance COPD therapy, such as daily inhaled corticosteroids, 
phosphodiesterase inhibitors (eg, roflumilast).  When necessary, subjects will be allowed to 
use sponsor-provided Ventolin (albuterol sulfate) HFA.   
A Placebo MDI arm will be included in the trial.  The Placebo MDI arm does not imply that 
this cohort is untreated.  Subjects will be permitted to receive maintenance inhaled steroids 
(ICS), and/or phosphodiesterase inhibitors if they were on a stable dose of these medications 
prior to enrolling in the study, and Ventolin (albuterol sulfate) HFA will be provided as 

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rescue medication.  No currently approved treatment prevents death or irreversible morbidity 
by influencing the course of disease.   
With respect to exacerbations, changing an ICS/LABA to an ICS and as needed (PRN) 
Ventolin (albuterol sulfate) HFA or changing Spiriva, Tudorza or Seebri to PRN Ventolin 
(albuterol sulfate) HFA is unlikely to cause significant short-term harm.  There are three 
further safeguards to ensure subject safety in this study.  First, roflumilast, a recently 
approved drug to prevent COPD exacerbations, is a permissible medication throughout the 
course of the study provided the subject was on a stable dose prior to enrollment.  Second, 
subjects experiencing more than two moderate exacerbations or one severe exacerbation will 
be discontinued from the study.  An independent data monitoring committee (DMC) will 
review significant safety findings on a periodic basis and can suggest modification or 
termination of the study based on the safety implications of the data.  

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5
STUDY POPULATION SELECTION AND WITHDRAWAL 
CRITERIA 
5.1 Inclusion Criteria 
Subjects eligible for enrollment in the study must meet all of the following criteria: 
1.
Give their signed written informed consent to participate. 
2.  Are at least 40 years of age and no older than 80 at Visit 1.
3.
A female is eligible to enter and participate in the study if she is of: 
-
Non-child bearing potential (i.e., physiologically incapable of becoming pregnant, 
including any female who is 2 years post-menopausal); or 
-
Child bearing potential, has a negative serum pregnancy test at Visit 1, and agrees to 
one of the following acceptable contraceptive methods used consistently and correctly 
as outlined below (i.e., in accordance with the approved product label and the 
instructions of the physician for the duration of the study – from Visit 1 (Screening) 
until 14 days after Visit 11 such as: 
-
Complete abstinence from intercourse (when it is the preferred and usual lifestyle 
of the subject); or 
-
Implants of levonorgestrel inserted for at least 1 month prior to the study drug 
administration but not beyond the third successive year following insertion; or 
-
Injectable progestogen administered for at least 1 month prior to study drug
administration; or 
-
Oral contraceptive (combined or progestogen only) administered for at least one 
monthly cycle prior to study drug administration; or 
-
Double barrier method: condom or occlusive cap (diaphragm or cervical/vault 
caps) plus spermicidal agent (foam/gel/film/cream/suppository); or 
-
An intrauterine device (IUD), inserted by a qualified physician, with published 
data showing that the highest expected failure rate is less than 1% per year; or 
-
Estrogenic vaginal ring; or 
-
Percutaneous contraceptive patches.
Note: The acceptable contraceptive methods listed above are subject to locally approved 
contraceptive methods. 
4. COPD Diagnosis: Subjects with an established clinical history of COPD as defined by 
the American Thoracic Society (ATS)/European Respiratory Society (ERS) (Celli, 2004) 
characterized by: 
-
Airflow limitation that is not fully reversible. Progressive airflow limitation 
associated with an abnormal inflammatory response of the lungs to noxious particles
or gases, primarily caused by cigarette smoking. 
5. Tobacco Use: Current or former smokers with a history of at least 10 pack-years of 
cigarette smoking.  [Number of pack-years = (number of cigarettes per day / 20) x

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number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day
for 20 years represent 10 pack-years)].  
6. Severity of Disease: Subjects with an established clinical history of COPD and severity
defined as:
-
At Visit 1, FEV1/FVC ratio of <0.70. 
-
At Visit 2, and 3, pre- and post-bronchodilator FEV1/FVC ratio of <0.70. 
-
At Visit 1, FEV1 must be <80% predicted normal value calculated using the Third 
National Health and Nutrition Examination Survey (NHANES III) reference 
equations. (Or reference norms applicable to other regions, e.g. for Japan, use Japan 
Respiratory Society (JRS) reference equations; [JRS, 2013].
-
At Visit 2, post-bronchodilator FEV1 must be <80% predicted normal value,
calculated using NHANES III reference equations (Or reference norms applicable to 
other regions, e.g. for Japan, use Japan Respiratory Society (JRS) reference 
equations; [JRS, 2013] and the measured FEV1 must also be mL if FEV1 <30% 
of predicted normal value.
Note: Applicable to EU-specific regions only - Subjects with very severe COPD disease 
(i.e., subjects with FEV1<30% of predicted and with an FEV1 750 mL) or with severe 
disease (i.e., subjects with FEV1 % and <50% of predicted) who have had one or 
more moderate or severe COPD exacerbations in the prior year must have been 
treated with an ICS and/or phosphodiesterase inhibitors for at least 3 months prior to 
screening. 
-
At Visit 4, pre-bronchodilator FEV1/FVC ratio of <0.70. 
-
At Visit 4, the average of the -60 min and -30 min pre-dose FEV1 assessments must be
<80% predicted normal value calculated using NHANES III reference equations (Or 
reference norms applicable to other regions, e.g. for Japan, use Japan Respiratory 
Society (JRS) reference equations; [JRS, 2013]. 
7. Subject is willing and, in the opinion of the Investigator, able to adjust current COPD 
therapy as required by the protocol  
8. Screening clinical laboratory tests must be acceptable to the Investigator. 
9. Screening ECG must be acceptable to the Investigator. 
10. Chest X-ray or computed tomography (CT) scan of the chest/lungs within 6 months prior 
to Visit 1 must be acceptable to the Investigator. Subjects who have a chest X-ray 
(or CT scan) that reveals clinically significant abnormalities not believed to be due to the 
presence of COPD should not be included. A chest X-ray must be conducted if the most 
recent chest X-ray or CT scan are more than 6 months old at the time of Visit 1 except in 
countries with restrictive radiology assessment practice (e.g. Germany) where only 
subjects who have had an x-ray or CT scan (thorax) performed outside of the study in the 
last 6 months are allowed to be enrolled.  Alternatively, in these countries, an MRI may 
be used instead of a CT scan or x-ray as per local practice assessment.
11. Compliance: Subjects must be willing to remain at the study center as required per
protocol to complete all visit assessments.

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5.2
Exclusion Criteria 
Subjects meeting any of the following criteria are to be excluded:
1. Significant diseases other than COPD, i.e., disease or condition which, in the opinion of 
the Investigator, may put the subject at risk because of participation in the study or may 
influence either the results of the study or the subject’s ability to participate in the study
2. Pregnancy: Women who are pregnant or lactating or women of childbearing potential 
who are not using an acceptable method of contraception. 
3. Respiratory
a) Asthma: Subjects, who in the opinion of the Investigator, have a current diagnosis 
of asthma. 
b) Alpha-1 Antitrypsin Deficiency: Subjects who have alpha-1 antitrypsin deficiency 
as the cause of COPD.
c) Other Respiratory Disorders: Subjects who have other active pulmonary disease
such as active tuberculosis, lung cancer, bronchiectasis (High Resolution CT 
evidence of bronchiectasis that cause repeated acute exacerbations), sarcoidosis, 
idiopathic interstitial pulmonary fibrosis (IPF), primary pulmonary hypertension, 
or uncontrolled sleep apnea (i.e., in the opinion of the Investigator severity of the 
disorder would impact the conduct of the study). Note: Allergic rhinitis is not 
exclusionary.
d) Lung Volume Reduction: Subjects who have undergone lung volume reduction 
surgery, lobectomy or bronchoscopic lung volume reduction (endobronchial 
blockers, airway bypass, endobronchial valves, thermal vapor ablation, biological 
sealants, and airway implants) within 1 year of Visit 1.
e) Hospitalization: Subjects who have been hospitalized due to poorly controlled 
COPD within 3 months prior to Visit 1 (Screening) or during the Screening Period 
(Visit 1 to Visit 4). 
f)
Poorly Controlled COPD: Subjects who have poorly controlled COPD, defined as
acute worsening of COPD that requires treatment with oral corticosteroids or 
antibiotics within 6 weeks prior to Visit 1 (Screening) or during the Screening 
Period (Visit 1 to Visit 4). Note: Subjects who are steroid dependent and 
maintained on an equivalent of 5 mg prednisone per day or 10 mg every other day 
for at least 3 months prior to Visit 1 are eligible for enrollment providing the dose 
of oral steroids remains stable during the screening period (V1-V4).
g) Lower Respiratory Tract Infection: Subjects who had lower respiratory tract
infections that required antibiotics within 6 weeks prior to Visit 1 (Screening) or 
during the Screening Period (Visit 1 to Visit 4). 
h) Spirometry Performance:  
a.
Acceptability: Subjects who cannot perform acceptable spirometry, 
i.e., meet ATS/ERS acceptability criteria 
b. Repeatability: Subjects who cannot perform technically acceptable 
spirometry with at least three acceptable flow-volume curves with two or 

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more meeting ATS repeatability criteria for FEV1during at least one of the 
pre-bronchodilator assessments at Visit 2 (-60 minute or -30 minute) and at 
the post-bronchodilator assessment at Visit 2
c.
FEV1 Baseline Stability: Subjects who cannot meet protocol-specified 
reproducible criteria. FEV1 Baseline Stability is defined as the average of 
the -60 min and -30 min pre-dose FEV1 assessments at Visit 4 being within 
±20% or 200 mL of the mean of the pre-bronchodilator FEV1 assessments 
obtained at the two preceding visits (average of pre-dose FEV1
assessments obtained at Visit 2 and Visit 3).
i)
Oxygen: Subjects receiving long-term-oxygen therapy (LTOT) or nocturnal
oxygen therapy required for greater than 12 hours a day.  Note: As needed oxygen 
use is not exclusionary. 
j)
Subject use of any non-invasive positive pressure ventilation (NIPPV).device 
Note: Subjects using continuous positive airway pressure (CPAP) or bilevel 
positive airway pressure (BiPAP) for Sleep Apnea Syndrome are allowed in the 
study.
k) Change in smoking status (i.e., start or stop smoking,) or initiation of a smoking 
cessation program within 6 weeks of Visit 1 and throughout the Screening Period 
(Visit 1 to Visit 4).
l)
Pulmonary Rehabilitation: Subjects who have participated in the acute phase of a
pulmonary rehabilitation program within 4 weeks prior to Visit 1 (Screening) or 
who will enter the acute phase of a pulmonary rehabilitation program during the 
study. Subjects who are in the maintenance phase of a pulmonary rehabilitation 
program are not to be excluded. 
m) Subjects who have initiated or altered the dose regimen of intranasal 
corticosteroids, intranasal antihistamines, or a combination thereof within 7 days 
prior to Visit 1 or during the Screening Period (Visit 1 to Visit 4)
4. Cardiac disease
a) Subjects who have unstable ischemic heart disease, left ventricular failure, or 
documented myocardial infarction within 12 months of enrollment.  Subjects with 
a recent history of acute coronary syndrome, or who have undergone 
percutaneous coronary intervention or coronary artery bypass graft within the past 
3 months are to be excluded. 
b) Subjects with congestive heart failure (CHF NYHA Class III/IV)
c) Clinically significant abnormal ECG: A clinically significant abnormal ECG is 
defined as (but not limited to) any of the following: 
1. Clinically significant conduction abnormalities [eg, left bundle branch 
block, Wolff-Parkinson-White syndrome or evidence of second degree 
(Mobitz Type II) or third degree atrioventricular (AV) block] 
2. Clinically significant arrhythmias (eg, atrial fibrillation with irregular 
ventricular response, atrial flutter, ventricular tachycardia). Note: atrial 
fibrillation that has been clinically stable for at least 6 months is 
appropriately treated with anticoagulation and controlled with a rate 

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control strategy (i.e., selective beta blocker, calcium channel blocker, 
digoxin or ablation therapy) for at least 6 months is allowed for inclusion. 
In such subjects, atrial fibrillation must be present at pre-randomization 
visits, with a resting ventricular rate < 100/min. At screening, the atrial 
fibrillation must be confirmed by central reading. 
3. A mean corrected QT interval using Fridericia’s correction factor (QTcF) 
value at screening >450 ms for males and >470 ms for females or an ECG
that is not suitable for QT measurements (eg, poorly defined termination 
of the T wave) at Visit 1 that remains elevated on repeat testing prior to 
Visit 2.
4. Ventricular rate <45 beats per minute (bpm) 
5. Pathological Q waves of 1 year 
6. ST- T wave abnormalities deemed to be clinically significant by the 
Investigator.  Note: Subjects with non-specific ST-T wave abnormalities
that are not deemed clinically significant (per Investigator) are allowed.
7. Any other ECG abnormalities not listed above that in the opinion of the 
Investigator are clinically significant.
d) Clinically Uncontrolled Hypertension: Subjects who have clinically significant 
uncontrolled hypertension. 
5. Neurological 
•
Subjects with seizures requiring anticonvulsants within 12 months prior to Visit 1 
(Screening). Note: Subjects treated with anticonvulsant medication for 12 months 
or more with no seizure events are eligible.
•
Subjects taking selective serotonin reuptake inhibitors (SSRIs) or serotonin–
norepinephrine reuptake inhibitors (SNRIs) whose dose has not been stable for at 
least four weeks prior to Visit 1 or is altered at any point during the Screening 
Period (Visit 1 to Visit 4), or exceeds the maximum recommended dose 
6. Renal 
a) Subjects with symptomatic prostatic hypertrophy that is clinically significant in 
the opinion of the Investigator.  Subjects with a trans-urethral resection of prostate 
(TURP) or full resection of the prostate within 6 months prior to Visit 1 are 
excluded from the study.  
b) Subjects with bladder neck obstruction or urinary retention that is clinically 
significant in the opinion of the Investigator.  
c) Subjects with a calculated creaWLQLQHFOHDUDQFHP/PLQXWHusing CKD-EPI 
(Chronic Kidney Disease Epidemiology Collaboration) formula (Levey 2009) at 
Visit 1 and on repeat testing prior to Visit 2. 
Note: Subjects with overactive bladder syndrome treated with oral 
anticholinergics who have been on treatment for at least 1 month are allowed in 
the trial.
7. Endocrine  

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a) Subjects, who in the opinion of the Investigator, have uncontrolled hypo-or 
hyperthyroidism, hypokalemia or hyperadrenergic state
b) Subjects, who in the opinion of the Investigator, have uncontrolled Type I or II 
diabetes
8. Liver: Subjects with abnormal liver function tests defined as AST, ALT, or total bilirubin 
 1.5 times upper limit of normal at Visit 1 and on repeat testing prior to Visit 2.
9. Cancer: Subjects who have cancer that has not been in complete remission for at least 
five years.  Note: Subjects with squamous cell carcinoma of the skin, basal cell
carcinoma of the skin, or localized prostate cancer are eligible, if in the opinion of the 
Investigator, the condition has been adequately worked up, is clinically controlled and the 
subject’s participation in the study would not represent a safety concern. 
10. Glaucoma: Subjects with a diagnosis of angle closure glaucoma will be excluded, 
regardless of whether or not they have been treated. Subjects with a diagnosis of open 
angle glaucoma  who have intraocular pressure controlled with medication(s) are eligible. 
All medications approved for control of intraocular pressures are allowed including 
topical ophthalmic non-VHOHFWLYHȕ-blockers such as betaxolol, carteolol, levobunolol, 
metipranolol, or timolol.
11. Drug Allergy: Subjects who have a history of hypersensitivity to ȕ2-agonists, 
glycopyrronium or other muscarinic anticholinergics, or any component of the MDI. 
12. Substance Abuse: Subjects, who in the opinion of the Investigator, significantly abuse 
alcohol or drugs (Refer to exclusion criterion 1). 
13. Medication prior to spirometry: Subjects who are medically unable to withhold their 
short-acting bronchodilators for the 6-hour period required prior to spirometry testing at
each study visit will be excluded. 
14. Prohibited Medications:  Subjects who, in the opinion of the Investigator, would be 
unable to abstain from protocol-defined prohibited medications during the screening 
period and treatment phases of this study (Refer to Tables 1-4 in Section 5.4).
15. Vaccinations:  Subjects who received a live attenuated vaccination within 30 days prior 
to Visit 1 (Screening) or during the Screening Period (between Visit 1 to Visit 4).  
Note: Inactivated influenza vaccination, pneumococcal vaccination or any other 
inactivated vaccine is acceptable provided it is not administered within 48 hours prior to 
Visit 1 (Screening) or Visit 4 (randomization).
16. Non-compliance: Subjects unable to comply with study procedures including non-
compliance with diary completion (i.e., <70% subject completion of diary assessments in 
the last 7 days preceding Visit 4).
17. Affiliations with Investigator site: Study Investigators, sub-Investigators, study
coordinators, employees of a participating Investigator or immediate family members of
the aforementioned are excluded from participation in this study.  
18. Questionable Validity of Consent: Subjects with a history of psychiatric disease, 
intellectual deficiency, poor motivation, substance abuse (including drug and alcohol), or 
other conditions that will limit the validity of informed consent to participate in the study. 
19. Subjects using prohibited medications (Refer to Table 4) 

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20. Investigational Drugs or Devices: Treatment with investigational study drug or device in 
another clinical trial within the last 30 days or five half-lives prior to Visit 1 (Screening), 
whichever is longer.  Note: Subject participation in observational studies (i.e., studies 
that do not require change to medication or an additional intervention) is not 
exclusionary. 
21. Hand-to-Breath Coordination:  Subjects who requires the use of a spacer device to 
compensate for poor hand-to-breath coordination with a MDI.  Note: Use of a nebulizer 
to deliver COPD medications is prohibited throughout the trial 
22. Previous Participation:  Subjects who were previously enrolled in any Pearl Therapeutics 
trial.
5.3
Subject Identification 
All subjects who undergo screening will be assigned a unique screening identification 
number at the Screening Visit (Visit 1).  Only subjects continuing to meet entry 
inclusion/exclusion criteria at Visit 4 will be assigned a unique subject randomization 
number. 
5.4 Prior, Concomitant, and Prohibited Medications  
All prescription and over-the-counter (OTC) medications taken by the subject within 30 days 
before Visit 1 (Screening) will be recorded on the prior/concomitant medications eCRF.  Any 
additions, deletions, or changes in the dose of these medications while in the study should be 
entered on the eCRF.  Any current ongoing medications, including OTC drugs and herbal 
supplements, will be allowed provided they are not prohibited by the protocol (refer to 
Section 5.4.1) and are approved by the Investigator.  Subjects should also be instructed to 
contact the Investigator if they develop any illnesses.  
All concomitant medications taken during the study will be recorded on the Concomitant 
Medications eCRF with indication, dose, dose regimen, and dates of drug administration. 
5.4.1 Prohibited COPD Medications
The following medications used for the treatment of COPD are not permitted during this 
study.  These medications must be discontinued at Visit 1 (Screening) and are not permitted 
during the Screening Period.  The minimum washout period between Visit 1 and Visit 2 is 
shown in Table 1.  
Table 1. COPD Medications: Required Washout Periods, Pre Visit 2
Required Washout Periods Prior to Visit 2
Class of medication
Minimum washout period prior to Visit 2
Long-acting anticholinergics
Tiotropium Bromide: 14 days 
Aclidinium: 7 days
Glycopyrronium: 10 days

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Table 1. COPD Medications: Required Washout Periods, Pre Visit 2
Required Washout Periods Prior to Visit 2
Class of medication
Minimum washout period prior to Visit 2
Short-acting anticholinergics
6 hours
Fixed dose combinations  of 
LABA/LAMA
Vilanterol/Umeclidinium: 3 days
Aclidinium/Formoterol: 7 days 
Indacaterol/Glycopyrronium: 14 days 
Olodaterol/Tiotropium: 14 days
Fixed dose combinations of 
LABA/ICS a
7 days (Vilanterol/Fluticasone Furoate: 5 days b);  
at Screening (Visit 1), these medications must be 
switched to the nearest equivalent dose of ICS 
monotherapy.
Fixed dose combinations of SABAs 
and short-acting anticholinergics
6 hours 
LABA a
48 hours (Indacaterol and Olodaterol: 14 days)
SABAs (including study rescue 
Ventolin (albuterol sulfate) HFA
6 hours 
Phosphodiesterase-4 inhibitor c
6 days
Theophylline (Allowable up to a 
total maximum daily dose of 400 
mg)*
7 days  
Abbreviations: COPD=chronic obstructive pulmonary disease; FF=fluticasone furoate; ICS=inhaled 
corticosteroid; LABA=long-DFWLQJȕ2-agonist; LAMA=long-acting muscarinic agonist; SABA=short-acting 
ȕ2-agonist; VI=vilanterol
a
Please note that the Washout Periods for the LABA/ICS fluticasone furoate and vilanterol inhalation 
powder and for the LABA indacaterol inhalation powder are 5 days and 14 days, respectively.  
b
Subject to their approval in the respective countries.
c
Subjects taking roflumilast are allowed provided they have been on stable dose of therapy for at least 
2 months prior to Randomization.
7KHRSK\OOLQHLVDOORZHGLIWKHWRWDOGDLO\GRVHLVPJSURYLGHGWKHVXEMHFWKDVEHHQRQDVWDEOHGRVHRI
therapy for at least 4 weeks prior to Randomization.  
Subjects that have received depot corticosteroids including, intra-articular or intraocular
corticosteroids require a 3-month washout prior to Visit 1.  Subjects that have received oral, 
intravenous or intramuscular corticosteroids for any reason require a 6 week washout prior to 
Visit 1. Any patient that requires systemic corticosteroids during the screening period (V1 to 
V4) will be screen failed.
Note:
•
6XEMHFWVZKRDUHVWHURLGGHSHQGHQWDQGPDLQWDLQHGRQDQHTXLYDOHQWRI mg oral 
SUHGQLVRQHSHUGD\RUPJRUDOSUHGQLVRQHHYHU\RWKHUGD\IRUDWOHDVW months prior 

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to Visit 1 are eligible providing the dose of oral steroids remains stable during the
screening period (V1-V4).
•
During the Treatment Period (Visit 4 to Visit 11), subjects may be treated with 
corticosteroids if required. 
Subjects who meet all entry criteria but are using one or more of the prohibited COPD 
medications (previously listed) will have their maintenance therapy for COPD adjusted as 
follows: 
•
Subjects taking COPD medications (listed previously) at Visit 1 (Screening) will 
discontinue these medications for the duration of the trial and be switched to 
sponsor-provided Atrovent (ipratropium bromide) HFA administered QID and 
sponsor-provided Ventolin (albuterol sulfate) HFA to be administered up to four times 
per day as needed for control of symptoms during the Screening Period. 
•
Subjects receiving a maintenance dose of an ICS as part of a fixed dose combination 
therapy containing fluticasone and salmeterol, mometasone and formoterol, budesonide 
and formoterol or fluticasone and formoterol must have been on the ICS component for at 
least 4 weeks prior to Visit 1 (Screening) and maintained on a stable dose for at least 4 
weeks prior to Visit 1 (Screening).  These subjects will be switched to the corresponding 
dose of fluticasone, mometasone or budesonide administered as a single agent BID, with
sponsor provided Atrovent (ipratropium bromide) HFA administered QID, and sponsor 
provided Ventolin (albuterol sulfate) HFA to be administered up to four times per day as 
needed for control of symptoms during the Screening Period. 
•
Subjects receiving a maintenance dose of an ICS that is not administered as a fixed-dose 
combination together with a LABA will be permitted to continue the ICS provided they
have been maintained on a stable dose for at least 4 weeks prior to Visit 1 (Screening). 
•
All subjects treated with either a LABA (salmeterol, formoterol, indacaterol) or currently 
marketed long- acting anti-muscarinic agent (LAMA) (tiotropium [eg, Spiriva], 
aclidinium, glycopyrronium bromide, [eg, Seebri]) administered alone or as part of a 
loose combination will have these medications discontinued and replaced with sponsor 
provided Atrovent (ipratropium bromide) HFA MDI administered QID, and sponsor 
provided Ventolin (albuterol sulfate) HFA  to be administered up to four times per day 
(QID), as needed, for control of COPD symptoms during the Screening Period. 
The following respiratory medications are not permitted during this study (Table 2).
Table 2. 
Other Respiratory/Nasal Medications: Required Washout Periods
Required Washout Periods Prior to Visit 2
Class of medication
Minimum cessation period prior to Visit 2
Leukotriene antagonists (eg, zafirlukast, 
montelukast, and zilueton)  
3 days 

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Table 2. 
Other Respiratory/Nasal Medications: Required Washout Periods
Required Washout Periods Prior to Visit 2
Class of medication
Minimum cessation period prior to Visit 2
Cromoglycate
7 days
Nedocromil
7 days
Ketotifen *
7 days
*Ketotifen eye drops are allowed
5.4.2 Other Prohibited Medications
The following medications should be used under the stated conditions during this study 
(Table 3).  Each concomitant drug must be individually assessed against all exclusion 
criteria.  If in doubt, the Investigator should contact the Pearl Therapeutics Medical Monitor 
before randomizing a subject or allowing a new medication to be started: 
Table 3. Non-COPD Medications Allowed Under Certain Condition
Medications allowed under certain 
conditions 
Condition 
Selective serotonin reuptake inhibitors 
(SSRIs) or serotonin–norepinephrine 
reuptake inhibitors (SNRIs) 
Treatment regimen has been stable for at 
least 4 weeks prior to Visit 1 (Screening) and 
not altered during the Screening Period and 
does not exceed the maximum recommended 
dose
Intranasal corticosteroids, intranasal 
antihistamines or combination thereof 
Administered at constant dose and dosing 
regimen for at least 7 days prior to Visit 1 
(Screening) and during the Screening Period
Subjects requiring the medications presented in Table 4 are prohibited from participating in 
this study. Subjects who recently discontinued use of these medications may be considered 
for study enrollment providing they have met the minimum washout period prior to Visit 1 
(Screening).  These medications are prohibited throughout the course of the study, and, 
should a subject require use of any of the listed medications, the subject should be 
discontinued from the study. 
Table 4. Prohibited Medications
Prohibited Medications
Minimum cessation period prior to Visit 1 
(Screening)
Any drug with potential to significantly 
prolong the QT interval
14 days or 5 half-lives, whichever is longer

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Table 4. Prohibited Medications
Prohibited Medications
Minimum cessation period prior to Visit 1 
(Screening)
Other investigational drugs
30 days or 5 half-lives, whichever is longer 
Non-selective beta-blocking agents 
7 days
Cardiac antiarrhythmics Class Ia, III
7 days; amiodarone, 3 months
Anticonvulsants for seizure disorder 
Allowed if stable dose for 12 months and 
free of seizures for 1 year 
Anticonvulsants for other indications 
Allowed if stable dose for at least 3 months 
and the Investigator confirms there have been 
no seizures within the past 12 months.
Tricyclic antidepressants
14 days
Monoamine oxidase inhibitors
14 days 
Anti-WXPRUQHFURVLVIDFWRUĮ71)Į
antibodies (eg, infliximab and any other 
members of this class of drugs)
30 days or 5 half-lives, whichever is longer 
Monoclonal antibodies
30 days or 5 half-lives, whichever is longer
Antipsychotic drugs a
30 days
Systemic calcineurin inhibitors, systemic 
antifungal agents, protease inhibitors and 
cimetidine
30 days 
Systemic anticholinergics b
7 days
Chinese complementary and alternative 
bronchodilatory medicines (CAM), i.e., 
herbal therapies (eg, Astragalus 
membranaceus [huáng qí], Panax ginseng 
[ginseng products] and Cordyceps sinensis. 
A. membranaceus [ghost moth caterpillar 
fungus])c
10 days 
a  Antipsychotic agents used for other indications may be allowed after consultation with the Medical Monitor 
of the trial.
b  If systemic anticholinergics are used for treatment of Overactive Bladder and the treatment has been constant 
for at least 1 month, they are allowed.
c Requires case-by-case review by the Investigator to determine appropriate wash-out period, if needed
Note: Benzodiazepines are not exclusionary.

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5.5 Other Restrictions, Illicit Drugs or Drugs of Abuse 
5.5.1 Illicit Drugs
Illicit drugs or drugs of abuse will not be allowed from the start of Screening (Visit 1) to the 
end of Visit 11 or to whenever the subject discontinues the study.  If any illicit drugs or drugs 
of abuse are used by the subject during the study, the dates of use and the amount will be 
documented, and the subject will be discontinued.  Medical marijuana is not an exclusionary 
drug if used for medical purposes, and there is no change in the dose or frequency of 
consumption.   
5.5.2 Dietary Restrictions
Subjects are encouraged to refrain from consuming grapefruits or grapefruit juice throughout 
the study.  Subjects must not ingest xanthine and/or xanthine analogue (caffeine)-containing 
foods and beverages for at least 6 hours prior to each study visit and for the duration of each 
study visit.  Examples of such products include coffee, tea, chocolate, and cola.  
Decaffeinated beverages are acceptable.
5.6 Smoking Status 
Changes in a subject’s smoking status (i.e., stopping or re-starting smoking) may have an 
impact on the efficacy outcome measures.  At all visits the subject will be asked about any 
recent change in their smoking status (i.e., whether a subject’s status has changed from 
smoker to non-smoker or vice versa).  Any change in smoking status during the Screening 
Period (Visit 1 to Visit 4) will result in a screen failure.  Smoking status changes during the 
24 week Treatment Period will be captured in the eCRF, but the subject will be permitted to 
continue in the study.  Subjects will be required to refrain from smoking (including medical 
marijuana and electronic cigarettes) for at least 4 hours prior to each study visit and 
throughout the duration of each study visit.  Study participants may utilize various nicotine 
replacement treatments such as chewing gum and patches (PRN), in accordance with 
recommendations from the Investigator during the entire study visit.
Note:  For this study, the use of electronic cigarettes will be treated in the same manner as 
smoking. 
5.7 Reasons and Procedures for Early Termination 
Subjects may be withdrawn from the study at any time at their own request, upon request of 
the Investigator, or by Pearl Therapeutics at any time or for any reason.  All subjects who 
discontinue the study because of AEs will be followed up at suitable intervals in order to 
evaluate the course of the AE and to ensure the reversibility or stabilization of the 
abnormality.  All subjects who prematurely discontinue the study after being randomized, 
regardless of the cause, should undergo the assessments outlined in Section 8.7 on the date of 
discontinuation.  If a subject experiences any of the changes of concern listed below, a repeat 
assessment should be obtained, and, if confirmed, the Investigator or designee needs to make 

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a determination as to the suitability of continuing the subject in the study.  The changes of 
concern include:
•
Following dosing, a heart rate increase of greater than 40 bpm from the pre-dose value 
obtained on that specific test day and the measured value is also > 120 bpm. 
Note: Applicable to EU-specific regions only - Following dosing, a heart rate increase of 
> 25 bpm from the pre-dose value obtained on that specific test day, without any 
threshold. 
•
Following dosing, a systolic BP (SBP) increase of more than 40 mmHg from the pre-dose 
value obtained on that specific test day and the measured value is also > 160 mmHg. 
Note: Applicable to EU-specific regions only - Following dosing, a systolic BP (SBP) 
increase of > 30 mmHg from the pre-dose value obtained on that specific test day, 
without any threshold, or a clinically relevant change from baseline as determined by the 
Investigator. 
•
Decrease in creatinine clearance to a value below 30 mL/min using CKD-EPI formula or 
a clinically relevant change from baseline as determined by the Investigator.
Note: Applicable to EU-specific regions only - A decrease of 33% in calculated 
creatinine clearance from baseline using CKD-EPI without any threshold. 
•
Hepatic impairment defined as abnormal liver function test of AST, ALT or total 
ELOLUXELQWLPHVXSSHUOLPLWRIQRUPDORQUHSHDWWHVWLQJ
•
Calculated QTcF intervals >500 msec, and have increased by 60 msec or more over test 
day baseline value.
Note: Applicable to EU-specific regions only - &DOFXODWHG47F)LQWHUYDOVPVHF25
PVHFRYHUWHVWGD\EDVHOLQH
•
Subjects who suffer a moderate exacerbation will remain in the study and continue to 
take their assigned study drug unless the Investigator decides that it is in the best interest 
of the subject to discontinue early from the study.  Any subject who suffers a severe 
exacerbation (requiring hospitalization) will be discontinued.  Subjects who suffer more 
than two moderate COPD exacerbations will be discontinued from the study. 
An exacerbation will be defined as a change in the subject’s baseline dyspnea, cough, and/or 
sputum (increase in volume or change in color towards purulence) that lasts 3 or more days, 
is beyond normal day-to-day variations, is acute in onset and may warrant a change in regular 
medication.  The severity of exacerbations will be classified as follows:
•
Mild: exacerbations that do not require systemic steroids or antibiotics, and do not result 
in hospitalization or death. 
•
Moderate: exacerbations that requires treatment with systemic steroids and/or antibiotics, 
and do not result in hospitalization or death. 
•
Severe: exacerbations that result in hospitalization or death. 

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If a subject requires the following prohibited medications they should be discontinued from 
the study: 
•
Initiation of maintenance therapy with any prohibited medications as listed in Table 4.
•
Initiation of maintenance therapy with a marketed LABA (eg, salmeterol, formoterol, 
indacaterol) administered alone or in combination with an ICS or a marketed LAMA 
(eg, tiotropium, aclidinium, or glycopyrronium bromide [Seebri]). 
If a female subject becomes pregnant during the course of the study, the subject will be 
discontinued and the pregnancy will be followed full-term through delivery or final outcome. 
(Refer to Section 7.2.7)

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6
LABELING, PACKAGING, STORAGE, DISPENSING, AND 
RETURN OF CLINICAL SUPPLIES 
6.1
Subject Information
Clinical supplies will be packaged to support enrollment of the study.  Study personnel will 
have access to an IWRS to allocate subjects, to assign drug to subjects and to manage the 
distribution of clinical supplies.  Clinical supplies will be packaged according to a component
schedule generated by the Sponsor.  Each person accessing the IWRS system must be 
assigned an individual unique personal identification number (PIN).  They must use only 
their assigned PIN to access the system and they must not share their assigned PIN with 
anyone.
Open-label Atrovent (ipratropium bromide) HFA MDIs will be provided from commercial 
supplies.  Manufacturer’s instructions for study drug administration will be provided. 
Open-label Ventolin (albuterol sulfate) HFA MDIs with dose counters will be provided 
from commercial supplies.
Manufacturer’s instructions for study drug administration will 
be provided. 
6.2 Product Descriptions and Primary Packaging and Labeling 
Information 
Investigational materials will be packaged by Pearl Therapeutics as summarized in Table 5.
Atrovent (ipratropium bromide) HFA and Ventolin HFA supplies will be supplied as open-
label MDIs.

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Packaging Lot Trace ID #
Space for entry of screening #
Component ID # 
Space for entry of randomization # 
Fill Count & Dosage Form 
Space for entry of Interval ID (Visit # only) 
Re-evaluation/Expiration date (if applicable)
Dosing Instructions
Storage Conditions 
Compound ID - Protocol #
Country regulatory requirements 
Sponsor address (If applicable)
Translation Key (If applicable)
6.3 Secondary Packaging and Labeling Information (Box) 
Blinded investigational drug and open-label (Atrovent [ipratropium bromide] HFA, and 
Ventolin [albuterol sulfate] HFA supplies will be packaged in individual boxes as outlined in 
Table 6.  Box configuration is subject to change as a result of packaging constraints. 
Table 6. Description of Boxes
Drug Supplies
Individual Box Contents
Blinded 
Atrovent (ipratropium bromide) HFA 
Ventolin (albuterol sulfate) HFA  
1 MDI 
1 MDI 
1 MDI 
Each box will be labeled with a two-part label printed with black ink and may include the 
following text:
Packaging Lot ID #
Space for entry of screening #
Component ID # 
Space for entry of randomization # 
Kit Contents (1 MDI) 
Space for entry of Interval ID
Re-evaluation/Expiration date (if applicable)
Dosing Instructions (if applicable) 
Storage Conditions 
Compound ID - Protocol #
Country regulatory requirements 
Sponsor address (If applicable)
Translation Key (If applicable)
6.4 Emergency Unblinding of Treatment Assignment  
The IWRS should be used in order to unblind subjects and to unmask drug identity.  When 
the Investigator contacts the system to unblind a subject, he/she must provide the requested 
subject identifying information and confirm the necessity to unblind the subject.  Pearl 
Therapeutics will not provide a disclosure envelope with the clinical supplies. 

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The Investigator or treating physician may unblind a subject’s treatment assignment only in 
the case of an emergency, when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject.
Whenever possible, the Investigator must first discuss options with the Medical Monitor or 
appropriate study personnel before unblinding the subject’s treatment assignment.  If this is 
impractical, the Investigator must notify Pearl Therapeutics as soon as possible, but without 
revealing the treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study.  The date and reason for the 
unblinding must be recorded in the appropriate data collection tool.
6.5
Storage Requirements
Blinded Supplies should be kept in a secured location. Store according to package/label 
directions.  
Ventolin (albuterol sulfate) HFA supplies should be kept in a secured location. Store 
according to package/label directions.
Atrovent (ipratropium bromide) HFA supplies should be kept in a secured location 
Store according to package/label directions. 
The clinical supplies storage area at the site must be monitored by the site staff for 
temperature consistency with the acceptable storage temperature range specified in 
accordance with the product label.  Documentation of temperature monitoring should be 
maintained.
6.6 Instructions for Preparation of Treatments for Administration and 
Dispensing 
6.6.1 GFF MDI, GP MDI, FF MDI, and Placebo MDI
Individual GFF MDI, GP MDI, FF MDI, and Placebo MDI will be packaged in a foil pouch 
and contained in an individual visit treatment box.  Both the visit treatment box and the foil 
overwrap will have a label with a component ID number.  Confirm that the identifier given 
by IWRS and the component ID number written on the label are the same.  The visit 
treatment box is labeled with a two-part label.  Write the subject number and treatment visit 
number on each of the two-part labels.  The ‘tear-off’ part of the label is to be placed onto the 
IWRS confirmation report. 
All MDIs must be primed before the first use.  Priming involves releasing a certain number 
of sprays (4) into the air before the first use of the inhaler.  Shaking and priming the inhaler 
fills a chamber inside the canister with the correct dose and mix of medication so that the
inhaler is ready to use.
The MDI must be primed in a separate room, away from the subject treatment area.  
Each dose will consist of 2 puffs from the MDI.  Subjects will be dispensed the MDI and 

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instructed to continue taking study medication twice daily, 2 puffs in the morning and 2 puffs 
in the evening approximately 12 hours apart, until subject returns to the clinic.  The MDI 
should be stored at room temperature by the subject, to avoid temperature extremes, and the 
products should not be stored in direct sunlight.  Refer to Appendix 4 for instructions on the 
administration of GFF MDI, GP MDI, and FF MDI.  Cleaning instructions are provided in 
Appendix 4. 
6.6.2 Atrovent (Ipratropium Bromide) HFA 
Individual MDIs will be contained in an individual visit treatment box.  The visit treatment 
box will have a label with a component ID number. Confirm that the identifier given by 
IWRS and the component ID number written on the label are the same.  The visit treatment 
box is labeled with a two-part label.  Write the subject number and treatment visit number on 
each of the two-part labels.  The ‘tear-off’ part of the label is to be placed onto the IWRS 
confirmation report. 
Atrovent (ipratropium bromide) HFA is a solution aerosol that does not require shaking.  
However, as with any other MDI, some coordination is required between actuating the 
canister and inhaling the medication.  Atrovent (ipratropium bromide) HFA should be primed 
per manufacturer’s instructions prior to dispensing to subject (i.e., "prime" or actuate 
Atrovent (ipratropium bromide) HFA before using for the first time by releasing 2 test sprays 
into the air away from the face).  In cases where the inhaler has not been used for more than 
3 days, prime the inhaler again by releasing 2 test sprays into the air away from the face.  
Subjects should avoid spraying Atrovent (ipratropium bromide) HFA into their eyes. 
Subjects will be dispensed the Atrovent (ipratropium bromide) HFA for COPD maintenance 
therapy during screening period (between Visit 1 and 4) per the manufacturer’s instruction, 2 
puffs with each administration four times a day, approximately 6 hours apart.  The MDI 
should be stored at room temperature by the subject, avoiding temperature extremes and 
storage in direct sunlight.  Refer to Appendix 5 for the manufacturer’s instructions on the 
administration of Atrovent (ipratropium bromide) HFA. 
6.6.3 Ventolin (Albuterol Sulfate) HFA
Individual MDIs will be contained in an individual visit treatment box.  The visit treatment 
box will have a label with a component ID number.  Confirm that the identifier given by 
IWRS and the component ID number written on the label are the same.  The visit treatment 
box is labeled with a two-part label.  Write the subject number and treatment visit number on 
each of the two-part labels.  The ‘tear-off’ part of the label is to be placed onto the IWRS 
confirmation report. 
Open-label Ventolin (albuterol sulfate) HFA will be provided by Pearl Therapeutics and 
stored in a secured location within the clinic or pharmacy facilities.  Ventolin (albuterol 
sulfate) HFA should be stored at room temperature by the subject.  Ventolin (albuterol 
sulfate) HFA should be primed per manufacturer’s instructions prior to dispensing to subject.  
Refer to Appendix 6 for the manufacturer’s instructions on the administration of Ventolin 

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(albuterol sulfate) HFA.  Study personnel will record the number displayed on the dose 
counter at the time of dispensing (following priming) and again upon return.  
6.7 Drug Accountability/Return of Clinical Supplies 
Under no circumstances will the Investigator(s) allow the study drug to be used other 
than as directed by this protocol.
Investigational clinical supplies must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secure location to which only the 
Investigator and designated assistants have access.  Storage conditions for the clinical 
supplies should be observed, monitored and documented.  Clinical supplies are to be 
dispensed only in accordance with the protocol.  The Investigator is responsible for keeping 
accurate records of the clinical supplies received from Pearl Therapeutics, the amount 
dispensed to and returned by the subject, and the amount remaining at the conclusion of the 
study. Study medication should be handled in accordance with Good Pharmacy Practices 
(i.e., gloves should always be worn by study personnel if directly handling tablets or capsules 
that are returned).  The Clinical Monitor should be contacted with any questions concerning 
investigational products where special or protective handling is indicated.  At the end of the 
study, all clinical supplies including partial and empty containers must be returned as 
directed by Pearl Therapeutics.
Sites should check with the Pearl Therapeutics representative for appropriate documentation 
that needs to be completed for drug accountability.
The Investigator or designated assistant should not open individual clinical supply containers 
until all pre-dose assessments have been completed and the subject is eligible to be 
randomized/continue with the study.  Any deviation from this must be discussed with the 
Clinical Monitor.
For each subject, all used study drug materials will be collected.  Used subject supplies will 
be kept at room temperature in a secure and locked cabinet until returned to Pearl 
Therapeutics or designee.  Note: Used study drug will be stored separately from unused 
study drug. 
All product complaints (including device malfunctions) must be reported to Pearl 
Therapeutics using the Product Complaints Form provided in each site’s regulatory binder. 
Pearl Therapeutics will contact the site to evaluate the nature of the complaint and determine 
what further action is needed.

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7
STUDY ASSESSMENTS
A time and events schedule is provided in Table 9. Detailed schedules for pre- and
post-dose procedures to be performed at each treatment visit are provided in Table 10. 
All assessments during Visits 4 to 11 are recommended to be conducted in the following 
order: vital signs, ECGs, clinical laboratory assessments, and spirometry. 

7.1 Pulmonary Function Tests  
Forced expiratory spirometry maneuvers for derivation of FEV1 and FVC will be assessed 
using a spirometer that meets or exceeds minimum performance recommendations of the 
ATS (Refer to Appendix 1).
The volume accuracy of the spirometer is to be checked daily using a 3 L syringe across 
3 flow ranges (i.e., low, medium and high flows), with temperature and barometric pressure 
correction.  The calibration syringe must meet ATS specifications and must not be used 
beyond the expiry date. Required accuracy is ± 3% (i.e., 3.09 L to 2.91 L) (ATS/ERS).  The 
results will be printed and maintained in a calibration log, which will be monitored for 
compliance during the monitoring visits (Refer to Appendix 2, Spirometry Assessment 
Criteria).
All pulmonary function tests including FEV1 and FVC as defined in ATS/ERS guidelines 
will be performed in accordance with ATS criteria (Miller , 2005). 
To standardize spirometry, all sites will be provided with identical spirometry systems 
 with customized, 
study-specific software.  All study staff responsible for performing pulmonary function 
testing will receive standardized training at the Investigator meetings.  All technicians are 
required to demonstrate proficiency in the use of the equipment and the ability to perform 
technically acceptable pulmonary function tests (ATS criteria, Miller , 2005) prior to 
performing testing on study subjects.  After each test is performed, the spirometry software 
will provide immediate feedback to the technician indicating whether the effort meets ATS 
acceptability and repeatability standards.  All efforts will be stored electronically.  After 
completion of testing, the study staff will electronically transmit the spirometric 
measurements for centralized quality assurance review 
.  Feedback on the quality of the measurements will be provided to the 
investigational site and to Pearl Therapeutics or designee for central data management.
Spirometry will be conducted at Visit 1. At Visit 2 and Visit 3, Spirometry will be conducted 
60 minutes and 30 minutes prior to bronchodilator administration and at 30 min 
post-bronchodilator (Refer to Section 7.1.1). Note: Spirometry must meet both acceptability 
and repeatability criteria (Refer to exclusion criterion 3h).
Spirometry will be conducted 60 minutes and 30 minutes prior to study drug administration 
at Visit 4 through Visit 11.  The mean of the -60 minutes and -30 minutes pre-dose 

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spirometry assessments conducted at Visit 4 will be used to establish baseline FEV1 and 
FVC.
At Visit 4 (Day 1), spirometry will be obtained at 5, 15 and 30 minutes, and 1 and 2 hours
post-dosing of study drug. Note: The 5-minute post-dose spirometry assessment will be 
obtained at Visit 4 (Day 1) only.
At Visit 5 (Week 2), Visit 7 (Week 8), Visit 8 (Week 12), Visit 10 (Week 20) and Visit 11
(Week 24) spirometry will be obtained at 15 and 30 minutes, and 1 and 2 hours post-dosing of 
study drug.  Post-dose spirometry assessments will not be conducted at Visit 6 (Week 4) and 
Visit 9 (Week 16). 
7.1.1 Characterization of Reversibility
Reversibility to Ventolin (albuterol sulfate) HFA will be evaluated at Visit 2.  Reversibility 
to Atrovent (ipratropium bromide) HFA will be evaluated at Visit 3.  The procedure will be 
as follows: 
•
Reversibility testing to Ventolin (albuterol sulfate) HFA (Visit 2 Only):
-
Perform pre-bronchodilator PFTs (-60 min and -30 min) prior to administration of 
Ventolin (albuterol sulfate) HFA. 
-
Administer 4 puffs of Ventolin (albuterol sulfate) HFA.
-
Perform post-bronchodilator PFT 30 min after the administration of Ventolin 
(albuterol sulfate) HFA.
•
Reversibility testing to Atrovent (ipratropium bromide) HFA (Visit 3 Only):
-
Perform pre-bronchodilator PFTs (-60 min and -30 min) prior to administration of 
Atrovent HFA.
-
Administer 4 puffs of Atrovent (ipratropium bromide) HFA.  
-
Perform post-bronchodilator PFT 30 minutes after the administration of Atrovent 
(ipratropium bromide) HFA. 
Reversibility will be a comparison of the average best FEV1 effort obtained at -60 min 
and -30 min pre-bronchodilator to the best FEV1 effort obtained at 30 minutes post- 
bronchodilator.  A subject is determined to be reversible to Ventolin (albuterol sulfate) HFA 
or Atrovent (ipratropium bromide) HFA if the improvement in FEV1 approximately 30 
minutes following administration of 4 puffs of Ventolin (albuterol sulfate) HFA or Atrovent 
LSUDWURSLXPEURPLGH+)$UHVSHFWLYHO\LVDQGP/5HYHUVLELOLW\WR9HQWROLQ
(albuterol sulfate ) HFA (obtained at Visit 2) will be used as a stratification variable at 
randomization to ensure an even distribution of reversibility across the treatment arms.
Reversibility to Atrovent (ipratropium bromide) HFA will be used to characterize the 
population. 

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7.1.2 FEV1 Baseline Stability Criteria
Since all comparisons will be made to the baseline (mean of 60 and 30 minutes prior to 
dosing) values obtained at Visit 4, it is important to ensure that the baseline FEV1 is stable 
and reflective of the subjects COPD severity prior to being randomized into the study.  
As such, the baseline FEV1 at Visit 4 must be within ±20% or 200 mL of the mean of the 
pre-dose FEV1 obtained at the two preceding visits (average of pre-dose FEV1 obtained at 
Visit 2 and Visit 3).  At Visit 4, if the pre-dose FEV1 average is outside of the ±20% or 
200 mL range, but the -30 min assessment is within ±22% or 220 mL, then another 
assessment may be conducted 30 minutes later. If the last two assessments meet the FEV1
Baseline Stability requirements (i.e., within ±20% or 200 mL), the initial 60 minute pre-dose 
assessment will not be used and the last two assessments will be used to establish the 
eligibility criteria.  If the test day FEV1 is not within ± 20% or 200 mL, the subject will not 
be randomized. 
7.1.3 Subject Electronic Diary Data Collection
Subjects will be provided with an eDiary to be completed twice daily to record time of study 
medication administration, morning and evening symptoms, and the use of rescue albuterol 
(Ventolin HFA) or comparable product. Before issuing the diary to the subject, site personnel 
will be responsible for programming the electronic diary and training the subject on the diary 
use. 
Subjects will be issued and trained on an eDiary use at Visit 1 (Screening) and instructed to 
collect data during the Screening Period (between Visit 1 to Visit 4).
Electronic Diary Compliance Requirement: Subject participation may be terminated at any 
time during the study for the following reason: 
•
Chronic failure, in the judgment of the Investigator, to comply with diary compliance, 
despite documentation at the site of repeated efforts to reinforce compliance.  As defined 
for this study, compliance requires >70% subject completion of diary assessments.  
The Sponsor may also instruct a site to discontinue a subject based on consistent 
noncompliance.   
•
Subjects who are unable to meet the compliance requirement (>70% subject completion 
of diary assessments) in the last 7 days preceding the Randomization Visit (Visit 4) will 
be considered a screen failure.
In-clinic dosing times and dose indicator readings will be documented in the eCRF by the 
site staff and will not be entered by the subject into their eDiary.  The dose indicator will be 
read and results recorded once a day.
During the Screening Period and for the duration of the Treatment Period, each subject will 
record his/her symptoms in the study-provided eDiary, twice daily (morning and evening).  
The subject will record his/her use of rescue Ventolin (albuterol sulfate), twice daily: 
morning and evening.  In addition, the subject will record study medication usage. 

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The eDiary data report will be available to site personnel through the vendor's server. The 
eDiary data report should be reviewed by the study personnel at each visit. The review 
should verify that morning and evening diary entries have been recorded by the subject for 
compliance requirements.  The subject should be reinstructed, as appropriate, on the 
importance of recording twice daily entries if missing entries are observed.
7.1.4 Rescue Product Use
The subject will record the total number of “puffs” of rescue Ventolin (albuterol sulfate) 
HFA used on a daily basis in the electronic diary.  The number of “puffs” of rescue product 
(albuterol sulfate) will be recorded as the number of actuations on the canister.  For example, 
when rescue product is required and 2 actuations are inhaled, this should be recorded as 2 
“puffs.”  In the event the subject requires 4 actuations, this should be recorded as 4 “puffs”.  
Subjects requiring more than 8 puffs per day on 3 consecutive days with worsening 
symptoms should contact the site. 
7.1.5 Medication Compliance
Time of dosing with study medication will be recorded in the subject’s eDiary for each day 
of treatment (except the in-clinic dosing time).  Study medication compliance will be 
checked at all visits, and any issues identified will be documented in the appropriate study 
files.
7.1.6 Recording of Dose Indicator Reading
Note: The dose indicator will be read and results recorded once a day in the evening by 
either the subject or site staff.
The GFF MDI, GP MDI, FF MDI and Placebo MDI are fitted with a dose indicator to track 
use of the MDI.
Subjects will be instructed to record the dose indicator reading from the MDI in their eDiary 
once a day in the evening. 
Prior to dosing at each Treatment Period Visit (Visit 4 to Visit 11) or at a Premature 
Discontinuation Visit, site personnel will observe the dose indicator reading on the study 
drug returned by the subject and record the dose indicator reading in the source.  
Note: The dose indicator reading recorded by the site staff will be the dose indicator reading 
observed prior to subject dosing.  For new MDIs the recorded count will be the count 
following the priming of the MDI but before the subject dose. 
At each visit, the site staff will compare the dose indicator reading from the one entered in 
the subject eDiary with the dose indicator reading recorded by the site staff.  For major 
discrepancies (i.e., >20 puff difference), the site staff will review the major discrepancy with 
the subject and document reason for the major discrepancy in the appropriate study source 

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and eCRF.  If appropriate, site staff will retrain the subject on the proper recording of dose 
indicator reading and/or proper use of the MDI. 
7.1.7 Subject Questionnaires
The following subject questionnaires will be completed by subjects using the study supplied 
electronic questionnaire devices at specified visits throughout the study: COPD Assessment 
Test (CAT), Modified Medical Research Council Dyspnea Scale (MMRC), and St. George 
Respiratory Questionnaire (SGRQ).  The Baseline Dyspnea Index (BDI) and Transition 
Dyspnea Index (TDI) will be administered by designated site personnel. When the BDI/TDI 
and SGRQ are obtained at the same visit, the BDI/TDI will be collected first followed 
immediately by the SGRQ.
7.1.7.1 COPD Assessment Test 
The CAT (http://www.catestonline.org/) is a self-administered questionnaire designed to 
assess the condition of subjects and overall impact of COPD.  It has been proven that the 
CAT has good repeatability and discriminative properties which suggest that it is sensitive to 
treatment effects at a group level.  Since the CAT is designed to assess the impact of COPD 
on the subject by measuring overall impairment, it has moderate correlations with other 
instruments, such as the MMRC dyspnea scale, SGRQ, and the 6-minute walk test.
Subjects will complete the CAT (Refer to Appendix 7) at Visit 2. 
The CAT score will describe the burden and symptomatic impact of COPD in subjects 
enrolled in the trial and will not be used to determine subject eligibility to participate in the 
study.
7.1.7.2
Modified Medical Research Council Dyspnea Scale 
The MMRC, uses a simple grading system to assess a subject's level of dyspnea, shortness of 
breath (Table 7).
Table 7. MMRC Dyspnea Scale
Grade
Description of Breathlessness
0
I only get breathless with strenuous exercise.
1
I get short of breath when hurrying on level ground or walking up a slight hill.
2
On level ground, I walk slower than people of the same age because of 
breathlessness, or have to stop for breath when walking at my own pace.
3
I stop for breath after walking about 100 yards or after a few minutes on level 
ground.
4
I am too breathless to leave the house or I am breathless when dressing.

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The MMRC scale is a five-point scale published in 1959 that considers certain activities, 
such as walking or climbing stairs, which provoke breathlessness (Fletcher 1959). In one 
minute, the subject selects a grade on the MMRC scale that most closely matches his/her 
severity of dyspnea. The MMRC scale is considered a discriminative instrument that can 
categorize subjects with COPD in terms of their disability.  The MMRC scale is not 
satisfactory as an evaluative instrument to measure changes in dyspnea, and its broad grades 
are generally unresponsive to interventions such as pharmacotherapy. 
Subjects will complete the MMRC at Visit 2, as a description of the symptomatic burden in 
study subjects. 
The MMRC will not be used to determine subject eligibility to participate in the study.
7.1.7.3
Baseline (BDI) and Transition (TDI) Dyspnea Indices (BDI/TDI)
Dyspnea is the primary symptom of COPD and its relief is an important goal of therapy.  In 
the evaluation of pharmacotherapy for COPD, several instruments are available to provide a 
discriminative and evaluative assessment of dyspnea.  Among these are the BDI and TDI 
dyspnea indices, which assess breathlessness in components related to functional impairment, 
magnitude of task and magnitude of effort.  The reliability and validity of the BDI have been 
reported (Mahler, 1984).  The validity of the BDI/TDI based on its association with other 
related measures has also been demonstrated (Witek, 2003).  The BDI/TDI questionnaire 
should always be completed before any other assessments are made to avoid influencing the 
responses. The interviewer-administered version of the BDI/TDI questionnaire will be used 
and can be found in Appendix 9, but is provided for illustrative purposes only.  The 
appropriate language version of the questionnaires will be used.  The BDI score ranges from 
0 (very severe impairment) to 4 (no impairment) for each domain and are summed to 
determine the BDI focal score (0 to 12) (i.e., the lower the score, the worse the severity of 
dyspnea).   
TDI components are: Change in Functional Impairment, Change in Magnitude of Task, and 
Change in Magnitude of Effort.  The TDI score ranges from -3 (major deterioration) to +3 
(major improvement) for each component.  The sum of all components yields the TDI focal 
score (- to +9) (i.e., the lower the score, the more deterioration in severity of dyspnea).  The 
questionnaires should be completed in a quiet area, and the subjects should be allowed to ask 
questions.  However site staff should take care not to influence the subject’s responses.  The 
subject will be instructed to provide the truest and for them best response.  The questionnaire 
will be checked for completeness and collected before the subject leaves the center.  At later 
visits subjects are not allowed to review their previous responses. 
The BDI will be completed at Visit 4 (Day 1, prior to study drug administration). 
The TDI will be completed at Visit 6 (Week 4), Visit 7 (Week 8), Visit 8 (Week 12), Visit 9 
(Week 16), Visit 10 (Week 20) and Visit 11 (Week 24) or Premature Discontinuation Visit. 
The BDI/TDI will be completed prior to study drug administration and before administration 
of SGRQ Questionnaire. 

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7.1.7.4
St. George’s Respiratory Questionnaire (SGRQ)   
The SGRQ will be used to provide the health status/health-related quality of life (HRQoL) 
measurements in this study (Refer to Appendix 8). For the purposes of this study when 
BDI/TDI and SGRQ are obtained at the same visit, whenever possible, the BDI/TDI 
questionnaire should be collected first followed immediately by the SGRQ.  The appropriate 
language version of the questionnaires will be available in each participating country.  The 
subject should complete the questionnaires in a quiet area and be allowed to ask questions; 
however site staff should take care not to influence the subject’s responses.  The subject will 
be instructed to provide the truest and for them best response.  The questionnaire will be
checked for completeness and collected before the subject leaves the center.  At later visits, 
subjects are not allowed to review their previous responses.  
The SGRQ contains 51 items divided into three domains: "Symptoms" concerned with 
respiratory symptoms, their frequency and severity; "Activity" concerned with activities that 
cause or are limited by breathlessness; and "Impacts" which covers a range of aspects 
concerned with social functioning and psychological disturbances resulting from airway 
disease.  A score will be calculated for each domain and a "Total" score will also be 
calculated.  In each case the lowest possible value is zero and the highest is 100.  Higher 
values correspond to greater impairment of quality of life.  Completed questionnaires will be 
reviewed and examined by the Investigator or designee, before the clinical examination, for 
responses which may indicate potential AEs or SAEs.  The Investigator should review not 
only the responses to the questions in the questionnaire but also for any unsolicited 
comments written by the subject.  Investigators should not encourage the subjects to change 
the responses reported in the questionnaire. 
The SGRQ (Refer to Appendix 8) will be completed by the subject at Visit 4 (Day 1, prior to 
study drug administration), Visit 8 (Week 12), Visit 9 (Week 16), Visit 10 (Week 20), and 
Visit 11 (Week 24) or Premature Discontinuation Visit. 
If AEs or SAEs are confirmed then the Investigator or designee must record the events as per 
instructions given in Section 7.2.5 of the protocol. 
7.1.8 COPD Exacerbations
Site personnel will evaluate whether the subject has experienced a worsening of their COPD 
that meets the definition of a COPD exacerbation since their last visit.  An exacerbation will 
be defined as a change in the subject’s baseline dyspnea, cough, and/or sputum (increase in 
volume or change in color towards purulence) that lasts 3 or more days, is beyond normal 
day-to-day variations, is acute in onset and may warrant a change in regular medication.  
All COPD exacerbations will be captured using a COPD Exacerbation eCRF and will not be 
reported as AEs unless considered an SAE. 
The severity of COPD exacerbations will be classified as follows:

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•
Mild: exacerbations that do not require systemic steroids or antibiotics, and do not result 
in hospitalization or death 
•
Moderate: exacerbations that require treatment with systemic steroids and/or antibiotics, 
and do not result in hospitalization or death.
•
Severe: exacerbations that result in hospitalization or death. 
7.2
Safety Assessments
The safety assessments include physical examination findings, vital signs, ECGs, clinical 
laboratory tests in addition to recording of AEs.  
7.2.1 Medical/Surgical History and Physical Examination
Medical history, including specific cardiovascular history details, will be collected at Visit 1 
(Screening) and updated during the Screening Period (Visit 1 to Visit 4).  The number of 
COPD exacerbations requiring oral steroids and/or oral antibiotics, or hospitalization within 
12 months of Visit 1 (Screening) will be collected.  A complete physical examination will be 
performed at Visit 1 (Screening) and at Visit 11 (Final Visit) or Premature Discontinuation 
Visit. A complete physical examination will include evaluation of the following: general 
appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest, 
heart, abdomen, extremities, and nervous system.  Weight, assessed in ordinary indoor 
clothing with shoes removed will be recorded at Visit 1 (Screening) and Visit 11 (Final Visit) 
only. Height will be recorded at Visit 1 (Screening) only. 
7.2.2 Vital Sign Measurements
Heart rate and systolic and diastolic blood pressure, and temperature (‘vital signs’) will be 
assessed as outlined below; assessments may be obtained in either the supine or seated 
position. Axillary temperature is allowed to be taken, and no conversion is required.  
A single set of vital signs will be obtained at Visit 1 (Screening) and the Premature 
Discontinuation Visit.
Vital signs will be obtained at Visit 2 and Visit 3 within 60 minutes pre-bronchodilator and at 
30 minutes post-bronchodilator.  
At Visit 4 (Randomization Visit) only, pre-dose vital signs will be obtained twice at least 
5 minutes apart within 1 hour prior to dosing. 
Note:  Only one pre-dose temperature measurement is required unless a repeat measurement 
is clinically indicated. Post-dose vital signs will be obtained 30 minutes and 2 hours post 
study drug dosing. 
At all visits post randomization (after Visit 4): 
•
Pre-dose vital signs will be obtained once within 1 hour prior to dosing. 

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•
Post-dose vital signs will be obtained at 30 minutes post study drug dosing. 
•
Post-dose vital signs will be obtained at 2 hours post study drug dosing at all visits except 
at Visit 6 (Week 4) and Visit 9 (Week 16). 
Temperature will be obtained at Visit 1 (Screening) and at pre-dose at all visits and will not 
be repeated post-dose at subsequent time points unless clinically indicated.
7.2.3 12-Lead Electrocardiogram 
An ECG will be obtained at the Visit 1 (Screening) and Premature Discontinuation Visit. 
ECGs will be obtained at Visit 2 and Visit 3 within 60 minutes pre-bronchodilator and at 
30 minutes post-bronchodilator.  
At Visit 4 only, pre-dose ECGs will be obtained twice at least five minutes apart within 
1 hour prior to dosing. 
Pre-dose ECG will be obtained once within one hour prior to dosing at Visit 5 (Week 2), 
Visit 6 (Week 4), Visit 8 (Week 12), and Visit 11 (Week 24). 
A post-dose ECG will be obtained at 30 minutes and two hours post study drug dosing at 
Visit 4 (Day 1), Visit 5 (Week 2), Visit 8 (Week 12), and Visit 11 (Week 24).  
To standardize ECG collection, all sites will be provided with identical ECG equipment 
 with 
customized study-specific software.  All study staff responsible for performing ECG 
collection will receive identical, detailed training at the Investigator meetings as well as site 
phone training sessions.  Each site is required to demonstrate proficiency in the use of the 
equipment and the ability to perform technically acceptable ECGs prior to performing testing 
on study subjects.  After each test is performed, the ECG data will be transmitted 
electronically for centralized quality assurance review 
.  Feedback on the quality of the ECGs will be provided to the investigational site 
via a site qualification form.
The ECG parameters that will be assessed include heart rate, PR interval, QRS axis, QRS 
interval, and QT/QTcF interval.   
QT intervals and calculated QTcF intervals will be reviewed and checked for gross 
inaccuracies by the Investigator or designated ECG reviewer.  If the calculated QTcF 
intervals are > 500 msec, and have increased by 60 msec or more over test day baseline 
value, the Investigator will make a determination on the suitability of continuing the subject 
in the study.  If QTcF interval prolongation exceeding these limits is verified during 
treatment, the subject’s medical history should be examined closely for risk factors that may 
have contributed to the event, including evidence of prior genotyping for hereditary long QT 
syndromes, if appropriate. 

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Any sign of arrhythmia should be noted.  During treatment, any indication of Torsade de 
Pointes, a polymorphic ventricular tachyarrhythmia that appears on the ECG as continuous 
twisting of the vector of the QRS complex around the isoelectric baseline, must be recorded 
as an AE and reported to the Pearl Therapeutics Medical Monitor.  
All such subjects, including subjects with cardiac arrhythmias, should be monitored closely.  
If appropriate, ECG monitoring should be performed until the QT and QTcF interval and 
waveform morphology have returned to normal. If the prolongation or abnormal rhythm 
persists, the Pearl Therapeutics Medical Monitor must be contacted immediately.
7.2.4 Clinical Laboratory Tests
Clinical safety laboratory tests will be analyzed by a central laboratory according to 
standardized, validated assays.  The laboratory will supply detailed instructions and all
containers for blood and urine investigations.  Blood sample volumes will meet the
laboratory’s specification. 
All clinical laboratory tests will be obtained at Visit 1 (Screening) and prior to dosing at 
Visit 4 (Day 1), Visit 6 (Week 4), Visit 8 (Week 12) and Visit 11 (Week 24) or Premature 
Discontinuation Visit.
7.2.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured at Visit 1 (Screening) and prior to dosing at Visit 4 (Day 1), 
Visit 6 (Week 4), Visit 8 (Week 12) and Visit 11 (Week 24) or Premature Discontinuation 
Visit.
7.2.4.2
Clinical Chemistry
Albumin, alkaline phosphatase, total bilirubin, calcium, total cholesterol, magnesium, 
phosphate, sodium, potassium, chloride, creatinine, Ț-GT, blood glucose, total protein, AST 
and ALT will be measured at Visit 1 (Screening) and prior to dosing at Visit 4 (Day 1), 
Visit 6 (Week 4), Visit 8 (Week 12) and Visit 11 (Week 24) or Premature Discontinuation 
Visit.
The Central Laboratory will supply procedures for the preparation and collection of these 
samples (Refer to Table 8).

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Table 8 Laboratory Parameters
Hematology
Hemoglobin 
Mean corpuscular hemoglobin (MCH)
Hematocrit 
Mean corpuscular hemoglobin concentration (MCHC)
White Blood Cell count with differential 
Mean corpuscular volume (MCV)
Red Blood Cell count 
Platelet Count 
Clinical Blood Chemistry
Liver Enzyme and Other Function Tests
Other Clinical Blood Chemistry
Alanine aminotransferase (ALT) 
Albumin
Aspartate aminotransferase (AST) 
Calciuma
Alkaline phosphatase 
Chloridea
Bilirubin, total 
Cholesterol 
Gamma-glutamyl transferase 
Bicarbonate
Creatininea
Glucosea
Magnesium 
Potassiuma
Phosphate
Protein, total 
Sodiuma
Triglycerides 
Other Tests:
Pregnancy test (women of child-bearing potential only): serum [human chorionic gonadotropin (HCG)] at
Visit 1 (Screening) and Final Visit (Visit 11) only and Urine HCG at Visit 8 ( Week12)
Creatinine clearance will be estimated by the CKD-EPI formula.
aParameters included in the Basic Metabolic Panel (BMP).
7.2.4.3
Urinalysis
Urinalysis will be measured at Visit 1 (Screening) and prior to dosing at Visit 4 (Day 1), 
Visit 6 (Week 4), Visit 8 (Week 12) and Visit 11 (Week 24) or Premature Discontinuation 
Visit.

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7.2.4.4
Pregnancy Test
The pregnancy test should be performed prior to ECG, spirometry, or blood collection for 
laboratory assessments.
A serum pregnancy test will be performed at the Central Laboratory in pre-menopausal 
women who are not surgically sterile at Visit 1 (Screening) and Visit 11 (Week 24 or 
Premature Discontinuation Visit. 
A urine pregnancy test will be performed on-site at Visit 8 (Week 12). 
If any of these tests are positive, the subject must be discontinued from the study. 
7.2.5 Adverse Events
7.2.5.1
Performing Adverse Events Assessments
The Investigator is responsible for promptly documenting and reporting all AEs observed 
during the study in the subject’s case report form and on the AE Reporting Form. If the AE is 
“alarming,” the Investigator must report the AE immediately to Pearl Therapeutics. In 
addition, certain AEs (as described in Section 7.2.5.8) are classified as "serious" and must be 
reported no later than 24 hours after the Investigator recognizes/classifies the event as a 
serious adverse event to Pearl Therapeutics or its designee.
In the case of SAEs, after discussing the details of the AE, the Investigator and the Medical 
Monitor may discontinue the subject prematurely. 
7.2.5.2
Adverse Event Definitions
The following definitions of terms are guided by the International Conference on 
Harmonization, the U.S. Code of Federal Regulations [21 CFR 312.32] and European Union 
Directive 2001/83/EC and are included herein. 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  An adverse event (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (eg, an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality.  An adverse event can arise from any use of the drug (eg, off-label 
use, use in combination with another drug) and from any route of administration, 
formulation, or dose, including an overdose. 
Adverse events include, but are not limited to: 
•
Any symptom or condition not previously reported by the subject (medical history).
•
An exacerbation of a pre-existing symptom or condition.
•
A significant increase in frequency or intensity of a pre-existing episodic event or 
condition. 

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•
A drug interaction
•
A condition first detected or diagnosed after study drug administration even though it 
may have been present prior to the start of the study. 
An AE does not include: 
•
Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, blood 
transfusion); the condition that leads to the procedure is an AE (eg, bleeding esophageal 
varices, dental caries).
•
Overdose of either study drug or concurrent medication without any clinical signs or 
symptoms.
•
Non-clinically significant abnormal laboratory values.  (If accompanied by 
signs/symptoms, the signs or symptoms are considered an AE).
7.2.5.3
Pre-Randomization Adverse Events
Adverse events that occur between the time subject signs the informed consent form for the 
study and the time when that subject is randomized will be summarized as medical history 
and not as a treatment emergent adverse event unless the event meets the definition of an 
SAE as defined below.
7.2.5.4
Severity
The Investigator must categorize the severity of each AE according to the following 
guidelines: 
Mild: Associated with no limitation of usual activities or only slight discomfort; generally 
not requiring alteration or cessation of study drug administration; and/or not needing 
therapeutic intervention. 
Moderate: Associated with limitation of usual activities or significant discomfort; generally 
requiring alteration or cessation of study drug administration; and/or requiring therapeutic 
intervention. 
Severe: Associated with inability of subject to carry out usual activities or very
marked discomfort; considered to be life-threatening; resulting in significant disability or 
incapacity; and requiring therapeutic intervention. 
7.2.5.5
Relationship
The relationship of each adverse event to the study drug administration will be assessed by 
the Investigator after careful consideration, and according to the following guidelines:
Definitely: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug; it disappears 

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or decreases on cessation or reduction in study drug dose; and/or it reappears or worsens 
when the study drug is administered. 
Probably: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug; and/or that 
could not be reasonably explained by other factors such as underlying disease, complications, 
concomitant drugs, or concurrent treatments. 
Possibly: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug, but that 
could reasonably have been produced by a number of other factors including underlying 
disease, complications, concomitant drugs, or concurrent treatments. 
Not Related: A reaction for which sufficient data exist to indicate that the etiology is 
unrelated to the study drug. 
7.2.5.6
Chronic Obstructive Pulmonary Disease Exacerbations
COPD exacerbations are expected events in subjects with moderate to very severe COPD. 
All COPD exacerbations will be captured using a COPD Exacerbation eCRF and will not be 
reported as adverse events (AEs) unless considered a serious AE (SAE).  Exacerbation(s) of 
COPD is expected to occur as a progression of disease despite standardized drug treatment, 
or treatment(s) with combination therapies.  As a result, the Sponsor has classified this event 
as a protocol specified criteria expected event.  Any individual case safety reports received 
related to exacerbation of COPD will not be submitted on an expedited basis as a Suspected 
Unexpected Serious Adverse Reaction (SUSAR) unless otherwise required as per the 
Sponsor’s medical assessment.
7.2.5.7
Clinical Laboratory Adverse Events
Many laboratory abnormalities observed during the course of a study will be included under 
a reported AE describing a clinical syndrome (eg, elevated BUN and creatinine in the setting 
of an adverse event of renal failure, or decreased hemoglobin in a case of bleeding 
esophageal varices).  Isolated laboratory abnormalities should be reported as AEs if they are 
considered to be clinically significant by the Investigator.
Criteria for a "clinically significant" laboratory abnormality are:
•
A laboratory abnormality that leads to a dose-limiting toxicity (eg, an abnormality that 
results in study drug dose reduction, suspension, or discontinuation) 
•
A laboratory abnormality that results in any therapeutic intervention (i.e., concomitant 
medication or therapy)
•
Other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (eg, significant fall in hemoglobin not requiring transfusion) 

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For laboratory abnormalities that do not meet the above criteria but are outside of normal 
range (eg, < or > normal reference range), the Investigator should indicate whether the value 
is clinically significant or not clinically significant for the subject.
An AE or suspected adverse reaction is considered unexpected if it is not listed in the current 
Investigator Brochure (IB) or is not listed at the specificity or severity that has been 
observed.  
7.2.5.8
Serious Adverse Events
An AE is considered “serious” if, in the view of the Investigator or Sponsor, it results in any 
of the following outcomes: 
•
Death
•
A life-threatening adverse event
•
In patient hospitalization or prolongation of existing hospitalization  
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
•
A congenital anomaly/birth defect.
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate judgment, they may 
jeopardize the subject or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition.  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 subject hospitalization, or the development of 
drug dependency or drug abuse. 
Hospitalization for a pre-existing condition, including elective procedures, which has not 
worsened, does not constitute an SAE. 
An adverse event is considered “life-threatening’ if, in the view of the Investigator or 
Sponsor, its occurrence places the subject or subject at immediate risk of death.  It does not 
include an adverse reaction or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death.
7.2.5.8.1 REPORTING SERIOUS ADVERSE EVENTS
In agreeing to the provisions of this protocol, the Investigator accepts all legal responsibilities 
for AE identification, documentation, grading, assignment of causality, and prompt notification 
of SAEs to Pearl Pharmacovigilance or designee.  All SAEs must be reported to Pearl 
Therapeutics no later than 24 hours after the Investigator recognizes/classifies the event as an 
SAE.  At a minimum, a description of the event and the Investigator’s judgment of causality 
must be provided at the time of the initial report using the appropriate form (eg, SAE Report 

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Form).  After the initial report, as necessary, the Investigator must provide any additional 
information on an SAE to Pearl Pharmacovigilance within 2 working days after he/she 
receives that information.  This follow-up information will be a detailed written report that 
may include copies of hospital records, case reports, and autopsy reports, and other pertinent 
documents. 
Post-study SAEs following the last dose of study drug must be reported to Pearl Therapeutics   
as described in Section 7.2.5.11.
The Investigator is responsible for continuing to report to the Medical Monitor any new or 
relevant follow-up information that he/she learns about the SAE. 
7.2.5.9
Supplemental Investigations of SAEs
The Investigator and supporting personnel responsible for subject care should discuss with 
the Medical Monitor any need for supplemental investigations of SAEs.  The results of these 
additional assessments conducted must be reported to Pearl Therapeutics.  If a subject dies 
during participation in the study and a post-mortem examination is performed, a copy of the 
autopsy report must be submitted to Pearl Therapeutics. 
7.2.5.10 Post-Study Follow-Up of Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 
eCRF. Pearl retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
7.2.5.11 Notification of Post-Study Serious Adverse Events
Investigators are not obligated to actively follow subjects after the completion of the study.  
However, if the Investigation becomes aware of a post-study SAEs occurring up to 14 days 
following the last dose of study drug must be reported to Pearl Therapeutics, whether or not 
the event is attributable to study drug.  All SAEs must be reported to Pearl Therapeutics no 
later than 24 hours after the Investigator recognizes/classifies the event as an SAE.
7.2.5.12 Investigational Research Board/Independent Ethics Committee Notification of 
Serious Adverse Events
The Investigator is responsible for promptly notifying her/his investigational research 
board/independent ethics committee (IRB/IEC) of all SAEs, including any follow-up 
information occurring at her/his site and any SAE regulatory report, including any follow-up 
reports that he/she receives from Pearl Therapeutics in compliance with local IRB/IEC 
reporting requirements.  Documentation of the submission to the IRB/IEC must be retained 
for each safety report.  The Investigator is also responsible for notifying Pearl Therapeutics if 
their IRB/IEC requires revisions to the informed consent form or other measures based on its 
review of an SAE report.

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7.2.5.13 Health Authority Safety Reports
Pearl or its representatives will submit a safety report to the appropriate regulatory agencies 
for any suspected adverse reaction that is both serious and unexpected within the appropriate 
time frame.
Pearl or its representatives will send copies of each safety report submitted to the regulatory 
agencies to the Investigators who are actively participating in Pearl-sponsored clinical 
studies.  Safety reports must also be submitted to the appropriate IRB/IEC as soon as 
possible.  Documentation of the submission to the IRB/IEC must be retained for each safety 
report.
7.2.6 Overdose
An overdose is defined as a dose greater than the high dose level evaluated in this study as 
described in Section 6.2 (Product Descriptions) that results in clinical signs and symptoms.  
In the event of an overdose of study medication, the Investigator should use clinical 
judgment in treating the overdose and contact the study Medical Monitor. The Investigator 
should refer to the relevant document(s) for detailed information regarding warnings, 
precautions, contraindications, adverse events, and other significant data pertaining to the 
study drug(s) being used in this study. Such document may include, but not be limited to, the 
Investigator’s brochure for GP MDI. 
7.2.7 Pregnancy
To ensure subject safety, each pregnancy in a female subject from Visit 1 (Screening) until 
study completion must be reported to Pearl Therapeutics within 24 hours of learning of its 
occurrence.  The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications.  
Pregnancy should be recorded on a paper Pregnancy Form and reported by the Investigator to 
Pearl Pharmacovigilance or designee.  Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the Pearl Therapeutics 
study drug of any pregnancy outcome.  Any SAE experienced during pregnancy must be 
reported on the SAE Report Form. 
7.2.8 Use of Steroids during the Trial
At each visit, subjects will be asked whether they have been administered oral, intramuscular 
or intravenous corticosteroids since last visit.  Use of oral, intramuscular or intravenous 
corticosteroids for the management of COPD exacerbations or other condition is not a reason 
for early termination.  Use of corticosteroids should be documented.  Subjects who are being 
treated for a COPD exacerbation with oral corticosteroids or have been treated for a COPD 
exacerbation with oral corticosteroids within 14 days of the scheduled visit will be allowed to 
perform pulmonary function tests under close medical supervision.  The Investigator can 
decide to stop pulmonary function tests if subject safety is at risk or symptoms make it 
difficult for the subject to continue. 

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Subjects treated with oral, intramuscular, or intravenous corticosteroids for other indications 
will follow their visit schedule.  If a subject requires intraocular corticosteroids this should be 
fully documented and the Investigator should make a determination as to the suitability of the 
subject continuing in the study. 
7.2.9 Adjudication Committee 
Adjudication Committees: 
Two external adjudication committees will be established for this study.  The committees 
will consist of independent experts outside of Pearl who are not involved in the study 
conduct.  Committee members will be blinded with respect to the subject’s study medication. 
At regular intervals, the Committee will review narratives, discharge summaries, and medical 
records, as available.  
•
Cardio- and Cerebro-vascular (CCV) Adjudication Committee will review and assess 
non-fatal serious CCV events as major cardiovascular events (MACE).  
•
Mortality Adjudication Committee will assess the cause of deaths for cardiovascular and 
respiratory related events.
7.2.10 Data Monitoring Committee
An independent, external Data Monitoring Committee (DMC) will be set up to review all 
serious adverse events (including deaths and all hospitalizations) and cardiovascular events.  
Members of the DMC will review summaries of these safety data generated externally and 
independently of Pearl Therapeutics in a semi-blinded or unblinded manner at predetermined 
intervals.  If significant safety issues arise in between scheduled meetings, ad hoc meetings 
will be scheduled to review the data.  Based on the safety implications of the data, the DMC 
may recommend modification or termination of the study.
7.3 Health Care Resource Utilization 
The number of days missed from work, and COPD-related and non-COPD related telephone 
calls and visits to healthcare providers, Emergency Room (ER) visits, and hospitalizations 
including days in hospital, days in Intensive Care Units (ICU), days in Coronary Care Units 
(CCU), and whether the subject was intubated will be captured at Visit 5 (Week 2), Visit 6 
(Week 4), Visit 7 (Week 8), Visit 8 (Week 12), Visit 9 (Week 16), Visit 10 (Week 20), 
Visit 11 (Week 24), and Premature Discontinuation Visit. 
7.4 Termination of the Study 
An Investigator may choose to discontinue study participation at any time with sufficient 
notice by the Investigator for any reason as per the terms of the contract with Pearl 
Therapeutics.  
Pearl Therapeutics reserves the right to discontinue the study at any time for clinical or 
administrative reasons.  Such a termination must be implemented by the Investigator, if 

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instructed to do so by Pearl Therapeutics, in a time frame that is compatible with the 
subjects’ well being.

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8
STUDY ACTIVITIES
A time and events schedule for the study is presented in Table 9. Table 10 presents details 
about activities conducted pre and post dose at Visits 4 through 11. 

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Table 9. Schedule of Events
Procedures
Screening Period
Treatment Period
Follow-
Up
Visit 1
Visit 2
Visit 3
Visit 4
Day 1
Visit 5
Week 2
Visit 6
Week 4
Visit 7
Week 8
Visit 8
Week 12
Visit 9
Week 16
Visit 10
Week 20
Visit 11
Week 24
Discon§
Visit
14 days 
Post-
Dose
Study Day/Weeka
Day 
-28 to -
9
Day 
-21 to -2 
Day 
-19 to -1 
Day 
1 
Wk 2
±2Daysa
Wk 4
±2Daysa
Wk 8
±2Daysa
Wk 12
±2Daysa
Wk 16
±2Daysa
Wk 20
±2Daysa
Wk 24
±2Daysa
Obtain Informed Consent
X
Review Incl/Excl Criteria
X
X
X
X
Verify Continued 
Eligibility
X 
X 
X 
X 
X 
X 
X 
Reversibilityb
X
X
Demographics & 
Medical/Surgical History
X 
X 
X 
X 
Smoking Status
X
X
X
X
X
X
X
X
X
X
X
COPD Assessment Test 
(CAT) c
X 
MMRC c
X
Prior/Concomitant 
Medicationsd
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometrye
X
X
X
X
X
X
X
X
X
X
X
Physical Examinationf
X
X
X
Vital Signsg
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGh
X
X
X
X
X
X
X
X
X
Pregnancy Testi
X
X
X
X
Clinical Laboratory 
Testingi
X 
X 
X 
X 
X 
X
Chest X-ray or CTj
X
Adjust COPD 
Medicationsk
X 
X 
X
COPD Exacerbations and 
Adverse Events
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
Inhalation Device 
Trainingl
X 
Study Drug 
Dispensing/Collection
Xm
X 
X 
X 
X 
X 
X 
X 
X

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Procedures
Screening Period
Treatment Period
Follow-
Up
Visit 1
Visit 2
Visit 3
Visit 4
Day 1
Visit 5
Week 2
Visit 6
Week 4
Visit 7
Week 8
Visit 8
Week 12
Visit 9
Week 16
Visit 10
Week 20
Visit 11
Week 24
Discon§
Visit
14 days 
Post-
Dose
Study Drug 
Administration n
X 
X 
X 
X 
X 
X 
X 
X 
BDI/TDI o
X
X
X
X
X
X
X
X
SGRQ o
X
X
X
X
X
X
eDiary Training p
X
Review of eDiary q
X
X
X
X
X
X
X
X
X
X
X
Review/Record Dose 
Indicator Reading r
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCRU s
X
X
X
X
X
X
X
X
Telephone Contact t
X
X
X
X
X
X
X
X
X
X
X
a
Scheduling Visits: The maximum Screening Period is 28 days; the earliest a subject can be randomized from Visit 1 Date is 9 Days (7 days for LABA washout plus 1 day 
between Visit 2 and 3 plus 1 day between Visit 3 and Visit 4) or 16 days if subject is washing off of tiotropium; Site should make every effort to maintain subjects within the 
scheduled visit window. Subjects who fall outside the visit window will be placed in the appropriate visit window at the next scheduled visit.
b
Subjects will be tested for reversibility to albuterol (Ventolin HFA) at Visit 2 and  reversibility to Atrovent  HFA at Visit 3; Refer to Section 7.1.1 for additional details
c
CAT and MMRC will be used to characterize the subject population only and not to be used to determine eligibility to participate in the study 
d
At all visits beyond Visit 1 (Screening), note time of last dose of short-acting bronchodilator and other COPD medications (if <6 hours, visit should be rescheduled).
e
Refer to Section 7.1 for spirometry assessments and specific time points to be performed at each treatment visit.
f
Includes evaluation weight at Visit 1 (Screening) and Visit 11 (Final Visit) and height at Visit 1 (Screening) only.
g
Refer to Section 7.2.2 for vital signs assessments and specific time points to be performed at each treatment visit. Weight will be obtained at Visit 1 (screening) and Visit 11 
(Final Visit) only.
h
Refer to Section 7.2.3 for ECG assessments and specific time points to be performed at each treatment visit
i
Refer to Section 7.2.4 for clinical laboratory assessments (hematology, chemistry and urinalysis) and specific time points to be performed at each treatment visit. Serum 
pregnancy test will be performed at Visit 1 (Screening) and Visit 11 (Week 24) and a urine pregnancy test will be done at Visit 8 (Week 12).
j
Obtain a new Chest X-ray if Chest X-ray or CT performed within the 6 months prior to Visit 1 (Screening) is not available except in countries with restrictive radiology 
assessment practice (e.g. Germany) where only subjects who have had an x-ray or CT scan (thorax) performed outside of the study in the last 6 months are allowed to be 
enrolled.  Alternatively, in these countries, an MRI should be used instead of a CT scan or x-ray as per local practice assessment.
k
At Visit 1 (Screening), stop prohibited COPD medications and change COPD medications as specified in Section 5.4 (i.e., Sponsor provided Atrovent HFA with or without 
ICS). At the end of Visit 11, return subject to pre-study or other appropriate inhaled maintenance COPD.
l
Sites may use sponsor provided Atrovent HFA or Ventolin HFA to train subjects on the use of MDIs
m
Sponsor provided Atrovent HFA or Ventolin HFA is dispensed only after a subject is determined to be eligible to proceed to Visit 2 (i.e., only if a subject meets COPD 
definition following spirometry assessments at screening).
n
In clinic dosing time is recorded as time of the second puff/inhalation. The in clinic dosing time should be timed to be within 12±2 hours of the prior evening dosing time.
o
When BDI/TDI and SGRQ are obtained at the same visit, it is recommended that the BDI/TDI should be collected first, followed immediately by the SGRQ.  The BDI/TDI 
and SGRQ should be completed prior to any other visit procedures.

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p
Issue and train subjects on eDiary use only after a subject is determined to qualify to proceed to Visit 2
q
Refer to Section 7.1.3 for details of electronic diary review.
r
Refer to Section 7.1.6 for details and instructions on recording dose indicator readings.
s
Refer to Section 7.3 for details on HCRU collection.
t
It is recommended that sites call the subject on the day before a scheduled visit and remind the subject of the expectations for the upcoming visit (eg, Dosing appropriately the 
day before the visit, withholding COPD medications the morning of the scheduled visit, bring all study drug and eDiary to the visit, etc).
§ - Illustrates the procedures that may be required at a premature discontinuation visit. Note: Premature discontinuation visits will be captured as unscheduled visits (Refer 
to  Section 8.7). 
Note: When data collection time-points are concurrent, it is recommended that variables be collected in the following order: BDI/TDI, SGRQ, vital signs, ECG, clinical laboratory 
assessments, and spirometry.

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Table 10. Timed Assessments during Treatment Period (Visits 4-11)
Pre-dosing
Post-dosing
Clinical Variablea
-1 hour
-30 minutes
5 minutes
15 minutes
30 minutes
1 hour
2 hours
BDI/TDIb
X†
SGRQb
X†
Review of Electronic Diary Data
X†
Vital Signsc
X 
X 
X 
12- Lead ECGd
Xd
X 
X 
Clinical Laboratory Testinge
X†
Spirometry (FEV1, FVC, PEFR) f
Xg
Xg
Xh
X 
X 
X 
X 
Study Drug Collectioni
X†
Record Dose Indicator Readingj
X†
Study Drug Dispensingk
X 
a.
In clinic dosing time is recorded as time of the second puff. Safety assessments ( vital signs, and ECG) should be started approximately 5 - 10 minutes ahead of the 
specified time point to ensure that spirometry for FEV1, FVC and PEFR assessments will be conducted as close to the specified time points as possible (i.e., FEV1, FVC, 
and PEFR assessments need to be conducted within ± 15 minutes of specified time prior to study drug administration; ± 5 minutes of specified time for the first 60 minutes 
post study drug administration; ± 15 minutes of specified time point for assessments obtained thereafter)
b.
When BDI/TDI and SGRQ are obtained at the same visit, it is recommended that the BDI/TDI will be collected first, followed immediately by the SGRQ.  The BDI/TDI
and SGRQ should be completed prior to any other visit procedures. The questionnaires must be completed prior to any other visit procedures. BDI/TDI will be obtained at 
all visits except Visit 5 (Week 2). SGRQ will be obtained at Visit 4 (Day 1), Visit 8 (Week 12), Visit 9 (Week 16), Visit 10 (Week 20), Visit 11 (Week 24) or Premature 
Discontinuation Visit
c.
At Visit 4 only, pre-dose vital signs will be collected twice at least five minutes apart. Vital signs will be obtained within one hour pre-dosing and at 30 minutes post study 
drug administration at all treatment visits. At all visits post randomization except Visit 6 (Week 4) and Visit 9 (Week 16) only, vital signs will be obtained at 2 hours post 
study drug dosing. Temperature will be obtained pre-dose; no further temperature assessments are required unless clinically indicated.
d.
At Visit 4 only, pre-dose ECG will be collected twice at least five minutes apart. An ECG will be obtained once pre-dose and at 30 minutes and 2 hours post-dose at Visit 4 
(Day 1), Visit 5 (Week 2) , Visit 8 (Week 12), and Visit 11 (Week 24).  At Visit 6 (Week 4), only a pre-dose ECG will be obtained. 
e.
Clinical laboratory tests (hematology, chemistry and urinalysis) will be obtained prior to dosing at Visit 4 (Day 1), Visit 6 (Week 4), Visit 8 (Week 12) and Visit 11 (Week 
24) only. Serum pregnancy test will be performed at Visit 11 (Week 24) and a urine pregnancy test will be done at Visit 8 (Week 12).
f.
Post-dose spirometry assessment will be obtained at all visits except Visit 6 (Week 4) and Visit 9 (Week 16).
g.
To be randomized, all subjects must meet FEV1 Baseline Stability criteria.  Refer to Section 7.1.2 for additional details.
h.
The 5-minute post-dose spirometry assessment will be obtained at Visit 4 (Treatment Day 1) only.
i.
At the start of each treatment visit, subject must withhold all COPD medications, prior to the study visit. Short-acting bronchodilators, rescue Ventolin HFA should be 
withheld for at least 6 hours prior to start of test day procedures.
j.
Site staff will record the dose indicator reading at each visit. The dose indicator reading recorded by the site staff will be dose indicator count observed prior to subject 

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dosing. For new MDIs the recorded count will be the count following the priming of the device but before the subject dose. Refer to Section 7.1.6 for more details
k.
Dispense study drug for at home use to subject following completion of all post-dose assessments. Refer to Section 6.6 for Instructions for Preparation of Treatments for 
Administration and Dispensing
†
This is not a timed assessment. Sites should plan to perform these activities so as not to interfere with collection of timed assessments such as spirometry.
Note: Where data collection time-points are concurrent, variables must be collected in the following order: BDI/TDI, SGRQ, vital signs, ECG, clinical laboratory assessments, 
and spirometry..

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8.1 Visit 1 
•
Obtain informed consent. 
•
Register subject in IWRS to obtain subject screening number  
•
Obtain demographic data, including age, race, smoking history, medical/surgical history 
(including cardiovascular risk factors and history), and age of onset of COPD. 
•
Review inclusion/exclusion criteria.
•
Obtain medication history, including COPD medications.
•
Conduct a serum pregnancy test for all female subjects unless it is documented in the 
medical history that the subject has been irreversibly surgically sterilized (hysterectomy, 
oophorectomy, or bilateral tubal ligation) or they are at least 2 years post-menopausal. 
•
Conduct a complete physical examination (general appearance, skin, head, eyes, ears, 
nose, throat, neck [including thyroid], lymph nodes, chest, heart, abdomen, extremities, 
and nervous system). 
•
Obtain height, weight, and vital signs (heart rate and blood pressure after being supine or 
seated for 5 minutes, and oral or tympanic temperature). 
•
Obtain a 12-lead ECG.
•
Conduct spirometry assessments. 
•
Confirm subject’s ability to use MDI correctly (provide coaching as needed).
•
If subject qualifies to continue to Visit 2 perform the following:
•
Obtain laboratory samples (hematology, chemistry and urinalysis). 
•
If Chest X-ray or CT within 6 months of Visit 1 (Screening) is not available, obtain a 
new Chest X-ray except in countries with restrictive radiology assessment practice 
(e.g. Germany) where only subjects who have had an x-ray or CT scan (thorax) 
performed outside of the study in the last 6 months are allowed to be enrolled.  
Alternatively, in these countries, an MRI may be used instead of a CT scan or x-ray 
as per local practice assessment.
•
Stop prohibited COPD medications and change concurrent COPD medications as 
specified in protocol (Refer to Section 5.4.1).  The Sponsor will provide Atrovent 
(ipratropium bromide) HFA QID for COPD maintenance and Ventolin (albuterol 
sulfate) HFA, PRN, for symptomatic relief.
•
Obtain subject assignment information of Atrovent (ipratropium bromide) HFA and 
Ventolin (albuterol sulfate) HFA from IWRS 
•
Dispense and train subject on eDiary use  
•
Schedule Visit 2
•
In order to allow for an adequate washout of previous maintenance medications, 
subjects will undergo a washout period of at least 1 week (at least 2 weeks if

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taking Spiriva or other LAMA), but not greater than 26 days in duration prior to
returning to the clinic for Visit 2.
•
Subjects will be instructed to bring their eDiary, sponsor provided Ventolin (albuterol 
sulfate) HFA and Atrovent (ipratropium bromide) HFA to the next scheduled clinic 
visit.
•
Adverse events must be recorded during the Screening Period, that is, from the time 
of consent to the start of study treatment.  
Note: Adverse events that occur between the time when the subject signs the informed 
consent form for the study and the time when that subject is dosed with study drug will be 
summarized as medical history and not as a study adverse event unless the event meets the 
definition of an SAE. 
8.2 Visit 2 
•
Review subject diary entries and retrain subject if subject has not met diary compliance 
requirement of >70% subject completion of diary assessments. 
•
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, Visit 2 must be rescheduled). 
•
Review inclusion/exclusion criteria and confirm subject eligibility to continue.
•
If not previously reviewed, review of clinical laboratory results from Visit 1.  Please note 
whether the results are clinically significant and include comments where applicable.
•
Record COPD exacerbations and adverse events (if any). 
Note: Adverse events that occur during the Screening Period (Visit 1 to Visit 4, pre study 
drug dosing) will be summarized as medical history and not as a study adverse event unless 
the event meets the definition of an SAE. 
•
Obtain COPD Assessment Test (CAT) and MMRC 
•
Review all prior medications, if any, and ensure adherence to COPD regimen. 
•
Obtain pre-bronchodilator vital signs and 12-lead ECG.
•
Perform reversibility test to Ventolin (albuterol sulfate) HFA and confirm subject 
continues to meet entry criteria based on pre- and post-dose spirometry quality (Refer to 
exclusion criterion 3h), and post-dose spirometry values. 
•
Obtain post-bronchodilator vital signs and 12-lead ECG.
•
Schedule Visit 3
•
Note: Visit 3 can be scheduled at minimum 1 day after Visit 2 and no later than 
27 days after Visit 1 (Screening)
•
Ensure subject has adequate supply of sponsor-provided Atrovent (ipratropium bromide) 
HFA and sponsor-provided rescue Ventolin (albuterol sulfate) HFA. 

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•
Subjects will be instructed to bring their eDiary, sponsor-provided Atrovent (ipratropium 
bromide) HFA, and sponsor-provided Ventolin (albuterol sulfate) HFA to the next 
scheduled clinic visit.
8.3 Visit 3  
•
Review subject diary entries and retrain subject if subject has not met diary compliance 
requirement of >70% subject completion of diary assessments. 
•
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, Visit 3 must be rescheduled). 
•
Review inclusion/exclusion criteria and confirm subject eligibility to continue.
•
Record COPD exacerbations and adverse events (if any). 
•
Note: Adverse events that occur during the Screening Period (Visit 1 to Visit 4, pre 
study drug dosing) will be summarized as medical history and not as a study adverse 
event unless the event meets the definition of an SAE. 
•
Review all prior medications, if any, and ensure adherence to COPD regimen. 
•
Obtain pre-bronchodilator vital signs and 12-lead ECG.
•
Perform reversibility test to sponsor-provided Atrovent (ipratropium bromide) HFA. 
(Refer to Section 7.1.1 for instructions). 
•
Obtain post-bronchodilator vital signs and 12-lead ECG.
•
Schedule Visit 4 (Randomization Visit, Day 1). 
•
Note: Visit 4 (Randomization Visit, Day 1) can be scheduled at minimum 1 day after 
Visit 3 and no later than 28 days after Visit 1 (Screening). 
•
Ensure subject has adequate supply of sponsor-provided Atrovent (ipratropium bromide) 
HFA and sponsor-provided rescue Ventolin (albuterol sulfate) HFA.
•
Subjects will be instructed to bring their eDiary, Atrovent (ipratropium bromide) HFA, 
and sponsor-provided Ventolin (albuterol sulfate) HFA to the next scheduled clinic visit. 
8.4 Visit 4 (Randomization) 
•
Review subject diary entries and screen fail subject if subject has not met diary 
compliance requirement of >70% subject completion of diary assessments in the last 
7 days preceding Visit 4.
•
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, Visit 4 must be rescheduled).
•
Complete BDI questionnaire followed by SGRQ questionnaire before any other study 
procedures are performed. 
•
Record COPD exacerbations and adverse events (if any). 

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•
Review all concomitant medications, if any, and ensure adherence to COPD regimen.
•
Collect sponsor-provided Atrovent (ipratropium bromide) HFA and sponsor-provided 
Ventolin (albuterol sulfate) HFA dispensed during the Screening Period. 
•
Review inclusion/exclusion criteria and confirm subject eligibility for randomization. 
-
Note: To be randomized, all subjects must meet the FEV1 Baseline Stability criteria.  
Refer to Section 7.1.2 for additional details.  If the FEV1 Baseline Stability entry 
criteria are not met at Visit 4 (Randomization) the subject will not be eligible to be 
randomized and will be screen failed.
•
Obtain subject randomization number and treatment assignment information from IWRS 
(Visit 4). 
•
Perform all pre-dose assessments (Refer to Table 10).
•
To allow for proper preparation of study drug, it is recommended that the seal around the 
study day treatment box is opened 15-30 minutes prior to dosing and the instructions for 
administration of study drug followed: 
•
Refer to Section 6.6 for detailed instructions for preparation of treatments for 
administration.  These instructions are to be adhered to and are relevant to all study 
treatment visits.
•
Record/document the dose indicator reading.  The dose indicator count recorded by 
the site staff will be dose indicator count observed after priming but prior to subject 
dosing. For new MDIs, the recorded count will be the count following the priming of 
the device but before the subject dose.  Refer to Section 7.1.6 for more details.
•
Subject will administer first dose of newly assigned study drug at the clinic. 
•
The subject is to be considered randomized after receiving a randomization number. 
•
Perform all post-dosing assessments (Refer to Table 10).
•
Return eDiary to subjects and provide retraining if appropriate. 
•
Subjects will be instructed to bring their eDiary and all study medication (including used 
study drug, replacement MDI kit and rescue Ventolin (albuterol sulfate) HFA to the next 
scheduled clinic visit.
•
Schedule next visit and ensure subject has adequate supply of study drug including a 
replacement MDI kit and rescue Ventolin (albuterol sulfate) HFA.
8.5 Visit 5 to Visit 10
•
Review subject diary for data collection compliance.
•
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, the visit must be rescheduled). 

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•
Confirm the subject took their last dose of randomized study medication as scheduled the 
prior evening.  If the time of dosing was not in accordance with the protocol, then the 
visit must be rescheduled.   
•
Confirm subject eligibility to continue.
•
If applicable, complete TDI questionnaire followed by SGRQ questionnaire before any 
other study procedures are performed,
•
Collect HCRU information.
•
Record COPD exacerbations and adverse events (if any). 
•
Review all concomitant medications, if any, and ensure adherence to COPD regimen.
•
Perform all pre-dose assessments (Refer to Table 10).
•
Return eDiary to subjects and provide retraining if appropriate. 
•
Prior to dosing (except at Visit 5), site personnel will use IWRS to assign subjects a new 
kit of study drug for in-clinic dosing and to continue dosing at home until the next 
scheduled visit. 
•
Refer to Section 6.6 for detailed instructions for preparation of treatments for 
administration.  These instructions are to be adhered to and are relevant to all study 
treatment visits.
•
Record/document the dose indicator readings of the used MDI and the replacement MDI.   
•
At Visit 5, the dose indicator count recorded by the site staff will be dose indicator count 
observed before and after subject dosing with the same MDI, and provided a photocopier 
is available, the dose indicator will be photocopied both before and after subject dosing.  
•
For new MDIs, the recorded count will be the count following the priming of the device 
but before the subject doses.  Refer to Section 7.1.6 for more details.
•
Administer in-clinic study drug dose from the new kit assigned at the visit.
•
Perform all post-dose assessments (Refer to Table 10).
•
Subjects will be instructed to track study drug dosing in their electronic diary between 
study clinic visits.
•
Subject will be instructed to dose while at home from the site-primed MDI only, unless 
all of the following replacement conditions are met:
•
Dose indicator is in the red zone (Refer to Appendix 10 for dose indicator reading 
instructions) 
•
7KHGRVHLQGLFDWRUUHJLVWHUVSXIIVUHPDLQLQJand their next scheduled study 
clinic visit is not the following day.
•
If these replacement conditions are met, subjects will be instructed to open their 
replacement kit, prime the MDI and start using for at home dosing until the next 
scheduled study clinic visit. 

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•
Subjects will be instructed to bring their eDiary and all study medication (including used 
study drug, replacement MDI kit and sponsor-provided rescue Ventolin (albuterol 
sulfate) HFA) to the next scheduled clinic visit.
•
Schedule next visit and ensure subject has adequate supply of study drug including a 
replacement MDI kit and sponsor-provided rescue Ventolin (albuterol sulfate) HFA. 
Visit 5 to Visit 10 Reminders:
•
At Visit 5 (Week 2) subjects will use the study medication dispensed at Visit 4 
(Randomization, Day 1) for Visit 5 (Week 2) in clinic dosing and to continue dosing at 
home until Visit 6.
•
TDI will be obtained at all visits except Visit 5 (Week 2).
•
SGRQ will be obtained at Visit 8 (Week 12), Visit 9 (Week 16), and Visit 10 (Week 20). 
•
Vital Signs:
•
Obtained within one hour pre-dosing and at 30 minutes post study drug 
administration at all treatment visits. 
•
Obtained at 2 hours post study drug dosing at all visits except Visit 6 (Week 4) and 
Visit 9 (Week 16). 
•
ECG:
•
An ECG will be obtained pre-dose within 1 hour prior to dosing and at 30 minutes 
and 2 hours post-dose at Visit 5 (Week 2) and Visit 8 (Week 12). 
•
At Visit 6 (Week 4), only a pre-dose ECG will be obtained. 
•
Clinical laboratory tests will be obtained prior to dosing at Visit 6 (Week 4) and Visit 8 
(Week 12). 
•
Post-dose spirometry assessments over two hours will be obtained at all visits except 
Visit 6 (Week 4) and Visit 9 (Week 16). 
8.6 Final Visit (Visit 11) 
•
Review subject eDiary for data collection compliance.
•
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, the visit must be rescheduled). 
•
Confirm the subject took their last dose of randomized study medication as scheduled the 
prior evening.  If the time of dosing was not in accordance with the protocol, then the 
visit must be rescheduled.   
•
Complete TDI questionnaire followed by SGRQ questionnaire before any other study 
procedures are performed.
•
Collect HCRU information.

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•
Record COPD exacerbations and adverse events (if any). 
•
Review all concomitant medications, if any, and ensure adherence to COPD regimen.
•
Confirm subject eligibility to continue.
•
Perform all pre-dose assessments (Refer to Table 10) including clinical laboratory 
assessment, physical examination and serum pregnancy test for women of child bearing 
potential.
•
Prior to dosing, site personnel will use IWRS to assign subjects a new kit of study drug 
for in clinic dosing. 
•
Refer to Section 6.6 for detailed instructions for preparation of treatments for 
administration.  These instructions are to be adhered to and are relevant to all study 
treatment visits.
•
Record/document the dose indicator readings of the used MDI and the replacement 
MDI.  
•
For the new MDI, the recorded count will be the count following the priming of the 
device but before the subject doses.  Refer to Section 7.1.6 for more details.
•
Administer in-clinic study drug dose from the new kit assigned at the visit. 
•
Perform all post-dose assessments (Refer to Table 10).
•
Collect subject eDiary.
•
Collect all study medication including sponsor-provided Ventolin (albuterol sulfate) HFA 
and Atrovent (ipratropium bromide) HFA. 
•
At completion of all Visit 11 assessments, return subject to pre-study or appropriate 
maintenance COPD medications.
•
Inform subject about reporting all SAEs up to 14 days following the last dose of study 
drug. 
•
Schedule the follow-up telephone call at least 14 days from Visit 11.  
8.7 Unscheduled Visit/Premature Discontinuation Visit
Repeat assessments, if needed, will be captured in unscheduled visits. 
Premature discontinuations visits will be captured as unscheduled visits.  The following 
minimum procedures should be completed at the premature discontinuation visit: 
•
Complete TDI questionnaire first followed by SGRQ questionnaire second before any 
other study procedures are performed.
•
Collect HCRU information.
•
Record COPD exacerbations and adverse events (if any).

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•
Review concomitant medications, if any.
•
Conduct a physical examination, including vital signs.
•
Perform ECG and collect blood samples for hematology and chemistry. 
•
Collect a blood sample for pregnancy test for women of child bearing potential. 
•
Collect subject eDiary.
•
Collect all study drugs, including rescue medications.  
•
Inform subject about reporting all SAEs up to 14 days following the last dose of study 
drug. 
•
Return subject to pre-study or appropriate maintenance COPD medications. 
•
Capture the subject discontinuation reason. 
•
Schedule a follow-up telephone call (TC) 14 days post last study drug dosing.  If the 
discontinuation visit is performed > 14 days post last study drug dosing a follow-up TC 
will not be required. 
8.8 Follow-Up Telephone Call 
Subjects will be followed-up through a TC 14 days post last study drug dosing.  The 
following information will be requested: 
•
Review previously on-going COPD exacerbations and adverse events and record AEs (if 
any).
•
Review concomitant medications, if any.

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8.9 Completion of the Study 
The Investigator will document the completion or the reason for early withdrawal by a 
subject in the eCRF.  The following categories should be used to describe these events in the 
eCRF:
•
Subject discretion (document reason) 
•
Investigator considers it to be in the best interest of the subject 
•
Adverse events(s)
•
Administrative reasons (eg, early termination of the study)
•
Subject lost-to-follow-up 
•
Lack of efficacy
•
Major protocol violation 
•
Death
•
Completion of the study 
•
Protocol specified criteria such as heart rate, systolic or diastolic blood pressure, or use of
prohibited medications (Refer to Section 5.7).

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9
PLANNED STATISTICAL METHODS
9.1 Introduction 
This study will be conducted as a double-blind, placebo-controlled, parallel group study 
evaluating the following treatments in approximately 1614 subjects: 
•
*))0',ȝJ%,'
•
*30',ȝJ%,'
•
))0',ȝJ%,'
•
Placebo MDI BID
The primary objective of this study is to confirm the efficacy of GFF MDI compared to its 
individual components and Placebo MDI as well as the efficacy of FF MDI and GP MDI 
compared to Placebo MDI. 
This study will include a 24-week Treatment Period, preceded by a Screening Period and 
followed a two-week follow-up telephone call.  The entire study is scheduled to take 
approximately 30 weeks for each individual subject from the time of Screening.  
9.2
Protocol Variables
9.2.1 Efficacy Endpoints
All efficacy assessments are relative to pre-dose baseline obtained at Visit 4.  Lung function 
measurements and symptom-based endpoints will be evaluated.  The primary endpoint 
differs by approach but is always based on morning pre-dose trough FEV1.
The three different registration approaches will be called: 1) US/China, 2) Japan, and 3) 
EU/S. Korea/Taiwan.  Evaluation of treatment efficacy at a landmark time point is required 
for the US and China, and the primary endpoint is identical for these two countries.  
However, the primary endpoint is assessed over 24 weeks for the EU/South Korea/Taiwan 
approach and over Weeks 12 to 24 in the Japan approach. The delineation of multiplicity 
controls for the primary and secondary measures are separated by approach in Section 9.3.4.
All inferential results will be based on analyses using the Intent-to-Treat (ITT) Population 
unless otherwise noted. In addition to the ITT analysis, symptomatic endpoints will also be 
analyzed using the Symptomatic Population. The primary analyses of rescue Ventolin usage 
will be conducted in the Rescue Ventolin User Population. 

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9.2.1.1
Primary Efficacy Endpoint
Primary Endpoint
The primary objective of this study is to confirm the efficacy of GFF MDI compared to its 
individual components and Placebo MDI as well as the efficacy of FF MDI and GP MDI 
compared to Placebo MDI. 
Primary Endpoint (US/China) 
•
For the US/China approach, the primary endpoint will be the change from baseline in 
morning pre-dose trough FEV1 at Week 24 of treatment.
Primary Endpoint (Japan) 
•
For the Japan approach, the primary endpoint will be the change from baseline in 
morning pre-dose trough FEV1 over Weeks 12 to 24 of treatment. 
Primary Endpoint (EU/South Korea/Taiwan)  
•
For the EU/South Korea/Taiwan approach, the primary endpoint will be the change from 
baseline in morning pre-dose trough FEV1 over 24 weeks of treatment.
9.2.1.2
Secondary Efficacy Endpoints
Secondary Efficacy Endpoints:  
•
TDI score over 24 weeks (US/China and EU/South Korea/Taiwan approaches) and over 
Weeks 12 to 24 (Japan approach) 
•
TDI score over 24 weeks (US/China and EU/South Korea/Taiwan approaches) and over 
Weeks 12 to 24 (Japan approach) in the Symptomatic Population 
•
Change from baseline in morning pre-dose trough FEV1 over 24 weeks (US/China 
approach)
•
Peak change from baseline in FEV1 within 2 hours post-dosing at Week 24 (US/China 
approach), over 24 weeks (EU/South Korea/Taiwan approach), and over Weeks 12 to 24 
(Japan approach) 
•
Change from baseline in SGRQ total score at Week 24 (US/China approach) and over 
Weeks 12-24 (EU/South Korea/Taiwan and Japan approaches)  
•
Change from baseline in SGRQ total score at Week 24 (US/China approach) and over 
Weeks 12-24 (EU/South Korea/Taiwan and Japan approaches) in the Symptomatic 
Population 

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•
Change from baseline in average daily rescue Ventolin (albuterol sulfate) HFA use over 
24 weeks (all approaches) in the Rescue Ventolin User Population
•
Time to onset of action on Day 1 (all approaches) 
9.2.1.3
Other Efficacy Endpoints 
9.2.1.3.1 DAY 1 ASSESSMENTS 
•
Change from baseline at each post-dose time point in FEV1 and forced vital capacity 
(FVC), as well as FEV1 AUC0-2
•
Proportion of subjects achieving an improvement from baseline in FEV1  using different 
thresholds (ie, P/P/DQGDQG mL)
9.2.1.3.2 ASSESSMENTS OVER 24 WEEKS (UNLESS OTHERWISE STATED) 
•
Rate of moderate to severe COPD exacerbations 
•
Time to the first moderate or severe COPD exacerbation
•
Rate of all COPD exacerbations 
•
Time to the first COPD exacerbation of any severity
•
Time to treatment failure
•
Time to first CID
•
Time to sustained CID
•
Change from baseline in morning pre-dose trough for FVC, as well as FEV1 AUC0-2 at 
each post-randomization visit, over 24 weeks, and over Weeks 12-24  
•
Peak change from baseline in FEV1 and FVC through 2 hours post-dose over 24 weeks, 
over Weeks 12-24, and at each post-randomization visit 
•
Percentage of days with ‘no rescue Ventolin (albuterol sulfate) HFA use’
•
Change from baseline in mean daily total symptom score as well as each individual 
symptom (cough, shortness of breath, sputum volume, nighttime awakenings, and rescue 
Ventolin HFA use), the mean morning total and individual symptom scores, and the 
mean evening total and individual symptom scores over 24 weeks, over Weeks 12-24, 
and over each 4-week interval of the 24 week Treatment Period. 
•
TDI focal score at each post-randomization visit 
•
Individual components of the TDI: functional impairment, magnitude of task, and 
magnitude of effort over 24 weeks, over Weeks 12 to 24,  and at each post-randomization 
visit
•
Percentage of subjects achieving a minimal clinically important difference (MCID) threshold 
RIXQLWRQDYHUDJHLQ7',IRFDOVFRUHRYHU24 weeks and separately over Weeks 12 to 
24

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•
Changes from baseline at each post-randomization visit for SGRQ total score 
•
Change in individual domain scores of SGRQ: Symptoms, Activity, and Impacts over 
Weeks 12 to 24 and at each post-randomization visit 
•
Percentage of subjects DFKLHYLQJDQ0&,'WKUHVKROGRIXQLWVRQDYHUDJHLQ6*54
total score over Weeks 12 to 24 and separately at Week 24  
9.2.2 Safety Endpoints 
The safety endpoints for this study include the following: 
•
AEs
•
12-Lead ECG: Change from baseline in heart rate, PR interval, QRS axis, QRS interval, 
QT interval, and QTcF (Fridericia Corrected QT) interval
•
Clinical Laboratory Testing
•
Vital Sign Measurements
9.2.3 Health Care Resource Utilization
The number of days missed from work, and COPD-related and non-COPD related telephone 
calls and visits to healthcare providers, Emergency Room (ER) visits, and hospitalizations 
including number of days in the hospital, number of days in Intensive Care Units (ICU), 
number of days in Coronary Care Units (CCU), and number of subject intubation events will 
also be captured and compared between treatment groups 

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9.3
Analysis
9.3.1 Primary Efficacy Analysis
For the primary comparisons, the null hypothesis for each pair-wise comparison will be that 
the mean test treatment effect is equal to that of Placebo MDI (or an individual component); 
the alternative hypothesis is then that the test treatment effect and that of Placebo MDI (or an 
individual component) are not equal.  P-values will thus be reported as two-sided. The 
primary null (H0) and alternative (H1) hypotheses with μ representing the mean are:
H0: μFF = μplacebo
H1: μFF placebo
H0: μGP = μplacebo
H1: μGP placebo
H0: μGFF = μplacebo
H1: μGFF placebo
H0: μGFF = μFF
H1: μGFF FF
H0: μGFF = μGP
H1: μGFF GP
9.3.1.1
Change from Baseline in Morning Pre-dose Trough FEV1
The change from baseline in pre-dose trough FEV1 will be analyzed using a repeated 
measures (RM) linear model.  The model will include baseline FEV1 and reversibility to 
Ventolin (albuterol sulfate) HFA as continuous covariates and visit, treatment, and the 
treatment by visit interaction as categorical covariates.  Baseline is defined as the average of 
the non-missing -60 min and -30 min values obtained prior to dosing at Visit 4.  An 
unstructured matrix will be used to model the variance-covariance structure within subject.  
If this model fails to converge, the heterogeneous Toeplitz (TOEPH) structure will be fit.  
Contrasts will be used to obtain estimates of the treatment differences at Week 24, over 
Weeks 12 to 24, and over 24 weeks.  Two-sided p-values and point estimates with two-sided 
95% confidence intervals (CIs) will be produced for each treatment difference.  The primary 
analysis will be conducted using the ITT Population. 
Additional supportive analyses of morning pre-dose trough FEV1 will include the change 
from baseline at Week 24, over Weeks 12 to 24, and over the entire 24-week treatment 
period in the PP Population and the treatment differences at individual time points estimated 
by the RM model.   

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Subgroup analyses for morning pre-dose trough FEV1 will be performed by country (e.g. 
Japan, China, etc.) and for the regional subgroups of Asia and all non-Japanese countries 
combined. Additional subgroup analyses may be defined in the Statistical Analysis Plan as 
appropriate. 
Sensitivity analyses to evaluate the robustness of the primary analyses to the nature of the 
missing data are discussed in Section 9.10.
9.3.2 Analysis of Secondary Endpoints 
Secondary variables are TDI (over 24 weeks US/China and EU and over Weeks 12 to 24 
Japan), morning pre-dose trough FEV1 over 24 weeks for the US/China (analysis described 
above), and onset of action on Day 1, peak FEV1 (at Week 24 for US/China, over 24 weeks 
for EU, and over Weeks 12 to 24 for Japan), rescue Ventolin (albuterol sulfate) HFA usage, 
and SGRQ (at Week 24 for US/China, over Weeks 12-24 for EU/South Korea/Taiwan and 
for Japan). Multiplicity will be controlled for the secondary variables as described in 
Section 9.3.4. All analyses will be performed with the ITT Population except for rescue 
Ventolin HFA usage which will be based on the Rescue Ventolin User Population. In 
addition to the ITT analysis, the symptomatic endpoints of TDI and SGRQ will also be 
analyzed using the Symptomatic Population. 
Subgroup analyses for secondary endpoints will be performed by country (e.g. Japan, China, 
etc.) and for the regional subgroups of Asia and all non-Japanese countries combined.  
Subpopulation analyses will also be conducted for TDI and SGRQ based on baseline CAT 
VFRUHWKUHVKROGVRI&$7&$7LH6\PSWRPDWLF3RSXODWLRQDQG&$7
Additional subgroup analyses for secondary endpoints may be defined in the Statistical 
Analysis Plan as appropriate.
9.3.2.1
TDI 
Assessments of dyspnea will be obtained using the interviewer-administered version of the 
BDI/TDI. The BDI/TDI questionnaire can be found in Appendix 9, but is provided for 
illustrative purposes only. 
At Visit 4, the severity of dyspnea at baseline will be assessed using the BDI.  At subsequent 
visits (as per schedule of events, Table 9) change from baseline will be assessed using the 
TDI.  The difference between treatment groups in TDI over 24 weeks and over Weeks 12 to 
24 will be evaluated using a similar RM approach as for the primary endpoint.  BDI will be 
included as a continuous covariate replacing baseline in the model.  Scoring and handling of 
missing items will be conducted in accordance with the user’s guide for the TDI score.  Two-
sided p-values and point estimates with two-sided 95% confidence intervals will be produced 
for each treatment difference. 
As supportive analyses, the difference between treatments at each of the individual visits will 
also be evaluated and summarized as well as the individual components of the TDI: 
functional impairment, magnitude of task, and magnitude of effort.  Furthermore as 
supportive analyses, responder analyses will be performed where responders are defined as a 

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response of 1.0 points or more on average over 24 weeks and separately over Weeks 12 to 
24.  Logistic regression will be used to compare the treatment groups with BDI and 
reversibility to Ventolin (albuterol sulfate) HFA as continuous covariates and treatment as
categorical covariates.  P-values and odds ratios with 95% CI will be produced for each 
treatment comparison. 
9.3.2.2
Peak FEV1
The peak change from baseline in FEV1 within 2 hours post-dosing at Week 24, over 
24 weeks and over Weeks 12 to 24 will be analyzed in a similar way to morning pre-dose 
trough FEV1.
9.3.2.3
St. George’s Respiratory Questionnaire 
The difference between treatment groups in the change from baseline in SGRQ at Week 24 
and over Weeks 12 to 24 will be evaluated using a similar RM approach as for the primary 
endpoint.  Scoring and handling of missing items will be conducted in accordance with the 
user’s guide for the SGRQ.  Each response is to be given a unique empirically derived weight 
between 0 and 100, the weights of all responses are then summed up and divided by the 
maximum possible score and expressed as a percentage.  Missing data of the SGRQ total 
score will not be imputed.  Two-sided p-values and point estimates with two-sided 95% 
confidence intervals will be produced for each treatment difference. 
As supportive analyses, the difference between treatments at each of the individual visits will 
also be evaluated and summarized.  Individual domains of the SGRQ will also be analyzed in 
a similar fashion as the overall score.  Furthermore as supportive analyses, responder 
analyses will be performed where responders are defined as an improvement of 4.0 points or 
more on average over Weeks 12 to 24 and separately at Week 24.  Logistic regression will be 
used to compare the treatment groups with baseline SGRQ and reversibility to Ventolin 
(albuterol sulfate) HFA as continuous covariates and treatment as a categorical covariate.  P-
values and odds ratios with 95% CI will be produced for each treatment comparison. 
9.3.2.4 Rescue Ventolin (albuterol sulfate) HFA Use 
The number of puffs of rescue Ventolin (albuterol sulfate) HFA taken in the previous 12 
hours will be recorded in the subject diary in the morning and evening.  For every period of 
time for which the mean number of puffs of rescue will be calculated, missing values will be 
ignored in both the numerator and denominator. As such, the denominator will be adjusted 
based on the number of days (including half days) with non-missing values.
The mean daily number of puffs of rescue Ventolin (albuterol sulfate) will be calculated 
overall and for each of the 4-week intervals during the Treatment Period.  Diary data 
recorded during the last 7 days of the 10-14 day screening period will be used to calculate the 
baseline.  The difference between treatment groups in the change from baseline in average 
daily rescue Ventolin (albuterol sulfate) HFA use over 24 weeks will be evaluated using a 
similar RM approach as for the primary endpoint.  Instead of visit, the number of the relevant 
4-week interval (1-6) will be used as a categorical covariate in the model.  As supportive 

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analyses, the treatment difference for each 4-week interval and over Weeks 12-24 will be 
evaluated and summarized.  Additionally as supportive analyses, daytime rescue Ventolin 
(albuterol sulfate) HFA use and night-time rescue Ventolin (albuterol sulfate) HFA use will 
be evaluated and summarized in a similar fashion.  Two-sided p-values and point estimates 
with two-sided 95% confidence intervals will be produced for each treatment difference.
9.3.2.5
Time to Onset of Action
The onset of action will be determined for each treatment using the 5 minutes and 15 minutes 
post-dosing FEV1 assessments from Day 1. The onset of action for each product (GP MDI, 
FF MDI, and GFF MDI) will be defined as the first timepoint where the difference from 
Placebo MDI is statistically significant (Refer to Section 9.3.4 for procedure to control 
Type I error).  Comparisons will be performed using an analysis of covariance (ANCOVA) 
model including baseline FEV1and reversibility to Ventolin (albuterol sulfate) HFA as 
continuous covariates.  
9.3.3  Analysis of Exploratory Endpoints 
9.3.3.1
Other Spirometry Endpoints
The analysis of the other comparisons of changes in morning pre-dose trough FEV1 over 
24 weeks has already been described in Section 9.3.1. Treatment differences in the change 
from baseline in FEV1 AUC0-2 and morning pre-dose trough FVC will be evaluated in a 
similar manner to the primary endpoint. 
On Day 1, during the first two hours post-dosing, the proportion of subjects achieving an 
improvement from baseline in FEV1 using different thresholds (ie, P/
200 mL, and 12% and 200 mL) will be estimated for each treatment. Logistic regression will 
be used to compare the treatment groups with baseline FEV1 and reversibility to Ventolin 
(albuterol sulfate) HFA as continuous covariates and treatment as a categorical covariate.  P-
values and odds ratios with 95% CI will be produced for each treatment comparison. 
9.3.3.2
Percentage of Days With “No Rescue Use” 
As a supportive analysis, percentage of days with ‘no rescue Ventolin (albuterol sulfate) 
HFA use’ over 24 weeks will be analyzed.  A ‘day with no rescue use’ is defined using 
rescue Ventolin (albuterol sulfate) HFA usage data from days where rescue Ventolin 
(albuterol sulfate) HFA data is non-missing as any day where the subject reported no puffs of 
rescue Ventolin (albuterol sulfate) HFA.  The percentage of days with ‘no rescue use’ will be 
summarized by treatment and analyzed using ANCOVA as for the time to onset of action 
described in Section 9.3.2.5 , but with baseline average daily rescue Ventolin (albuterol 
sulfate) HFA use instead of baseline FEV1 as a covariate.
9.3.3.3
COPD Exacerbations
The severity of exacerbations will be classified as follows:

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•
Mild: exacerbations that do not require systemic steroids or antibiotics, and do not result 
in hospitalization or death. 
•
Moderate: exacerbations that require treatment with systemic steroids and/or antibiotics, 
and do not result in hospitalization or death. 
•
Severe: exacerbations that result in hospitalization or death.  
The rate of all COPD exacerbations of any severity will be analyzed using negative binomial 
regression.  COPD exacerbations will be considered separate events provided that 7 or more 
days are between the recorded stop date of the earlier event and start date of the later. 
Exposure to randomized medication will be used as an offset variable. Time during an 
exacerbation or in the 7 days following an exacerbation will not be included in the 
calculation of exposure.  Treatments will be compared adjusting for baseline percent 
predicted FEV1, baseline CAT score, baseline COPD exacerbation history, smoking status at 
baseline, and ICS use at baseline. 
The time to first COPD exacerbation of any severity will be analyzed using Cox regression 
model for the ITT population.  The model will include treatment, baseline percent predicted 
FEV1, baseline COPD exacerbation history, baseline CAT score, smoking status at baseline, 
and ICS use at baseline. The adjusted hazard ratios relative to the comparator will be 
displayed along with the associated Wald two-sided 95% confidence interval and p-values.  
Time to first moderate or severe COPD exacerbation as well as the time to first COPD 
exacerbation will be displayed graphically for each treatment group using a Kaplan-Meier 
curve.  Subjects who did not experience a COPD exacerbation will be censored at the Week 
24 visit. Subjects who withdrew from the study without experiencing a COPD exacerbation 
will be censored at the date of withdrawal.
The rate of moderate and severe COPD exacerbations and the time to first moderate or severe 
COPD exacerbation will be analyzed similarly to the rate of COPD exacerbations of any 
severity and the time to first COPD exacerbation of any severity.
Additional analyses of the rate of COPD exacerbations will be performed with imputation of 
a moderate exacerbation at the time of dropout for subjects withdrawing prematurely from 
the trial, unless an exacerbation has already been recorded at that time. 
9.3.3.4
Time to Treatment Failure
Treatment failure will be defined as a moderate or severe COPD exacerbation or 
discontinuation from the study for any reason. The time to treatment failure will be analyzed 
using a Cox regression model for the ITT Population.  The model will include treatment, 
baseline percent predicted FEV1, baseline COPD exacerbation history, baseline CAT score, 
smoking status at baseline, and ICS use at baseline. The adjusted hazard ratios will be 
displayed along with associated 95% confidence interval and p-values.  Time to treatment 
failure will be displayed graphically for each treatment group using a Kaplan-Meier curve.  
Subjects who did not experience a treatment failure will be censored at Week 24. 

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9.3.3.5
Time to First and Sustained Clinically Important Deterioration
Clinically important deterioration (CID) will be defined as the first occurrence of one of the 
IROORZLQJHYHQWVDGHFOLQHRIP/LQWURXJK)(91; 2) a moderate to severe COPD 
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above due to FEV1 or SG54EXWRFFXUULQJRQFRQVHFXWLYHYLVLWVZHHNVDSDUWRUIRU
>50% of all available subsequent visits. The time to first CID and time to sustained CID will 
each be analyzed using a Cox regression model for the ITT Population. The model will 
include treatment, baseline percent predicted FEV1, baseline COPD exacerbation history, 
baseline CAT score, smoking status at baseline, and ICS use at baseline. The median time to 
CID and the adjusted hazard ratios will be displayed along with associated 95% confidence 
interval and p-values. Time to first CID and time to sustained CID will both be displayed 
graphically for each treatment group using a Kaplan-Meier curve. Subjects who did not 
experience a CID will be censored at the Week 24 visit or Day 183, whichever was earlier. 
The basic assumptions of the model will be checked including the proportional hazards 
assumption. 
9.3.3.6
Symptom Scores (Daily, Morning and Evening Symptom Scores)
All subjects will be provided with an electronic subject diary to record daily, morning and 
evening clinical symptoms of cough, shortness of breath, sputum volume, night-time 
awakenings, and Ventolin (albuterol sulfate) HFA use.  
The mean daily total symptom score, the mean morning symptom score and the mean 
evening symptom score will be calculated for each subject over each 4-week interval of the 
24-week Treatment Period.  The last seven days of the 10-14 day Screening Period will be 
used to calculate the baseline.  The mean change from baseline in the daily, morning and 
evening symptom scores will be analyzed using a similar model as for morning pre-dose 
trough FEV1 to estimate treatment effects over 24 weeks and over Weeks 12-24.  In addition, 
summaries of the daily, morning and evening symptom scores will be provided for each 
4-week period.  The above summaries will be repeated for individual symptom score. 
9.3.4 Control of Type I Error 
There are three separate plans for control of Type I error: 1) US/China, 2) EU/South 
Korea/Taiwan, and 3) Japan.
9.3.4.1
United States/China Endpoints
Strong control of the Type I error rate will be maintained at the two-sided 0.05 level for the 
primary endpoint across products using a sequential approach and then within each 
comparison for the secondary measures using a simultaneous approach as detailed below.  
Based on positive dependence of the test statistics (Sarkar 2008 ; Sarkar1997), simultaneous 
control of Type I error for the secondary measures will be achieved using the Hochberg 
procedure (Hochberg, 1988). All endpoints will be tested using the ITT Population unless 
otherwise noted. 

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For GP MDI, Type I error control will be achieved by comparing GP MDI to Placebo MDI 
using a two-sided alpha of 0.05 for the change from baseline in morning pre-dose trough 
FEV1 at Week 24 first and continuing to assessment of secondary measures if this 
comparison is statistically significant. The secondary endpoints [TDI over 24 weeks, TDI 
over 24 weeks in the Symptomatic Population, change in morning pre-dose trough FEV1 over 
24 weeks, peak change in FEV1 at Week 24, change in SGRQ at Week 24, change in SGRQ 
at Week 24 in the Symptomatic Population, change in rescue Ventolin (albuterol sulfate) 
HFA use over 24 weeks in the Rescue Ventolin User Population, FEV1 at 5 minutes post-
dosing on Day 1, and FEV1 at 15 minutes post-dosing on Day 1] will be tested 
simultaneously using the Hochberg procedure with a two-sided alpha of 0.05. 
Provided that the comparison between GP MDI and Placebo MDI is significant for the 
primary endpoint, comparisons using FF MDI will be interpreted inferentially.  Type I error 
control will be achieved by comparing FF MDI to Placebo MDI using a two-sided alpha of 
0.05 for the change from baseline in morning pre-dose trough FEV1 at Week 24 first and 
continuing to assessment of secondary measures if this comparison is statistically significant. 
The secondary endpoints [TDI over 24 weeks, TDI over 24 weeks in the Symptomatic 
Population, morning pre-dose trough FEV1 over 24 weeks, peak FEV1 at Week 24, SGRQ at 
Week 24, SGRQ at Week 24 in the Symptomatic Population, rescue Ventolin (albuterol 
sulfate) HFA use over 24 weeks in the Rescue Ventolin User Population, FEV1 at 5 minutes 
post-dosing on Day 1, and FEV1 at 15 minutes post-dosing on Day 1] will be tested 
simultaneously using the Hochberg procedure with a two-sided alpha of 0.05. 
Provided that the comparisons between FF MDI and Placebo MDI and between GP MDI and 
Placebo MDI are significant for the primary endpoint, comparisons using GFF MDI will be 
interpreted inferentially.  Type I error will be strictly controlled for the primary endpoint and 
will be controlled within each treatment comparison for the secondary assessments.  GFF 
MDI will be compared to Placebo MDI, then FF MDI, and finally GP MDI for morning 
pre-dose trough FEV1 at Week 24 using a two-sided alpha level of 0.05 and continuing 
sequentially if each comparison is statistically significant.  If GFF MDI is significantly 
superior to its components for the primary endpoint, the secondary measures of TDI over 24 
weeks, TDI over 24 weeks in the Symptomatic Population, morning pre-dose trough FEV1
over 24 weeks, peak FEV1 at Week 24, SGRQ at Week 24, SGRQ at Week 24 in the 
Symptomatic Population, rescue Ventolin (albuterol sulfate) HFA use over 24 weeks in the 
Rescue Ventolin User Population, and for GFF MDI vs. Placebo MDI in order to evaluate 
onset of action, FEV1 at 5 minutes post-dosing on Day 1 and FEV1 at 15 minutes post-dosing 
on Day 1 will be evaluated for significance.  Type I error will be controlled at the two-sided 
alpha of 0.05 within each comparison (GFF MDI vs. Placebo MDI, GFF MDI vs. FF MDI, 
and GFF MDI vs. GP MDI) using a simultaneous approach based on the Hochberg 
procedure. 
9.3.4.2
Japan Endpoints
Strong control of the Type I error rate will be maintained at the two-sided 0.05 level for the 
primary endpoint across products using a sequential approach and then within each 
comparison for the secondary measures using a simultaneous approach as detailed below.  

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Based on positive dependence of the test statistics (Sarkar 2008; Sarkar1997), simultaneous 
control of Type I error for the secondary measures will be achieved using the Hochberg 
procedure (Hochberg, 1988). All endpoints will be tested using the ITT Population unless 
otherwise noted. 
For GP MDI, Type I error control will be achieved by comparing GP MDI to Placebo MDI 
using a two-sided alpha of 0.05 for the change from baseline in morning pre-dose trough 
FEV1 over Weeks 12 to 24 first and continuing to assessment of secondary measures if this 
comparison is statistically significant.  The secondary endpoints [TDI over Weeks 12 to 24, 
TDI over Weeks 12 to 24 in the Symptomatic Population, peak FEV1 over Weeks 12 to 24, 
SGRQ over Weeks 12 to 24, SGRQ over Weeks 12 to 24 in the Symptomatic Population, 
rescue Ventolin (albuterol sulfate) HFA use over 24 weeks in the Rescue Ventolin User 
Population, FEV1 at 5 minutes post-dosing on Day 1, and FEV1 at 15 minutes post-dosing on 
Day 1) will be tested simultaneously using the Hochberg procedure with a two-sided alpha of 
0.05.
Provided that the comparison between GP MDI and Placebo MDI is significant for the 
primary endpoint, comparisons using FF MDI will be interpreted inferentially.  Type I error 
control will be achieved by comparing FF MDI to Placebo MDI using a two-sided alpha of 
0.05 for the change from baseline in morning pre-dose trough FEV1 over Weeks 12 to 24 
first and continuing to assessment of secondary measures if this comparison is statistically 
significant. The secondary endpoints [TDI over Weeks 12 to 24, TDI over Weeks 12 to 24 in 
the Symptomatic Population, peak FEV1 over Weeks 12 to 24, SGRQ over Weeks 12 to 24, 
SGRQ over Weeks 12 to 24 in the Symptomatic Population, rescue Ventolin (albuterol 
sulfate) HFA use over 24 weeks in the Rescue Ventolin User Population, FEV1 at 5 minutes 
post-dosing on Day 1, and FEV1 at 15 minutes post-dosing on Day 1) using the Hochberg 
procedure with a two-sided alpha of 0.05. 
Provided that the comparison between FF MDI and Placebo MDI and between GP MDI and 
Placebo MDI are significant for the primary endpoint, comparisons using GFF MDI will be
interpreted inferentially.  Type I error will be strictly controlled for the primary endpoint and 
will be controlled within each treatment comparison for the secondary assessments.  GFF 
MDI will be compared to Placebo MDI, then FF MDI, and finally GP MDI for morning 
pre-dose trough FEV1 over Weeks 12 to 24 using a two-sided alpha level of 0.05 and 
continuing sequentially if each comparison is statistically significant.  If GFF MDI is 
significantly superior to its components for the primary endpoint, the secondary measures of 
TDI over Weeks 12 to 24, TDI over Weeks 12 to 24 in the Symptomatic Population, peak 
FEV1 over Weeks 12 to 24, SGRQ over Weeks 12 to 24, SGRQ over Weeks 12 to 24 in the 
Symptomatic Population, rescue Ventolin (albuterol sulfate) HFA use over 24 weeks in the 
Rescue Ventolin User Population, and for GFF MDI vs. Placebo MDI in order to evaluate 
onset of action, FEV1 at 5 minutes post-dosing on Day 1 and FEV1 at 15 minutes post-dosing 
on Day 1 will be evaluated for significance.  Type I error will be controlled at the two-sided 
alpha of 0.05 within each comparison (GFF MDI vs. Placebo MDI, GFF MDI vs. FF MDI, 
and GFF MDI vs. GP MDI) using a simultaneous approach based on the Hochberg 
procedure. 

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9.3.4.3
European Union/South Korea/Taiwan Endpoints
Strong control of the Type I error rate will be maintained at the two-sided 0.05 level for the 
key comparisons for each product using the approaches detailed below and across products 
for the primary endpoint for GFF MDI. All endpoints will be tested using the ITT Population 
unless otherwise noted. For FF MDI, Type I error control will be achieved by comparing FF 
MDI to Placebo MDI using a two-sided alpha of 0.05 for the change from baseline in 
morning pre-dose trough FEV1 over 24 weeks first and continuing to assessment of 
secondary measures if this comparison is statistically significant.  The secondary measures 
[TDI over 24 weeks, TDI over 24 weeks in the Symptomatic Population, peak FEV1 over 24 
weeks, SGRQ over Weeks 12-24, SGRQ over Weeks 12-24 in the Symptomatic Population, 
rescue Ventolin (albuterol sulfate) HFA use over 24 weeks in the Rescue Ventolin User 
Population, FEV1 at 5 minutes post-dosing on Day 1, and FEV1 at 15 minutes post-dosing on 
Day 1 will be tested simultaneously using the Hochberg procedure with a two-sided alpha of 
0.05.
For GP MDI, Type I error control will be achieved by comparing GP MDI to Placebo MDI 
using a two-sided alpha of 0.05 for the change from baseline in morning pre-dose trough 
FEV1 over 24 weeks first and continuing to assessment of secondary measures if this 
comparison is statistically significant.   The secondary measures [TDI over 24 weeks, TDI 
over 24 weeks in the Symptomatic Population, peak FEV1 over 24 weeks, SGRQ over Weeks 
12-24, SGRQ over Weeks 12-24 in the Symptomatic Population, rescue Ventolin (albuterol 
sulfate) HFA use over 24 weeks in the Rescue Ventolin User Population, FEV1 at 5 minutes 
post-dosing on Day 1, and FEV1 at 15 minutes post-dosing on Day 1) will be tested 
simultaneously using the Hochberg procedure with a two-sided alpha of 0.05. 
If the comparisons of FF MDI and GP MDI to Placebo MDI are significant for morning pre-
dose trough FEV1, then GFF MDI will be sequentially compared to: 1) Placebo MDI using 
morning pre-dose trough FEV1; 2) FF MDI using morning pre-dose trough FEV1; and 3) GP 
MDI using morning pre-dose trough FEV1 using a two-sided alpha level 0.05.  Provided the 
comparisons of GFF MDI to its components are significant for morning pre-dose trough 
FEV1, the secondary endpoints of TDI over 24 weeks, TDI over 24 weeks in the 
Symptomatic Population, peak FEV1 over 24 weeks, SGRQ over Weeks 12-24, SGRQ over 
Weeks 12-24 in the Symptomatic Population, rescue Ventolin (albuterol sulfate) HFA use 
over 24 weeks in the Rescue Ventolin User Population, and for GFF MDI vs. Placebo MDI 
in order to evaluate onset of action, FEV1 at 5 minutes post-dosing on Day 1 and FEV1 at 15 
minutes post-dosing on Day 1, will be evaluated for significance. Type I error will be 
controlled at the two-sided alpha of 0.05 within each comparison (GFF MDI vs. Placebo 
MDI, GFF MDI vs. FF MDI, and GFF MDI vs. GP MDI) using the Hochberg procedure.  

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9.3.5 Safety Analysis
9.3.5.1
Adverse Events
The version of the Medical Dictionary for Regulatory Activities (MedDRA) that is current at 
the time of database lock will be used to code verbatim terms for AEs for final analysis of the 
data.  AEs will be tabulated by MedDRA system organ class (SOC) and preferred term (PT).  
Tabulations will be broken down by severity, by relationship to study drug, and AEs leading 
to treatment discontinuation. No hypothesis tests will be performed. 
Adverse events (AEs) within each treatment arm will be summarized by the number and 
percent of subjects experiencing an event.  They will be tabulated at the level of the 
MedDRA preferred term, and the MedDRA System Organ Class and analyzed using the 
version of MedDRA current at the time of database lock.  Tabulations will be broken down 
by severity, by relationship to study drug, and AEs leading to withdrawal.  No hypothesis 
tests will be performed.  Tables will show the overall incidence of adverse events, and the 
incidence for each treatment.  
9.3.5.2
Cardio- and Cerebrovascular and Mortality Events Determined by Adjudication 
Committee
CCV and Mortality Adjudication Committees will review and adjudicate serious CCV events 
as MACE. MACE events are defined as the following: 
•
Cardiovascular death
•
Non-fatal myocardial infarction (MI)
•
Non-fatal stroke 
The adjudication committees will review and assess these non-fatal serious CCV events and 
all deaths as to whether or not they fulfill criteria (based on adjudication committee working 
practices) for MACE.
MACE events will be summarized by treatment group.
9.3.6 Clinical Laboratory Measurements
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) for the 
baseline assessment (Day 1) and for the pre-dose value and change from baseline at pre-dose 
value of post-baseline visits with scheduled lab assessments of continuous laboratory 
variables, including serum potassium and glucose, will be tabulated. 
Shift tables relative to the normal reference ranges will be produced using the categories 
defined by the CTCAE Version 4.03 grades.  For these shift tables, for each treatment, the 
subject’s pre-dose grade will be cross-tabulated by the subject’s maximum post-baseline 
grade during the treatment; also, the subject’s maximum post-baseline grade during treatment 
will be tabulated for all baseline grades combined.

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The number and percent of subjects with potentially clinically significant (PCS) lab values 
will be summarized. PCS values for serum potassium are < 3.0 mmol/L or > 6.0 mmol/L and 
for blood glucose < 2.2 mmol/L or > 13.9 mmol/L. PCS values for additional labs will be 
defined in the SAP. No hypothesis tests will be performed.
9.3.7 Vital Signs
Summary statistics (mean, median, standard deviation and range) for absolute values and 
change from baseline values will be tabulated for each treatment and assessment time. For 
vital signs, baseline values will be defined as the average of the values prior to dosing at the 
randomization visit (Visit 4).  PCS values for vital signs will be defined in the SAP and the 
percentage of subjects with PCS values will be summarized. No hypothesis tests will be 
performed.
9.3.8 ECGs
Summary statistics (mean, median, standard deviation and range) for raw values and change 
from baseline values in Heart Rate, RR Interval, PR Interval, QRS Axis, QRS Interval, QT 
Interval and QTcF interval will be calculated, where baseline is defined as the average of the 
pre-dose measurements taken prior to the start of treatment at the randomization visit (Visit 
4).  The QTcF (Fridericia Corrected QT) is defined as (QT/(RR 1/3)). Heart rate (bpm) is 
estimated as 60,000/RR.  These assessments will be tabulated for each treatment and 
assessment time.  PCS values for ECG parameters will be defined in the SAP, and the 
percentage and number of subjects with PCS ECG values will be tabulated.  No hypothesis 
tests will be performed.
9.3.9 Health Care Resource Utilization
COPD-related and non-COPD-related HCRU will be summarized by treatment group.
9.4 Randomization 
Subjects will be randomly assigned to one of the 4 treatment arms using an IWRS in a 
7:6:6:3 ratio with less subjects being assigned to the Placebo MDI arm and more subjects 
being assigned to the GFF MDI arm.  Randomization will be stratified by disease severity 
(moderate vs. severe or very severe) and reversibility to Ventolin (albuterol sulfate) HFA 
(yes or no).  Center will not be used as a stratification factor given the impracticality of 
enrolling a large enough number of subjects to ensure balance in each of the four strata 
formed by combining disease severity and reversibility.
9.5 Experimental Design 
This study is a multi-center, double-blind, parallel-group, placebo-controlled design.  All 
study treatments are given in addition to permitted COPD background therapy. There will be 
a screening visit where informed consent is obtained.  Current COPD medications are 
reviewed and if necessary arrangements are made to adjust prohibited COPD therapy to 
allowable COPD therapy. 

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9.6
Sample Size
It is estimated that a sample size of 1614 subjects (514 subjects in the GFF MDI arm, 
440 subjects each in the GP MDI, and FF MDI arms, and 220 subjects in the Placebo MDI 
arm) will provide approximately 91% power with type I error controlled at a two-sided alpha 
level of 0.05 to detect differences for all five primary comparisons if the true differences 
from placebo are 90 mL for FF MDI, 100 mL for GP MDI, and 150 mL for GFF MDI 
resulting in corresponding differences between GFF MDI and FF MDI and GP MDI of 
60 mL and 50 mL, respectively, in morning pre-dose trough FEV1 at Week 24, 
approximately 99% power for morning pre-dose trough FEV1 over 24 weeks and 
approximately 99% power for morning pre-dose trough FEV1 over Weeks 12 to 24.  
Assumptions regarding variability for the primary endpoint are based on Pearl Therapeutics’ 
experience with Phase IIb clinical studies and on published data for within patient variation 
(D’Urzo, 2001, van Noord , 2005; Maesen, 1995) and between patient variation (Dahl, 2001, 
Calverley, 2003).  A composite value standard deviation (SD) of 200 mL has been assumed.  
A within subject correlation structure has been assumed combining a block diagonal structure 
LQGXFHGE\XVLQJVXEMHFWDVDUDQGRPHIIHFWZLWKDQ$5VWUXFWXUHZLWKȡ 
Differential dropout rates have been assumed with increased dropout due to lack of efficacy 
ranging up to 25% in the Placebo MDI arm.  Under these assumptions, based on this sample 
size, the study will have approximately 99% power to detect differences between FF MDI 
and Placebo MDI and between GP MDI and Placebo MDI in morning pre-dose trough FEV1
at Week 24, over 24 weeks or over Weeks 12-24 using a two-sided alpha level of 0.05. 
9.7 Data Validation and Transformation 
In general the distribution of spirometry measures is well-approximated by a normal 
distribution.  Under some circumstances, however, (for example during a COPD 
exacerbation, unrelated to treatment) extreme and atypical values can arise.  Such values 
have high influence on estimation of variance parameters and on standard errors of fixed 
effect estimates.  The distribution and potential influence of outliers will be evaluated and 
additional sensitivity analyses will be conducted if warranted to demonstrate the robustness 
of the primary and secondary results. 
9.8
Analysis Plan
All analyses will be specified in a detailed statistical analysis plan (SAP) that will be 
accompanied by table and data listing shells with mock graphical representations.  The 
analysis plan will be approved by signature before database lock and unblinding. 
9.9 Study Populations 
The following analysis populations are defined in this study: 
x
The Intent-To-Treat (ITT) Population is defined as all subjects who are randomized to 
treatment and receive at least one dose of the study treatment.  Subjects will be analyzed 
according to the treatment they were assigned to at randomization. (Note that a subject 

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who used a study treatment, but took less than one full dose of treatment will qualify for 
this population). 
x
The Per-Protocol (PP) Population is a subset of the ITT Population defined as all 
subjects with post-randomization data obtained prior to any major protocol deviations.  
Data obtained after any major protocol deviation will be excluded.  Since receiving the 
wrong treatment will be a major protocol deviation, subjects in the PP population will be 
analyzed as randomized (which for this population if identical to analysis by the actual 
treatment received).  Any evaluability criteria with a potential impact on efficacy results 
will be identified in a blinded fashion from review of data listings prior to unblinding. 
Major protocol deviations (protocol violations), therefore, can result in exclusion of all 
data from a particular subject from the PP population or require exclusion of data from a 
specific timepoint and/or subsequent timepoints for an endpoint. 
x
The Safety Population is similar to the ITT Population (all subjects who are randomized 
to treatment and receive at least one dose of the study treatment).  However, subjects will 
be analyzed according to treatment received rather than randomized.  If a subject received 
more than one randomized treatment, they will be analyzed and included in summaries 
according to the treatment they received the most. (Note:  A subject who used a study 
treatment, but took less than one full dose of treatment will qualify for this population). 
Note: The statement that a subject had no adverse events also constitutes a safety 
assessment.
x
The Symptomatic Population is defined as all subjects in the ITT Population with CAT 
VFRUHVRIDW9LVLW
x
Regional differences in rescue Ventolin HFA usage are expected, with some regions 
using virtually no rescue medication at study entry.  Therefore, the Rescue Ventolin 
User Population is defined as all subjects in the ITT Population with average baseline 
Rescue Ventolin use RISXIIGD\
Analyses will be performed as follows: 
Demographics will be summarized for the ITT, PP, Symptomatic, Rescue Ventolin User and 
Safety Populations and the Non-Randomized analysis set.  Extent of exposure will be 
summarized for the Safety Population. The Safety Population will be used to summarize 
safety. Efficacy Analyses will be performed for the ITT Population. The PP Population will 
be used to perform sensitivity analyses of trough FEV1 only.  The Symptomatic Population 
will be used for the efficacy analysis of symptomatic endpoints. Rescue Ventolin endpoints 
will be analyzed with the Rescue Ventolin User population. 
9.10 Handling of Missing Data 
All observed values will be included in the ITT population and the primary and secondary 
analyses. As a maximum likelihood method, RM is valid for missing-at-random (MAR) 
missingness (Little, 2002). If the nature and magnitude of the missing data leads to concerns 
about potential biases in the evaluation of treatment effects, sensitivity analyses will be 
performed using multiple imputation under varying assumptions about treatment effects in 
the unobserved data.  Missing data will be classified as missing completely at random 
(MCAR), MAR, or not MAR (NMAR) based on the reason for the missing value captured in 

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10 ADMINISTRATIVE CONSIDERATIONS
10.1 Regulatory Authority Approval
Pearl Therapeutics will obtain approval to conduct the study from the appropriate regulatory 
agency in accordance with any applicable country-specific regulatory requirements prior to a 
site initiating the study in that country. 
10.2 Ethical Conduct of the Study and Institutional Review Board (IRB) 
or Independent Ethics Committee (IEC) Approval 
The study will be conducted in accordance with Good Clinical Practice (GCP).  These 
standards respect the following guidelines: 
•
Guideline for Good Clinical Practice E6(R1):  Consolidated Guideline (International 
Conference on Harmonization of Technical Requirements for the Registration of 
Pharmaceuticals for Human Use, May 1996). 
•
US Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR parts 50, 
54, 56, and 312). 
•
Declaration of Helsinki, concerning medical research in humans (Ethical Principles for 
Medical Research Involving Human Subjects) 
[http://www.wma.net/en/10home/index.html]. 
•
Any additional regulatory requirements.
The Investigator (or Pearl Therapeutics, where applicable) is responsible for ensuring that
this protocol, the site’s informed consent form (ICF), and any other information that will be 
presented to potential subjects (eg, advertisements or information that supports or 
supplements the ICF) are reviewed and approved by the appropriate IRB/IEC.  The 
Investigator agrees to allow the IRB/IEC direct access to all relevant documents.  The 
IRB/IEC must be constituted in accordance with all applicable regulatory requirements.   
Pearl Therapeutics will provide the Investigator with relevant document(s)/data that are 
needed for IRB/IEC review and approval of the study.  If the protocol, the ICF, or any other 
information that the IRB/IEC has approved for presentation to potential subjects is amended 
during the study, the Investigator is responsible for ensuring the IRB/IEC reviews and 
approves, where applicable, these amended documents.  The Investigator must follow all 
applicable regulatory requirements pertaining to the use of an amended ICF including 
obtaining IRB/IEC approval of the amended form before new subjects consent to take part in 
the study using this version of the form.  The IRB/IEC approval of the amended ICF/other 
information and the approved amended ICF/other information must be forwarded to Pearl 
Therapeutics promptly. 

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10.3 Subject Information and Consent 
The study will be conducted in accordance with applicable subject privacy requirements.  
The proposed ICF, which must be in compliance with applicable regulations, must be 
reviewed and approved by the IRB/IEC and Pearl Therapeutics prior to initiation of the 
study.   
The Investigator will be responsible for obtaining written informed consent from potential 
subjects prior to any study-specific screening and entry into the study.  A copy of the signed 
ICF will be provided to the subject.  The original will be retained by the Investigator.
10.4 Laboratory Accreditation
Any laboratory facility intended to be used for analysis of clinical laboratory samples 
required by this protocol must provide evidence of adequate licensure or accreditation 
according to the prevailing regulations in that state and/or country.  Reference values and/or 
normal ranges for the test results must be provided to Pearl Therapeutics.  Pearl Therapeutics 
must be notified promptly in writing of any changes occurring in reference values during the 
course of the study. 
10.5 Confidentiality 
10.5.1 Confidentiality of Data
By signing this protocol, the Investigator affirms to Pearl Therapeutics that information 
furnished to the Investigator by Pearl Therapeutics will be maintained in confidence and such 
information will be divulged to the IRB/IEC, or similar or expert committee; affiliated 
institution; and employees only under an appropriate understanding of confidentiality with 
such board or committee, affiliated institution and employees.  Data generated by this study 
will be considered confidential by the Investigator, except to the extent that it is included in a 
publication. 
10.5.2 Confidentiality of Subject/Patient Records
By signing this protocol, the Investigator agrees that Pearl Therapeutics (or representative), 
IRB/IEC, or Regulatory Agency representatives may consult and/or copy study documents in 
order to verify worksheet/case report form data.  By signing the consent form, the 
subject/patient agrees to this process.  If study documents will be photocopied during the 
process of verifying worksheet/case report form information, the subject/patient will be 
identified by unique code only; full names/initials will be masked prior to transmission to 
Pearl Therapeutics.  In addition, the Investigator agrees to treat all subject data used and 
disclosed in connection with this study in accordance with all applicable laws (i.e., Health 
Insurance Portability and Accountability Act), rules and regulations. 

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10.6 Quality Control and Assurance
Pearl Therapeutics is responsible for implementing and maintaining quality control and 
quality assurance systems with written standard operating procedures (SOPs) to ensure that 
trials are conducted and data are generated, documented, and reported in compliance with the 
protocol, accepted standards of GCP, and all applicable federal, state, and local laws, rules 
and regulations relating to the conduct of the clinical study. 
10.7 Data Management 
Data management procedures and information for this protocol will be provided by Pearl 
Therapeutics or their designee.
10.8 Study Monitoring 
In accordance with applicable regulations, GCP, and Pearl Therapeutics procedures, clinical 
monitors will contact the site prior to subject enrollment to review the protocol and data 
collection procedures with site staff.  In addition, the monitor will periodically contact the 
site, including conducting on-site visits.  The extent, nature, and frequency of on-site visits 
will be based on such considerations as the study objective and/or endpoints, the purpose of 
the study, study design complexity, and enrollment rate. 
During these contacts, the monitor will:
•
Check the progress of the study. 
•
Review study data collected.
•
Conduct source document verification. 
•
Identify any issues and address their resolution. 
This will be done in order to verify that the: 
•
Data are authentic, accurate, and complete.
•
Safety and rights of subjects are being protected.
•
Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements.

The Investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any 
relevant issues.
Upon completion of the study, the monitor will conduct the following activities in 
conjunction with the Investigator or site staff, as appropriate: 

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•
Return of all study data to Pearl Therapeutics.
•
Data queries. 
•
Accountability, reconciliation, and arrangements for unused investigational 
product(s).
•
Review of site study records for completeness.
After the final review of the study files, the files should be secured for the appropriate time 
period as specified in Section 10.9. The Investigator will also permit inspection of the study 
files by Pearl Therapeutics’s Quality Assurance auditors, and authorized representatives of 
the FDA or other applicable regulatory agencies. 
10.9 Retention of Data 
Documents that individually and collectively permit evaluation of the conduct of the study 
and the quality of the data produced must be maintained for review by Pearl Therapeutics' 
quality assurance auditors and by all applicable regulatory authorities.  The period of time 
these documents must be maintained is governed by applicable regulations.  Pearl 
Therapeutics or its designee will inform the Investigator when these documents may be 
destroyed.  Pearl Therapeutics or its designee must be notified in writing at least 6 months 
prior to the intended date of disposal of any study record related to this protocol to allow 
Pearl Therapeutics to make alternate storage arrangements.
10.10 Financial Disclosure 
The principal Investigator or sub-Investigators named on the Form FDA 1572 will need to 
complete a financial disclosure form prior to study initiation, at any time during the study 
execution if new information needs to be disclosed, and for 1 year after study completion.  
Investigators should make the IRB/IEC aware of any financial interests that the Investigator 
has in the investigational product.
10.11 Investigator's Final Report 
Shortly after completion of the Investigator's participation in the study, the Investigator will 
submit a written report to Pearl Therapeutics.
10.12 Publication Policy 
Pearl Therapeutics intends to publish the results of all of the clinical studies that it sponsors 
in compliance with the Declaration of Helsinki (http://www.wma.net/en/10home/index.html).  
Consistent with the recommendations of the editors of several leading medical journals, the 
International Committee of Medical Journal Editors (ICMJE), authorship of publications 
resulting from Pearl Therapeutics-sponsored studies should fairly recognize the activities of 
those that have made a significant contribution to the study.  Thus, it is anticipated that

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authorship will reflect the contribution made by Pearl Therapeutics personnel, the 
Investigators and others involved, such as statisticians. 
In recent years, issues about conflicts of interest and accuracy of the study data have been 
raised in the medical press.  Accordingly, Pearl Therapeutics has developed publication 
guidelines as described below:
1. Responsibility: Each principal Investigator is responsible for the accuracy and 
completeness of all data from their site.  Pearl Therapeutics (or its representatives) is 
responsible for the accuracy of the data entered into the study databases and for the 
accuracy of the analyses conducted.
2. Authorship and Publication Committee: Pearl Therapeutics, in collaboration with the 
Investigators, will establish the appropriate authorship and responsibility for drafting 
study documents in accordance with the principles of the ICMJE.  It is anticipated that a 
publication committee will be formed to assume oversight of these activities.  All 
manuscripts will be reviewed and agreed upon before submission for publication by all 
authors. 
3. Sponsor Review of External Manuscripts: Consistent with the previous bullet point, 
drafts of any and all publications or presentations that may arise from this study must be 
submitted at least 30 days prior to submission for publication or presentation to Pearl 
Therapeutics for review, approval, and to ensure consistency with the policy in this 
protocol.  Pearl Therapeutics will have the right to request appropriate modification to 
correct facts and to represent its opinions, or the opinions of the publication committee, if 
these differ with the proposed publication. 
4. Confidentiality: Investigators will conduct all interactions with Pearl Therapeutics and 
with third parties consistent with the executed confidentiality agreements.  While 
publication, by intention, presents the critical scientific data in a public forum, some 
information (such as future plans, results of nonclinical studies, or chemical formulae) 
may still need to remain confidential.
5. Medical Journal Review: Consistent with the intention of Pearl Therapeutics to publish 
the study in a fair and accurate manner, Pearl Therapeutics supports diligence in the 
publication review process of medical journals.  Accordingly, upon request, all pertinent 
study data and information will be made available as supplemental information for 
journal editors and reviewers to evaluate and audit, eg, protocol and amendments, data 
tabulations, etc. The journal and reviewers will need to make arrangements to maintain 
the confidentiality of such supplemental information, where relevant, and Pearl 
Therapeutics will make suitable arrangements to ensure that the identity of journal 
reviewers is kept confidential.  Records will be maintained of reviewers and the 
respective documents and datasets that were reviewed by each of them.
6. Reporting of Clinical Trials Results:  To provide transparency in the conduct and 
reporting of randomized clinical trials, Pearl reports clinical findings based on the 
guidance of The CONSORT (CONsolidated Standards of Reporting Trials) Statement 
[CONSORT, 2010] and a 25-item checklist which is intended to improve the reporting of 
a randomized controlled trial, and to facilitate reader understanding of the trial design, 

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conduct, analysis and interpretation, and to support their ability to assess the validity of 
its results.
7. Internet Clinical Trial Listing: In addition, also consistent with the recommendations of 
the ICMJE, Pearl Therapeutics will make available appropriate information regarding the 
study via the internet.  This will include registration and listing of the study on 
www.clinicaltrials.gov, the US National Institutes of Health listing of clinical trials, and 
other clinical trial listings as appropriate.  Per Astra Zeneca policy, Pearl Therapeutics 
posts clinical study protocols for public viewing when a manuscript is published in a 
medical journal.  Prior to being made public, the protocol is reviewed by Astra Zeneca 
Intellectual Property.  

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Appendix 1 Spirometry Performance Recommendations 
Spirometry data of the highest quality must be obtained for proper interpretation of the 
results of this protocol.  To these ends, a standard spirometer will be used (provided by Pearl 
Therapeutics), central training provided, qualification will be required, and specific operating 
instruction will also be provided. 
Series “ATS/ERS Task Force: Standardization of Lung Function Testing:  Number 2 in 
Series.  European Respiratory Journal 2005;26(2):319-338. 
FEV1 AND FVC MANEUVERS 
Equipment Requirements
The spirometer must be capable of accumulating volume for >15 s (longer times are 
recommended) and measuring volumes of >8 L (body temperature (i.e., 37°C), ambient 
pressure, saturated with water vapor, BTPS) with an accuracy of at least +3% of reading or 
+0.050 L, whichever is greater, with flows between 0 and 14 L-s-1.  The total resistance to 
airflow at 14.0 L-s-1 must be <1.5 cmH2O L-1s-1 (0.15 kPa L-1s-1).  The total resistance must 
be measured with any tubing, valves, pre-filter, etc. included that may be inserted between 
the subject and the spirometer.  Some devices may exhibit changes in resistance due to water 
vapor condensation, and accuracy requirements must be met under BTPS conditions for up to 
eight successive FVC maneuvers performed in a 10-minute period without inspiration from 
the instrument.
Display
For optimal quality control, both flow–volume and volume–time displays are useful, and test 
operators should visually inspect the performance of each maneuver for quality assurance 
before proceeding with another maneuver.  This inspection requires tracings to meet the 
minimum size and resolution requirements set forth in this standard.  Displays of flow versus 
volume provide more detail for the initial portion (first 1 s) of the FVC maneuver.  Since this 
portion of the maneuver, particularly the peak expiratory flow (PEF), is correlated with the 
pleural pressure during the maneuver, the flow–volume display is useful to assess the 
magnitude of effort during the initial portions of the maneuver.  The ability to overlay a 
series of flow–volume curves registered at the point of maximal inhalation may be helpful in 
evaluating repeatability and detecting sub-maximal efforts.  However, if the point of maximal 
inhalation varies between blows, then the interpretation of these results is difficult because 
the flows at identical measured volumes are being achieved at different absolute lung 
volumes.  In contrast, display of the FVC maneuver as a volume–time graph provides more 
detail for the latter part of the maneuver.  A volume–time tracing of sufficient size also 
allows independent measurement and calculation of parameters from the FVC maneuvers.  In 
a display of multiple trials, the sequencing of the blows should be apparent to the user.  For 
the start of test display, the volume–time display should include >0.25 s, and preferably 1 s, 
before exhalation starts (zero volume).  This time period before there is any change in 
volume is needed to calculate the back extrapolated volume (EV) and to evaluate effort 
during the initial portion of the maneuver.  Time zero, as defined by EV, must be presented 

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as the zero point on the graphical output.  The last 2 s of the maneuver should be displayed to 
indicate a satisfactory end of test.
When a volume–time curve is plotted as hardcopy, the volume scale must be >10 mm L-1
(BTPS). For a screen display, 5 mm L-1 is satisfactory (Table A1-1).   
Table A1-1. Recommended Minimal Scale Factors for Time, Volume and Flow on 
Graphical Output
Parameter
Instrument Display
Hardcopy Graphical 
Output
Resolution Required
Scale Factor
Resolution Required
Volume*
0.050 L
5 mm-L-1
0.050 L
Flow*
0.200 L-s-1
2.5 mm L-1 s-1
0.200 L-s-1
Time
0.2 s
10 mm-s-1
0.2 s
*The correct aspect ratio for flow versus volume display is two units of flow per one unit of volume
The time scale should be >20 mm-s-1, and larger time scales are preferred (>30 mm-s-1) when 
manual measurements are made.  When the volume–time plot is used in conjunction with a 
flow–volume curve (i.e., both display methods are provided for interpretations and no hand 
measurements are performed), the time scale requirement is reduced to 10 mm-s-1 from the 
usually required minimum of 20 mm-s-1 (Table A1-1). The rationale for this exception is that 
the flow–volume curve can provide the means for quality assessment during the initial 
portion of the FVC maneuver.  The volume–time curve can be used to evaluate the latter part 
of the FVC maneuver, making the time scale less critical.
Validation 
It is strongly recommended that spirometry systems should be evaluated using a computer-
driven mechanical syringe or its equivalent, in order to test the range of exhalations that are 
likely to be encountered in the test population.  Testing the performance of equipment is not 
part of the usual laboratory procedures.
Quality Control 
Attention to equipment quality control and calibration is an important part of good laboratory 
practice.  At a minimum, the requirements are as follows: 1) a log of calibration results is 
maintained; 2) the documentation of repairs or other alterations which return the equipment 
to acceptable operation; 3) the dates of computer software and hardware updates or changes; 
and 4) if equipment is changed or relocated (eg, industrial surveys), calibration checks and 
quality-control procedures must be repeated before further testing begins. 
Key aspects of equipment quality control are summarized in Table A1-2.  

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Table A1-2. Summary of Equipment Quality Control
Test
Minimal 
Interval
Action
Volume
Daily
Calibration check with a 3 L syringe
Leak
Daily
2 cm H2O (0.3 kPa) constant pressure for 1 minute
Volume 
Linearity
Quarterly
1 L increments with a calibrating syringe measured over 
the entire volume range
Flow Linearity
Weekly
Test at least three different flow ranges
Time
Quarterly
Mechanical recorder check with stop watch
Software
New versions 
Log installation date and perform test using “known” 
subject
Calibration is the procedure for establishing the relationship between sensor-determined 
values of flow or volume and the actual flow or volume.  A calibration check is different 
from calibration and is the procedure used to validate that the device is within calibration 
limits, eg, +3% of true. If a device fails its calibration check, then a new calibration 
procedure or equipment maintenance is required.  Calibration checks must be undertaken 
daily, or more frequently, if specified by the manufacturer.  The syringe used to check the 
volume calibration of spirometers must have an accuracy of +15 mL or +0.5% of the full 
scale (15 mL for a 3-L syringe), and the manufacturer must provide recommendations 
concerning appropriate intervals between syringe calibration checks.  Users should be aware 
that a syringe with an adjustable or variable stop may be out of calibration if the stop is reset 
or accidentally moved.  Calibration syringes should be periodically (eg, monthly) leak tested 
at more than one volume up to their maximum; this can be done by attempting to empty them 
with the outlet corked.  A dropped or damaged syringe should be considered out of 
calibration until it is checked.
With regard to time, assessing mechanical recorder time scale accuracy with a stopwatch 
must be performed at least quarterly.  An accuracy of within 2% must be achieved. 
Quality Control for Volume-Measuring Devices
The volume accuracy of the spirometer must be checked at least daily, with a single 
discharge of a 3-L calibrated syringe.  Daily calibration checking is highly recommended so 
that the onset of a problem can be determined within 1 day, and also to help define day-to-
day laboratory variability.  More frequent checks may be required in special circumstances, 
such as: 1) during industrial surveys or other studies in which a large number of subject 
maneuvers are carried out, the equipment’s calibration should be checked more frequently 
than daily; and 2) when the ambient temperature is changing (eg, field studies), volume 
accuracy must be checked more frequently than daily and the BTPS correction factor 
appropriately updated.   

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The accuracy of the syringe volume must be considered in determining whether the measured 
volume is within acceptable limits.  For example, if the syringe has an accuracy of 0.5%, a 
reading of +3.5% is appropriate. 
The calibration syringe should be stored and used in such a way as to maintain the same 
temperature and humidity of the testing site. This is best accomplished by keeping the 
syringe in close proximity to the spirometer, but out of direct sunlight and away from heat 
sources.
Volume-type spirometer systems must be evaluated for leaks every day.  The importance of 
undertaking this daily test cannot be overstressed.  Leaks can be detected by applying a 
constant positive pressure of >3.0 cmH2O (0.3 kPa) with the spirometer outlet occluded 
(preferably at or including the mouthpiece).  Any observed volume loss of 30 mL after 1 
minute indicates a leak and needs to be corrected.
At least quarterly, volume spirometers must have their calibration checked over their entire 
volume range using a calibrated syringe or an equivalent volume standard.  The measured 
volume should be within +3.5% of the reading or 65 mL, whichever is greater. This limit 
includes the 0.5% accuracy limit for a 3-L syringe.  The linearity check procedure provided 
by the manufacturer can be used if it is equivalent to one of the following procedures: 1) 
consecutive injections of 1-L volume increments while comparing observed volume with the 
corresponding cumulative measured volume, eg, 0–1,1–2, 2–3,…6–7 and 7–8 L, for an 8-L
spirometer; and 2) injection of a 3-L volume starting at a minimal spirometer volume, then 
repeating this with a 1-L increment in the start position, eg, 0–3, 1–4, 2–5, 3–6, 4–7 and 5–8 
L, for an 8-L spirometer.  The linearity check is considered acceptable if the spirometer 
meets the volume accuracy requirements for all volumes tested.
Quality Control for Flow-Measuring Devices
With regards to volume accuracy, calibration checks must be undertaken at least daily, using 
a 3-L syringe discharged at least three times to give a range of flows varying between 0.5 and 
12 L-s-1 (with 3-L injection times of 6 s and 0.5 s).  The volume at each flow should meet the 
accuracy requirement of +3.5%.  For devices using disposable flow sensors, a new sensor 
from the supply used for patient tests should be tested each day.
For linearity, a volume calibration check should be performed weekly with a 3-L syringe to 
deliver three relatively constant flows at a low flow, then three at a mid-range flow and 
finally three at a high flow.  The volumes achieved at each of these flows should each meet 
the accuracy requirement of +3.5%. 
VC MANEUVERS 
Equipment
For measurements of VC, the spirometer or flow meter must comply with the requirements 
for FVC (as described previously) and be capable of accumulating volume for >30 s.  
Expiratory maneuvers or, ideally, both inspiratory and expiratory maneuvers should be 

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included in the display of VC maneuver.  Regardless of whether the inspiratory or expiratory 
maneuver is used for deriving measurements, a display of the entire recorded VC maneuver 
must be provided.  The maximal expiratory volume must be assessed to determine whether 
the subject has obtained a plateau in the expiratory effort. For display of the slow VC, the 
time scale may be reduced to 5 mm-s-1. 
TECHNICAL CONSIDERATIONS 
Minimal recommendations for spirometry systems
Accurate results require accurate equipment.  Spirometer equipment recommendations apply 
to all spirometers and are minimal requirements. In some circumstances, it may be 
appropriate to exceed these requirements (i.e., in some research/surveillance applications).  
Instrumentation recommendations should be followed to provide accurate spirometric data 
and information that is comparable from laboratory to laboratory and from one time period to 
another.  The accuracy of a spirometry system depends on characteristics of the entire 
system, from the volume or flow transducer and the use of an in-line filter, to the recorder, 
display or processor.  Changes in any aspect of the equipment or errors at any step in the 
process can affect the accuracy of the results. For example, if the BTPS correction factor is 
wrong, an accurately measured FVC will be incorrectly reported.  Spirometers are not 
required to measure all of the indices in Table A1-1, but must meet the recommendations for 
those that are measured. Accuracy and repeatability recommendations apply over the entire 
volume range of the instrument.  
Table A1-3. Range and Accuracy Recommendations Specified for Forced Expiratory 
Maneuvers
Test
Range/Accuracy 
(BTPS)
Flow 
Range 
(L-s-1)
Time 
(s)
Resistance and 
Back Pressure
Test Signal 
VC
0.5–8 L, +3% of reading 
or +0.050 L, whichever is 
greater
0-14 
30
3-L Calibration 
syringe
FVC
0.5–8 L, +3% of reading 
or +0.050 L, whichever is 
greater
0-14 
15
<1.5 cm H2O L-1 s-1 
(0.15 kPa L-1s-1) 
24 ATS 
waveforms, 3-
L Cal Syringe
FEV1
0.5–8 L, +3% of reading 
or +0.050 L, whichever is 
greater
0-14 
1
<1.5 cm H2O L-1 s-1 
(0.15 kPa L-1s-1) 
24 ATS 
waveforms
Time 
Zero
The time point from 
which all FEVt
measurements are taken. 
Back extrapolation
FEVt: forced expiratory volume in t seconds

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BTPS correction
All spirometry values should be reported at BTPS by any method (measuring temperature 
and barometric pressure) proven effective by the manufacturer. For volume-type spirometers, 
the temperature inside the spirometer should be measured for each breathing maneuver.  
Regardless of the BTPS correction technique used, the ambient temperature must always be 
recorded with an accuracy of +1°C.  In situations where the ambient air temperature is 
changing rapidly (>3°C in <30 min), continuous temperature corrections may be necessary.  
Spirometer users should be aware of potential problems with testing performed at lower 
ambient temperatures: 17°C is the lower limit for ambient temperature, unless a manufacturer 
states that their spirometer will operate accurately at lower ambient temperatures.  If 
barometric pressure is not used in calculating the BTPS correction factor, the range of 
barometric pressures over which the BTPS correction factor is valid must be published.  

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Appendix 2 Spirometry Assessment Criteria 
Acceptable Versus Usable Tests
Acceptable Tests must meet the following 7 Criteria:
1. Acceptable start of exhalation with brisk upstroke, no hesitation or false start, and back 
extrapolation volume (EV) < 5% of FVC or 0.150 L, whichever is the greater. (Refer to 
example in Figure A2-1) 
2. No cough during the first second. 
3. No valsalva maneuver.
4. No leak.
5. No obstruction of mouthpiece. 
6. No extra breaths.
7. Plateau achieved, i.e., the volume-time curve shows no change in volume (<0.025 L) for 
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An acceptable test meets all 7 criteria listed.  This is to be considered the “gold standard”.
Useable spirometry tracings are those that only meet criteria 1 and 2.  When this occurs, 
repeat testing up to 8 attempts in an effort to obtain 3 acceptable spirograms.  If only Usable 
tests are obtained, report results based on the 3 best Usable trials with observed limitations. 
Figure A2-1. Example of a Usable Spirogram 
The expanded version of the early part of a subject’s volume-time spirogram, illustrating 
back extrapolation through the steepest part of the curve, where flow is peak expiratory flow 
(PEF), to determine the new “time zero”. Forced vital capacity (FVC)-4.291 L; back 
extrapolated volume (EV) – 0.123 L (2.9% FVC): back extrapolation line through PEF. 

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Between-Maneuver Reproducibility Criteria
After three acceptable spirograms have been obtained, apply the following tests
•
The two largest values of FVC must be within 0.150 L of each other 
•
The two largest values of FEV1 must be within 0.150 L of each other 
If these criteria are met, the spirometry testing for that time-point may conclude.  The highest 
FEV1 and the highest FVC obtained at each testing time-point (even if from different 
reproducible tracings), will be collected. 
If acceptability criteria are not met, continue testing until they are met or the patient cannot/ 
should not continue (Maximum of 8 attempts).  

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Appendix 3 Classification of Severity - GOLD Guidelines (2014)
The GOLD staging system classifies people with COPD based on their degree of airflow 
limitation (obstruction). The airflow limitation is measured during pulmonary function tests 
(PFTs).
Because of lung damage, people with COPD take longer to blow air out.  This impairment is 
called obstruction or airflow limitation.  An FEV1 less than 70% of FVC can make the 
diagnosis of COPD in someone with compatible symptoms and history. 
In GOLD COPD, classifications are then used to describe the severity of the obstruction or 
airflow limitation.
Table A3-1. Classification of Severity of Airflow Limitation in COPD (Based on 
Post-Bronchodilator FEV1)
In patients with FEV1/FVC <0.70
GOLD 1
Mild
FEV1 SUHGLFWHG
GOLD 2
Moderate
50% < FEV1 <80% predicted
GOLD 3
Severe
30% < FEV1 < 50% predicted
GOLD 4
Very Severe
FEV1 <30% predicted

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Appendix 4 Subject Instructions for Use of GFF,GP, FF and Placebo 
MDI 
Before using GFF MDI, GP MDI, FF MDI, and Placebo MDI
1. Take the inhaler out of the foil pouch.  Safely throw away the pouch and the drying 
packet that comes inside the pouch.  Check the indicator at the top of the canister; the 
indicator should read as shown in Figure 2. 
Figure 2. Indicator at Top of Canister
2. Take the cap off the inhaler and inspect the front of the inhaler and make sure there is 
nothing inside the mouthpiece of the inhaler.  Make sure the canister is fully and firmly 
inserted into the actuator. 
3. The inhaler should be stored at room temperature. 
How to prime GFF MDI, GP MDI, FF MDI, and Placebo MDI 
1. The inhaler must be primed before the first use.  Priming involves releasing a certain 
number of sprays (4) into the air before the first use of the inhaler.  Shaking and priming 
the inhaler fills a chamber inside the canister with the correct dose and mix of medication 
so that the inhaler is ready to use.   
2. Take the cap off the mouthpiece of the actuator.
3. To prime the inhaler, gently shake the inhaler for 5-10 seconds and then spray once into 
the air away from yourself and others.   
4. Wait approximately 5-10 seconds and repeat the process three more times.
How to take a dose from GFF MDI, GP MDI, FF MDI, and Placebo MDI 
Steps 3-6 below should be done one after the other. 
1. Take the cap off the mouthpiece of the actuator.
2. Hold the inhaler with the mouthpiece down. 
3. Shake the canister for 5-10 seconds. 
4. Breathe out fully through mouth, expelling as much air from the lungs as possible.  

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5. Tilt head back slightly, place the mouthpiece into mouth, and close lips around it.  To 
allow the medication to enter the lungs, keep tongue flat on the floor of your mouth.  
Keep the mouthpiece at the bottom and the dose indicator at the top. 
6. While breathing in deeply and slowly, press down on the center of the dose indicator with 
finger.  Fully depress the canister until it stops moving in the actuator while delivering 
the dose.  Note: It is normal to hear a soft click from the indicator as it counts down 
during use. 
7. Hold breath as long as possible, up to 10 seconds, and then breathe normally. 
8. Repeat steps 3 to 7, with gentle shaking for 5-10 seconds before the second spray. 
9. Put the cap back on the mouthpiece after every time the inhaler is used, and make sure it 
is firmly seated in place.
How to clean GFF MDI, GP MDI, FF MDI, and Placebo MDI 
It is very important to keep the plastic actuator clean so the medicine does not build-up and 
block the spray.  The inhaler may stop spraying if it is not cleaned correctly.  Do not clean 
the metal canister or let it get wet.
Wash the actuator once a week for the first three weeks as directed below.
1. Take the canister out of the actuator, and take the cap off the mouthpiece.  
2. Wash the actuator through the top of the actuator with warm running water for 
30 seconds (Refer to Figure 3).  
Figure 3. Wash Actuator through Top of Actuator
3. Then wash the actuator again through the mouthpiece (Refer to Figure 4).

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Figure 4. Wash Actuator through Mouthpiece
4. Shake off as much water from the actuator as you can.  Look into the mouthpiece to make 
sure any medicine build-up has been completely washed away.  If there is any visible 
build-up, repeat steps 2 and 3. 
5. Let the actuator air dry completely, such as overnight. 
6. When the actuator is dry, put the canister in the actuator, making sure the canister is fully 
and firmly fitted into the actuator.  Shake the inhaler gently for 5-10 seconds and spray it 
2 times into the air away from your face, shaking gently 5-10 seconds before each spray.  
Put the cap back on the mouthpiece. 
If the actuator becomes blocked
Blockage from medicine build-up is more likely to happen if the actuator is not routinely 
cleaned and the actuator is not air-dried completely.  If the actuator gets blocked so that little 
or no medicine comes out of the mouthpiece, wash the actuator as described in cleaning steps 
1-6. 
If the inhaler is needed before the actuator is completely dry, shake as much water off the 
actuator as possible.  Put the canister in the actuator and make sure it fits firmly.  Shake the 
inhaler gently for 5-10 seconds and spray it 2 times into the air away from your face, shaking 
gently 5-10 seconds before each spray.  Then take the dose as prescribed and described 
above.  Then clean and air-dry it completely.
How to read the inhaler dose indicator
The inhaler is fitted with a dose indicator which shows how much medicine is left during use.  
The dose indicator display will move after every tenth puff.  The dose indicator pointer will 
start to point to the red area when there are 20 puffs remaining.  This means that the inhaler 
needs to be replaced soon.  

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Figure 5. Metered Dose Inhaler Parts

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Appendix 5 Instructions for Use of Atrovent HFA Inhalation Aerosol 
Device 

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Appendix 6 Instructions for Use of Ventolin HFA Inhaler 
The Parts of Your VENTOLIN HFA Inhaler

Glycopyrronium and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc.
Clinical Trial Protocol: PT003014-05
Version 6.0, 
Confidential and Proprietary
Page 150 of 169

Glycopyrronium and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc.
Clinical Trial Protocol: PT003014-05
Version 6.0, 
Confidential and Proprietary
Page 151 of 169

Glycopyrronium and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc.
Clinical Trial Protocol: PT003014-05
Version 6.0, 
Confidential and Proprietary
Page 152 of 169

Glycopyrronium and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc.
Clinical Trial Protocol: PT003014-05
Version 6.0, 
Confidential and Proprietary
Page 153 of 169

Glycopyrronium and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc.
Clinical Trial Protocol: PT003014-05
Version 6.0, 
Confidential and Proprietary
Page 167 of 169
Appendix 10 
Dose Indicator Display Reading Instructions 
For the purposes of this study, when recording the dose indicator display value, review the 
indicator display at the top of the MDI and record the number of inhalations remaining that 
matches the chart below: 
130 Count (Actuation) Version Shown

If your dose 
indicator 
display looks 
like this record 
120+ 

If your dose 
indicator 
display looks 
like this record 
120

If your dose 
indicator 
display looks 
like this record 
110

If your dose 
indicator 
display looks 
like this record 
100

If your dose 
indicator display 
looks like this 
record 90

If your dose 
indicator 
display looks 
like this record 
80

If your dose 
indicator 
display looks 
like this record 
70

If your dose 
indicator 
display looks 
like this record 
60

If your dose 
indicator 
display looks 
like this record 
50

If your dose 
indicator display 
looks like this 
record 40

If your dose 
indicator 
display looks 
like this record 
30

If your dose 
indicator 
display looks 
like this record 
20

If your dose 
indicator 
display looks 
like this record 
10

If your dose 
indicator 
display looks 
like this record 
0 


Glycopyrronium and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc.
Clinical Trial Protocol: PT003014-05
Version 6.0, 
Confidential and Proprietary
Page 169 of 169
Appendix 12 Investigator’s Agreement and Signature Page 
Study Title:
A Randomized, Double-Blind, Chronic Dosing (24 Weeks), 
Placebo-Controlled, Parallel Group, Multi-Center Study to Assess 
the Efficacy and Safety of PT003, PT005, and PT001 in Subjects 
with Moderate to Very Severe COPD, Compared with Placebo
Study Number:
PT003014-05
Final Date:
I agree:
•
To assume responsibility for the proper conduct of the study at this site. 
•
To conduct the study in compliance with the protocol and with any other study conduct procedures 
provided by Pearl Therapeutics.
•
Not to implement any changes to the protocol without agreement from the Sponsor and prior review and 
written approval from the IRB/IEC, except where necessary to eliminate an immediate hazard to the 
subjects, or for administrative aspects of the study (where permitted by all applicable regulatory 
requirements).
•
That I am aware of, and will comply with good clinical practices (GCP) and all applicable regulatory 
requirements.
•
That I am thoroughly familiar with the appropriate use of the investigational product(s), and other 
information provided by the Sponsor including, but not limited to, the following: the protocol and the 
current Investigator’s Brochure (IB).
•
To ensure that all persons assisting me with the study are qualified, adequately informed about the 
investigational product(s) and of their study-related duties and functions.
•
To supply Pearl Therapeutic with any necessary information regarding ownership interest and financial 
ties; to promptly update this information if any relevant changes occur during the course of the study and 
for 1 year following completion of the study; and agree that Pearl Therapeutics may disclose any
information it has about such ownership interests and financial ties to regulatory authorities.
•
I agree to report all information or data in accordance with the protocol and any other study conduct 
procedures provided by Pearl Therapeutics
•
That since the information in this protocol and IB is confidential, I understand that its disclosure to any 
third parties, other than those involved in approval, supervision or conduct of the study is prohibited.
•
To accurately transfer all required data from each subject’s source document to the case report forms 
(CRFs).  The CRFs will be provided to the Sponsor in a timely manner at the completion of the study, or as 
otherwise specified by the Sponsor.
•
To allow authorized representatives of Pearl Therapeutics or regulatory authority representatives to conduct 
on-site visits to review, audit and copy study documents.  I will personally meet with these representatives 
to answer any study-related questions.
Signature: 
 
Date: 
 
Name:   
 
 
 
 
 
 
 
 
 
 
 
 
Affiliation: