Clinical trial NCT02343458
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD
Sponsor: Pearl Therapeutics, Inc.
Start date: 2015-03-30; Completion date: 2017-08-31
Enrollment: 1756 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A chronic dosing (24 weeks) study to assess the efficacy and safety GFF MDI; PT003), FF MDI; PT005, and GP MDI; PT001) in subjects with moderate to very severe COPD, compared with placebo.

Detailed description:
A randomized, double-blind, chronic dosing (24 weeks), placebo-controlled, parallel group, multi-center study to assess the efficacy and safety of glycopyrronium and formoterol fumarate inhalation aerosol (GFF; PT003), formoterol fumarate inhalation aerosol (FF; PT005), and glycopyrronium inhalation aerosol (GP; PT001) in subjects with moderate to very severe COPD, compared with placebo.

Arms: arm 1: Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI; PT003); Glycopyrronium and Formoterol Fumarate Inhalation Aerosol administered as 2 inhalations twice-daily (BID) arm 2: Formoterol Fumarate Metered Dose Inhaler (FF MDI; PT005); Formoterol Fumarate Inhalation Aerosol administered as 2 inhalations twice-daily (BID) arm 3: Glycopyrronium Metered Dose Inhaler (GP MDI; PT001); Glycopyrronium Inhalation Aerosol administered as 2 inhalations twice-daily (BID) arm 4: Placebo (matching) for GFF MDI, FF MDI, and GP MDI administered as 2 inhalations twice-daily (BID)
Interventions: intervention 1: GFF MDI (PT003) intervention 2: FF MDI (PT005) intervention 3: GP MDI (PT001) intervention 4: Placebo MDI
Intervention descriptions: intervention 1: Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI; PT003); Glycopyrronium and Formoterol Fumarate Inhalation Aerosol administered as 2 inhalations twice-daily (BID) intervention 2: Formoterol Fumarate Metered Dose Inhaler (FF MDI; PT005); Formoterol Fumarate Inhalation Aerosol administered as 2 inhalations twice-daily (BID) intervention 3: Glycopyrronium Metered Dose Inhaler (GP MDI; PT001); Glycopyrronium Inhalation Aerosol administered as 2 inhalations twice-daily (BID) intervention 4: Placebo (matching) for GFF MDI, FF MDI, and GP MDI administered as 2 inhalations twice-daily (BID)

Protocol documents:
Prot_000.pdf: 
 
 
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 
 
 
 


Glycopyrronium and Formoterol Fumarate Inhalation Aerosol
Pearl Therapeutics, Inc.
Clinical Trial Protocol:  PT003014-05
Version 6.0, 
Confidential and Proprietary
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 
H[DFHUEDWLRQRUDQLQFUHDVHRIXQLWVRQWKH6*54$VXVWDLQHG&,'LVGHILQHGDV
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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pulmonary disease: a randomized, controlled, 3-month trial. European Respiratory Journal 
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Anderson GP. Formoterol: pharmacology, molecular basis of agonism, and mechanism of 
long duration of a highly potent and selective beta 2-adrenoceptor agonist bronchodilator. 
Life Science. 1993;52(26):2145-2160. 
Atrovent Prescribing Information (US), Boehringer Ingelheim, 2012. 
Calverley P, Lee A, Towse L, et al. Effect of tiotropium bromide on circadian variation in 
airflow limitation in chronic obstructive pulmonary disease. Br Medical J. 2003;58(10):855– 
860.
Calverley P, Anderson J, Celli B, Ferguson G, Jenkins C, Jones P, Yates J, and Vestbo J, 
Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary 
Disease: New England Journal of Medicine 2007;356:775-89. 
Campbell M, Elias A, Johansson G, et al. Formoterol for maintenance and as-needed 
treatment of chronic obstructive pulmonary disease. Respiratory Medicine 2005; 
99:1511-1520. 
Campbell, SC, Crier, GJ, Levine, BE, Simon, SJ, Smith, JS, Orevillo, C. et al. Cardiac safety 
of formoterol 12 μg twice daily in patients with chronic obstructive pulmonary disease. 
Pulmonary Pharmacology and Therapeutics 2007; 20:571-579. 
Casaburi R, Mahler DA, Jones PW, Wannerz A, San Pedro G, ZuWallack RL, Menjoge SS, 
Serby CW, Witek T. A long-term evaluation of once-daily inhaled tiotropium in chronic 
obstructive pulmonary disease. Eur Respir J 2002; 19: 217–224. 
Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S. Improvement in exercise 
tolerance with the combination of tiotropium and pulmonary rehabilitation in subjects with 
COPD. Chest 2005;127:809–817. 
Celli B, MaNee W, Agusti A, et al. Standards for the diagnosis and treatment of subjects with 
COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004; 23:932-946. 
Committee for Medicinal Products for Human Use (CHMP) Assessment Report for Seebri 
Breezhaler, 2012.  Accessed on 17 July 2014.  Available online at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/002430/WC500133771.pdf 
Consolidated Standards of Reporting Trials (CONSORT) Statement 2010.  Accessed on 
17 July 2014.  Available online at: http://www.consort-statement.org/consort-2010 


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COPD Assessment Test (CAT) (http://www.catestonline.org/).
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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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Clinical Trial Protocol: PT003014-05
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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


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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 





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Clinical Trial Protocol: PT003014-05
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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:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
 
Study Code 
PT003014 
Date 
07 March 2017 
NCT#  
NCT02343458 
 
 
 
 
 
 
 
 
 
 
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 
 
 
 
 


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
(Page 1 of 97)
Confidential and Proprietary
STATISTICAL ANALYSIS PLAN FOR STUDY PT003014
Study Number:
PT003014
Investigational Drug and 
Drug Number:
Glycopyrronium and Formoterol Fumarate Inhalation 
Aerosol (GFF MDI); PT003
Glycopyrronium Inhalation Aerosol (GP MDI); PT005
Formoterol Fumarate Inhalation Aerosol (FF MDI);
PT001
Indication:
COPD
Dosage Form/Strength:
GFF MDI 14.4/9.6 ȝJH[-actuator BID
GP MDI 14.4 ȝJH[-actuator BID
FF MDI 9.6 ȝJH[-actuator BID
PT003014 Protocol 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
Date of Issue:
07 Mar 2017
Version:
Final Version






Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
(Page 4 of 97)
Confidential and Proprietary
Change Log
Version No.
Effective Date
Reason for the Change / Revision
Supersedes


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
(Page 5 of 97)
Confidential and Proprietary
TABLE OF CONTENTS
LIST OF TABLES................................................................................................................................................7
LIST OF FIGURES..............................................................................................................................................7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................................................8
1. 
INTRODUCTION .....................................................................................................................................12
2. 
STUDY OBJECTIVES AND ENDPOINTS............................................................................................12
2.1 
STUDY OBJECTIVES............................................................................................................................12
2.1.1
Primary Objective...............................................................................................................12
2.1.2 
Secondary Objectives .........................................................................................................12
2.1.3 
Other Efficacy Objectives ..................................................................................................13
2.1.4 
Safety Objectives................................................................................................................13
2.1.5 
Healthcare Resource Utilization Objective.........................................................................13
2.2 
STUDY ENDPOINTS.......................................................................................................................13
2.2.1
Efficacy Endpoints .............................................................................................................13
2.2.2 
Safety Endpoints.................................................................................................................16
3. 
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS.............................................................16
3.1 
STUDY DESIGN...................................................................................................................................16
3.1.1 
Overall Study Design and Plan...........................................................................................16
3.1.2 
Prior, Concomitant, Post-Treatment, Prohibited Medications, and Other Restrictions ......23
3.2
TREATMENT BLINDING AND RANDOMIZATION ..................................................................................23
3.3 
HYPOTHESIS TESTING ........................................................................................................................23
3.4 
INTERIM ANALYSIS ............................................................................................................................24
3.5 
SAMPLE SIZE......................................................................................................................................24
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE........................................................................25
5. 
ANALYSIS POPULATIONS ...................................................................................................................25
5.1
POPULATION DEFINITIONS .................................................................................................................25
5.1.1 
Intent-to-Treat (ITT) Population.........................................................................................25
5.1.2 
Per Protocol (PP) Population..............................................................................................25
5.1.3 
Symptomatic Population.....................................................................................................26
5.1.4 
Rescue Ventolin User Population.......................................................................................26
5.1.5 
Safety Population................................................................................................................26
5.2
POPULATIONS FOR PRIMARY AND SENSITIVITY ANALYSES................................................................26
5.3 
POPULATIONS FOR SUBJECTS WITH MULTIPLE SUBJECT IDS .............................................................26
5.4 
CHINA AND ASIA POPULATIONS.........................................................................................................27
6. 
STATISTICAL ANALYSIS .....................................................................................................................28
6.1 
GENERAL DATA HANDLING RULES AND DEFINITIONS.......................................................................28
6.1.1 
Data Exclusion and Missing Data Imputation ....................................................................28
6.1.2
Study Dates and Day of Assessment or Event....................................................................30
6.2 
SUBJECT DISPOSITION AND ANALYSIS POPULATIONS ........................................................................30
6.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS AND EXTENT OF EXPOSURE ................................31
6.3.1 
Demography, Physical Characteristics, CAT, and MMRC ................................................31
6.3.2 
COPD History, Screening/Baseline Spirometry, and Reversibility....................................33
6.3.3 
Medical and Surgical History at Screening, Reproductive Status and Pregnancy 
Testing, and COPD-related and non-COPD related Prior Medication for COPD..............35
6.3.4 
Prior, Concomitant, and Post-Treatment Medications/Treatments.....................................35


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
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6.3.5 
Extent of Exposure to Study Medication and Compliance.................................................36
6.4 
EFFICACY ANALYSES.........................................................................................................................36
6.4.1 
Primary Efficacy Analyses .................................................................................................38
6.4.2 
Analysis of Secondary and Other Endpoints Related to Secondary...................................45
6.4.3 
Analysis of Other Endpoints...............................................................................................49
6.4.4 
Control of Type I Error.......................................................................................................56
6.5 
HEALTHCARE RESOURCE UTILIZATION..............................................................................................67
6.6 
SAFETY ANALYSIS .............................................................................................................................68
6.6.1 
Adverse Events...................................................................................................................68
6.6.2 
Clinical Laboratory Measurements.....................................................................................72
6.6.3 
Vital Signs ..........................................................................................................................75
6.6.4 
12-Lead Electrocardiogram Measurements........................................................................77
6.6.5 
Physical Examination .........................................................................................................79
6.7 
SUBGROUP ANALYSES .......................................................................................................................79
6.7.1 
China and Asia ...................................................................................................................83
7. 
ANALYSES PERFORMED BEFORE DATABASE CLOSURE.........................................................83
8. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL ....................................................83
9. 
STATISTICAL SOFTWARE ..................................................................................................................84
10. REFERENCES ..........................................................................................................................................85
APPENDIX 1: DATA HANDLING RULES....................................................................................................87
APPENDIX 2: ANALYSIS DATASET SPECIFICATIONS .........................................................................87
APPENDIX 3: SAS CODE FOR STATISTICAL ANALYSES .....................................................................87
APPENDIX 4: CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES..................................97
APPENDIX 5: STANDARD MEDDRA QUERIES (SMQ)............................................................................97
APPENDIX 6: MOCK-UP TABLES, LISTINGS, AND FIGURES..............................................................97
APPENDIX 7: TABLE OF CONTENTS FOR POST-TEXT TLFS IN THE CHINA POPULATION.....97
APPENDIX 8: TABLE OF CONTENTS FOR POST-TEXT TLFS IN THE ASIA POPULATION.........97


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
(Page 7 of 97)
Confidential and Proprietary
List of Tables
Table 1 
Schedule of Events............................................................................................................ 18 
Table 2 
Timed Assessments During Treatment Period (Visits 4-11) ............................................ 21 
Table 3 
Approach for Handling Data Analysis for Subjects Who Participated More Than 
Once in Study PT003014 at Different Sites or in More than One Pearl 
Efficacy/Safety Study ....................................................................................................... 27 
Table 4 
MMRC Dyspnea Scale ..................................................................................................... 32 
Table 5 
Analysis Study Time Windows for Spirometry Assessments .......................................... 37 
Table 6 
Models Used To Produce Estimates for Pattern Figures (Figures 2.1.4.16 to 2.1.4.30)... 44 
Table 7 
Numeric Scoring for Symptoms Diary Questions ............................................................ 53 
Table 8 
Scaling of Rescue Ventolin Use for Calculation of Symptom Scores.............................. 55 
Table 9 
Adverse Events of Special Interest ................................................................................... 70 
Table 10 
Lab Parameters ................................................................................................................. 72 
Table 11 
Potentially Clinically Significant (PCS) Laboratory Parameter Criteria.......................... 74 
Table 12 
Potentially Clinically Significant (PCS) Criteria for Systolic and Diastolic Blood 
Pressure Parameters.......................................................................................................... 76 
Table 13 
Potentially Clinically Significant Criteria for Heart Rate Parameters .............................. 76 
Table 14 
Analysis Study Time Windows for Vital Signs Assessments........................................... 77 
Table 15 
Analysis Study Time Windows for ECG Assessments .................................................... 78 
Table 16 
Criteria for Potentially Clinically Significant (PCS) ECG Values ................................... 79 
List of Figures
Figure 1 
PT003014 Study Flow Diagram ....................................................................................... 17 
Figure 2 
Type I Error Control for GP MDI (US/China) ................................................................. 57 
Figure 3 
Type I Error Control for FF MDI (US/China).................................................................. 58 
Figure 4 
Type I Error Control for GFF MDI (US/China) ............................................................... 59 
Figure 5 
Type I Error Control for GP MDI (Japan)........................................................................ 61 
Figure 6 
Type I Error Control for FF MDI (Japan)......................................................................... 62 
Figure 7 
Type I Error Control for GFF MDI (Japan)...................................................................... 63 
Figure 8 
Type I Error Control for FF MDI (EU/South Korea/Taiwan) .......................................... 64 
Figure 9 
Type I Error Control for GP MDI (EU/South Korea/Taiwan).......................................... 65
Figure 10 
Type I Error Control for GFF MDI (EU/South Korea/Taiwan) ....................................... 66 


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
(Page 8 of 97)
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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
BDI
Baseline Dyspnea Index
BID
bis in die, twice daily
BMI 
Body mass index
BMP
Basic metabolic panel
BP
Blood pressure
BPM
Beats per minute
BUN
Blood urea nitrogen
CAT
COPD Assessment Test
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMP
Comprehensive metabolic panel
COPD
Chronic obstructive pulmonary disease
CTCAE
Common Terminology Criteria for Adverse Events
DBP
Diastolic blood pressure
dL
Deciliter
DMC
Data monitoring committee
ECG
Electrocardiogram
eCRF
Electronic case report form
eDiary
Electronic diary
e.g.
Exempli gratia, for example 
ER
Emergency room
ERS
European Respiratory Society
EU
European Union
ex-actuator
Dose delivered from the actuator (i.e., mouthpiece) of the MDI
FEV1
Forced expiratory volume in 1 second 
FF MDI
Formoterol fumarate MDI
FVC
Forced vital capacity
GFF MDI
Glycopyrronium and formoterol fumarate MDI
GP MDI
Glycopyrronium MDI
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HCG
Human chorionic gonadotropin
HCRU
Healthcare resource utilization
HLT
High level term
HO
Health Outcome
HR
Heart rate
HFA
Hydrofluoroalkane


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
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i.e.
Id est, that is
ICU
Intensive care unit
ICS
Inhaled corticosteroid
ITT
Intention-to-treat
IWRS
Interactive web response system
L
Liter
LABA
Long-acting beta agonist
LAMA
Long-acting antimuscarinic antagonists
MAR
Missing at random
MCAR
Missing completely at random
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCID
Minimum clinically important difference
MCV
Mean corpuscular volume
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
mmHg
Millimeters of mercury
MMRC
Modified Medical Research Council
MNAR
Missing not at random
ms
Millisecond
NHANES III
Third National Health and Nutrition Examination Survey
NMAR
Not missing at random
OTC 
Over-the-counter
PCS 
Potentially clinically significant
PEFR
Peak expiratory flow rate
PFT
Pulmonary function test
PP
Per Protocol
QD
Quaque die; once a day
QT
Time from electrocardiogram Q wave to the end of the T wave 
corresponding to electrical systole
QTcF
QT corrected using Fridericia’s formula [QT/(RR1/3)]
RM
Repeated measures
RR
Time from electrocardiogram R wave to the next R wave 
corresponding to electrical systole
SABA
Short-acting beta agonist
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SGRQ
St.  George Respiratory Questionnaire
SMQ
Standard MedDRA Query
SOP
Standard operating procedure
STDM
Study Data Tabulation Model
TDI
Transition Dyspnea Index


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
(Page 10 of 97)
Confidential and Proprietary
US
United States


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
(Page 11 of 97)
Confidential and Proprietary
Trademark Information
Trademarks Not Owned By Pearl
Ventolin
Atrovent


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
(Page 12 of 97)
Confidential and Proprietary
1.
INTRODUCTION
Pearl Therapeutics, Inc., a member of the AstraZeneca group of companies (hereafter 
referred to as Pearl) is developing a combination product, Glycopyrronium and Formoterol 
Fumarate Inhalation Aerosol (hereafter referred to as GFF MDI), as a twice daily (BID) 
maintenance bronchodilator treatment in patients with Chronic Obstructive Pulmonary 
disease (COPD).  Pearl 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 BID maintenance bronchodilator treatments in 
patients with COPD.
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary 
and analysis of data to be performed at the end of Study PT003014.
The SAP should be read in conjunction with the study Protocol and the electronic Case 
Report Forms (eCRFs) for this study. This version of the SAP has been developed using the 
PT003014-05 Protocol (Version 6.0, Amendment 5, dated Jan. 20, 2017) and the CRFs 
Revision 04 dated Sept. 4, 2015.
In this study, GFF MDI 14.4/9.6 μg represents a dose of 14.4 μg of glycopyrronium and 
9.6 μg of formoterol fumarate and GP MDI 14.4 μg represents a dose of 14.4 μg of 
glycopyrronium.  FF MDI 9.6 μg represents a dose of 9.6 μg of formoterol fumarate.  
GFF MDI, GP MDI, and FF MDI are administered twice daily (BID).
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1
Study Objectives
The overall objective of Study PT003014 is to assess the efficacy and safety of treatment 
with GFF MDI (14.4/9.6 ȝJH[-actuator, BID), FF MDI (9.6 ȝJH[-actuator, BID), and GP 
MDI (14.4 ȝJH[-actuator, BID) compared with each other and Placebo MDI over 24 weeks 
in subjects with moderate to very severe COPD.
2.1.1
Primary Objective 
The primary objective 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.
2.1.2
Secondary Objectives
x
To compare the effects of GFF MDI, FF MDI, GP MDI, and Placebo MDI on dyspnea 
using the Transition Dyspnea Index (TDI) focal score.
x
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.


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
(Page 13 of 97)
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x
To compare the effects of GFF MDI, FF MDI, GP MDI, and Placebo MDI on symptoms 
using the change in rescue Ventolin HFA use as an indirect measure of COPD symptom 
control.
x
To determine the time to onset of action on Visit 4 (Day 1).
2.1.3
Other Efficacy Objectives
x
To evaluate the effects of GFF MDI, FF MDI, GP MDI, and Placebo MDI on pulmonary 
function test (PFT) parameters.
x
To assess the effects of GFF MDI, FF MDI, GP MDI, and Placebo MDI on COPD 
exacerbations.
x
To evaluate the effect of treatments on nighttime awakenings, daytime and nighttime 
rescue Ventolin HFA use, breathlessness, cough, and sputum production as assessed by 
subjects’ electronic diary (eDiary) entries.
2.1.4
Safety Objectives
x
To assess the safety of GFF MDI, FF MDI, and GP MDI relative to Placebo MDI based 
on adverse events (AEs), vital sign measurements, electrocardiograms (ECGs), and 
clinical laboratory evaluations.
2.1.5
Healthcare Resource Utilization Objective
x
To assess overall and COPD-specific healthcare resource utilization (HCRU) between 
treatment groups.
2.2
STUDY ENDPOINTS
2.2.1
Efficacy Endpoints
2.2.1.1
Primary Efficacy Endpoint
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 is separated 
by approach and detailed in Section 6.4.4.


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
(Page 14 of 97)
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All inferential results will be based on analyses using the Intent-to-Treat (ITT) Population 
unless otherwise noted. In addition to the ITT analysis, symptom 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 5.1).
Primary Endpoint (US/China)
x
The primary endpoint will be the change from baseline in morning pre-dose trough FEV1
at Week 24 of treatment. 
Primary Endpoint (Japan)
x
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
The primary endpoint will be the change from baseline in morning pre-dose trough FEV1
over 24 weeks of treatment.
2.2.1.2
Secondary Efficacy Endpoints
x
TDI score over 24 weeks (US/China and EU/South Korea/Taiwan approaches) and over 
Weeks 12 to 24 (Japan approach)
x
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
x
Change from baseline in morning pre-dose trough FEV1 over 24 weeks (US/China 
approach)
x
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)
x
Change from baseline in SGRQ total score at Week 24 (US/China approach) and over 
Weeks 12 to 24 (Japan and EU/South Korea/Taiwan approaches)
x
Change from baseline in SGRQ total score at Week 24 (US/China approach and over 
Weeks 12 to 24 (EU/South Korea/Taiwan and Japan approaches) in the Symptomatic 
Population
x
Change from baseline in average daily rescue Ventolin (albuterol sulfate) HFA use over 
24 weeks (all approaches) in the Rescue Ventolin User Population
x
Time to onset of action on Day 1 (all approaches)
2.2.1.3
Other Efficacy Endpoints
Day 1 Assessments
x
Change from baseline at each post-dose time point in FEV1, forced vital capacity (FVC), 
and FEV1 AUC0-2


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
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x
Proportion of subjects achieving an improvement from baseline in FEV1 using different 
thresholds (i.e.,   P/ P/DQGDQG mL)
Assessments Over 24 Weeks (Unless Otherwise Stated)
x
Rate of moderate or severe COPD exacerbations
x
Time to the first moderate or severe COPD exacerbation
x
Rate of all COPD exacerbations
x
Time to the first COPD exacerbation of any severity
x
Time to treatment failure
x
Time to first clinically important deterioration (CID)
x
Time to first sustained CID
x
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
x
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
x
Percentage of days with ‘no rescue Ventolin (albuterol sulfate) HFA use’
x
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
x
TDI focal score at each post-randomization visit
x
Individual components of the TDI: functional impairment, magnitude of task, and 
magnitude of effort over 24 weeks, over Weeks 12-24, and at each post-randomization 
visit
x
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 12-24
x
Changes from baseline at each post-randomization visit for SGRQ total score 
x
Change in individual domain scores of SGRQ: Symptoms, Activity, and Impacts over 
Weeks 12-24, and at each post-randomization visit 
x
3HUFHQWDJHRIVXEMHFWVDFKLHYLQJDQ0&,'WKUHVKROGRIXQLWVRQDYHUDJHLQ6*54
total score over Weeks 12-24 and separately at Week 24
2.2.1.4
Healthcare Resource Utilization Endpoints
Healthcare resource utilization (HCRU) endpoints will include the following: the number of 
days missed from work, and COPD-related and non-COPD related telephone calls and visits 
to health care providers, Emergency Room (ER) visits, and hospitalizations including days in 


Statistical Analysis Plan
Protocol Number:  PT003014
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hospital, days in Intensive Care Units (ICUs), days in Coronary Care Units (CCUs), and 
subject intubation events.
2.2.2
Safety Endpoints
The safety endpoints include:
x
AEs
x
12-Lead ECG: change from baseline for heart rate, PR interval, QRS axis, QRS interval, 
QT interval, and QTcF (Fridericia Corrected QT) interval
x
Clinical laboratory testing
x
Vital sign measurements
3.
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS
3.1
Study Design
Study PT003014 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), GP MDI (14.4 μg ex-actuator, BID), and FF MDI (9.6 μg
ex-actuator, BID) compared with Placebo MDI in subjects with moderate to very severe
COPD.
3.1.1
Overall Study Design and Plan
Study PT003014 will be conducted at approximately 180 sites, contributing approximately 10
subjects per site. Across these sites, it is planned that 1614 subjects with moderate to very 
severe COPD will be randomized into the study to provide approximately 1300 subjects to 
complete the study (see Study Flow Diagram Figure 1). 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) (yes or no) 
and by disease severity (moderate vs. severe or very severe) to ensure a distribution of 
subjects in a 7:6:6:3 (GFF MDI:FF MDI:GP MDI:Placebo MDI) ratio within each stratum.
The entire study period is scheduled to take a maximum of 30 weeks for each individual
subject (see Figure 1). The study is anticipated to run for approximately 18 months and
should not exceed 24 months.


Statistical Analysis Plan
Protocol Number:  PT003014
Version:  7 Mar 2017
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Figure 1
PT003014 Study Flow Diagram
Section 4 of the Protocol provides details on study design and plan.  The Schedule of Events 
for the study is shown in Table 1.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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Table 1
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


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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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 (electronic diary) 
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 Protocol 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 Protocol 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 Protocol 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 Protocol Section 7.2.3 for ECG assessments and specific time points to be performed at each treatment visit.
i.
Refer to Protocol 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 Protocol 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.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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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.
p.
Issue and train subjects on eDiary use only after a subject is determined to qualify to proceed to Visit 2.
q.
Refer to Protocol Section 7.1.3 for details of electronic diary review.
r.
Refer to Protocol Section 7.1.6 for details and instructions on recording dose indicator readings.
s.
Refer to Protocol 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 (e.g., 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 Protocol 
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.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 21 of 97)
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Table 2
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 Protocol 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.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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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 dosing.  For 
new MDIs the recorded count will be the count following the priming of the device but before the subject dose.  Refer to Protocol 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 Protocol 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.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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Inclusion criteria for the study are listed in Section 5.1 of Protocol PT003014.  Subjects eligible
for enrollment in the study must meet all of the inclusion criteria.
Exclusion criteria for the study are listed in Section 5.2 of Protocol PT003014.  Subjects meeting 
any of the exclusion criteria are to be excluded from the study.
3.1.2
Prior, Concomitant, Post-Treatment, Prohibited Medications, and Other 
Restrictions
All concomitant medications taken during the study will be recorded on the Concomitant 
Medications eCRF page with indication, dose, dose regimen, and dates of drug administration.  
Medications are considered concomitant if they were reported as being taken at any point from 
the start of randomized study medication to the date of Visit 11, the date of the Discontinuation 
Visit, or the date of the last in-clinic or diary data.  Medications with an onset date of the date of 
Visit 11, the date of a Discontinuation Visit, or the last in-clinic or diary data collection or after 
will not be considered concomitant, but will be considered post-treatment medications.
Prohibited medications are identified in Section 5.4 of Protocol PT003014. Other restrictions are 
identified in Section 5.5 of Protocol PT003014.
3.2
Treatment Blinding and Randomization
The subject, clinical site personnel and Pearl will be unaware of the treatment assigned to a 
subject when the treatment is GFF MDI, GP MDI, FF MDI, or Placebo MDI. If a subject is 
assigned GFF MDI, GP MDI, FF MDI, or Placebo MDI, it will not be possible to differentiate 
between these 4 treatments since they will be identical in all aspects. 
Subjects will be randomly assigned to one of the 4 treatment arms using an interactive web-
response system (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. 
3.3
Hypothesis Testing
For the primary comparisons, the null hypothesis for each pairwise 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:
x
H0: μFF = μplacebo
H1: μFF placebo


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 24 of 97)
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x
H0: μGP = μplacebo
H1: μGP placebo
x
H0: μGFF = μplacebo
H1: μGFF placebo
x
H0: μGFF = μFF
H1: μGFF FF
x
H0: μGFF = μGP
H1: μGFF GP
Secondary and other efficacy analyses will involve the above hypotheses applied to secondary 
efficacy endpoints.
3.4
Interim Analysis
Interim analyses for the purpose of evaluation of efficacy are not planned for this study.  
However, as specified in the Data Monitoring Committee (DMC) Charter for this study, the 
DMC members will be provided pre-specified safety analyses at pre-determined intervals which 
will use semi-blinded treatment codes (A, B, C, and Placebo MDI).  As such, the DMC may 
require the unblinding key if they feel such actions are necessary to evaluate the safety of study 
subjects.
3.5
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’s experience with Phase IIb clinical studies and on published data for within-subject 
variation (D’Urzo, 2001, van Noord , 2005; Maesen, 1995) and between-subject 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 
VWUXFWXUH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 with Type I error controlled at a two-sided alpha 
level of 0.05 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.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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4.
DATA AND ANALYTICAL QUALITY ASSURANCE
The overall quality assurance procedures for the study data, statistical programming and analyses 
are described in Standard Operating Procedures (SOPs) of Everest Clinical Research (hereafter 
referred to as Everest).  Detailed data management procedures are documented in the study Data 
Management Plan, Data Validation Check Specifications, and Integrated Safety Data Review 
Plan. Detailed statistical and programming quality control and quality assurance procedures are 
documented in the Statistical Analysis and Programming QC/QA Plan.
Transfer of PFT data from the central PFT laboratory (iCardiac Technologies, Inc.) to Everest 
will be defined in the iCardiac Technologies DMP (Data Management Plan), and data handling 
rules related to this data are included in Appendix 1 of this SAP. The quality of all PFTs 
obtained at each timepoint will be graded independently at iCardiac Technologies by qualified 
personnel. Quality grading assessments will be based on ATS/ERS criteria and will be included 
in data transfers.
5.
ANALYSIS POPULATIONS
5.1
Population Definitions
5.1.1
Intent-to-Treat (ITT) Population
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 who used 
a study treatment, but took less than one full dose of treatment will qualify for this population.)
5.1.2
Per Protocol (PP) Population
The Per Protocol (PP) Population is a subset of the ITT Population defined as all subjects with 
post-randomization data obtained prior to a major protocol deviation.  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 is identical to analysis by the actual treatment received).  Post-randomization visits 
will be excluded from the Per Protocol set if there is no evidence in the e-diary that the as-
randomized study medication was used the evening prior to the scheduled visit.
Any evaluability criteria with a potential impact on efficacy results will be identified in a blinded 
fashion aided by a review of data listings prior to database lock.  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.  Protocol deviations for exclusion of data from the ITT Population 
will be agreed by the study team and documented prior to database lock.
Reasons for exclusion from the PP Population will documented in the Blinded Data Review 
meeting minutes prior to database lock; these minutes will be included in an appendix to the 
Clinical Study Report.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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5.1.3
Symptomatic Population
The Symptomatic Population is defined as all subjects in the ITT Population with CAT scores 
of 15 at Visit 4.
5.1.4
Rescue Ventolin User Population
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 (RVU) 
Population is defined as all subjects in the ITT Population with average baseline Rescue 
Ventolin use of SXIIGD\
5.1.5
Safety Population
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 that 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.
5.2
Populations for Primary and Sensitivity Analyses
Demographics will be summarized for the ITT, PP, Symptomatic, Rescue Ventolin User and 
Safety Populations and the Non-Randomized analysis set.  The Safety Population will be used to 
summarize safety and healthcare resource utilization.  The Safety and Rescue Ventolin User 
Populations will be used to summarize extent of exposure.  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 symptom 
endpoints.  Rescue medication endpoints will be analyzed with the Rescue Ventolin User 
Population. 
5.3
Populations for Subjects with Multiple Subject IDs
Every effort will be made to prevent subjects from participating at more than 1 site within the 
study or in more than one Pearl study. However, in the event that there are subjects with 
multiple subject identification numbers (IDs) who participated at more than 1 site within the 
study or in more than one Pearl study, the following rules will be used to determine into which 
efficacy and safety population analyses the collected data will be included.
In the event that there are subjects with multiple subject identification numbers (IDs) who 
participated at more than 1 site within Study PT003014, but who did overlap in Investigational 
Product (IP) exposure, these subjects will be included in the All Subjects Randomized 
tabulations and listings only.  The safety of these subjects will be summarized separately in a 
narrative in the Clinical Study Report and identified in the CSR as not reported in the analysis 
output.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 27 of 97)
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In the event that there are subjects with multiple IDs who participated at more than 1 site within 
Study PT003014, but who did not overlap in treatment exposure; these subjects will be included 
in the ITT, Safety, RVU, and PP Populations for the treatment received at the first site/exposure 
and only in the Safety Population for the treatment received at the second site/exposure. The 
subjects’ data from the second or higher exposure(s) will be excluded from the ITT, RVU, and 
PP Populations as intra-subject correlation (i.e., subject in the same study more than once) would 
not be modeled correctly in statistical analyses.
For subjects who did not have overlap in IP exposure and participated in more than one Pearl 
efficacy/study, the subjects’ data will be included in the ITT, PP, RVU, and Safety Populations 
for the first exposure.  For the second and higher exposure(s), the subjects’ data will be included 
in the ITT, RVU, and Safety Populations and excluded from the PP Population.
Table 3 summarizes the approach for handling data analysis for these subjects by Pearl.
Table 3
Approach for Handling Data Analysis for Subjects Who Participated More Than 
Once in Study PT003014 at Different Sites or in More than One Pearl 
Efficacy/Safety Study
Subject Type 
Analysis Population Inclusion for Subject Data 
First Study Exposure 
Second or Higher Study Exposure 
Overlap in IP Exposure 
Exclude data from ITT, PP, 
Symptomatic, RVU, and Safety 
Populations 
Exclude data from ITT, PP, 
Symptomatic, RVU, and Safety 
Populations 
No overlap in IP exposure 
but participated in Study 
PT003014 more than once 
Include data in ITT, PP, 
Symptomatic, RVU, and Safety 
Populations 
Include data in Safety Population 
and exclude data from ITT, PP, 
Symptomatic, and RVU Populations 
No overlap in IP exposure 
but participated in more than 
one Pearl efficacy/safety 
study  
Include data in ITT, PP, 
Symptomatic, RVU, and Safety 
Populations 
Include data in ITT, Symptomatic, 
RVU, and Safety Populations and 
exclude data from PP Population 
Abbreviations:  IP=Investigational Product; ITT=Intent-to-Treat, PP=Per Protocol, RVU=Rescue Ventolin User
5.4
China and Asia Populations
The China Population is defined as all subjects enrolled in sites in China.
The Asia Population is defined as all subjects enrolled in sites located in Japan, China, South 
Korea, and Taiwan.
Corresponding ITT, PP, Symptomatic, RVU and Safety analysis populations, as well as other 
relevant analysis sets, for the China and Asia Populations are defined as described in Section 5.1
and restricted to the China/Asia Populations. China/Asia-specific primary and sensitivity 


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analysis populations are defined as described in Section 5.2, specifically for the US/China 
approach, and restricted to the China/Asia Populations.
6.
STATISTICAL ANALYSIS
All data collected on eCRFs and contributing to the analysis will be provided in listings, except 
for data collected only for confirmation of study entry criteria and for study management 
purposes. Data for all subjects who are randomized will be included in the subject data listings. 
Data for non-randomized subjects will be listed where available.
All safety and efficacy parameters will be summarized by treatment (unless specified otherwise).  
Summary statistics for safety will be provided for the Safety Population.
Continuous variables will be summarized with descriptive statistics (the number of non-missing 
values, mean, standard deviation, median, minimum, and maximum).  Additionally, the 25th and 
75th percentiles will be presented when appropriate based on historical knowledge of the 
distribution of underlying data.
Categorical variables will be summarized with frequency counts and percentages (where 
appropriate).
6.1
General Data Handling Rules and Definitions
6.1.1
Data Exclusion and Missing Data Imputation
The exclusion of data from the PP Population has been discussed in Section 5.1. Unless 
excluded as specified in Section 5.1, all lung function assessments analyzed that have at least one 
effort that meets ATS/ERS criteria for acceptability will be considered acceptable and contribute 
to the post-dose assessments for a population. If the PFT assessments at a specific timepoint 
were deemed to be unacceptable quality, i.e., none of the efforts met ATS/ERS criteria for 
acceptability, the PFT assessments obtained at the timepoint will not be included in any efficacy 
analysis and will be considered missing (Miller et al., 2005). Thus, all observed data will be 
included in the ITT Population analysis, with the exception of data at a timepoint which had 
unacceptable quality based on ATS/ERS criteria.
Change from baseline in morning pre-dose trough FEV1 and other lung function measures at 
each visit is defined as the average of all available pre-dose values minus baseline.  In subjects 
with only one pre-dose assessment, the value will be calculated from the single measurement.  In 
subjects with no pre-dose values, the pre-dose trough FEV1 value at that visit will not be 
calculated and will be considered missing with two exceptions:  non-missing pre-dose data from 
an unscheduled visit will be mapped to a scheduled visit, if a dose is taken at that scheduled visit; 
and if there is no clinic dose at the scheduled visit or the scheduled visit is not done, unscheduled 
data on a single day will be mapped to the scheduled visit with the pre-dose trough FEV1 
calculated as the average of all data for that day.


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For the ITT Population, the determination of peak change from baseline in FEV1 requires at least 
one non-missing FEV1 value during the first 2 hours post-dose.
All observed data will be used with the trapezoidal rule to calculate AUC0-2 for a spirometry 
parameter using change from baseline values.  For the purpose of AUC calculations, the value of 
the spirometry parameter at time 0 will be the change from baseline in morning pre-dose trough 
at the visit.  To aid in interpretation, all AUC values will be normalized by dividing the AUC by 
the time from the first to the last non-missing value (typically 2 hours).  If AUC is based on just 
one 1 assessment, that value will be the value of the AUC (the trapezoidal rule and normalization 
will not apply as the area is 0 and the time interval is 0).
For the final analysis, the primary efficacy endpoint data will be examined to determine if the 
nature and magnitude of the missing data leads to concerns about potential biases in the 
evaluation of treatment effects.  It is expected that the amount of missing data will be sufficient 
enough to warrant a sensitivity analysis (with missing data imputation) to determine the 
robustness of the primary endpoint analysis (National Research Council of National Academy of 
Sciences, 2010).  A discussion of the impact of missing data will be included in the clinical study 
reports.
The imputation approach used for assessing the robustness of the primary endpoints is described 
in Section 6.4.1.
For the TDI, at each visit, if a response to any of the three questions is missing, then the focal 
score will also be considered missing. For the TDI responder analyses, subjects without post-
baseline data will be considered to be non-responders for the analysis.
For the SGRQ, scoring and handling of missing items will be conducted in accordance with the 
user’s guide for the SGRQ.  For the SGRQ responder analyses, subjects without post-baseline 
data will be considered to be non-responders for the analysis.
For rescue Ventolin HFA use, for every period of time for which the mean number of puffs of 
rescue Ventolin HFA 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.
Missing data will be maintained as missing in the analysis datasets, unless specified otherwise.  
For variables where missing data are imputed, another analysis dataset will contain a variable 
with the imputed value.  Thus, the original variable value will be maintained as missing in one of 
the analysis datasets.
Data Imputation for Adverse Events Summaries by Severity and Relationship to Study Drug
For the AE summaries by severity, an AE with missing severity will be deemed as severe.  For 
the AE summaries by relationship to study drug, an AE with a missing relationship to study drug 
will be deemed as definitely related.  Imputed values will not be listed in data listings.


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Data Imputation for Laboratory, Vital Sign, and ECG Summaries (Continuous Parameters)
Data from unscheduled visits will not be used for this analysis, unless a prior or subsequent visit 
is missing where a value was scheduled to be collected.  That is, data obtained during 
unscheduled visits will be allocated to the scheduled visit prior to the unscheduled visit if it was 
missed or to the next missing scheduled visit (not more than 4 weeks subsequent) if the previous 
scheduled visit was not missing.
Data Imputation (All Laboratory Summaries)
Laboratory values of ‘>=x’ or ‘<=x’ will be taken as the value of x in the analyses.  If a 
laboratory value is prefixed with‘>’: the available original value +0.001 will be used for table 
summaries; if a laboratory value is prefixed with ‘<’, then the original value –0.001 will be used 
in table summaries.
6.1.2
Study Dates and Day of Assessment or Event
Study Day and Day of Assessment or Event definitions are provided in Appendix 1, Data 
Handling Rules.
6.2
Subject Disposition and Analysis Populations
A disposition table for all subjects randomized will be provided (Table 1.1.1 and Listing 1.2).  
This tabulation will include the number of subjects in each randomized treatment who were not 
treated, who received the study treatment, who were withdrawn prematurely, and who completed 
Week 12, Week 24, and the Follow-up Telephone Call of the study.  The number and percentage 
of randomized subjects who were included in the ITT, PP, Symptomatic, Rescue Ventolin User, 
and Safety Populations will also be tabulated (Table 1.1.1).
The number of subjects randomized will be provided by treatment for each country and regional 
subgroup (Table 1.1.2).  The numbers of subjects randomized and in the analysis populations 
will be provided for each country/regional subgroup and treatment overall and also by country, 
center, and treatment in Table 1.1.3.  If there are any subjects who took study treatment other 
than what was randomized during the study, both the treatment assigned at randomization and 
actual treatment(s) received during the Treatment Period will be listed (Listing 1.3).  The 
duration of actual treatment will be listed (Listing 1.3).
Note that the date of Discontinuation (withdrawal) shown in Listing 1.2 is designed to be useful 
in narrative writing and is different than the definition of the end of the treatment period.  For 
this listing, the date of withdrawal for discontinued subjects is defined as the later of the last visit 
date, the date of the last dose of study medication, or the date of last contact for subjects lost-to-
follow-up; the date of death will be listed separately for this listing.
A summary table (Table 1.1.4) and a listing (Listing 1.4) of reasons subjects were not 
randomized will be provided for the Non-Randomized analysis set.  Reasons for early 
discontinuation will be summarized for all subjects randomized (Table 1.2.1). The number and 


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percentage of subjects withdrawn for each reason for early discontinuation will be tabulated by 
randomized treatment for the ITT, Rescue Ventolin User, and PP Populations (Table 1.2.2
overall and by CAT Score Subpopulation, including Symptomatic Population [CAT Score 
@DQd Table 1.2.3); and by treatment actually received for the Safety Population 
(Table 1.2.4).
The reason for exclusion from the PP Population will be tabulated by study treatment for all ITT 
subjects (Table 1.3).  The reason for exclusion from the PP Population of a subject or of partial 
data for a subject will be listed for all randomized subjects, in addition to any subjects excluded 
from the ITT, Symptomatic, Rescue Ventolin User, and Safety Populations (Table 1.1.5).  A 
listing of subjects who did not comply with restrictions on smoking, use of rescue Ventolin, and 
xanthine (and/or xanthine analogue)-containing products (protocol deviations requiring removal 
of data from the PP Population analysis) just prior to spirometry will be provided in 
Listing 6.1.1.  Use of rescue Ventolin at pre-dose or during the post-dose assessments on each 
specific test day (yes/no), will be provided in Listing 6.1.3.  In addition, the eligibility 
information (inclusion/exclusion criteria with any waivers granted) of all subjects who are 
randomized will be listed (Listing 2.1).
The number and percentage of subjects with changes in smoking status after the start of study 
treatment will be tabulated by randomized treatment and across all treatments, by visit during the 
study, in Table 1.13 (Listing 1.5).
6.3
Demographic and Baseline Characteristics and Extent of Exposure
The definitions for the derived demographic or characteristic variables can be found in 
Appendix 1.
6.3.1
Demography, Physical Characteristics, CAT, and MMRC
Subject demographics and smoking status/history will be summarized for the ITT, PP, Rescue 
Ventolin User, and Safety Populations and for the Non-Randomized analysis set (Tables 1.4.1 
through 1.4.5, respectively, and Listing 1.2). A summary of subject demographics and smoking 
status/history by CAT Score Subpopulation will also be provided for the ITT Population, 
LQFOXGLQJWKH&$76FRUH6XESRSXODWLRQRI(i.e., Symptomatic Population)(Table 1.4.1).
Inhaled corticosteroid use (yes/no) will be summarized for all populations except for the Non-
Randomized analysis set. The Pearl Medical Monitoring team will identify which medications 
captured on the eCRF are ICS medications.
The COPD Assessment Test (CAT) is a short self-administered questionnaire designed to assess 
the condition of subjects and overall impact of COPD.  The CAT will be done at Screening 
Visit 2.  It will be utilized to describe the burden and symptomatic impact of COPD in the study
populations.
The MMRC scale is a five-point scale that considers certain activities, such as walking or 
climbing stairs, which provoke breathlessness (Fletcher 1959).  At Screening Visit 2, in one 
minute, the subject selects a grade on the MMRC scale that most closely matches his/her severity 


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of dyspnea.  The MMRC scale is considered a discriminative instrument that can categorize 
subjects with COPD in terms of their disability.  The MMRC grade will be used to describe the 
symptomatic burden in the study populations.  The MMRC Scale uses a simple grading system 
to assess a subject's level of dyspnea, shortness of breath, as follows:
Table 4
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.
Demographic and baseline characteristic variables summarized will include the following:
x
Age
x
Gender
x
Race
x
Ethnicity
x
BMI
x
Weight
x
Height
x
Smoking status (current vs. former smoker)
x
Used inhaled corticosteroids at Baseline (all populations except for the Non-Randomized 
analysis set)
x
Number of years smoked
x
Average number of cigarettes smoked per day
x
Number of pack years smoked, calculated as (number of cigarettes per day/20) x number of 
years smoked
x
&23'$VVHVVPHQW7HVW&$7WRWDOVFRUHDQGWRWDOVFRUHFDWHJRU\

x
Modified Medical Research Council (MMRC) Scale grade.
Screening CAT data will be listed (Listing 4.2). The categories of the CAT total score (<10,
DQGZLOOEHVXPPDUL]HG(Tables 1.4.1 through 1.4.5 for the ITT, PP, 
Rescue Ventolin User, and Safety Populations and for Non-Randomized analysis set,
respectively); this summary will also be provided by CAT Score Subpopulation for the ITT 


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Population (Table 1.4.1). The MMRC grade will also be summarized similarly (Tables 1.4.1 
through 1.4.5 and Listing 4.3).
6.3.2
COPD History, Screening/Baseline Spirometry, and Reversibility
The number of years prior to the start of study medication that COPD was first diagnosed 
calculated as (Date of First Dose of Study treatment in the study – Date COPD First Diagnosed) 
/365.25 will be summarized for the ITT, PP, Rescue Ventolin User, and Safety Populations by 
treatment and listed (Tables 1.5.1 through 1.5.4 and Listing 4.1). Severity of COPD (GOLD 
2014 grade) and GOLD 2017 categories (A, B, C, and D) at Screening Visit 2 post-Ventolin 
(albuterol sulfate) HFA will also be included in these summaries.  These summaries will also be 
provided by CAT Score Subpopulation for the ITT Population, including for the CAT Score 
6XESRSXODWLRQRIi.e., Symptomatic Population) (Table 1.5.1).  History of moderate or 
severe COPD exacerbation in the prior year will be summarized for the ITT Population and 
listed (Table 1.9.3 and Listing 4.4).
Descriptive statistics will be provided for Screening Period pre-bronchodilator and 
post-bronchodilator and baseline spirometry parameters (Tables 1.6.1 and 1.6.3 for the ITT, PP, 
and Rescue Ventolin User Populations, respectively, and Listing 2.2); descriptive statistics will 
also be provided by CAT Score Subpopulation for the ITT Population, including for the CAT 
6FRUH6XESRSXODWLRQRI15 (i.e., Symptomatic Population) (Table 1.6.1).
Characterization of Reversibility:
Reversibility to Ventolin (albuterol sulfate) HFA (SABA) will be evaluated at Visit 2.
Reversibility to Atrovent (ipratropium bromide) HFA (short-acting anticholinergic) will be 
evaluated at Visit 3.  The procedure will be as follows:
Reversibility testing to Ventolin (albuterol sulfate) HFA (Visit 2 Only):
x
Perform pre-bronchodilator PFTs (-60 min and -30 min) prior to administration of 
Ventolin (albuterol sulfate) HFA.
x
Administer 4 puffs of Ventolin (albuterol sulfate) HFA.
x
Perform post-bronchodilator PFT 30 min after the administration of Ventolin (albuterol 
sulfate) HFA.
Reversibility testing to Atrovent (ipratropium bromide) HFA (Visit 3 Only):
x
Perform pre-bronchodilator PFTs (-60 min and -30 min) prior to administration of 
Atrovent (ipratropium bromide) HFA.
x
Administer 4 puffs of Atrovent (ipratropium bromide) HFA.
x
Perform post-bronchodilator PFT 30 minutes after the administration of Atrovent 
(ipratropium bromide) HFA.


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Reversibility will be a comparison of the average of all best FEV1 efforts 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 if the improvement 
in FEV1 approximately 30 minutes following administration of 4 puffs of Ventolin (albuterol 
VXOIDWH+)$LVDQG mL.  A subject is determined to be reversible to Atrovent 
(ipratropium bromide) HFA if the improvement in FEV1 approximately 30 minutes following 
DGPLQLVWUDWLRQRISXIIVRI$WURYHQWLSUDWURSLXPEURPLGH+)$LVDQG mL.  
However, if the subject fails the reversibility criteria at 30 minutes post-dose, any other available 
post-dose timepoint will be used instead to determine if reversibility was achieved.
Bronchodilator reversibility to Ventolin (albuterol sulfate) HFA at Screening Visit 2 and 
reversibility to Atrovent (ipratropium bromide) HFA at Screening Visit 3 will be summarized for 
the ITT, PP, and Rescue Ventolin User Populations (Tables 1.7.1 through 1.7.3 for Ventolin HFA 
reversibility, respectively, and Tables 1.8.1 through 1.8.3 for Atrovent HFA reversibility,
respectively; a summary will also be provided by CAT Score Subpopulation, including CAT 
6FRUH [i.e., Symptomatic Population][Tables 1.7.1 and 1.8.1]; Listing 2.2 for Ventolin HFA 
and Atrovent reversibility and Listing 5.1.2 for Ventolin HFA and Atrovent HFA dispensing).
Also, the following will be summarized: 
1. The percentage of reversible subjects
2. The change in FEV1 from pre-dose FEV1 to post-bronchodilator assessment
3. Percent reversibility, defined as 100 x (the change from pre-Ventolin HFA to post for 
FEV1)/pre-Ventolin HFA FEV1.
When multiple timepoints are available post-bronchodilator, the last assessment will be used.  
For Tables 1.7.1 through 1.7.3, if a subject is missing a Post-Ventolin or Pre-Ventolin FEV1
value at Screening Visit 2, these values will be replaced by the Pre-Atrovent and Post-Atrovent 
values from Screening Visit 3.  The percentage of subjects reversible to Ventolin HFA only, 
Atrovent HFA only, and to both Ventolin HFA and Atrovent HFA will be provided (Table 1.8.4, 
ITT Population).
Additionally, the percentage of subjects meeting each of the following response criteria will be 
summarized for both Ventolin (albuterol sulfate) HFA and Atrovent (ipratropium bromide) HFA 
bronchodilators:
x
LPSURYHPHQWSRVW-bronchodilator in FEV1 from pre-bronchodilator
x
 mL improvement post-bronchodilator in FEV1 from pre-bronchodilator
x
 mL improvement post-bronchodilator in FEV1 from pre-bronchodilator


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6.3.3
Medical and Surgical History at Screening, Reproductive Status and Pregnancy 
Testing, and COPD-related and non-COPD related Prior Medication for COPD
Medical and Surgical History at Screening will be summarized for the Safety Population and 
listed for all randomized subjects (Table 1.9.1 and Listing 4.5.1).  Cardiovascular risk factors of 
interest at Screening which are explicitly captured on the eCRF will be summarized for the 
Safety Population and listed for all randomized subjects (Table 1.9.2 and Listing 4.5.2).
Screening Reproductive Status and Pregnancy Testing Results will be listed (Listing 4.6).
6.3.4
Prior, Concomitant, and Post-Treatment Medications/Treatments
All prescription and over-the-counter (OTC) medications taken by the subject during 30 days 
before Screening will be recorded on the Concomitant Medications eCRF page.  All concomitant 
medication/treatment taken by the subject while on study will be recorded in the eCRF.
Coding: Everest will be responsible for coding medication/treatment verbatim terms, using the 
latest version of the World Health Organization Drug Dictionary Enhanced and the Herbal 
Dictionary (WHO-DDE + WHO-HD, version 1Q2015 or later).  Corresponding preferred terms 
(preferred base names) will be assigned to the medication/treatment verbatim terms along with 
appropriate ATC (Anatomic Therapeutic Chemical) drug classifications.
Multiple ATC assignments: If there are multiple ATC codes assigned to the same 
prior/concomitant medication, the “primary” one based on a Pearl medical evaluation will be 
used.
Prior medication/treatment is any medication/treatment taken prior to study treatment, even if 
this medication continued to be taken on the day of the start of study treatment in the study or 
afterward (Appendix 1).
Concomitant medication/treatment is any medication/treatment reported as being taken at any 
point from the date of randomization (Visit 4) to the date of Visit 11, the date of a 
Discontinuation Visit or the last contact date (the date of the last in-clinic or diary data collection 
or after).  A medication with an onset date of the date of Visit 11, the date of a Discontinuation 
Visit or the last contact date will not be considered concomitant, but will be considered a 
Post-Treatment medication/treatment.
As a consequence of the definition of a concomitant medication, the rate of use of prohibited 
COPD medications may appear higher in the summary table of COPD concomitant medications, 
(Table 1.11.1).  This rate of prohibited medication use may appear higher since it will include 
subjects who used the prohibited medication after stopping study treatment but before the 
subjects had a discontinuation visit that would classify the medication as post-treatment. 
Any medication/treatment which cannot be identified as Prior, Concomitant, or Post-Treatment 
will be considered as being in each of the categories that are possible from the available 
information.


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Concomitant COPD and Non-COPD medications/treatments will be summarized by preferred 
term and actual treatment received for the Safety Population (Tables 1.11.1 and 1.11.2, 
respectively).  Prior, concomitant/post-treatment COPD and Non-COPD medications will be 
displayed in separate listings (Listings 4.7 and 4.8, respectively).
Reported Prior Medication for COPD and non-COPD-Related Medications will be tabulated 
(Tables 1.10.1 and 1.10.2, respectively) and listed separately (Listings 4.7 and 4.8, respectively).
6.3.5
Extent of Exposure to Study Medication and Compliance
Subject’s exposure to a study treatment will be determined by the duration of time (days) for 
which the doses were administered, defined as “((End date of treatment – Date of first dose of 
treatment) + 1)”.
Percent compliance is defined as (total number of puffs of study treatment taken on a study 
day/total puffs expected to be taken on a study day) averaged across all days of a subject’s 
dosing between start of study treatment and last day on study treatment) x 100.  The expected 
number of puffs for a test day which is the last date of treatment will be 2, the expected number 
of puffs for the last date of treatment which is not a test day will be 4 when a PM dose is taken 
and then 2 otherwise; the expected number of puffs on dates prior to the last date of treatment 
will be 4.
The number of days of exposure to study treatment and the number of puffs of study medication 
will be summarized for each treatment for the Safety Populations (Table 1.12). The total person-
years of exposure for a treatment group, defined as the total exposure in the study across all 
subjects in the treatment, will also be provided by treatment (Table 1.12). These Safety 
Population tabulations will be done by actual treatment received most often in the study, as 
specified in Section 5.1.5.
In addition, a summary of treatment compliance will be provided. The treatment compliance 
will be categorized into 7 different groups depending on the degree of compliance: 0 – <20%, 
20 – <40%, 40 – <60%, 60 – <80%, 80 – 100%, >100 – 120%, and >120% (Table 1.12). Also 
provided in this summary will be descriptive statistics (n, mean, standard deviation, median, 
minimum and maximum) for percent compliance by treatment. Treatment compliance will be 
reported in Listing 5.2. A listing of treatment dosing information will be provided in 
Listing 5.1.1. Any comments related to study medication or any other additional study 
comments will be listed (Listing 9.4).
6.4
Efficacy Analyses
Lung function measurements and symptom-based endpoints will be evaluated.
There are 6 possible pairwise comparisons of treatments. Five of the 6 comparisons are 
considered important as outlined in Section 6.4.4 Control of Type I Error. While all 6 
comparisons will be presented for each efficacy endpoint, only the 5 key comparisons will be 


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performed for the purpose of testing superiority. Summary statistics will be provided by 
randomized treatment and for each treatment difference for all possible comparisons.
Baselines for Analysis:
The mean of all available evaluable 60- and 30-minute pre-dose spirometry assessments 
conducted at Day 1 (Visit 4) will be used to establish baseline for all FEV1 and FVC parameters.
For the diary symptom score parameters and rescue Ventolin HFA usage, baseline will be the 
average of the non-missing values from the e-diary data collected in the last seven days of the 
Screening Period.
For the SGRQ scores, baseline will be the value of the score calculated using the Day 1 
questionnaire data collected prior to the start of study treatment.
The BDI assessment will be the baseline for the TDI analyses.
Visits and Time Windows for Spirometry Assessments
Efficacy data obtained during unscheduled visits will not be used in analyses but will be listed.
For efficacy analysis or derivation of AUC based on timepoints, the change from baseline in 
FEV1 assessments will be allocated to derived nominal collection time windows using the time 
intervals specified for each below.
Table 5
Analysis Study Time Windows for Spirometry Assessments
Calculated
Study Time Window
Time Interval for the Study Time 
Window
Pre-dose 60 min
PLQSULRUWRGRVH
Pre-dose 30 min
WRPLQSULRUWRGRVH
Post-dose 5 min
>0 to 9 min Post-dose
Post-dose 15 min
10 to 22 min Post-dose
Post-dose 30 min
23 to 44 min Post-dose
Post-dose 1 hr
45 to 89 min Post-dose
Post-dose 2 hrs
90 min Post-dose or more
Note: The time of the study drug dose will be available to the minute. The 
time of the spirometry assessment, will be available to the second, and will 
be truncated downward to whole minutes prior to calculation of the study 
time window.  Any assessments for which the time interval is 0 due to 
truncation but are marked as post-dose nominally, will be assigned to the 5 
min post dose time window. 


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If there are multiple spirometry values for the same parameter within the same post-dose study 
time window on the same day, the last value will be chosen for analysis with one exception: if 
multiples with the exact same time (in minutes and seconds) occur within a window, then the last 
value based on the nominal time window will be chosen for analysis.  Queries to the site (prior to 
database lock and unblinding) will be used to ascertain which assessment actually occurred first.
6.4.1
Primary Efficacy Analyses 
Analyses for the primary endpoints for each approach are presented in this section along with 
analyses for any of the secondary or other efficacy endpoints related to the primary endpoints. 
6.4.1.1
Change From Baseline in Morning Pre-dose Trough FEV1
The change from baseline in morning pre-dose trough FEV1 will be analyzed using a repeated 
measures (RM) linear model.  Data from all study treatments will be included in the modeling.
The linear RM 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 all available evaluable 60- and 30-
minute 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 used to model correlation between time points 
from the same subject.  Contrasts will be used to obtain estimates of the treatment differences at 
Week 24, over Weeks 12-24, and over 24 weeks. The over 24 weeks treatment difference is a 
model-based estimate of the average treatment effect using all scheduled visits. The over 12-24
weeks treatment difference is a model-based estimate of the average treatment effect using all 
scheduled visits within the 12-24 week interval. The analysis of the average over the entire 24 
weeks is a secondary endpoint for the US/China approach and a primary endpoint for the 
EU/South Korea/Taiwan approach. The analysis of the average over Weeks 12-24 is a primary 
endpoint for the Japan approach. Two-sided p-values and point estimates with two-sided 95% 
confidence intervals will be produced for each treatment difference. The primary analysis will 
be conducted using the ITT Population. All non-missing data will be used.
Additional supportive analyses of morning pre-dose trough FEV1 will include the change from 
baseline at Week 24, over Weeks 12-24, and over the entire 24-week treatment period in the PP 
Population and treatment differences at individual timepoints estimated by the RM model.
The least squares (LS) mean and the standard error of this mean with the corresponding 
two-sided 95% confidence interval will be provided for each treatment based on the models.  The 
LS mean difference for all of the possible pairwise treatment comparisons, as well as the 
corresponding two-sided 95% confidence interval will be provided based on the models.  The LS 
means presented for the population will be estimated assuming arithmetic mean levels of 
baseline FEV1 and reversibility to Ventolin (albuterol sulfate) HFA.  In addition, descriptive 
statistics for unadjusted change from baseline in morning pre-dose trough FEV1 will be 
presented for each treatment by scheduled week of assessment.  Summary statistics and the 
results of statistical testing for this analysis will be provided in Table 2.1.1 with the LS Mean 


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change from baseline plotted by treatment and study week, along with the LS Mean estimates at 
Week 24 and over 24 weeks for each treatment (Figure 2.1.1.1) for the ITT Population 
(Table 2.1.2 and Figure 2.1.2 for the PP Population analysis).  Differences from Placebo MDI 
will be plotted for change in trough FEV1 (Figure 2.1.1.2 for the ITT Population).  The results of 
the ITT Population analysis will be considered primary; the PP Population analysis will be a 
supportive analysis.
Assumptions Checks and Removal of Outliers in Sensitivity Analyses
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. Prior to database lock 
and unblinding, the change from baseline values for efficacy endpoints will be examined as part 
of data quality management.  This will include production of normal probability plots, kernel 
density estimates, and normal order outlier statistics.  Based on this blinded evaluation, if 
extreme values are identified, nonparametric methods or data transformations (e.g., Logarithmic 
or normal rank transformation) will be considered.  If erroneous values are detected, every effort 
will be made to correct them prior to database lock, however if these values cannot be corrected, 
they will be considered for removal from analysis.  These analyses will be conducted if 
warranted to demonstrate the robustness of the primary and secondary results and reported in the 
statistical methods appendix.
The assumption of normality in the change from baseline in the morning pre-dose trough FEV1 
data will be checked by visually inspecting the distribution of the residuals. Also, model fit and 
the assumption of homogeneity of variance among treatments will be verified by inspection of 
scatter plots of predicted vs. residuals, residuals vs. treatment, and by box plots of residuals for 
model variables with a potential effect on variance (treatment and visit). Plots for scaled 
(marginal) residuals will be prepared (option=VCIRY on the model statement and ODS graphics 
option allows the production of plots using these residuals). As a sensitivity analysis, if 
appropriate, the linear RM model analysis will be conducted by allowing for heterogeneity of 
variance between treatments and visits (if unstructured covariance model failed to converge). 
Note that the unstructured covariance structure allows for heterogeneity among the visits.
Sensitivity Analyses
Sensitivity analyses will be conducted to evaluate the robustness of the primary analysis findings 
to missing data.  The estimand of interest in this study is the effect of treatment compared to 
control (for example GFF MDI vs. GP MDI) at Week 24 of treatment, or over 24 weeks of 
treatment, or over Weeks 12-24.  Since the primary analyses of morning pre-dose trough FEV1
use maximum likelihood based approaches, they are valid under the missing at random (MAR) 
assumption (Little and Rubin, 2002).  The MAR assumption means that missingness is 
independent of the unobserved outcome values after accounting for the appropriate observed data 
and covariates in the model.  In order to evaluate the robustness of the findings to this 
assumption, sensitivity analyses will be performed under varying assumptions for data 


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considered likely to be missing not at random (MNAR).  MNAR means that missingness 
depends on the unobserved values, and cannot be predicted solely based on the subject’s 
observed data.
Several types of statistical models have been proposed to analyze clinical study data under such 
assumptions.  The first approach that will be implemented for this study is the use of 
pattern-mixture models (PMMs).  PMMs have the advantages of allowing transparent and 
clinically interpretable formulations of the assumptions regarding unobserved data (Little and 
Rubin 2002).  The second approach will implement a cumulative responder analysis.
Pattern Mixture Models
The details for implementation of a sensitivity analysis within the PMM framework were 
recently summarized by Ratitch et al. (2013) and are described below as implemented for this 
study.  Multiple imputation (MI) methods for imputing missing data available in PROC MI are 
incorporated.  Using MI as an integral part of a PMM-based analysis has a great advantage in 
that MI procedures produce correct variance estimates that account for uncertainty associated 
with the imputation process.
Methodology for Missing Data Imputation
The methods employed for missing data imputation are dependent on whether the reason for 
missingness is MAR (missing at random) or MCAR (missing completely at random) vs. MNAR 
(missing not at random).  Thus, reasons for discontinuation as captured on the eCRF will have 
been classified as MCAR/MAR or MNAR.  Additionally, in order to impute missing data for a 
visit prior to the discontinuation visit, the reasons for having missed the visit (captured on the 
eCRF) will be classified as COPD Related (MNAR), Not COPD Related (MAR/MCAR), and 
Unknown (Listing 6.1.2).  For the purpose of the sensitivity analysis, an Unknown reason for 
having missed a visit will be considered to be MNAR.  Also, if the spirometry data quality 
obtained for a subject at any timepoint does not meet minimal acceptability requirements per 
ATS/ERS criteria, as determined during the blinded spirometry over read process, data for that 
timepoint will be considered MNAR.  If both of the 60- and 30-minute pre-dose spirometry 
assessments are missing at a visit, but the visit is not missing, then this will be considered 
MNAR.
Unique patterns of missing values across visits will be summarized for change from baseline in 
FEV1 (Table 2.1.3.2 for the ITT Population) with numbers and percentages by treatment.  These 
and all reasons for missing values at a visit will be listed (Listing 6.1.2) and summarized in Table 
2.1.3.1 for the change from baseline in morning pre-dose trough FEV1.  Additionally, these 
summary tables will provide a breakdown of the total missing count by MAR/MCAR and 
MNAR.
It is expected that the great majority of missing data will be caused by subjects discontinuing 
from the trial prematurely.  The resulting missing data will have a monotone pattern, meaning 
that, once a subject has missing data for some visit, data will be missing for all subsequent visits.  


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The methodology described below will be used to address this type of missing data pattern.  It is 
also expected that a small amount of non-monotone missing data (when subjects skip 
intermediate visits, but return for evaluations at subsequent visits) will be present.  The 
intermittent missing data will be imputed prior to the imputation of the monotone missing data.  
Intermittent missing data classified as MNAR will be imputed using the Monte Carlo Markov 
Chain (MCMC) approach and then the imputed values will be decreased by delta as defined in 
the following section.  Intermittent missing data classified as MAR/MCAR will be imputed using 
MCMC imputation without decreasing the imputed values by delta.  Using the MCMC approach, 
missing visits will be imputed from the posterior distributions, derived from the joint distribution 
of morning trough FEV1 at all visits within each treatment.  There will be no conditioning on the 
covariates for this intermittent imputation.  Intermittent missing values will not be used to define 
separate patterns.  Patterns will be defined on the basis of the nature of the missingness in 
addition to completion status (completer or dropout).  Each pairwise comparison will be 
evaluated separately.  For purposes of explaining the procedure, the treatment with the presumed 
larger benefit will be labeled as Treatment, while the treatment to which it is being compared 
will be labeled Comparator.  For example, for the comparison of GFF MDI to FF MDI, GFF 
MDI will be labeled Treatment and FF MDI will be labeled Comparator.  The patterns used for 
analysis will be Treatment Completers, Comparator Completers, Treatment Dropouts 
MAR/MCAR, Treatment Dropouts MNAR, and Comparator Dropouts.  This will be 
implemented through running separate sets of imputations and analyses for each of the 3 
treatments (GFF, GP and FF), which are being considered for delta adjustment.  The set where 
GFF will be delta-adjusted will provide estimates for the 3 key comparisons with GFF, i.e., GFF-
FF, GFF-GP and GFF-Placebo.  The set where FF will be delta-adjusted will provide estimates 
for the key comparison FF-Placebo, and the set where GP will be delta-adjusted will provide 
estimates for the key comparison GP-Placebo.
Each single imputation will be performed on the entire ITT set, regardless of the key comparison 
being evaluated.  The key comparison will only determine the treatment to which the delta 
adjustment will be applicable (GFF, FF or GP).  Accordingly, the analysis (RM ANCOVA) will 
be performed on the full ITT set with the observed and imputed values.  Since the same set of 
subjects will be used as the main analysis, the results can be compared.
For each key comparison and each value of delta, 10 independent imputations will be done.  The 
resulting 10 estimates of the treatment effect will then be combined into the final estimate for 
this combination of the key comparison and delta, using SAS PROC MIANALYZE.
Pattern Mixture Modeling with Delta Adjustment
Delta-adjusted PMM imputation will be used for sensitivity analysis under a clearly formulated 
clinical assumption about an MNAR mechanism.  More specifically, the assumption is that 
subjects from the GFF MDI arm for the comparisons of GFF MDI to its components and Placebo 
MDI, or the GP MDI and FF MDI arms used for comparisons to Placebo, who discontinue at a 
given timepoint would have, on average, their unobserved efficacy score worse by some amount 
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timepoint.  For purposes of the sensitivity analyses, subjects who discontinue from the 


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Comparator arm are treated as if they would have exhibited the same evolution of the disease and 
same benefit from treatment with the comparator as comparator subjects that stayed on the study.
Delta values will be based on the estimated treatment difference from comparator taken from the 
primary analysis in the ITT Population where values will vary from 0 to the estimated treatment 
difference in increments of 0.010 L for change from baseline in FEV1 trough.
For datasets with monotone missingness, regression-based imputation for monotone missingness 
(Rubin, 1987) will be applied and has the flexibility that it may be performed in a sequential 
manner using univariate models with a number of predictor variables.  For example, the earliest 
visit will be imputed first, then the next one, and so on using outcomes from previous visits as 
predictors.  This sequential approach is considered to perform well in practice with monotone 
missingness even when normality assumptions do not hold (Little, 2002; Molenberghs and 
Kenward, 2007; White, Royston, and Wood, 2011).
A sequential regression-based MI procedure was suggested for the implementation of the 
delta-adjustment strategy in the National Research Council (NRC) report on missing data 
(National Research Council of National Academy of Sciences, 2010) so that timepoints are 
LPSXWHGRQHDWDWLPHDQGWKDWįDGMXVWPHQWFDQEHSURSDJDWHGWKURXJKWLPHE\XVLQJWKH
adjusted values as predictors.  This procedure follows the general principles of PMM with 
identifying restrictions (assumptions) discussed above and is summarized as follows:
i.
Missing values at timepoint 1 (Week 2 for FEV1) will be imputed using a regression 
based MI method for monotone missingness (100 iterations per timepoint per delta).  All 
covariates in the final RM ANCOVA model (except for visit and treatment by visit 
interaction) will be included in the modelling (baseline FEV1, percent reversibility, and 
randomized treatment). $WWKLVVWDJHWKHLPSXWHGYDOXHVZLOOQRW\HWEHį-adjusted for 
any subjects in the Treatment Dropouts MNAR pattern. 
ii. After imputations are obtained in Step (i), for subjects missing data at timepoint 1 in the 
Treatment Dropouts MNAR pattern, the imputed value at timepoint 1 will be made worse 
E\DYDOXHRIį6LQFHORZHUVFRUHVIRUWKHSULPDU\HQGSRLQWs for this study represent 
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be made for the other patterns.
iii. All remaining timepoints will be imputed sequentially by repeating Steps (i–ii) for each 
timepoint including lag values from earlier timepoints in the imputation model (lag 
values will include imputed values from the previous step) in addition to the covariates 
specified above in Step (i).  Data from subjects who have already had their responses 
decreaVHGE\įLQWKHSUHYLRXVVWHSVZLOOQRWEHIXUWKHUGHFUHDVHGE\įDJDLQVLQFHWKH
regression on the previous value carries this decrease forward.  This principle also 
extends to the preliminary step of imputing intermittently missing visits.  Thus, if an
intermittent MNAR value is encountered for a subject, delta adjustment will not apply for 
the subsequent imputations of the monotone part of the missing visits, for that subject.


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iv. Analyze multiply-imputed datasets by the same method used for the primary analysis 
(linear RM ANCOVA described above) and combine the results based on a standard MI 
methodology (Rubin, 1987).
Tipping Point Analysis
A series of analyses will be performed for each key pairwise comparison with a range of 
LQFUHDVLQJįYDOXHVIURPto the estimated treatment difference from the primary analysis) so 
that one can assess at which point the study conclusions change from favorable to unfavorable, 
that is, so that one can find a tipping point. Then, a clinical interpretation regarding the įYDOXH
representing the tipping point will be considered to judge whether the corresponding differences 
between the dropouts and completers are plausible. Delta increments will be chosen to be 
0.010 L for FEV1 out of practicality concerns, with the intent to refine the grid around the tipping 
point, if it is observed. The largest value of delta considered for a given comparison will be the 
estimated treatment difference from the primary analysis, rounded upwards to the nearest 
0.010 L.
A plot of p-valueVE\įZLOOEHSURYLGHGIRUHDFKRIWKHSULPDU\WUHDWPHQWFRPSDULVRQVDQGIRU
each of the primary endpoints including the primary endpoint of change from baseline in trough 
FEV1 at Week 24 for the US/China approach, the primary endpoint of change from baseline in 
trough FEV1 for over Weeks 12-24 for the Japan approach, and the primary endpoint of change 
from baseline in trough FEV1 over 24 Weeks for the EU/South Korea/Taiwan approach (Tables 
2.1.4.1 through 2.1.4.3 and Figures 2.1.4.1 through 2.1.4.15 for change in FEV1 trough at Week 
24, over 24 weeks, and over Weeks 12-24, ITT Population). It is acknowledged that the process 
of imputation will incur a certain degree of noise due to the limited number of imputations (10).  
In order to better see the trend in the p-values with increasing delta, a smoother will be added to 
the graphs.  Smoothing will be done by fitting a linear model (in delta) to the estimated standard 
errors, and then a weighted linear model to the estimated treatment effects.  Smoothed p-values 
will then be derived from the smoothed treatment effects and standard errors.
AddLWLRQDOO\IRUDVXEVHWRIVSHFLILFį¶VDQGIRUHDFKRIWKHNH\SDLUZLVHFRPSDULVRQV*))
MDI with comparators of Placebo and components, and for each component compared to the 
Placebo comparator) plots will be prepared displaying the mean adjusted estimates for each visit 
as well as over 24 weeks (Figures 2.1.4.16 to 2.1.4.30 for change in trough FEV1 at Week 24, for 
over 24 weeks, and for over Weeks 12-24, ITT Population). For each key pairwise 
comparison, one model will be run for each imputation dataset generated for each of the į¶VWKDW
represent roughly 0%, 25%, 50%, and 100% of the estimated treatment difference for the given 
comparison.  The models used the same covariates as the primary analysis model, but the 
treatments were: Treatment Completers, Comparator Completers, Treatment Dropouts 
MAR/MCAR, Treatment Dropouts MNAR, and Comparator Dropouts (Figures 2.1.4.16 to 
2.1.4.30 for change in trough FEV1 at Week 24, for over 24 weeks, and for over Weeks 12-24,
ITT Population). Table 6 identifies the models used to produce estimates plotted in these pattern 
figures.


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Table 6
Models Used To Produce Estimates for Pattern Figures (Figures 2.1.4.16 to 
2.1.4.30)
Models 1a, 1b, and 
1c for plotting key 
comparisons of GFF 
to each Comparator
Model 1A:
GFF vs. Placebo
Key Comparison:
Groups included in the 
model were:
1.
GFF Completers
2.
GFF MNAR
3.
GFF MAR/MCAR
4.
Placebo Completers
5.
Placebo Dropouts
Model 1B: 
GFF vs. GP
Key Comparison:
Groups included in the 
model were:
1.
GFF Completers
2.
GFF MNAR
3.
GFF MAR/MCAR
4.
GP Completers
5.
GP Dropouts
Model 1C: 
GFF vs. FF
Key Comparison:
Groups included in the 
model were:
1.
GFF Completers
2.
GFF MNAR
3.
GFF MAR/MCAR
4.
FF Completers
5.
FF Dropouts
Model 2 for plotting 
key comparison of 
GP to Comparator
Groups included in the model were:
1.
GP Completers
2.
GP MNAR
3.
GP MAR/MCAR
4.
Placebo Completers
5.
Placebo Dropouts
Model 3 for plotting 
key comparison of 
FF to Comparator
Groups included in the model were:
1.
FF Completers
2.
FF MAR/MCAR
3.
FF MNAR
4.
Placebo Completers
5.
Placebo Dropouts
Cumulative Responder Analysis
US/China
Additional sensitivity analyses will be implemented based on a cumulative responder approach 
as described in Farrar et al. 2006 for the change from baseline in morning pre-dose trough FEV1
at Week 24 (Table 2.1.4.4).  A cumulative distribution plot by treatment arm (Farrar et al., 2006) 
will also be produced.  The observed change from baseline in morning pre-dose trough FEV1 at 
Week 24 will be plotted on the X axis, while the proportion of responders (subjects that equal or 
exceed that level of change) will be plotted on the Y axis (Figure 2.1.4.31).  Subjects with 
missing data at Week 24 will be considered non-responders.  The cumulative responder curves 
for each treatment will then be compared pairwise using Kolmogorov-Smirnov tests.
Japan
The methodology described above for the US/China approach will be applied using the mean 
change from baseline in morning pre-dose trough FEV1 over Weeks 12-24 (Table 2.1.4.6).  The 
mean observed change from baseline in morning pre-dose trough FEV1 over Weeks 12-24 will


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be plotted on the X axis, while the proportion of responders (subjects that equal or exceed that 
level of change) will be plotted on the Y axis (Figure 2.1.4.33).  Subjects with missing data from 
Week 12 onward will be considered non-responders.
EU/South Korea/Taiwan
The methodology described above for the US/China approach will be applied using the mean 
change from baseline in morning pre-dose trough FEV1 over 24 weeks (Table 2.1.4.5).  The 
mean observed change from baseline in morning pre-dose trough FEV1 over 24 weeks will be 
plotted on the X axis, while the proportion of responders (subjects that equal or exceed that level 
of change) will be plotted on the Y axis (Figure 2.1.4.32).  Subjects with missing data after 
baseline will be considered non-responders.
6.4.2
Analysis of Secondary and Other Endpoints Related to Secondary
Secondary variables include TDI (over 24 weeks for US/China and EU/South Korea/Taiwan and 
over Weeks 12 to 24 for 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/South Korea/Taiwan, and over Weeks 12 to 24 for Japan), rescue Ventolin 
HFA usage, and SGRQ (at Week 24 for US/China and over Weeks 12 to 24 for EU/South 
Korea/Taiwan and Japan). All analyses will be performed with the ITT Population except for 
rescue Ventolin usage which will be based on the Rescue Ventolin User Population. In addition, 
analyses of symptom endpoints of TDI and SGRQ will also be performed in the Symptomatic 
Population. Multiplicity will be controlled for the secondary variables as described in 
Section 6.4.4.
6.4.2.1
TDI
Assessments of dyspnea will be obtained using the BDI/TDI.  The interviewer-administered 
version of the BDI/TDI questionnaire can be found in Appendix 9 of the Protocol.  Previous 
Pearl studies utilized the SAC (self-administered computerized) version of the BDI/TDI.
At Visit 4, the severity of dyspnea at baseline will be assessed using the BDI.  BDI components 
are functional impairment, magnitude of task, and magnitude of effort (Listing 6.1.8).  The 
possible range of values for each BDI component score is 0 (very severe impairment) to 4 (no 
impairment).  The BDI component scores are summed to determine the BDI focal score (0 to 12) 
(i.e., the lower the score, the worse the severity of dyspnea).
At subsequent visits (as per schedule of events, Table 1) change relative to baseline will be 
assessed using the TDI.  TDI components are: Change in Functional Impairment, Change in 
Magnitude of Task, and Change in Magnitude of Effort (Listing 6.1.8).  The TDI component 
score ranges from -3 (major deterioration) to +3 (major improvement).  The sum of all 
component scores yields the TDI focal score (-9 to +9) (i.e., the lower the score, the more 
deterioration from baseline). 


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The difference between treatments in TDI focal score over 24 weeks and over Weeks 12-24 will 
be evaluated using a similar repeated measures approach as for the change from baseline in 
morning pre-dose trough.  BDI will be included as a continuous covariate replacing baseline 
FEV1 in the model.  At each visit, if a response to any of the three questions is missing, then the 
focal score will also be considered missing. Two-sided p-values and point estimates with two-
sided 95% confidence intervals will be produced for each treatment difference.
Primary analyses of the TDI will use the ITT Population (Table 2.2.1 and Figures 2.2.1.1.1 and 
2.2.1.1.2) and Symptomatic Population (CAT score 15; Table 2.2.1). The analysis of the TDI 
IRFDOVFRUHIRUWKHVXESRSXODWLRQVRIWKH&$76FRUHDQGZLOOEHVLPLODUWRWKHSULPDU\
analyses of the TDI focal score (Table 2.2.1 and Figures 2.2.1.2.1 to 2.2.1.2.3). Analyses of the 
individual components of the TDI: functional impairment, magnitude of task, and magnitude of 
effort over 24 weeks, over Weeks 12-24, and by post-baseline visit will be summarized 
(Table 2.2.2 for the ITT Population and by CAT Score Subpopulation; and Figures 2.2.2.1,
2.2.2.2., and 2.2.2.3 for the functional impairment, magnitude of task, and magnitude of effort 
components for the ITT Population overall and by CAT Score Subpopulation, including the CAT 
Score Population of 15 (i.e., Symptomatic Population). Furthermore as supportive analyses, 
responder analyses will be performed where responders are defined as subjects who achieved a 
PLQLPDOFOLQLFDOO\LPSRUWDQWGLIIHUHQFH0&,'WKUHVKROGRIXQLWRQDYHUDJHLQ7',IRFDO
score over 24 weeks (or separately over Weeks 12-24).  Subjects without TDI data will be 
considered to be non-responders. Logistic regression, performed with PROC GENMOD, will be 
used to compare the treatments, adjusting for BDI and reversibility to Ventolin (albuterol sulfate) 
HFA as continuous covariates (Table 2.2.3.1 for the ITT Population and by CAT Score 
Subpopulation, including CAT Score Population of 15 (i.e., Symptomatic Population). The 
odds ratios for relative treatment differences will be determined, along with Wald two-sided 95% 
confidence intervals. The odds ratios presented will assume arithmetic mean levels of the BDI 
focal score and reversibility to Ventolin (albuterol sulfate) HFA. The Wald chi-square test will 
be used to calculate p-values for comparisons between treatments.
As additional supportive analyses, the difference between treatments at each of the individual 
post-baseline visits will also be evaluated and summarized (Table 2.2.1 for the ITT Population 
and by CAT Score Subpopulation, including CAT Score Population of 15 (i.e., Symptomatic 
Population).  The difference between treatments over time will be plotted in Figures 2.2.1.1.1
and 2.2.1.1.2 for the ITT Population and Figures 2.2.1.2.1 through 2.2.1.2.3 for the CAT Score 
Subpopulations.
The assumption of normality in the TDI data will be checked by visually inspecting the 
distribution of the residuals. Also, model fit and the assumption of homogeneity of variance 
among treatments will be verified by inspection of scatter plots of predicted vs. residuals and 
residuals vs. treatment, and by box plots of residuals for model variables with a potential effect 
on variance (treatment and visit). Plots for scaled (marginal) residuals will be prepared 
(option=VCIRY on the model statement and ODS graphics option allows the production of plots 
using these residuals). As a sensitivity analysis, if appropriate, the linear RM model analysis will 
be conducted by allowing for heterogeneity of variance between treatments and visits (if 


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unstructured covariance model failed to converge). Note that the unstructured covariance 
structure allows for heterogeneity among the visits.
6.4.2.2
Peak FEV1
The peak change from baseline in FEV1 within 2 hours post-dosing at Week 24 (US/China), over 
24 weeks (EU/South Korea/Taiwan), and over Weeks 12-24 (Japan) will be analyzed and 
summarized similarly to morning pre-dose trough FEV1 (Table 2.3.1 and Figure 2.3.1 for the ITT 
Population).  The peak change from baseline on Day 1 and at each post randomization visit will 
also be analyzed.  For the ITT, at each visit, the determination of peak value requires at least one 
non-missing value post-dose assessment.
6.4.2.3
St. George Respiratory Questionnaire (SGRQ)
The SGRQ will be used to provide the health status/health-related Quality of Life (QoL) 
measurements in this study (see Appendix 8 of the Protocol).  The SGRQ contains 50 rated 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 component and a 
"Total" score will also be calculated (Listings 6.1.9 and 6.1.10).  In each case, the lowest 
possible value is zero and the highest is 100.  Higher values correspond to greater impairment of 
quality of life.
The differences between treatments in the change from baseline in SGRQ at Week 24 
(US/China) and over Weeks 12-24 (EU/South Korea/Taiwan and Japan), 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 weighted 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. 
The primary analyses of the SGRQ will use the ITT Population (Table 2.4.1 and Figure 2.4.1.1) 
and Symptomatic Population (CAT 6FRUH7DEOH. The subpopulations of the CAT 
6FRUH and 20 will be analyzed similarly (Table 2.4.1 and Figures 2.4.1.2 to 2.4.1.4). As 
additional supportive analyses, the differences between treatments at each of the individual post-
baseline visits will also be evaluated and summarized (Table 2.4.1 and Figure 2.4.1.1 for the ITT 
Population and Table 2.4.1 and Figures 2.4.1.2 to 2.4.1.4 for the CAT Score Subpopulations).
Individual domains of the SGRQ (Symptoms, Activity, and Impacts) over Weeks 12-24 and for 
each post-baseline visit will also be analyzed in a similar fashion as for the overall score 
(Table 2.4.2). Furthermore as supportive analyses, responder analyses will be performed where 
responders are defined as VXEMHFWVDFKLHYLQJDQ0&,'WKUHVKROGRIXQLWVRQDYHUDJHLQ6*54
total score over Weeks 12-24 (or separately at Week 24). Subjects without SGRQ data will be 
considered to be non-responders.  Logistic regression, performed with PROC GENMOD, will be 
used to compare the treatments, adjusting for baseline SGRQ and reversibility to Ventolin 


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Protocol Number:  PT003014
Final Version:  07 Mar 2017
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(albuterol sulfate) HFA as continuous covariates (Table 2.4.3 for the ITT Population and by CAT 
Score Subpopulation, including for the CAT Score Subpopulation of  [i.e., Symptomatic 
Population]). The odds ratios for relative treatment differences will be determined, along with 
the Wald two-sided 95% confidence intervals. The odds ratios presented will assume arithmetic 
mean levels of the baseline SGRQ and reversibility to Ventolin (albuterol sulfate) HFA. The 
Wald chi-square test will be used to calculate p-values for comparisons between treatments.
6.4.2.4
Rescue Ventolin HFA Use
The number of puffs of rescue Ventolin HFA taken in the previous 12 hours will be recorded in 
the subject diary in the morning and evening.  The number of puffs of rescue Ventolin HFA used 
by subjects during the study will be provided in a diary data listing (Listing 6.1.6).
For every period of time for which the mean number of puffs of rescue Ventolin 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 HFA 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 
treatments in the change from baseline in rescue Ventolin HFA use over 24 weeks will be 
evaluated using a similar RM approach as for the primary endpoint (Table 2.5.1 and 
Figure 2.5.1.1 for the Rescue Ventolin User Population, the subset of subjects using an average 
of at least 1 puff per day of rescue Ventolin at baseline). Instead of visit, the number of the 
relevant 4-week interval (1-6) will be used as a categorical covariate in the model. As a 
supportive analysis, the treatment differences for each 4-week interval and over Weeks 12-24
will be evaluated and summarized similarly (Table 2.5.1 and Figure 2.5.1.1 for the Rescue 
Ventolin User Population). Additionally as supportive analyses, daytime rescue Ventolin HFA 
use and nighttime rescue Ventolin HFA use will be evaluated and summarized in a similar 
fashion (Table 2.5.1 and Figures 2.5.1.2 and 2.5.1.3). Two-sided p-values and point estimates 
with two-sided 95% confidence intervals will be produced for each treatment difference.
6.4.2.5
Time to Onset of Action
The onset of action will be determined for each treatment using the 5 and 15 minute 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 for 
change from baseline in FEV1 is statistically significant (the two-sided alpha level will be based 
on the Hochberg procedure for each comparison to Placebo MDI, see Section 6.4.4). ITT 
Population analyses will be performed to compare treatments using ANCOVA; the ANCOVA 
will include baseline FEV1 and percent reversibility to Ventolin (albuterol sulfate) HFA as 
continuous covariates.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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Results will be summarized and the adjusted mean change from baseline in FEV1 will be plotted 
by treatment across timepoints (Table 2.6.1 and Figure 2.6.1 for the ITT Population, and 
Listing 6.1.4).
6.4.3
Analysis of Other Endpoints
6.4.3.1
Other Spirometry Endpoints
FEV1 AUC0-2 will be calculated using the trapezoidal rule and transformed into a weighted 
average by dividing by the time in hours from dosing of the last measurement included (typically 
2 hours).  FEV1 AUC0-2 will be evaluated in a similar manner to the primary endpoint using the 
ITT Population.  Summaries of analyses by visit, over Weeks 12-24, and over 24 weeks will be 
provided (Table and Figure 2.7 for FEV1 AUC 0-2).  The differences between treatments in FEV1
AUC0-2 will be evaluated using an ANCOVA with baseline FEV1 and Screening reversibility to 
Ventolin (albuterol sulfate) HFA as continuous covariates and treatment as a categorical 
covariate.  Two-sided p-values and point estimates with two-sided 95% confidence intervals will 
be produced for each treatment difference at each timepoint.
Treatment differences in the peak change from baseline in FVC within 2 hours post-dose, FVC 
AUC0-2 and changes from baseline in morning pre-dose trough FVC will be evaluated in a 
similar manner (Table and Figure 2.9 for peak change from baseline within 2 hours for FVC for 
the ITT Population; Table and Figure 2.8 for AUC0-2 for FVC for the ITT Population; and 
Table and Figure 2.10 for change from baseline in FVC trough, for the ITT Population, 
respectively).
Treatments will be compared using change from baseline at each post-dose timepoint over 
2 hours for the following variables: FEV1 and FVC (Tables and Figures 2.6.1 for FEV1 and 2.12 
for FVC for the ITT Population using ANCOVA to compare treatments with baseline FEV1 and
percent reversibility to Ventolin (albuterol sulfate) HFA as continuous covariates and Listings 
6.1.4 and 6.1.5; plots will display AUC0-2 estimates also).
On Day 1 during the first two hours post-dosing and by timepoint, the proportion of subjects 
achieving an improvement from baseline in FEV1 using different thresholds (i.e., 
 P/ P/DQGDQG mL) will be estimated for each treatment.  Subjects 
without post-baseline data will be considered to be non-responders.  Logistic regression,
performed with PROC GENMOD, will be used to compare the treatments, adjusting for baseline 
FEV1 and reversibility to Ventolin (albuterol sulfate) HFA as continuous covariates.  The odds 
ratios for the relative treatment differences will be determined, along with the Wald two-sided 
95% confidence intervals.  The odds ratios presented will use the arithmetic mean levels of 
baseline FEV1 and reversibility to Ventolin (albuterol sulfate) HFA. The Wald chi-square test 
will be used to calculate p-values for comparisons between treatments (Tables 2.11.1 through 
2.11.5 for the ITT Population).


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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Confidential and Proprietary
Percentage of Days With “No Rescue Ventolin Use” Over the Treatment Period
As a supportive analysis, percentage of days with ‘no rescue Ventolin HFA use’ over 24 weeks 
will be analyzed. A ‘Day with no rescue use’ is defined, using rescue Ventolin HFA usage data 
from days where rescue Ventolin HFA usage data is non-missing, as any day where the subject 
reported no puffs of rescue Ventolin HFA.  The percentage of days with ‘no rescue use’ will be 
summarized by treatment and analyzed using ANCOVA to evaluate the treatment  difference 
using baseline average daily rescue Ventolin HFA and percent reversibility to Ventolin HFA as 
covariates (Table 2.5.2 for the Rescue Ventolin User Population).
COPD Exacerbations
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.
The number of exacerbations and the percentage of subjects who experience exacerbations will 
be summarized for all severities combined and by severity.  The rate of all COPD exacerbations 
of any severity will be analyzed using negative binomial regression as implemented in PROC 
GENMOD.  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.  For any 
subject with exposure calculated to be 0 due to removal of all exposure using this rule above, 
exposure for analysis purposes will be considered to be 1 day.  Treatments will be compared 
adjusting for baseline percent predicted FEV1, baseline CAT score, baseline COPD exacerbation 
history, smoking status at baseline, baseline continuous eosinophil count, and ICS use at baseline 
(Table 2.13.1 for the ITT Population and by CAT Score Subpopulation, including the CAT Score 
6XESRSXODWLRQRI [i.e., Symptomatic Population] and Listing 6.1.8).
Adjusted rates of exacerbations will be estimated using data-based weights from the study 
population for the categorical covariates of baseline COPD Exacerbation history, smoking status 
at baseline, and ICS use at baseline, and the arithmetic mean level of the continuous covariate, 
baseline percent predicted FEV1 and baseline continuous eosinophil count.
The time to first COPD exacerbation of any severity will be analyzed up through Day 183
(Week 26) using a Cox regression model (ITT Population and by CAT Score Subpopulation, 
LQFOXGLQJWKH&$76FRUH6XESRSXODWLRQRI, i.e., Symptomatic Population).  Treatment 
comparisons will be performed using the model, adjusting for baseline percent predicted FEV1,


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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baseline COPD exacerbation history, baseline CAT score, smoking status at baseline, baseline 
continuous eosinophil count, and ICS use at baseline.  SAS PROC PHREG will be used.  
Estimated adjusted hazard ratios relative to the comparator for each treatment comparison will be 
displayed along with the associated Wald two-sided 95% confidence intervals and p-values 
(Table 2.14 and Listing 6.1.8). Hazard ratios will be estimated using the categorical covariates 
of baseline COPD Exacerbation history, smoking status at baseline, and ICS use at baseline, and 
the arithmetic mean level of the continuous covariates, baseline percent predicted FEV1 and 
baseline continuous eosinophil count,
Time to first COPD exacerbation of any severity will be displayed graphically for each treatment 
using a Kaplan-Meier curve (Figure 2.14.1.x for the ITT Population and by CAT Score 
6XESRSXODWLRQLQFOXGLQJWKH&$76FRUH6XESRSXODWLRQRI [i.e., Symptomatic Population]).
Subjects who do not experience a COPD exacerbation will be censored at the Week 24 visit or 
Day 183, whichever is earlier.  Subjects who withdraw from the study without experiencing a 
COPD exacerbation will be censored at the date of withdrawal or the last date of treatment, 
whichever is later (but on Day 183 or earlier).
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 (Tables 2.13.1 and 2.14 and 
Figure 2.14.2 for the ITT Population and by CAT Score Subpopulation and Listing 6.1.8).
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.  Analyses with imputation 
will be provided in Table 2.13.2 for the ITT Population and by CAT Score Subpopulation, 
including the CAT Score SuESRSXODWLRQRIi.e., Symptomatic Population).
Exacerbations starting after the end of treatment which are noted at the follow-up telephone call 
will not be included in the inferential analyses, but will be reported in the data listing 
(Listing 6.1.8).
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 up through Day 183 (Week 26) will 
be analyzed using a Cox regression model for the ITT Population and by CAT Score 
6XESRSXODWLRQLQFOXGLQJWKH&$76FRUH6XESRSXODWLRQRI (i.e., Symptomatic Population).
The model will include treatment, baseline percent predicted FEV1, baseline COPD exacerbation 
history, baseline CAT score, smoking status at baseline (current vs former), baseline continuous 
eosinophil count, and ICS use at baseline.  Estimated adjusted hazard ratios will be displayed 
along with associated 95% confidence interval and p-values (Table 2.15).  Time to treatment
failure will be displayed graphically for each treatment group using a Kaplan-Meier curve 
(Figure 2.15.x for the ITT Population and by CAT Score Subpopulation, including the CAT 
6FRUH6XESRSXODWLRQRI [i.e., Symptomatic Population]).  Subjects who did not experience a 


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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Confidential and Proprietary
treatment failure will be censored at the Week 24 visit or Day 183, whichever was earlier.  The 
basic assumptions of the model including the proportional hazards assumption will be checked.
Time to First Clinically Important Deterioration (CID) and Time to First Sustained CID
First clinically important deterioration (CID) will be defined as the first occurrence of one of the 
IROORZLQJHYHQWVP/GHFOLQHLQWURXJK)(91; 2) a treatment emergent moderate/severe 
COPD exacerbation; or LQFUHDVHRIXQLWVRQWKH6*54$VHFRQGGHILQLWLRQRI&,'ZLOO
include a 4th condition for death.
A sustained decline in trough FEV1 ZLOOEHGHILQHGDVP/GHFOLQHLQWURXJK)(91 on 2 
FRQVHFXWLYHDQDO\VLVYLVLWVRUIRURIDOOVXEVHTXHQWDnalysis visits with available trough 
FEV1.
/LNHZLVHDVXVWDLQHG6*54LQFUHDVHZLOOEHGHILQHGDVSRLQWVLQFUHDVHLQ6*54RQ
FRQVHFXWLYHDQDO\VLVYLVLWVRUIRURIDOOVXEVHTXHQWDQDO\VLVYLVLWVZLWKDYDLODEOH6*54
First sustained CID will be defined as the first occurrence of one of the following events: 1) a 
sustained decline in trough FEV1; 2) a sustained SGRQ increase; or 3) a treatment emergent 
moderate/severe COPD exacerbation. 
Time to first event analysis will be produced for CID, CID with death, sustained CID, and each 
of their individual component events, using the Cox regression model for the ITT Population 
RYHUDOODQGE\&$76FRUH6XESRSXODWLRQLQFOXGLQJ&$76FRUH (i.e., Symptomatic 
Population). The regression will adjust for baseline percent predicted FEV1, baseline CAT score, 
baseline COPD exacerbation history (yes/no), smoking status at baseline (former smoker/current 
smoker), baseline continuous eosinophil count, and inhaled corticosteroid use at baseline 
(yes/no). Estimated adjusted hazard ratios will be displayed along with associated 95% 
confidence interval and p-values (Tables 2.16.1, 2.16.2, and 2.17.1). Median time to first CID 
will be provided. Time to first CID, first CID with death, and first sustained CID will be 
displayed graphically for each treatment group using a Kaplan-Meier curve (Figures 2.16.1.x, 
2.16.2.x, and 2.17.1., respectively, for the ITT Population and by CAT Score Subpopulation, 
including CAT  [i.e., Symptomatic Population]). Subjects who did not experience a 
component event will be censored at the Week 24 visit or Day 183, whichever was earlier. The 
basic assumptions of the model including the proportional hazards assumption will be checked.
Time to first trough FEV1 event will be the study day of the post-baseline analysis visit when 
change from baseline in trough FEV1 ZDV-100 mL.  If this event did not occur, the observation 
will be censored at the last analysis visit where trough FEV1 was evaluated.  Time to first 
sustained decline in trough FEV1 will be the study day of the initial decline, satisfying the 
sustained definition.  If the subject did not experience a sustained trough FEV1 decline, censoring 
will occur at the second-last analysis visit where trough FEV1 was evaluated.
Similar considerations apply to time to first SGRQ event and first sustained SGRQ event.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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Time to a CID event or sustained CID event will be based on the time of the component event 
which occurred first.  Subjects who did not have a CID event will be censored at the earliest 
censoring day among the component censoring times.  COPD exacerbations occurring past 
Day 183 will not be counted as CID events.
Symptom Scores (Daily, Daytime and Nighttime Symptom Scores)
All subjects will be provided with an electronic subject diary to record daytime and nighttime 
clinical symptoms: cough, shortness of breath, sputum volume, nighttime awakenings and 
medication (albuterol sulfate and salbutamol) use (Listing 6.1.7).
For the purpose of statistical analysis, the following numeric scores will be assigned to responses 
for the symptoms questions:
Table 7
Numeric Scoring for Symptoms Diary Questions
Question 
Response 
How many times did you wake up last 
night? 
0 = None
1 = 1
2 = 2
3 = 3
4 = 4
5 = 5 or more times
6 = I was awake most or all of the night
How short of breath were you last night?
0 = Not at all
1 = Mild
2 = Moderate
3 = Severe
4 = Very severe
How many puffs of rescue medication 
(Ventolin HFA) have you taken since you 
took your study medication last night (this 
morning)? 
0 = 0
1 = 1
2 = 2
3 = 3
4 = 4
5 = 5
6 = 6
7 = 7
8 = 8
9 = 9
10 = 10
Etc.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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Question 
Response 
How often did you cough last night (today)?
0 = Not at all
1 = Rarely
2 = Frequently
3 = Almost constantly
How much mucus (phlegm) did you cough 
up last night (today)?
0 = None
1 = Less than 1 teaspoon (5 mL)
2 = 1-2 teaspoon (5-10 mL)
3 = More than 2 teaspoons (10 mL)
Did you feel short of breath today? and 
When did you feel short of breath? (highest 
response would be selected for analysis) 
0 = Not at all, and I was active
1 = Not at all, and I rested today
*=Yes, I felt short of breath today
2 = During exercise
3 = Walking upstairs, uphill, or quickly
4 = Walking slowly or during light activity
5 = Washing or dressing
6 = Sitting or resting
*Depends on response to follow up question
Individual missing scores for a symptom will be imputed in order to calculate the total symptoms 
score.  Individual scores on a study day will be imputed using the average of the day prior and 
the day after.  If data are not available for these days, the average of the score on the day will be 
imputed using the average of scores for the day for the subject’s treatment group.
The analysis of rescue Ventolin HFA use has already been described in Section 6.4.2.4 above.
The mean daily total symptom score, the mean daytime symptom score and the mean nighttime 
symptom score will be calculated for each subject over 24 weeks, over Weeks 12-24, and for 
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.  Calculation of the symptom scores will 
be based on scaled rescue Ventolin HFA use with the following categories: 


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 55 of 97)
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Table 8
Scaling of Rescue Ventolin Use for Calculation of Symptom Scores
Variable
Scaling
Total Symptom Score
Using the total number of daytime and nighttime puffs of 
rescue Ventolin HFA:
0 = No rescue Ventolin HFA use
1=1-2 puffs
2=3-4 puffs
3=5-6 puffs
4=7-8 puffs
5=9-10 puffs
6=>10 puffs
Daytime Symptom Score
Using number of daytime puffs of rescue Ventolin HFA:
0 = No rescue Ventolin HFA use 
1 = 1-2 puffs
2 = 3-4 puffs
3 = 5-6 puffs
4 = > 6 puffs
Nighttime Symptom Score
Using number of nighttime puffs of rescue Ventolin HFA:
0 = No rescue Ventolin HFA use 
1 = 1-2 puffs
2 = 3-4 puffs
3 = 5-6 puffs
4 = > 6 puffs
The mean changes from baseline in the daily, daytime and nighttime symptom scores will be 
analyzed using a similar model as for morning pre-dose trough FEV1 in Section 6.4.2.4 above in 
order to estimate treatment effects over 24 weeks and over Weeks 12-24 (Table and
Figure 2.18.1 for the ITT Population).  In addition, summaries of the daily, daytime and 
nighttime symptom scores will be provided for each 4-week period (Table and Figure 2.18.1 for 
the ITT Population).  The above summaries will be repeated for each individual symptom score 
(Tables and Figures 2.18.2 through 2.18.5 for cough, shortness of breath, sputum volume, and 
nighttime awakenings for the ITT Population; note that nighttime awakenings will be captured 
only in the morning and will be provided for morning summaries only).


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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Correlations Among Measures
Pearson and Spearman rank correlations within subjects will be estimated between pairs of 
variables (Table 2.19.1 and 2.19.2 and Figures 2.19.1 through 2.23.55).  Where appropriate, the 
variable averages across visits will be used to estimate the correlations using all data available.
The following variables will be correlated pairwise:
x
Change from baseline in morning pre-dose trough FEV1 at Week 24
x
Peak change from baseline in FEV1 at Week 24
x
Change from baseline in SGRQ total score at Week 24
x
Change from baseline in morning pre-dose trough FEV1 over 24 weeks
x
TDI focal score over 24 weeks
x
Peak change from baseline in FEV1 over 24 weeks
x
Change from baseline in rescue Ventolin HFA use over 24 weeks
Additionally, the following variables will be correlated with the above variables and with each 
other separately:
x
Change from baseline in morning pre-dose trough FEV1 over Weeks 12-24
x
Peak change from baseline in FEV1 over Weeks 12-24
x
Change from baseline in SGRQ total score over Weeks 12-24
x
TDI focal score over Weeks 12-24
6.4.4
Control of Type I Error
There are three separate approaches for the control of Type I error: 1) US/China, 2) EU/South 
Korea/Taiwan, and 3) Japan.
6.4.4.1
US/China Approach
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; Sarkar, 1997), 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. 
Control of Type I Error for GP MDI
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 


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 57 of 97)
Confidential and Proprietary
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.
This strategy is illustrated in Figure 2.
Figure 2
Type I Error Control for GP MDI (US/China)
7KH&$7SRSXODWLRQLVWKH6\PSWRPDWLF3RSXODWLRQ
Control of Type I Error for FF MDI
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 


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 58 of 97)
Confidential and Proprietary
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.
This strategy is illustrated in Figure 3.
Figure 3
Type I Error Control for FF MDI (US/China)
7KH&$7SRSXODWLRQLVWKH6\PSWRPDWLF3RSXODWLRQ
Control of Type I Error for GFF MDI
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 


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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Confidential and Proprietary
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.
This strategy is illustrated in Figure 4.
Figure 4
Type I Error Control for GFF MDI (US/China)
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Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 60 of 97)
Confidential and Proprietary
6.4.4.2
Japan Approach
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; Sarkar, 1997), 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.
Control of Type I Error for GP MDI
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. This strategy is 
illustrated in Figure 5.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 61 of 97)
Confidential and Proprietary
Figure 5
Type I Error Control for GP MDI (Japan)
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Control of Type I Error for FF MDI
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) will be tested simultaneously using the Hochberg procedure 
with a two-sided alpha of 0.05.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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This strategy is illustrated in Figure 6.
Figure 6
Type I Error Control for FF MDI (Japan)
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Control of Type I Error for GFF MDI
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 


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 63 of 97)
Confidential and Proprietary
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.
This strategy is illustrated in Figure 7.
Figure 7
Type I Error Control for GFF MDI (Japan)
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6.4.4.3
EU/South Korea/Taiwan Approach
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. 


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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Control of Type I Error for FF MDI
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. 
This strategy is illustrated in Figure 8.
Figure 8
Type I Error Control for FF MDI (EU/South Korea/Taiwan)
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Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 65 of 97)
Confidential and Proprietary
Control of Type I Error for GP MDI
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.
This strategy is illustrated in Figure 9.
Figure 9
Type I Error Control for GP MDI (EU/South Korea/Taiwan)
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Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 66 of 97)
Confidential and Proprietary
Control of Type I Error for GFF MDI
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.  This strategy is illustrated in Figure 10.
Figure 10
Type I Error Control for GFF MDI (EU/South Korea/Taiwan)
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Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 67 of 97)
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6.5
Healthcare Resource Utilization
Data on healthcare resource utilization will be collected at all visits post-baseline.
The following variables will be calculated unadjusted (per subject) over the entire Treatment 
Period and also adjusted (per subject per year) and tabulated by actual treatment received for 
those subjects for whom they or one or more of their family members missed work:
x
The number of days missed work
x
The number of days that family members of subjects missed from work
The following variables will be tabulated by actual treatment received and relationship to COPD 
(COPD-related, not COPD-related, and combined).  The means calculated across all subjects in a 
treatment will be calculated unadjusted (per subject) and also adjusted (per subject per year). 
x
The percentage of subjects with telephone calls to health care providers
x
The mean number of telephone calls to health care providers
x
The percentage of subjects with visits to health care providers
x
The mean number of visits to health care providers
x
The percentage of subjects with ER visits
x
The mean number of visits to ERs
x
The percentage of subjects hospitalized
x
The mean number of subject hospitalizations 
x
The mean number of days in the hospital
x
The percentage of subjects in the ICU
x
The mean number of days in ICUs
x
The percentage of subjects in the CCU
x
The mean number of days in CCUs
x
The percentage of subjects intubated of those who were hospitalized.
Analyses will be performed using the Safety Population.
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will be 
provided by actual treatment received for the number of days missed from work per year, the 
number of days that family members of subjects missed from work per year overall during the 
study (Table 2.38.1 and Listing 6.2).
Also, descriptive statistics will be provided by actual treatment received and relationship to 
COPD (related, not-related, and total) overall during the entire Treatment Period for the 
following variables: the number of telephone calls to health care providers, the number of visits 
to health care providers, the number of ER visits, the number of subject hospitalizations, the 


Statistical Analysis Plan
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number of days in the hospital, the number of days in the ICU, and the number of days in the 
CCU (Table 2.38.2 and Listing 6.2).  The percentage of subjects intubated of those who were 
hospitalized will also be summarized by actual treatment received and relationship to COPD 
(related, non-related, and total).
The following tabulations will also be prepared for hospitalizations that were designated by the 
investigator as drug-related on the AE eCRF: the number and percentage of subjects 
hospitalized, the number of subject hospitalizations, the number of days in the hospital, the 
number and percentage of subjects with stays in the ICU, the number of days in the ICU, the 
number and percentage of subjects with stays in the CCU, and the number of days in the CCU 
(Table 2.38.2 and Listing 6.2).  The percentage of subjects intubated of those who were 
hospitalized will also be summarized by actual treatment received.
HCRU data will be combined with economic data collected independently of the study to 
construct comparative health economic analyses between treatment groups.  This analysis will be 
reported separate from the main study report.
6.6
Safety Analysis
All safety analyses are based on the Safety Population.  Hypothesis testing will not be performed 
for any safety analyses.
6.6.1
Adverse Events
Adverse events will be collected.  Coding of adverse events for database lock will be done using 
Version 20.0 of the Medical Dictionary for Regulatory Activities (MedDRA). A glossary of 
MedDRA preferred terms used for adverse events reported in the study along with the associated 
Investigator’s verbatim text will be provided in Listing 7.2. During the study coded terms will 
be updated as later versions of MedDRA become available, but updates will not occur after 
Version 20.0 of MedDRA.
Adverse events that occur between the time the subject signs the informed consent form for the 
study and the time when that subject is randomized were to be recorded as medical history and 
not as a study adverse event unless the event meets the definition of a serious adverse event 
(SAE).
An adverse event is considered treatment-emergent if the date of onset is on or after the date of 
first dose of study medication in the study.  An adverse event would be considered attributable to 
a treatment if the onset of the AE was during the Treatment Period or occurred in the follow-up
period afterwards.  Adverse events after the Follow-up Telephone Call scheduled at least 14 days 
after Visit 11 or a discontinuation visit will not be considered treatment-emergent, but will be 
listed in adverse event data listings.  
Analysis endpoints for adverse events include both the numbers of treatment-emergent adverse 
events as observed by the investigational team or reported by the subject, and the incidence rates 


Statistical Analysis Plan
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of treatment-emergent adverse events.  The incidence of a treatment-emergent adverse event will 
be defined as the number and percentage of subjects experiencing an event.
Events with Irregular Onset Dates: All treatment-emergent adverse events will be included in 
the data listings regardless of the completeness of the onset dates.  Partial dates will be imputed 
in order to determine if an AE is treatment-emergent using the imputation rules in Appendix 1;
however, imputed dates will not be provided in the data listings.
All adverse events, whether treatment-emergent or not, will be included in the listings.  Reported 
adverse events by system organ class, preferred term, treatment, country, center, subject and 
onset day will be provided (Listing 7.1).  Reported adverse events by treatment, country, center, 
subject, and onset date will be presented in Listing 7.3.
The listing of adverse events will provide the severity, maximum severity, relationship to study 
drug, action taken and outcome for each adverse event. Any SAEs reported will be listed 
(Tables 3.8.1 and 3.8.2, by treatment and region subgroup and country). Adverse events leading 
to discontinuation of study medication will be listed (Table 3.6, by region subgroup and 
country).  A listing of any reported deaths during the study (prior to randomization, during 
treatment, within 14 days post-treatment, or after 14 days post-treatment) will be provided 
(Table 3.13, by treatment and region subgroup and country); study treatment taken prior to the 
death and the number of days since the last dose of this study treatment at the time of the death 
will be included in the listing.  An overview table will be prepared with the incidences of 
subjects, for all subjects and for each treatment, with the following: at least one treatment-
emergent adverse event, at least one treatment-emergent related adverse event, at least one 
treatment-emergent serious adverse event, at least one treatment-emergent serious related 
adverse event, at least one treatment-emergent adverse event leading to early withdrawal, at least 
one treatment-emergent serious adverse event leading to withdrawal, and a report of death 
(Tables 3.1.2.x, overall and by China and Japan regional subgroups and for the regional
subgroups of non-Japan, Asia, as well as by country).
For the purpose of determining if a death occurred during a Treatment Period (for Tables 3.13 
and 3.1.2.x), the end of the Treatment Period is defined as the date of the last visit in the 
Treatment Period, the date of the Discontinuation Visit in the Treatment Period, or if these dates 
were missing, the date of the last data collection for the Treatment Period (i.e., date of death).
The incidence of an adverse event (AE) will be defined as the number and percentage of subjects 
experiencing an event.  Summary tabulations of the following will be prepared for all subjects, 
for each treatment, for each primary system organ class, and for each preferred term within a
system organ class:
4. The incidence of all treatment-emergent adverse events (Table 3.2.1.1.1)
5. The incidence of treatment-emergent adverse events with onset after the last date on 
treatment (Table 3.2.1.2.1)


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6. The incidence of non-serious treatment-emergent DGYHUVHHYHQWVRFFXUULQJLQRI
subjects in a treatment (Table 3.2.4.1)
7. The incidence of all treatment-related treatment-emergent adverse events (Table 3.4.1)
8. The incidence of discontinuation from the study due to a treatment-emergent adverse event 
(Table 3.5.1.1)
9. The incidence of treatment-emergent serious adverse events overall and by region 
subgroup/country (Table 3.7.1.1)
10. The incidence of treatment-emergent serious adverse events with onset after the last date on 
treatment (Table 3.7.2.1)
11. The incidence of treatment-emergent serious related adverse events (Table 3.10.1)
12. The incidence of all treatment-emergent adverse events by highest severity to treatment 
(Table 3.11.1.1)
13. A summary tabulation will also be prepared for the incidence of treatment-emergent adverse 
events occurring in at least 2% of subjects in any treatment (Table 3.2.2.1, sorted by 
descending frequency of events in a preferred term).
14. In addition, to control for possible differences in exposure between the treatments, the 
following AE and SAE summaries will be presented with the frequency and rate of 
occurrence (total number of events per 1000 person-years of exposure) by treatment, primary 
system organ class, and preferred term: 
a) Frequency and rate of AEs (Table 3.3.1)
b) Frequency and rate of SAEs (Table 3.9.1).
6.6.1.1
Adverse Events of Special Interest
Adverse events of special interest have been defined based on known effects of LAMAs and 
LABAs; these include cardiovascular effects, ocular disorders, urinary retention, gastrointestinal 
disorders, and anticholinergic effects for LAMAs and cardiovascular and tremor effects for 
LABAs (Table 9).  Standard MedDRA queries (SMQs) will be utilized when possible and a 
selection of preferred terms in other situations (Appendix 5).
Table 9
Adverse Events of Special Interest
AE Group
Selection of Terms
Cardiovascular
Cardiac Arrhythmias SMQ
Cardiac Failure SMQ
Myocardial Infarction SMQ
Other Ischaemic Heart Disease SMQ
CNS Haemorrhages and Cerebrovascular Conditions SMQ
Sudden Death (collection of PTs)
Torsade de Pointes/QT Prolongation SMQ


Statistical Analysis Plan
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Final Version:  07 Mar 2017
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AE Group
Selection of Terms
Tremor
Collection of PTs
Urinary Retention
Urinary Tract Signs and Symptoms High Level Group Term 
(HLGT)
Ocular Effects
Visual Disorders High Level Term (HLT)
Glaucoma SMQ
Gastrointestinal
Gastrointestinal Obstruction SMQ
Anticholinergic Effects
Anticholinergic Syndrome SMQ
Appendix 5 is currently based on Version 19.1 of MedDRA and provides detail on selection of 
terms (narrow/wide designations for preferred terms are provided). The selection of terms may 
change when Appendix 5 is updated using Version 20.0 of MedDRA prior to database lock of 
PT003014. 
A summary tabulation of the incidence of treatment-emergent adverse events occurring in 
SMQs/groupings of interest will be prepared for all subjects, for each treatment, for each primary 
system organ class, and for each preferred term within a system organ class (Table 3.2.3.1).
6.6.1.2
Cause of Death Determined by Adjudication Committees
Causes of death will be listed (Table 3.13) by subject and summarized by treatment for (1) all-
cause mortality, (2) mortality of probable cardiovascular cause, (3) mortality of probable 
respiratory cause and (4) mortality of probable other causes using the Safety Population based on 
(A) cases reported during the active Treatment Period and (B) cases reported during the active 
Treatment Period plus the following 14 days (Table 3.1.1).  The percentage of subjects with a 
death event will be tabulated by primary system organ class, preferred term and treatment
(Table 3.12.1).


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
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6.6.2
Clinical Laboratory Measurements
Lab parameters collected include the following:
Table 10
Lab Parameters
Hematology
Hemoglobin
Mean corpuscular hemoglobin (MCH)
Hematocrit
Mean corpuscular hemoglobin concentration 
(MCHC)
White Blood Cell count with differential
(including eosinophils)
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 Screening and Final Visit (Visit 11) only and Urine HCG at Visit 8 (Week 12) 
Glomerular filtration rate will be estimated by the central laboratory using the CKD EPI 
equation.
a Parameters included in the Basic Metabolic Panel (BMP).


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A Clinically Significant Laboratory Abnormality as identified by the investigator after the 
start of study treatment will be recorded as an Adverse Event and tabulated as an AE in the AE 
analysis.  Abnormalities occurring prior to the start of treatment will be noted in medical history 
and presented in a data listing.  Per protocol, the criteria for a "clinically significant" laboratory 
abnormality are:
x
A laboratory abnormality that leads to a dose-limiting toxicity (e.g., an abnormality that 
results in study drug dose reduction, suspension or discontinuation)
x
A laboratory abnormality that results in any therapeutic intervention (i.e., concomitant 
medication or therapy)
x
Other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (e.g., significant fall in hemoglobin not requiring transfusion)
All laboratory data will be stored in the database with the units in which they were originally 
reported.  Laboratory data not reported in International System of Units (SI units; Système 
International d’Unités) will be converted to SI units before data analysis.
Individual clinical laboratory variables for hematology and clinical chemistry and kidney 
function, including creatinine clearance, will be provided in listings (Listing 8.1 for hematology, 
Listing 8.2 for morphology, Listing 8.3 for blood chemistry and kidney function, Listing 8.4 for 
urinalysis, and Listing 9.3 for pregnancy test results after the start of treatment).  Data will be 
listed in SI units where available.  Comments for laboratory testing will be listed (Listing 8.5).
For listings, laboratory values will be flagged as Low or High based on the reference ranges 
provided by the central laboratory, LabCorp Laboratories (Appendix 4).
The baseline measurement for a laboratory parameter will be the last available measurement 
prior to the start of dosing at Day 1 (Visit 4).
If there are multiple laboratory values for the same parameter at pre-dose of a visit, the last value 
will be chosen for analysis.
Summary statistics (n, mean, median, standard deviation, minimum, and maximum) for the 
baseline assessment and for the pre-dose value and change from baseline at each post-baseline 
visit and end of treatment for scheduled lab assessments of continuous laboratory variables 
including serum potassium and glucose will be tabulated. “End of Treatment” is defined as the 
last non-missing assessment during the treatment period. Data from unscheduled visits will not 
be used for this analysis, unless a prior or subsequent visit is missing where a laboratory value 
was scheduled to be collected.  That is, laboratory data obtained during unscheduled visits will 
be allocated to the scheduled visit prior to the unscheduled visit if it was missed or to the next 
missing scheduled visit (not more than 4 weeks subsequent) if the previous scheduled visit was 
not missing.  If there is not an adjacent missing visit, then the data will not be used in analyses, 
but will be listed.  This implies that laboratory data obtained during a premature discontinuation 
visit will generally be assigned to the next missing scheduled visit.  The summaries will be 


Statistical Analysis Plan
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provided by treatment (Table 3.14.1, Table 3.14.2, 3.14.3, and Table 3.14.4, for hematology, 
blood chemistry, kidney function, and urinalysis pH and specific gravity, respectively).
Other than for the change from baseline analyses mentioned above, all available data 
post-baseline including data from unscheduled visits will be used for laboratory analyses.
Shift tables will be produced using the categories defined by the CTCAE Version 4.03 grades 
(Tables 3.14.5, Table 3.14.6, and Table 3.14.7 for hematology, chemistry, and kidney function, 
respectively).  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.  Percentages of subjects in each maximum post-baseline grade for a treatment will be 
calculated for each pre-dose grade for the treatment and also for all baseline grades combined.  
Laboratory abnormal values on-treatment will be flagged as High or Low values based on 
laboratory reference ranges provided by LabCorp Laboratories as per Pearl.  These flags along 
with the reference ranges will be provided in the laboratory data listings.
Potentially Clinically Significant Laboratory Values Above/Below a Clinically Relevant 
Threshold on-treatment, based on CTCAE 4.03 and other criteria, will be identified based on the 
following thresholds:
Table 11
Potentially Clinically Significant (PCS) Laboratory Parameter Criteria
Parameter
Post-Baseline Criteria
Hematology
Hemoglobin 
<8.0 g/dL (<80 g/L)
Increase of >40 g/L to a value above the ULN
White Blood Cell Count
<2000/mm3 (<2 x 109/L)
>100,000/mm3 (>100 x 109/L)
Platelet Count
<50,000/mm3 (<50 x 109/L)
>700,000/mm3 (>700 x 109/L)
Chemistry
eGFR-EPI 
<30 mL/min/1.73 m2
GGT
>2.5 x ULN
AST
>3 x ULN
ALT
>3 x ULN
Alkaline Phosphatase
>5 x ULN
Total Bilirubin
>1.5 x ULN
Triglycerides
>500 mg/dL (>5.65 mmol/L)
Cholesterol 
>400 mg/dL (>10.34 mmol/L)
Albumin
<2 g/dL (<20 g/L)


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Parameter
Post-Baseline Criteria
Blood Glucose*
(random values)
<2.2 mmol/L
>13.9 mmol/L
Serum Potassium
<3.0 mmol/L
>6.0 mmol/L
*CTCAE 4.03 criteria are based on fasting glucose values.  However, 
subjects were not required to fast prior to obtaining blood glucose values.
The number and percentage of subjects with newly occurring or worsening potentially clinically 
significant laboratory values above or below a clinically relevant threshold value on-treatment 
will be summarized (Table 3.14.8 except for the PCS high Hemoglobin criteria).  The number 
and percentage of subjects with a potentially clinically significant hemoglobin increase 
post-baseline of >40 g/L to a value above the ULN will be tabulated similarly (Table 3.14.8).
Since a reduction in potassium and an increase in blood glucose are known class effects of 
beta-agonists, all potassium or glucose assessments for subjects who experienced newly 
occurring or worsening potentially clinically significant values after start of the study treatment 
will be provided in separate listings (Tables 3.14.9 and 3.14.10).  For all laboratory parameters 
other than glucose and potassium noted in Table 11, all laboratory data for the parameter 
identified as potentially clinically significant for a subject will be listed (Table 3.14.11).
6.6.3
Vital Signs
Changes from Baseline in on-treatment supine systolic blood pressure, supine diastolic blood 
pressure, heart rate, and body temperature will be evaluated, where baseline is defined as the 
average of all available pre-dose measurements taken prior to the start of dosing for the 
Treatment Period (two measurements are scheduled pre-dose within 5 minutes apart for all 
parameters except body temperature where only one measurement is planned). 
A Clinically Significant Abnormality in vital signs identified by the investigator will be 
recorded as an Adverse Event if it occurs after the start of treatment.  These adverse events will 
be included in the AE summaries; abnormalities prior to the start of treatment will be noted in 
medical history and listed.
Potentially clinically significant changes in systolic and diastolic blood pressure will be 
defined based on the following criteria provided by Pearl:


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Table 12
Potentially Clinically Significant (PCS) Criteria for Systolic and Diastolic 
Blood Pressure Parameters
Parameter (mmHg)
Post-Baseline Criteria
Systolic Blood Pressure, increase
PP+JDQGLQFUHDVHIURPEDVHOLQHPP+J
Systolic Blood Pressure, decrease
PP+JDQGGHFUHDVHIURPEDVHOLQHPP+J
Diastolic Blood Pressure, increase
PP+JDQGLQFUHDVHIURPEDVHOLQHPP+J
Diastolic Blood Pressure, decrease
PP+JDQGGHFUHDVHIURPEDVHOLQHPP+J
Potentially clinically significant (PCS) changes in heart rate will be assessed as follows:
Table 13
Potentially Clinically Significant Criteria for Heart Rate Parameters
Parameter
Post-Baseline Criteria
Tachycardia Event
ESPDQGLQFUHDVHIURPEDVHOLQH
Bradycardia Event
ESPDQGGHFUHDVHIURPEDVHOLQH
Vital sign measurements (heart rate, systolic blood pressure, diastolic blood pressure, body 
temperature, weight, and height) during the study will be displayed in a vital signs listing 
(Listing 9.1).
A summary of baseline weight, height, and BMI will be presented by treatment (Tables 1.4.1, 
1.4.2, and 1.4.4 for the ITT, PP, and Safety Populations, respectively).
Baseline will be defined as the average of the values prior to dosing at Visit 4 (Day 1).  Summary 
statistics (n, mean, median, standard deviation and range) of the measured value and change 
from baseline for heart rate, systolic blood pressure, diastolic blood pressure, and body 
temperature will be tabulated by treatment, visit, and timepoint.  These summaries will be 
prepared for baseline and each scheduled post-baseline nominal timepoint at each scheduled 
post-baseline visit and end of treatment.  “End of Treatment” will be summarized for each 
scheduled post-baseline timepoint (pre-dose, post-dose 30 minutes, and post-dose 2 hours).  End 
of Treatment for each of these assessment points is defined as the last non-missing on-treatment 
assessment available for the timepoint. Data from unscheduled visits will not be used for this 
analysis, unless a prior or subsequent visit is missing where a vital sign value was scheduled to 
be collected.  That is, vital sign data obtained during unscheduled visits will be allocated to the 
scheduled visit prior to the unscheduled visit if it was missed or to the next missing scheduled 
visit (not more than 4 weeks subsequent) if the previous scheduled visit was not missing.  If there 
is not an adjacent missing visit, then the data will not be used in analyses, but will be listed.  This 
implies that vital sign data obtained during a premature discontinuation visit will generally be 
assigned to the next missing scheduled visit.  Time windows will be derived for each 
post-baseline visit using the time intervals for the study time windows detailed below in Table 14
(Table 3.15.1).


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Table 14
Analysis Study Time Windows for Vital Signs Assessments
Calculated Study Time Window
Time Interval for the Study Time Window
Pre-dose
PLQ Prior to dose
Post-dose 30 min
>0 to <75 min Post-dose
Post-dose 2 hrs
PLQto <4 hrs post-dose
Note that minutes are rounded to the nearest whole number before applying time windows.
If there are multiple vital sign values for the same parameter at pre-dose assessments after Visit 4
or within the same post-dose study time window at a visit, the last value will be chosen for 
analysis.
The percentage of subjects with potentially clinically significant values for vital signs at any time 
post-dose at a visit will be summarized by treatment based on the criteria in Table 12 and 
Table 13 (Table 3.15.2); the percentage of visits where a post-baseline value was PCS will also 
be provided for each treatment group in Table 3.15.2.  For this analysis, all available data post-
baseline including data from unscheduled visits will be used.
All vital sign assessments for subjects with potentially clinically significant values will be listed 
(Tables 3.15.3 and 3.15.4).
6.6.4
12-Lead Electrocardiogram Measurements
Changes from baseline in Heart Rate, PR Interval, QRS Axis, QRS Interval, QT Interval and 
QTcF interval will be calculated where baseline is defined as the average of all available 
pre-dose measurements taken prior to the start of dosing for the treatment (two measurements are 
scheduled pre-dose within 5 minutes apart).  The QTcF (Fridericia Corrected QT) is defined as 
[QT/(RR1/3)].
A Clinically Significant Abnormality for a 12-Lead ECG measurement identified by the 
investigator as a clinically significant abnormality will be recorded as an Adverse Event if it 
occurred after the start of study treatment.  These adverse events will be included in the AE 
summaries.
All 12-Lead ECG measurements for the Safety Population will be listed (Listing 9.2).  Summary 
statistics (mean, median, standard deviation and range) for raw values and change from baseline 
values in Heart Rate, 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 Visit 4 (Day 1).  These assessments will be tabulated for each 
treatment and each scheduled post-dose nominal timepoint (derived using the time intervals for 
the study time windows detailed below in Table 15) at each visit and at end of treatment 
(Table 3.16.1).  “End of Treatment” will be summarized for each scheduled post-baseline 
timepoint (pre-dose, post-dose 30 minutes, and post-dose 2 hours).  End of Treatment for each of 
these assessment points is defined as the last non-missing on-treatment assessment available for 


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the timepoint. Data from unscheduled visits will not be used for this analysis, unless a prior or 
subsequent visit is missing where an ECG parameter value was scheduled to be collected.  That 
is, an ECG parameter value obtained during unscheduled visits will be allocated to the scheduled 
visit prior to the unscheduled visit if it was missed or to the next missing scheduled visit (not 
more than 4 weeks subsequent) if the previous scheduled visit was not missing.  If there is not an 
adjacent missing visit, then the data will not be used in analyses, but will be listed.  This implies 
that an ECG parameter value obtained during a premature discontinuation visit will generally be 
assigned to the next missing scheduled visit.  Mean pre-dose change from baseline for QTcF and 
heart rate will be plotted across post-baseline visits by treatment (Figure 3.16.1a and Figure 
3.16.1c).  Mean change from baseline for QTcF and heart rate across the 2-hour post-dose 
interval will be plotted by treatment (Figures 3.16.1b and 3.16.1d, respectively).
ECG data from subjects with pacemakers will not be included in analyses, but will be listed.
Table 15
Analysis Study Time Windows for ECG Assessments
Calculated Study Time Window
Time Interval for the Study Time Window
Pre-dose
PLQ Prior to dose
Post-dose 30 min
>0 to <75 min Post-dose
Post-dose 2 hrs
PLQWRKUV Post-dose
Note: The minutes are rounded to the nearest whole number before applying time windows.
If there are multiple ECG values for the same parameter at pre-dose of a visit date (other than for 
Visit 4) or within the same post-dose study time window on a visit date, the last value will be 
chosen for analysis.
Other than for the change from baseline analyses mentioned above, all available data 
post-baseline including data from unscheduled visits will be used for ECG parameter analyses.


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Table 16
Criteria for Potentially Clinically Significant (PCS) ECG Values
Parameter 
Post-Baseline Criteria 
QTcF Prolongation 
x
Post-baseline value is >450 msec for male subjects or 
>470 msec for female subjects
x
Post-baseline value is >500 msec
x
Increase from baseline is >30 msec
x
Increase from baseline is >60 msec
x
Post-baseline value is >500 msec and increase from 
baseline >30 msec
x
Post-baseline value is >500 msec and increase from 
baseline >60 msec
PR Interval Increase 
Increase from baseline of >50 msec 
QRS Prolongation 
Prolongation of >40 msec from baseline 
Potentially clinically significant ECG parameter values will be identified based on criteria listed 
in Table 16 (provided by Pearl).  The number and percentage of subjects who had such values 
observed any time post-dose will be tabulated for each treatment (Table 3.16.2) and listed 
(Tables 3.16.3, 3.16.4, and 3.16.5, for QTcF prolongation, PR interval increase, and QRS 
prolongation, respectively).  No hypothesis tests will be performed.
6.6.5
Physical Examination
Any physical examination abnormality reported after the start of treatment for a subject is to be 
reported as an adverse event.  Thus, these will be included in listings of adverse events and 
summarized in adverse event summaries.  Abnormalities seen at the Screening physical 
examinations will be recorded as Medical History and listed.
6.7
Subgroup Analyses
Subgroup analyses will be conducted to support local registration requirements including by-
country and by-region assessments of consistency. Subgroups are defined as Asia (defined by 
country and not by race), non-Japan, Europe, and each individual country. Asia includes Japan, 
China, South Korea, and Taiwan.
By country/region subgroup analyses of efficacy endpoints will implement the same 
methodology as described for the overall ITT population. Forest plots will be provided for each 
endpoint. In addition, Galbraith plots, and Q-Q plots will aid in the consistency assessment of 
treatment effects across countries/regional subgroups. Safety assessments will include by-
country/region tabulations of adverse events.
In addition, subgroup analyses for the lung function endpoints, change from baseline in morning 
pre-dose trough FEV1 and peak change from baseline in FEV1, will also be conducted based on


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GOLD 2017 categories (A, B, C, and D) and GOLD 2, 3, and 4 subgroups. Forest plots will be 
provided by subgroup.
Disposition, Demography, Baseline Characteristics, and Efficacy Summaries
Tabulations will be provided for subgroups of the ITT Population unless otherwise noted. The 
following tables will be provided for both region/country, GOLD A, B, C, and D category, and 
GOLD 2, 3, and 4 (unless it is specified below that subgroup tables will only be provided for 
region/country):
x
Subject disposition by region/country (Tables 2.20.x)
x
Reason for early discontinuation by region/country (Tables 2.21.x)
x
Demographics and baseline characteristics (Tables 2.22.1.x through Table 2.22.3)
x
Screening pre- and post-bronchodilator and baseline spirometry parameters by 
region/country (Tables 2.23.x)
x
Severity and duration of COPD (Tables 2.24.1.x through Table 2.24.3)
x
Reversibility to Ventolin HFA (Tables 2.25.1.x through Table 2.25.3)
x
Reversibility to Atrovent HFA (Tables 2.26.1.x through Table 2.26.3)
x
Exposure and compliance (Tables 2.27.1.x through Table 2.27.3 for the Safety Population)
x
Change from baseline in trough FEV1 (Tables 2.28.1.x through Table 2.28.3;Forest,
Galbraith, and Q-Q Plots for region subgroup/ country will be provided in Figures 2.28.1.1 
through 2.28.1.3.3; Forest plots for GOLD category and severity subgroups will be provided 
in Figures 2.28.2.1 through 2.28.3.3)
x
TDI focal score by region/country (Tables 2.29.x; Forest, Galbraith, and Q-Q Plots: 
Figures 2.29.1 through 2.29.3.2)
x
Peak change from baseline in FEV1 (L) Within 2 Hours Post-Dose (Tables 2.30.1.1.x, 
through 2.30.3; Forest Plots for all subgroups, and Galbraith and Q-Q Plots for region 
subgroup/country only: Figures 2.30.1.1 through 2.30.3.3)
x
Change from baseline in SGRQ total score by region/country (Tables 2.31.1.x; Forest, 
Galbraith, and Q-Q Plots: Figures 2.31.1.1 through 2.31.3.2) (these will be descriptive 
analyses only)
x
Response in SGRQ total score DFKLHYHPHQWRIDQ0&,'WKUHVKROGRIXQLWVRQDYHUDJHLQ
SGRQ total score) over Weeks 12-24 and separately at Week 24 by Region/Country 
(Tables 2.32.x; Forest Plot: Figure 2.32)
x
Change from baseline in mean daily number of puffs of rescue Ventolin HFA by 
region/country (Table 2.33.1.x for the ITT Population and Table 2.33.2.x in the Rescue 
Ventolin User Population; Forest, Galbraith, and Q-Q Plots in the ITT Population: Figures 
2.33.1.1through 2.33.1.3.2; Forest, Galbraith and Q-Q Plots in the Rescue Ventolin User 
Population: Figures 2.33.2.1through 2.33.2.3.2 ); this analysis will be repeated in the Rescue 
Ventolin User Population if sample sizes permit (Modelling will be performed for countries 


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with a sample size of 30, for which the sample size is no lower than 6 for any one treatment 
(Bell et al, 2010)
x
Change from baseline in FEV1 at 5 min post-dose on Day 1 by region/country (Table 2.34;
Forest, Galbraith, and Q-Q Plots: Figures 2.34.1 through 2.34.3).
x
Change from baseline in FEV1 at 15 min post-dose on Day 1 by region/country (Table 2.35;
Forest , Galbraith, and Q-Q Plots: Figures 2.35.1 through 2.35.3)
Subgroup analyses by CAT Score Subpopulation &$7VFRUHVRIDQGhave been 
covered above (Section 6.4) for the following symptom endpoints:
x
TDI endpoints (Tables 2.2.1 for TDI focal score, Table 2.2.2.1 for individual components, 
and Table 2.2.3 for TDI responder rates)
x
SGRQ endpoints (Tables 2.4.1 for SGRQ total score, Table 2.4.2 for individual domains, and 
Table 2.4.3 for SGRQ responder rates)
x
COPD exacerbation endpoints (Tables 2.13.1 for rate of COPD exacerbations of any severity 
and rate of moderate and severe COPD exacerbations, Table 2.13.2 for rate of COPD 
exacerbations of any severity and rate of moderate and severe COPD exacerbations with 
imputation, Table 2.14 for time to COPD exacerbation of any severity and time to moderate 
and severe COPD exacerbation, and Table 2.15 for time treatment failure).
For the efficacy endpoints (except for change from baseline in FEV1 at 5 and 15 mins post-dose 
on Day 1), a separate model will be fit for each subgroup category including terms for baseline 
for the specific endpoint, percent reversibility to Ventolin HFA, visit, treatment, and the 
treatment-by-visit interaction. The unstructured matrix will be used to model the variance-
covariance structure within subject.  If this model fails to converge, the heterogeneous Toeplitz 
(TOEPH) will be fit. As sample sizes will be relatively small in some countries, a compound 
symmetric structure will be used in the event that neither the unstructured nor the heterogeneous 
Toeplitz models converge. Modelling will be performed for countries with a sample size of 30,
for which the sample size is no lower than 6 for any one treatment (Bell et al, 2010).
The subgroup analyses for change from baseline in FEV1 at 5 and 15 mins post-dose on Day 1
will be analyzed using a model including terms for baseline FEV1 and percent reversibility to 
Ventolin HFA and treatment. Estimates for the treatment effect and for the treatment difference 
for all pairwise comparison of treatments will be displayed in the efficacy endpoint tables for 
each subgroup.
For each subgroup analysis (excluding CAT Score Subpopulations), a test for the treatment-by-
subgroup interaction will be performed using a model containing the following terms: baseline 
for the specific endpoint (baseline FEV1 or BDI), percent reversibility to Ventolin HFA, visit, 
treatment, treatment-by-visit interaction, subgroup, and the treatment-by-subgroup interaction.  
A table will be provided with the p-value for the test of the treatment-by subgroup interaction 
and with the p-value for the subgroup main effect (Table 2.37).  Should any country/region 


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subgroup effects be identified, shrinkage estimates may be generated in order to further 
understand the impact of these effects (Carroll and Fleming, 2013).
Safety Summaries:
An overview table will be prepared with the incidences of subjects, for all subjects in the safety 
population and for each treatment, with the following: at least one treatment-emergent adverse 
event, at least one treatment-emergent related adverse event, at least one treatment-emergent 
serious adverse event, at least one treatment-emergent serious related adverse event, at least one 
treatment-emergent adverse event leading to early withdrawal, at least one treatment-emergent 
serious adverse event leading to withdrawal, and a report of death (Tables 3.1.2.x, by China and 
Japan regional subgroups and for the regional subgroups of non-Japan, Asia, as well as by 
country).
Summary tabulations of the following will be prepared for all subjects, for each treatment, for 
each primary system organ class, and for each preferred term within a system organ class, by 
region subgroup/country: 
1. The incidence of all treatment-emergent adverse events by region subgroup/country 
(Tables 3.2.1.1.x)
2. The incidence of treatment-emergent adverse events with onset after the last date on 
treatment by region subgroup/country (Tables 3.2.1.2.x)
3. The incidence of treatment-emergent adverse events occurring in SMQs (Standard MedDRA 
Queries)/groupings of interest by region subgroup/country (Tables 3.2.3.x)
4. The incidence of non-serious treatment-HPHUJHQWDGYHUVHHYHQWVRFFXUULQJLQRI
subjects in a treatment by region subgroup/country (Tables 3.2.4.x)
5. The incidence of all treatment-related treatment-emergent adverse events by region 
subgroup/country (Tables 3.4.x)
6. The incidence of discontinuation from the study due to a treatment-emergent adverse event
by region subgroup/country (Tables 3.5.1.x)
7. The incidence of treatment-emergent serious adverse events by region subgroup/country 
(Tables 3.7.1.x)
8. The incidence of treatment-emergent serious adverse events with onset after the last date on 
treatment by region subgroup/country (Tables 3.7.2.x)
9. The incidence of treatment-emergent serious related adverse events by region 
subgroup/country (Tables 3.10.x)
10. The incidence of all treatment-emergent adverse events by highest severity to treatment by 
region subgroup/country (Table 3.11.1.2 through 3.11.4.x)
11. A summary tabulation will also be prepared for the incidence of treatment-emergent adverse 
events occurring in at least 2% of subjects in any treatment by region subgroup/country
(Tables 3.2.2.x, sorted by descending frequency of events in a preferred term).


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12. In addition, to control for possible differences in exposure between the treatments, the 
following AE and SAE summaries will be presented with the frequency and rate of 
occurrence (total number of events per 1000 person-years of exposure) by treatment, primary 
system organ class, and preferred term, by region subgroup/country: 
a) Frequency and rate of AEs (Tables 3.3.x)
b) Frequency and rate of SAEs (Tables 3.9.x).
13. The percentage of subjects with a death event will be tabulated by primary system organ 
class, preferred term, and treatment by region subgroup/country (Tables 3.12.x).
6.7.1
China and Asia
To support registration in China, a separate Clinical Study Report will be written to present the 
study results in the China and Asia Populations with the objective of demonstrating consistency 
with the overall Study PT003014 population. Select subject disposition, demographic and 
baseline characteristics and extent of exposure, efficacy, and safety analyses will be repeated for 
the China and Asia Populations using the analysis sets described in Section 5.4, including 
relevant subgroup and sensitivity analyses; healthcare resource utilization analyses will be 
provided in the China Population. Appendix 7 and Appendix 8 contain the table of contents for 
Post-Text TFLs in the China and Asia Populations, respectively.
Efficacy analyses in the China and Asia Populations will proceed as described in Section 6.7.
All statistical analyses based on the China and Asia Populations will be considered exploratory. 
No adjustment for multiplicity will be made and so the hierarchical testing detailed in 
Section 6.4.4 to control the Type I error will not be employed directly to the China Population 
results.
Safety analyses will include tabulations of adverse events, laboratory parameters, vital signs, and 
ECGs.
7.
ANALYSES PERFORMED BEFORE DATABASE CLOSURE
Interim analyses for the purpose of evaluation of efficacy are not planned for this study.  
However, as planned, the Data Monitoring committee will be provided with pre-specified safety 
analyses at pre-determined intervals which will be provided using semi-blinded treatment codes 
(A, B, C, and Placebo MDI) and may require the code to fully unblind analyses if they feel that 
these are necessary to evaluate the safety of study subjects.
The DMC Charter specifies the analyses and output that will be performed and provided 
approximately every six months until the completion of the Phase III trials.  These reports will be 
provided in an appendix to the clinical study report.
8.
CHANGES FROM METHODS PLANNED IN THE PROTOCOL
The Protocol incorrectly characterized the other efficacy endpoints for total and individual 
symptoms scores as “morning” and “evening” which would imply a shorter duration of 


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assessment than what was intended.  These other efficacy endpoints should actually be referred 
to as “daytime” and “nighttime” total and individual symptoms scores to better reflect the 12-
hour assessment period.
As planned per protocol, analyses of the rate of all COPD exacerbations of any severity will be 
performed using negative binomial regression. The model has been revised to include an 
additional covariate of baseline continuous eosinophil count.  Adjusted rates of exacerbations 
will be estimated using data-based weights from the study population for the categorical 
covariates of baseline COPD Exacerbation history, smoking status at baseline, and ICS use at 
baseline, and the arithmetic mean level of the continuous covariate, baseline percent predicted 
FEV1 and baseline continuous eosinophil count.
As planned per protocol, analyses of the time to first COPD exacerbation of any severity will be 
performed using a Cox regression model.  The model has been revised to include an additional 
covariate of baseline continuous eosinophil count.  Hazard ratios will be estimated using the 
categorical covariates of baseline COPD Exacerbation history, smoking status at baseline, and 
ICS use at baseline, and the arithmetic mean level of the continuous covariates, baseline percent 
predicted FEV1 and baseline continuous eosinophil count.
All analyses of the rate of moderate and severe COPD exacerbations and the time to first 
moderate or severe COPD exacerbation will be performed similarly to the rate of COPD 
exacerbations of any severity and the time to first COPD exacerbation of any severity (described 
above).
As planned in the protocol, 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.  The model has been revised to include an additional covariate of baseline continuous 
eosinophil count.
As planned in the protocol, the time to treatment failure will be analyzed using a Cox regression 
model. The model has been revised to include an additional covariate of baseline continuous 
eosinophil count.
Any changes to methods planned in this statistical analysis plan will be documented in a revision 
to this statistical plan prior to database lock, or identified in the clinical study report.
9.
STATISTICAL SOFTWARE
Data processing, statistical screening, descriptive reporting and analysis of the efficacy and 
safety data will be performed using SAS (Version 9.4 or higher).  Graphs may also be produced 
using R (R Development Core Team, 2003).


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10.
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dependent test statistics.  Journal of the American Statistical Association, 1997; 92 1601–1608.
van Noord JA.  Comparison of tiotropium once daily, formoterol twice daily and both combined 
once daily in subjects with COPD.  European Respiratory Journal. 2005; 26(2): 214–222.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 87 of 97)
Confidential and Proprietary
APPENDIX 1: DATA HANDLING RULES
Programming of the tables, listings and figures will be performed using SAS Version 9.4 or a 
more recent version.  This appendix will be provided as a separate document.
APPENDIX 2: ANALYSIS DATASET SPECIFICATIONS
Analysis datasets will be built to gain efficiency and ensure consistency in data analyses and 
presentation for this trial.  The specifications for each analysis data set will be prepared 
separately and will not be a part of this SAP.
APPENDIX 3: SAS CODE FOR STATISTICAL ANALYSES
Test
Template SAS Code for Modeling (SAS Version 9.4)
Linear 
Repeated 
Measures 
(RM) 
Analysis of 
Covariance 
for primary 
and 
applicable 
secondary or 
other efficacy 
analyses (not 
for analyses 
of time to 
onset of 
action and 
percent 
response 
variables)
ODS GRAPHICS ON;
PROC MIXED PLOTS =ALL;
TITLE2 ‘UNSTRUCTURED COVARIANCE MATRIX';
TITLE3 'Y IS CHANGE FROM BASELINE IN MORNING PRE-
DOSE TROUGH’;
CLASS SUBJECT TRT VISIT;
MODEL Y= BASEFEV1 REVVEN VISIT TRT TRT*VISIT 
/DDFM=KR INFLUENCE 
OUTP=PREDICT;
REPEATED VISIT / TYPE = UN  SUBJECT=SUBJECT;
LSMEANS TRT | VISIT/PDIFF CL; 
*SAS default: LSMEANS will be provided at the average level of the 
continuous baseline covariates where the average was defined as the average 
taken across all observations used in the analysis;
LSMEANS TRT/PDIFF CL; /*over 12-24 weeks*/
ODS GRAPHICS OFF;
Where BASEFEV1 is baseline FEV1, TRT is treatment, and REVVEN is percent 
reversibility to Ventolin HFA at Visit 2.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 88 of 97)
Confidential and Proprietary
Test
Template SAS Code for Modeling (SAS Version 9.4)
THE PLOTS=ALL OPTION FOR PROC MIXED WILL BE USED TO GET 
PLOTS TO PERFORM MODEL DIAGNOSTICS.  Influence statistics will be 
requested using the “influence (<options>)” option on the model statement.
LSMEANS TRT | VISIT/PDIFF; /* This lsmeans statement shown in the model 
above will automatically compute the lsmeans at the mean values of the two 
covariates in the data being analyzed, BASEREV1 and REVVEN (V1 and V2, 
respectively).
*The following code could be used to compute and compare means that will be 
averaged across the last four visit values (weeks 12, 16, 20, and 24) where v1 
and v2 are the values of the two covariates, then the means were obtained from;
ESTIMATE ‘TRT 1 LAST 4’ INTERCEPT 1   
BASEFEV1 v1   REVVEN v2   VISIT 0 0 0 .25 .25 .25 .25   TRT 1 0 0 0   
TRT*VISIT 0 0 0 .25 .25 .25 .25   0 0 0 0 0 0 0   
0 0 0 0 0 0 0   0 0 0 0 0 0 0/ CL;
ESTIMATE ‘TRT 2 LAST 4’ INTERCEPT 1   
BASEFEV1 v1   REVVEN v2   VISIT 0 0 0 .25 .25 .25 .25   TRT 0 1 0 0   
TRT*VISIT   0 0 0 0 0 0 0   0 0 0 .25 .25 .25 .25   
0 0 0 0 0 0 0   0 0 0 0 0 0 0/ CL;
ESTIMATE ‘TRT 3 LAST 4’ INTERCEPT 1   
BASEFEV1 v1   REVVEN v2   VISIT 0 0 0 .25 .25 .25 .25   TRT 0 0 1 0   
TRT*VISIT   0 0 0 0 0 0 0   0 0 0 0 0 0 0   
0 0 0 .25 .25 .25 .25   0 0 0 0 0 0 0/ CL;
ESTIMATE ‘TRT 4 LAST 4’ INTERCEPT 1 
BASEFEV1 v1   REVVEN v2   VISIT 0 0 0 .25 .25 .25 .25   TRT 0 0 0 1   
TRT*VISIT   0 0 0 0 0 0 0   0 0 0 0 0 0 0   
0 0 0 0 0 0 0   0 0 0 .25 .25 .25 .25/ CL;
/* PAIRWISE DIFFERENCES AMONG THE TRTS
WHEN AVERAGING OVER THE LAST FOUR 


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 89 of 97)
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Test
Template SAS Code for Modeling (SAS Version 9.4)
VISITS WERE GIVEN BY: */
ESTIMATE ‘TRT 1 VS 2 LAST 4’   
TRT 1 -1 0 0
TRT*VISIT 0 0 0 .25 .25 .25 .25   0 0 0 -.25 -.25 -.25 -.25
0 0 0 0 0 0 0   0 0 0 0 0 0 0/ CL;
ESTIMATE ‘TRT 1 VS 3 LAST 4’   
TRT 1 0 -1 0
TRT*VISIT 0 0 0 .25 .25 .25 .25   0 0 0 0 0 0 0   
0 0 0 -.25 -.25 -.25 -.25   0 0 0 0 0 0 0/ CL;
ESTIMATE ‘TRT 1 VS 4 LAST 4’   
TRT 1 0 0 -1
TRT*VISIT 0 0 0 .25 .25 .25 .25   0 0 0 0 0 0 0   
0 0 0 0 0 0 0   0 0 0 -.25 -.25 -.25 -.25/ CL;
ESTIMATE ‘TRT 2 VS 3 LAST 4’   
TRT 0 1 -1 0
TRT*VISIT 0 0 0 0 0 0 0   0 0 0 .25 .25 .25 .25   
0 0 0 -.25 -.25 -.25 -.25   0 0 0 0 0 0 0/ CL;
ESTIMATE ‘TRT 2 VS 4 LAST 4’   
TRT 0 1 0 -1
TRT*VISIT 0 0 0 0 0 0 0   0 0 0 .25 .25 .25 .25   
0 0 0 0 0 0 0   0 0 0 -.25 -.25 -.25 -.25/ CL;
ESTIMATE ‘TRT 3 VS 4 LAST 4’   
TRT 0 0 1 -1
TRT*VISIT   0 0 0 0 0 0 0   0 0 0 0 0 0 0   
0 0 0 .25 .25 .25 .25   0 0 0 -.25 -.25 -.25 -.25/ CL;
ESTIMATE "Treatment 1 at 4 Weeks" INTERCEPT 1 BASEFEV1 v1   
REVVEN v2   VISIT 1 0 0 0 0 0 0   TRT 1 0 0 0   TRT*VISIT   1 0 0 0 0 0 0   0 
0 0 0 0 0 0   0 0 0 0 0 0 0   0 0 0 0 0 0 0/ cl;


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 90 of 97)
Confidential and Proprietary
Test
Template SAS Code for Modeling (SAS Version 9.4)
Etc...  To estimate the treatment effect for a treatment at a specific visit.
FOR DIAGNOSTIC PLOTS, THE FOLLOWING SAS CODE WILL BE 
USED:
proc sort data=predict;
by resid;
proc plot data=predict;
plot resid*pred
resid*TRT;
proc sort data=predict;
by TRT;
proc univariate normal plot data=predict;
id usubjid;
var resid;
by TRT;
Negative 
binomial 
using PROC 
GENMOD
PROC GENMOD;
CLASS SMKSTAT ICSUSE COPDEXFL TRT STUDY;
MODEL Y=PPFEV1 CATSCR EOS COPDEXFL TRT SMKSTAT ICSUSE;
LINK=LOG DIST=NEGBIN OFFSET=LYRS;
LSMEANS TRT / DIFF CL;
ODS OUTPUT LSMEANDIFFS = LSDIFS ESTIMATES=EST 
LSMEANS=LSMEANS PARAMETERESTIMATES=PE;
*LYRS is the logarithm of the amount of time in years (since first dose) over 
which the subject was observed for the count variable Y.
PPFEV1 is screening continuous percent predicted FEV1.
EOS is baseline continuous eosinophil count.
CATSCR is screening continuous CAT Score.
COPDEXFL is COPD exacerbation history (1 for yes and 0 for no) where no 
will be the reference group.
ICSUSE is ICS use at baseline (1 for yes and 2 for no) where no will be the 
reference group.
Smoking status is 1 for current smoker and 2 for former smoker, where current 
smoker will be the reference group.
Treatment will be coded: 1=GFF 2=GP 3=FF and 4=Placebo where Placebo will 
be the reference group.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 91 of 97)
Confidential and Proprietary
Test
Template SAS Code for Modeling (SAS Version 9.4)
/* verify lsmeans*/ ****macro variables specified below are the 
weights/arithmetic means for the covariates;
ESTIMATE '1' INT 1 PPFEV1 &MP CATSCR &MC EOS &MEOS 
COPDEXFL &COPDEXFL1 &COPDEXFL2 
TRT01PN 1 0 0 0;
ESTIMATE '2' INT 1 PPFEV1 &MP CATSCR &MC EOS &MEOS 
COPDEXFL &COPDEXFL1 &COPDEXFL2 
TRT01PN 0 1 0 0;
ESTIMATE '3' INT 1 PPFEV1 &MP CATSCR &MC EOS &MEOS 
COPDEXFL &COPDEXFL1 &COPDEXFL2 
TRT01PN 0 0 1 0;
ESTIMATE '4' INT 1 PPFEV1 &MP CATSCR &MC EOS &MEOS 
COPDEXFL &COPDEXFL1 &COPDEXFL2 
TRT01PN 0 0 0 1;
data lsdifs;
set lsdifs;
rateratio=exp(estimate);
lcl_rateratio=exp(lowercl);
ucl_rateratio=exp(uppercl);
The following NLMIXED model will be used to get the estimates of the 
treatment differences based on rates.
PROC NLMIXED;
PARMS /DATA=PE1; *note that parameter estimates from PROC GENMOD 
are fed into proc nlmixed as starting values; PE1 is based on PE and has B0 to 
B9 variables;
*b0 is the intercept.  K is the dispersion parameter.
LINP=LYRS+ 
B0+B1*(TRT01PN=1)+B2*(TRT01PN=2)+B3*(TRT01PN=3)+B4*EOS
+B5*CATSCR+B6*(ICSUSE='Y')+B7*(SMKSTAT=2)+B8*PPFEV1
+B9*COPDEXFL;
MU = EXP(LINP);
P = 1/(1+MU*K);
MODEL Y ~ NEGBIN(1/K,P);
ESTIMATE '1' 


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 92 of 97)
Confidential and Proprietary
Test
Template SAS Code for Modeling (SAS Version 9.4)
EXP(B0+B1+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMK
STAT +B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25; *ESTIMATE IN 
DAYS;
ESTIMATE '2' 
EXP(B0+B2 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25;
ESTIMATE '3' 
EXP(B0+B3 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25;
ESTIMATE '4' 
EXP(B0+B4 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25;
/* A CHECK TO MATCH GENMOD RESULT */
ESTIMATE '12' 
EXP(B0+B1 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1)*365.25-
EXP(B0+B2 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25;
ESTIMATE '13' 
EXP(B0+B1 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1+B9*&MCOPDEXF)*365.25-
EXP(B0+B3 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25;
ESTIMATE '14' 
EXP(B0+B1 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25-
EXP(B0+B4 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 93 of 97)
Confidential and Proprietary
Test
Template SAS Code for Modeling (SAS Version 9.4)
+B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25;
ESTIMATE '23' 
EXP(B0+B2 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25-
EXP(B0+B3 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25;
ESTIMATE '24' 
EXP(B0+B2 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25-
EXP(B0+B4 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25;
ESTIMATE '34'
EXP(B0+B3 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1 +B9*&MCOPDEXFL)*365.25-
EXP(B0+B4 
+B4*&MEOS+B5*&MCATSCR+B6*&MICSUSE+B7*&MSMKSTAT 
+B8*&MPPFEV1+B9*&MCOPDEXFL)*365.25;
&MEOS is a macro variable with the value of the mean EOS value.
&MCATSCR is a macro variable with the value of the mean CATSCR value.
&MPPFEV1 is a macro variable with the value of mean PPFEV1 value. 
&MCOPDEXFL is a macro variable with the weight for COPDEXFL=’Y’.
&MICSUSE is macro value with the weight for ICSUSE=’Y’.
&MSMKSTAT is a macro value with weight for SMKSTAT=2 which is former 
smoker.
Logistic 
regression 
using PROC 
GENMOD 
ods output Estimates = est;
ods output lsmeans=lsmeans;
ods output LSMeanDiffs=diffs;
proc genmod data=<dataset> descending;
by &by;
class usubjid trt (ref=’4’);
model respn = trt base revven / dist=bin;
lsmeans trt / diff;


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 94 of 97)
Confidential and Proprietary
Test
Template SAS Code for Modeling (SAS Version 9.4)
*to verify the lsmeans;
estimate '1' int 1 trt 1 0 0 0 base &mbase revven &mrevven; *verify lsmeans;
estimate '2' int 1 trt 0 1 0 0 base &mbase revven &mrevven; *verify lsmeans;
estimate '3' int 1 trt 0 0 1 0 base &mbase revven &mrevven; *verify lsmeans;
estimate '4' int 1 trt 0 0 0 1 base &mbase revven &mrevven; *verify lsmeans;
*estimate treatment differences;
estimate '12' trt 1 -1 0 0/* not using /exp option as it will not provide 
p-values in those rows */
estimate '13' trt 1 0 -1 0;
estimate '14' trt 1 0 0 -1;
estimate '23' trt 0 1 -1 0;
estimate '24' trt 0 1 0 -1;
estimate '34' trt 0 0 1 -1;
Where:
RESPN is a binary response variable with values of either 1 (responder) or 0 
(not a responder).
BASE is baseline continuous value and is the baseline for RESPN.
REVVEN is screening continuous percent reversibility.
TRT will be coded: ‘1’=GFF ‘2’=GP ‘3’=FF and ‘4’=Placebo where Placebo 
will be the reference group.
&mbase macro variable is average level of covariate base, where average is 
calculated over non-missing base and percent reversibility to Ventolin HFA; 
*study cannot be missing.
&mrevven macro variable is the average level of covariate percent reversibility 
to Ventolin HFA, where average is calculated over non-missing base and 
percent reversibility to Ventolin HFA;
data lsm; /* proportions */
set est where length(label)=1;
trt=input(label,1.);
keep &by trt mean:;
data or;   /* odds ratios */
set est;
where length(label)=2;
trt=input(substr(label,1,1),1.);
trt=input(substr(label,2,1),1.);


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 95 of 97)
Confidential and Proprietary
Test
Template SAS Code for Modeling (SAS Version 9.4)
lbetaestimate=exp(lbetaestimate);
lbetalowercl=exp(lbetalowercl);
lbetauppercl=exp(lbetauppercl);
keep &by trt _trt lbetaestimate lbetalowercl lbetauppercl probchisq;
ods output additionalestimates=diff;   /* differences in proportions */
proc nlmixed data=&dsin;
by &by;
parms /data=pe1;*b0 is the intercept;
eta=b0+b1*(trt=1)+b2*(trt=2)+b3*(trt=3)+b4*base+b5*revven;
p=exp(eta)/(1+exp(eta));
model respn ~ binomial(1,p);
estimate "d12"
1/(1+exp(b0+b1+b4*&mbase+b5*&mrevven))-
1/(1+exp(b0+b2+b4*&mbase+b5*&mrevven));
estimate "d13"
1/(1+exp(b0+b1+b4*&mbase+b5*&mrevven))-
1/(1+exp(b0+b3+b4*&mbase+b5*&mrevven));
estimate "d14"
1/(1+exp(b0+b1+b4*&mbase+b5*&mrevven))-
1/(1+exp(b0+b4+b4*&mbase+b5*&mrevven));
estimate "d23"
1/(1+exp(b0+b2+b4*&mbase+b5*&mrevven))-
1/(1+exp(b0+b3+b4*&mbase+b5*&mrevven));
estimate "d24"
1/(1+exp(b0+b2+b4*&mbase+b5*&mrevven))-
1/(1+exp(b0+b4+b4*&mbase+b5*&mrevven));
estimate "d34" 
1/(1+exp(b0+b3+b4*&mbase+b5*&mrevven))-
1/(1+exp(b0+b4+b4*&mbase+b5*&mrevven));
Cox 
regression 
model for 
time to 
COPD 
ODS GRAPHICS ON;
PROC PHREG PLOTS (OVERLAY)=(SURVIVAL CUMHAZ);
STRATA TREATMENT;
MODEL TIME*CENSOR(0)=COVARIATE1 COVARIATE2 ….;
OUT=PRED1 SURVIVAL=_ALL_ / ROWID=SUBJECT;


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 96 of 97)
Confidential and Proprietary
Test
Template SAS Code for Modeling (SAS Version 9.4)
exacerbation 
and time to 
first moderate 
or severe 
COPD 
exacerbation
ODS GRAPHICS OFF;
Hazard ratios with Wald two-sided 95% confidence limits for these ratios will 
also be provided for all treatment comparisons.
The time to first COPD exacerbation of any severity will be analyzed up through 
Day 183 (Week 26).
Kaplan-Meier 
Survival 
method for 
time to 
COPD 
exacerbation 
and time to 
first moderate 
or severe 
COPD 
exacerbation 
--95% two-
sided 
confidence 
interval (CI) 
for 
cumulative 
response rate
PROC LIFETEST METHOD=KM PLOTS = (S) OUTSURV=OUT1;
TIME TIME*CENSOR(0);
STRATA TREATMENT;
Get 95% CI from dataset ‘out1’. 
** event=1; censored=0;
Subjects who do not experience a COPD exacerbation will be censored at the 
Week 24 visit or Day 183, whichever is earlier.  Subjects who withdraw from 
the study without experiencing a COPD exacerbation will be censored at the 
date of last contact, the date of the last visit, or the last date of treatment, 
whichever is latest but on Day 183 or earlier.


Statistical Analysis Plan
Protocol Number:  PT003014
Final Version:  07 Mar 2017
(Page 97 of 97)
Confidential and Proprietary
APPENDIX 4: CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES
This appendix is provided as a separate document.
APPENDIX 5: STANDARD MEDDRA QUERIES (SMQ)
This appendix is provided as a separate document.
APPENDIX 6: MOCK-UP TABLES, LISTINGS, AND FIGURES
Mock-up tables, listings, and figures are presented in a separate document.
APPENDIX 7: TABLE OF CONTENTS FOR POST-TEXT TLFs IN THE CHINA 
POPULATION
The table of contents for Post-Text TFLs in the China Population is presented in a separate 
document.
APPENDIX 8: TABLE OF CONTENTS FOR POST-TEXT TLFs IN THE ASIA 
POPULATION
The table of contents for Post-Text TFLs in the Asia Population is presented in a separate 
document.


GFF MDI/GP MDI/FF MDI 
PT003014 
Final Version 
07 Mar 2017 
Page 1 of 9 
 
 
APPENDIX 1: DATA HANDLING RULES 
 
Study Number: 
PT003014 
Investigational Drug and 
Drug Number: 
Glycopyrronium and Formoterol Fumarate Inhalation 
Aerosol (GFF MDI); PT003 
Glycopyrronium Inhalation Aerosol (GP MDI); PT005 
Formoterol Fumarate Inhalation Aerosol (FF MDI); 
PT001 
Indication: 
COPD 
Dosage Form/Strength: 
GFF MDI 14.4/9.6 μg ex-actuator BID 
GP MDI 14.4 μg ex-actuator BID 
FF MDI 9.6 μg ex-actuator BID 
 
 
PT003014 Protocol 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 
 
 
 


GFF MDI/GP MDI/FF MDI 
PT003014 
Final Version 
07 Mar 2017 
Page 2 of 9 
 
Programming of the tables, listings and figures will be performed using SAS Version 9.4 or a 
more recent version. 
The following table presents the algorithms to be used in SAS to calculate the derived variables, 
including rules for handling other missing data or partial dates, or irregular/unexpected data 
issues.  Additional variables and rules may be found in the ADaM specification document. 
 
Category 
 
Description 
 
Data Handling Rule 
 
1. Pulmonary 
Function 
Testing data 
iCardiac Technologies, 
Inc. (nSpire Health) 
data transferred 
x Only data of rank =1 (best effort) will be 
transferred; data transferred will be grade 1 
= acceptable, grade 2 = borderline, or 
grade = 3 (unacceptable).  Only data of 
grade = 1 or grade = 2 will be included in 
baseline or on-treatment spirometry 
calculations. 
x All data transferred from  iCardiac 
Technologies, Inc. (grade = 1, 2, or 3) will 
be listed in data listings with the grade. 
2. Age (years) 
Age (years) 
Age = integer part of (Visit 1 date – Birth date 
+1)/365.25. 
3. Smoking 
History 
Number of pack years 
smoked 
Number of pack years smoked = (number of 
cigarettes per day/20) x number of years 
smoked. 
Former smoker 
Former smokers are defined as those who have 
stopped smoking for at least 6 weeks prior to 
Screening (Visit 1). 
Weeks Since a Former 
Smoker Quit 
(Date of Screening Visit 1 – Date Former 
Smoker Quit)/7. 
4. Severity of 
COPD 
Severity of COPD: 
GOLD 2, 3, and 4 
Based on post-bronchodilator FEV1, severity 
of COPD at Screening is defined as follows, 
where % predicted values are values derived 
by iCardiac Technologies, Inc. (formerly 
nSpire Health for PT003006 and PT003007) 
using NHANES III reference equations: 
x Moderate = 50% ≤ FEV1 <80% predicted 
x Severe = 30% ≤ FEV1 <50% predicted 
x Very Severe = FEV1 <30% predicted 
 
GOLD 2017 COPD 
Assessment Categories: 
A, B, C, and D 
A (low exacerbation risk [0 or 1 exacerbation 
not leading to hospitalization], less symptoms 
[CAT <10] 
B (low exacerbation risk [0 or 1 exacerbation 


GFF MDI/GP MDI/FF MDI 
PT003014 
Final Version 
07 Mar 2017 
Page 3 of 9 
 
 
Category 
 
Description 
 
Data Handling Rule 
 
 
not leading to hospitalization], more 
symptoms[CAT ≥10] ) 
C (high exacerbation risk [≥2 exacerbations or 
≥1 exacerbation leading to hospitalization], 
less symptoms [CAT <10] ) 
D (high exacerbation risk [≥2 exacerbations or 
≥1 exacerbation leading to hospitalization] , 
more symptoms [CAT ≥10]) 
5. COPD 
Diagnosis 
Missing Date COPD 
First Diagnosed 
Day of Diagnosis will be imputed for all 
subjects as the 1st of the month.  Missing 
month of Diagnosis will be imputed as June, or 
the month in which 1st will be the latest before 
informed consent date, whichever is earliest. 
Years Prior to First 
Dose in the Study 
When COPD First 
Diagnosed 
(Date of First Dose of Study Treatment in the 
study – Date COPD First Diagnosed)/365.25. 
6. Medical 
History  
Medical History Begin 
Date of Condition 
Missing month of Condition will be imputed as 
June, or the month in which 1st will be the 
latest before informed consent date, whichever 
is earliest.  Begin date of Condition will be 
imputed for all subjects as the 1st of the month. 
 
Medical History End 
Date of Condition 
Other than for ‘Ongoing’ conditions, missing 
month of End Date of Condition will be 
imputed as June, or the month in which 1st will 
be the latest before informed consent date, 
whichever is earliest.  End date of Condition 
will be imputed for all subjects as the 1st of the 
month. 
7. Surgical 
History  
Surgical History Date 
of Surgery 
Missing month of Surgery will be imputed as 
June, or the month in which 1st will be the 
latest before informed consent date, whichever 
is earliest.  Begin date of Surgery will be 
imputed for all subjects as the 1st of the month. 
8. First and Last 
Treatment 
Dates 
date/time of first and 
last dose of a study 
treatment 
The date and time (24 hr. clock) of the first 
dose of study treatment will be taken from the 
Dosing eCRF.  The date of the last dose of 
study treatment will be the later of the last date 
of dosing from the eDiary or the last date of 
dosing from the Dosing eCRF for the 


GFF MDI/GP MDI/FF MDI 
PT003014 
Final Version 
07 Mar 2017 
Page 4 of 9 
 
 
Category 
 
Description 
 
Data Handling Rule 
 
treatment. 
9. Last Visit 
Date 
Date of Last Visit 
Date of last visit according to the Visit eCRF. 
10. Last Study 
Participation 
Date (STDM 
variable, 
RFPENDTC) 
Last Study 
Participation Date 
(STDM variable, 
RFPENDTC) 
Last study participation date is defined as last 
known date of contact which would be the 
later of the following dates: last visit date, date 
of the last dose, date of last contact if lost-to-
follow-up, date of telephone follow-up, or 
death date. 
11. Study Day 
Definitions 
Study Day for 
assessment/event which 
occurs on or after the 
start of study treatment 
Study Day = Date of assessment/event – date 
of the first dose of study treatment + 1. 
Study Day for 
assessments/events on 
days prior to the first 
dose of study treatment 
in the study 
Study Day = date of assessment/event – first 
dose date of treatment in the study. 
Study Day Post-
Treatment of 
Assessment or event 
which occurs after 
study treatment 
Study Day = ‘P’ concatenated with the number 
of days post-treatment that the assessment or 
event occurred which is defined as Date of 
assessment/event – date of last dose of study 
treatment. 
Study Day of 
Randomization 
Study Day of Randomization = date of 
randomization – date of the first dose of study 
treatment in the study + 1.  Study Day is 1 if 
baseline day is on the day of randomization. 
First Dose Day 
First Dose Day in the study is defined as the 
study day of the first dose of study treatment in 
the study (Study Day 1). 


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Category 
 
Description 
 
Data Handling Rule 
 
Last Study Day  
For subjects who did not receive study 
treatment in the study (e.g., Non-
Randomized subjects), Last Study Day is 
defined as (the later of the last visit date and 
the date of last contact for subjects  
lost-to-follow-up from the Study 
Completion/Early Discontinuation eCRF) – 
Date of Screening Visit + 1. 
For subjects who received study treatment 
in the study, Last Study Day is defined as (the 
later of the last visit date and the date of last 
contact for subjects lost-to-follow-up from the 
Study Completion/Early Discontinuation 
eCRF) – first dose date in the study + 1. 
Days Since Last Dose 
for event (e.g., Death) 
Days Since Last Dose is defined as date of 
event – date of last dose of study treatment. 
12. Duration of 
event  
The duration of any 
event  
The duration of any event is defined as (stop 
date – start date + 1). 
13. Multiple 
assessments 
for the same 
visit 
Vital Sign, ECG, and 
Laboratory assessments 
x All data will be listed in data listings. 
x The last of multiple valid assessments 
within a post-baseline study time window 
will be used for summaries and statistical 
testing. 
x If there are multiple laboratory values for 
the same parameter at pre-dose of a visit, 
the last value will be chosen for analysis. 
x If there are multiple ECG values for the 
same parameter at pre-dose of a visit date, 
the last value will be chosen for analysis. 
x The average of all available pre-dose vital 
sign measurements for a vital sign 
parameter taken prior to the start of dosing 
for the Treatment Period will be used for 
calculation of baseline for a parameter. 
Spirometry assessments x The last of multiple valid assessments 
within a post-baseline study time window 
will be used for summaries and statistical 
testing. 
14. Special Lab 
Value 
Lab values with a 
prefix such as: ‘>’, ‘<’, 
x ‘>’: use the available original value +0.001 
in the analyses. 


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Category 
 
Description 
 
Data Handling Rule 
 
Handling (not 
including PK 
values) 
‘+’ and ‘Less than’ 
etc… 
 
x ‘<’: use the available original value –0.001 
in the analyses. 
x ‘+’: use the available original value 
without the prefix in the analyses. 
x ‘>=’: use the available original value in the 
analyses. 
x ‘<=’: use the available original value in the 
analyses. 
15. Prior. 
concomitant, 
and post-
treatment 
medication / 
treatment 
Prior, concomitant, and 
post-treatment 
medication/treatment 
1. Prior medication/treatment: is any 
medication/treatment taken prior to the first 
dose of study medication in the study (or 
the date of the randomization visit, Visit 4, 
if the date of the start of study medication 
is missing), even if this 
medication/treatment continued into the 
study medication treatment period.  A 
medication/treatment will be considered 
prior if the start and end date of the 
medication/treatment are missing OR the 
start date is missing and the end date is on 
or after the first dose date of study 
medication in the study, or either the 
medication/treatment start date or end date 
or both are before first dose date of study 
medication in the study (or the date of the 
randomization visit, Visit 4, if the date of 
the start of study medication is missing). 
2. A medication/treatment will be identified 
as a concomitant medication/treatment if 
any of the following are true:  
o The start date is on or after the date of 
the start of study treatment (or the date 
of randomization, Visit 4, if missing), 
but prior to the date of Visit 11a, the 
date of the Discontinuation Visit, or the 
date of the last in-clinic or diary data 
collection. 
o The end date is prior to the date of Visit 
11a, the date of the Discontinuation 
Visit, or the date of the last in-clinic or 
diary data, but the end date is on or after 


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Category 
 
Description 
 
Data Handling Rule 
 
the start of study medication in the study 
(or the date of the randomization visit, 
Visit 4, if missing).  The 
medication/treatment is checked as 
‘Ongoing’, and the start date of the 
medication/treatment is prior to the date 
of Visit 11a, the date of the 
Discontinuation Visit, or the date of the 
last in-clinic or diary data collection.   
3. A medication with an onset date of the date 
of Visit 11a, the date of the 
Discontinuation Visit, or the date of the 
last in-clinic or diary data collection or 
after will not be considered concomitant, 
but will be considered a Post-Treatment 
medication/treatment. 
4. Note that for Completers, the Visit 11a 
date used for the rules above was the later 
of the Visit 11a date and the last date of 
treatment.  For those who discontinued, 
and with a discontinuation visit, the date of 
the Discontinuation Visit used for the rules 
above is the later of the Discontinuation 
Visit date or the last diary date.  The date 
of the last in-clinic or diary data collection 
date used for the rules above was the death 
date or the date of the last treatment when 
these dates were later than the last in-clinic 
visit or the last diary date. 
5. Any medication/treatment which cannot be 
identified as Prior, Concomitant, or Post-
Treatment will be considered as being in 
each of the possible categories depending 
on available information 
16. Adverse 
event 
Missing severity 
For the AE summary by severity, an AE with 
missing severity will be deemed as Severe.  
Imputed values will not be listed in data 
listings. 
Missing relationship to 
study drug 
For AE summary by relationship, an AE with a 
missing relationship to study drug will be 
deemed as Definitely related.  Imputed values 
will not be listed in data listings. 


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Category 
 
Description 
 
Data Handling Rule 
 
Treatment-emergent 
adverse event  
An adverse event is considered treatment-
emergent if the date of onset is on or after the 
date of first dose of study medication.  Adverse 
events after the Follow-up Telephone Call 
scheduled at least 14 days after Visit 11a or a 
discontinuation visit will not be considered 
treatment-emergent, but will be listed in 
adverse event data listings. 
If the AE start date is partial/missing, then 
x If AE start date is completely missing, then 
the AE is considered as treatment 
emergent. 
x If both AE start month and day are missing 
and AE start year is the same or after the 
first dose year, then the AE is considered 
as treatment emergent. 
x If AE start day is missing and AE start year 
and month are the same or after the first 
dose year and month, then the AE is 
considered as treatment emergent. 
Missing/incomplete (partial) AE start and end 
dates will not be imputed for data listings. 
17. AE rate 
adjusted for 
exposure 
Rate of AEs per 1000 
person-years 
Adjusted rate per 1000 person-years = 1000 x 
(Total number of AEs/Total years of exposure 
across all subjects for the treatment). 
18. Time to death Time to death in weeks 
Time to death (weeks) = (date of death – first 
treatment administration date +1)/7. 
19. Treatment 
Duration 
Treatment Duration 
Treatment duration is defined as Date of last 
dose of a study treatment - Date of first dose of 
a study treatment +1. 
20. Total Years 
of Exposure 
Total years of exposure 
to study treatment 
Total exposure (years) for a treatment as a 
whole is defined as the sum of all days of 
exposure for a treatment /365.25. 
21. Exposure 
(days) 
Exposure (days) 
Exposure (days) is defined as (Date of the last 
dose of the study treatment – Date of first dose 
of the study treatment + 1). 
22. Total 
Expected 
Puffs of 
Study 
Medication 
Total expected number 
of puffs taken of a 
study treatment 
The expected number of puffs for a test day 
which is the last date of treatment will be 2, the 
expected number of puffs for the last date of 
treatment which is not a test day will be 4 
when a PM dose has been taken and then 2 


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Category 
 
Description 
 
Data Handling Rule 
 
otherwise, and the expected number of puffs 
on dates prior to the last date of treatment will 
be 4. 
23. Treatment 
Compliance 
(%) 
Treatment Compliance 
(%) for a treatment  
Percent compliance is defined as (total number 
of puffs of study treatment taken on a study 
day/total expected puffs taken on a study day) 
averaged across all days of a subject’s dosing 
between start of study treatment and last day 
on study treatment) x 100.  The expected 
number of puffs for a test day which was the 
last date of treatment will be 2, the expected 
number of puffs for the last date of treatment 
which was not a test day will be 4 when a PM 
dose was taken and then 2 otherwise; the 
expected number of puffs on dates prior to the 
last date of treatment will be 4. 
24. Hard coding 
Hard coding for data 
analysis 
Hard Coding is not allowed during data 
analysis unless agreed to in writing by Pearl. 
25. AUC 
calculation for 
spirometry 
endpoints 
AUC0-2 
AUC0-2 will be calculated using the trapezoidal 
rule and actual time of assessment when 
available and nominal time of assessment 
otherwise. 
26. HCRU 
Number of days in 
CCU and ICU 
Unknown ICU stay (and CCU) responses will 
be included as zero days in the ICU/CCU for 
the summary stats.  If the response was yes 
that there was a stay in the ICU/CCU, but the 
number of days is missing, then the average 
value for ICU/CCU stays in the treatment 
group should be used. 
 


 
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APPENDIX 4 
CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES 
 
Study Number: 
PT003014 
Investigational Drug and Drug 
Number: 
Glycopyrronium and Formoterol Fumarate Inhalation 
Aerosol (GFF MDI); PT003 
Glycopyrronium Inhalation Aerosol (GP MDI); PT005 
Formoterol Fumarate Inhalation Aerosol (FF MDI); 
PT001 
Indication: 
COPD 
Dosage Form/Strength: 
GFF MDI 14.4/9.6 μg ex-actuator BID 
GP MDI 14.4 μg ex-actuator BID 
FF MDI 9.6 μg ex-actuator BID 
 
 
PT003014 Protocol 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 
 
 
 


 
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CTCAE LABORATORY TEST CRITERIA 
 
Investigations 
  
  
  
  
  
Grade 
Adverse Event 
1 
2 
3 
4 
Alanine 
aminotransferase 
increased 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Alkaline phosphatase 
increased 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Aspartate 
aminotransferase 
increased 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Blood bilirubin 
increased 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
Cholesterol high 
>ULN – 300 mg/dL; 
>ULN -7.75 mmol/L 
>300 – 400 mg/dL; >7.75 
-10.34 mmol/L 
>400 – 500 mg/dL; 
>10.34 -12.92 mmol/L 
>500 mg/dL; >12.92 
mmol/L 
Creatinine increased 
>1 – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 x ULN 
>6.0 x ULN 
GGT increased 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Hemoglobin increased 
Increase in >0 – 2 
gm/dL above ULN or 
above baseline if 
baseline is above 
ULN  
Increase in >2 – 4 gm/dL 
above ULN or above 
baseline if baseline is 
above ULN 
Increase in >4 gm/dL 
above ULN or above 
baseline if baseline is 
above ULN 
n/a 


 
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Investigations 
  
  
  
  
  
Grade 
Adverse Event 
1 
2 
3 
4 
Anemia (hemoglobin 
decreased) 
LLN- 10g/dL;  
<LLN – 6.2 mmol/L; 
<LLN – 100 g/L 
<10.0 – 8.0 g/dL;  
<6.2 – 4.9 mmol/L;  
<100 – 80g/L 
<8.0 g/dL; <4.9 mmol/L; 
<80 g/L; transfusion 
indicated 
Life-threatening 
consequences; urgent 
intervention 
indicated 
Leukocytosis (White 
blood cell increased) 
(a) 
>ULN – 40,000/mm3 
>40,000 – 100,000/mm3  
>100,000/mm3 
Clinical 
manifestations of 
leucostasis; urgent 
intervention 
indicated 
White blood cell 
decreased 
<LLN – 3000/mm3; 
<LLN – 3.0 x 109/L 
<3000 – 2000/mm3; 
 <3.0 – 2.0 x 109 /L 
<2000 – 1000/mm3; 
<2.0 – 1.0 x 109 /L 
<1000/mm3;  
<1.0 x 109 /L 
Platelet count 
decreased 
<LLN - 75,000/mm3;  
<LLN - 75.0 x 109/L 
<75,000 - 50,000/mm3;  
<75.0 - 50.0 x 109/L 
<50,000 - 25,000/mm3; 
<50.0 - 25.0 x 109/L 
<25,000/mm3; 
 <25.0 x 109/L 
 


 
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Metabolism and Nutrition Disorders 
  
Grade 
Adverse Event 
1 
2 
3 
4 
Hypercalcemia 
Corrected serum 
calcium of >ULN - 11.5 
mg/dL; >ULN - 2.9 
mmol/L; Ionized 
calcium >ULN - 1.5 
mmol/L 
Corrected serum 
calcium of >11.5 - 
12.5 mg/dL; >2.9 - 
3.1 mmol/L; Ionized 
calcium >1.5 - 1.6 
mmol/L; 
symptomatic 
Corrected serum calcium 
of >12.5 - 13.5 mg/dL; 
>3.1 - 3.4 mmol/L; Ionized 
calcium >1.6 - 1.8 
mmol/L; hospitalization 
indicated 
Corrected serum 
calcium of >13.5 
mg/dL; >3.4 mmol/L; 
Ionized calcium >1.8 
mmol/L; life-
threatening 
consequences 
Hyperglycemia 
Fasting glucose value 
>ULN - 160 mg/dL; 
Fasting glucose value 
>ULN - 8.9 mmol/L 
Fasting glucose 
value >160 - 250 
mg/dL; Fasting 
glucose value >8.9 - 
13.9 mmol/L 
>250 - 500 mg/dL; >13.9 - 
27.8 mmol/L; 
hospitalization indicated 
>500 mg/dL; >27.8 
mmol/L; life-
threatening 
consequences 
Hyperkalemia 
>ULN - 5.5 mmol/L 
>5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L; 
hospitalization indicated 
>7.0 mmol/L; life-
threatening 
consequences 
Hypermagnesemia 
>ULN - 3.0 mg/dL; 
>ULN - 1.23 mmol/L 
n/a 
>3.0 - 8.0 mg/dL; >1.23 - 
3.30 mmol/L 
>8.0 mg/dL; >3.30 
mmol/L; life-
threatening 
consequences 
Hypernatremia (Sodium 
Increased) 
>ULN - 150 mmol/L 
>150 - 155 mmol/L 
>155 - 160 mmol/L; 
hospitalization indicated 
>160 mmol/L; life-
threatening 
consequences 


 
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Metabolism and Nutrition Disorders 
  
Grade 
Adverse Event 
1 
2 
3 
4 
Hypoalbuminemia 
(Albumin Decreased) 
<LLN - 3 g/dL; <LLN - 
30 g/L 
<3 - 2 g/dL; <30 - 20 
g/L 
<2 g/dL; <20 g/L 
Life-threatening 
consequences; urgent 
intervention 
indicated 
Hypocalcemia (Calcium 
Decreased) 
Corrected serum 
calcium of <LLN - 8.0 
mg/dL; <LLN - 2.0 
mmol/L; Ionized 
calcium<LLN - 1.0 
mmol/L 
Corrected serum 
calcium of  <8.0 - 7.0 
mg/dL; <2.0 - 1.75 
mmol/L; Ionized 
calcium <1.0- 0.9 
mmol/L; 
symptomatic 
Corrected serum calcium 
of  <7.0 - 6.0 mg/dL; 
<1.75 - 1.5 mmol/L; 
Ionized calcium <0.9 - 0.8 
mmol/L; 
hospitalizationindicated 
Corrected serum 
calcium of <6.0 
mg/dL; <1.5 
mmol/L;Ionized 
calcium <0.8 
mmol/L;life-
threatening 
consequences 
Hypoglycemia (Glucose 
Decreased) 
<LLN - 55 mg/dL; <LLN 
- 3.0 mmol/L 
<55 - 40 mg/dL; <3.0 
- 2.2 mmol/L 
<40 - 30 mg/dL; <2.2 - 1.7 
mmol/L 
<30 mg/dL; <1.7 
mmol/L; life-
threatening 
consequences; 
seizures 
Hypokalemia 
(Potassium Decreased) 
<LLN - 3.0 mmol/L 
<LLN - 3.0 mmol/L; 
symptomatic; 
intervention 
indicated 
<3.0 - 2.5 mmol/L; 
hospitalization indicated 
<2.5 mmol/L; life-
threatening 
consequences 
Hypomagnesemia 
(Magnesium 
Decreased) 
<LLN - 1.2 mg/dL; <LLN 
- 0.5 mmol/L 
<1.2 - 0.9 mg/dL; 
<0.5 - 0.4 mmol/L 
<0.9 - 0.7 mg/dL; <0.4 - 
0.3 mmol/L 
<0.7 mg/dL; <0.3 
mmol/L; life-
threatening 
consequences 


 
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Metabolism and Nutrition Disorders 
  
Grade 
Adverse Event 
1 
2 
3 
4 
Hyponatremia (Sodium 
Decreased) 
<LLN - 130 mmol/L 
n/a 
<130 - 120 mmol/L 
<120 mmol/L; life-
threatening 
consequences 
Hypophosphatemia 
(Phosphate Decreased) 
<LLN - 2.5 mg/dL; <LLN 
- 0.8 mmol/L 
<2.5 - 2.0 mg/dL; 
<0.8 - 0.6 mmol/L 
<2.0 - 1.0 mg/dL; <0.6 - 
0.3 mmol/L 
<1.0 mg/dL; <0.3 
mmol/L; life-
threatening 
consequences 
 
 
Renal and Urinary 
Disorders 
  
  
  
  
  
Grade 
Adverse Event 
1 
2 
3 
4 
Chronic kidney disease 
eGFR (estimated 
Glomerular 
Filtration Rate) or CrCl 
(creatinine clearance) 
<LLN -60 ml/min/1.73 
m2 or proteinuria 2+ 
present; urine 
protein/creatinine >0.5 
eGFR or CrCl 59 - 30 
ml/min/1.73 m2 
eGFR or CrCl 29 - 15 
ml/min/1.73 m2 
eGFR or CrCl <15 
ml/min/1.73 m2; 
dialysis or renal 
transplant indicated 
(a) Grade 1 and Grade 2 not categorized in CTCAE4; Grade 1 and 2 based on reference laboratory alert criteria of 40,000 /mm3 
(LabCorp) 
 


 
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APPENDIX 5 STANDARD MEDDRA VERSION 19.1 
QUERIES (SMQs) 
 
Study Number: 
PT003014 
Investigational Drug and Drug 
Number: 
Glycopyrronium and Formoterol Fumarate Inhalation 
Aerosol (GFF MDI); PT003 
Glycopyrronium Inhalation Aerosol (GP MDI); PT005 
Formoterol Fumarate Inhalation Aerosol (FF MDI); 
PT001 
Indication: 
COPD 
Dosage Form/Strength: 
GFF MDI 14.4/9.6 μg ex-actuator BID 
GP MDI 14.4 μg ex-actuator BID 
FF MDI 9.6 μg ex-actuator BID 
 
PT003014 Protocol 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 
 
 
 


 
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Standard MedDRA Query (SMQ) 
Cerebrovascular disorders 
Central nervous system haemorrhages and cerebrovascular conditions (SMQ) 
Haemorrhagic central nervous system vascular conditions (SMQ) 
Narrow 
Basal ganglia haemorrhage 
Basal ganglia stroke 
Brain stem haematoma 
Brain stem haemorrhage 
Brain stem microhaemorrhage 
Brain stem stroke 
Carotid aneurysm rupture 
Central nervous system haemorrhage 
Cerebellar haematoma 
Cerebellar haemorrhage 
Cerebellar microhaemorrhage 
Cerebral aneurysm perforation 
Cerebral aneurysm ruptured syphilitic 
Cerebral arteriovenous malformation haemorrhagic 
Cerebral haematoma 
Cerebral haemorrhage 
Cerebral haemorrhage foetal 
Cerebral haemorrhage neonatal 
Cerebral microhaemorrhage 
Cerebrovascular accident 
Cerebrovascular disorder 
Epidural haemorrhage 
Extradural haematoma 
Haemorrhage intracranial 
Haemorrhagic cerebral infarction 
Haemorrhagic stroke 
Haemorrhagic transformation stroke 
Intracerebral haematoma evacuation 
Intracranial haematoma 
Intracranial tumour haemorrhage 
Intraventricular haemorrhage 
Intraventricular haemorrhage neonatal 
Meningorrhagia 
Perinatal stroke 
Pituitary haemorrhage 
Putamen haemorrhage 
Ruptured cerebral aneurysm 
Spinal cord haemorrhage 
Spinal epidural haematoma 
Spinal epidural haemorrhage 
Spinal haematoma 


 
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Spinal subarachnoid haemorrhage 
Spinal subdural haematoma 
Spinal subdural haemorrhage 
Stroke in evolution 
Subarachnoid haemorrhage 
Subarachnoid haemorrhage neonatal 
Subdural haematoma 
Subdural haematoma evacuation 
Subdural haemorrhage 
Subdural haemorrhage neonatal 
Thalamus haemorrhage 
 
Basal ganglia haematoma 
 
Basilar artery perforation 
 
Carotid artery perforation 
 
Cerebral artery perforation 
 
Extra-axial haemorrhage 
 
Periventricular haemorrhage neonatal 
 
Spinal cord haematoma 
 
Subarachnoid haematoma 
 
Vertebral artery perforation 
 
Ischaemic central nervous system vascular conditions (SMQ) 
Narrow 
Amaurosis fugax 
Basal ganglia infarction 
Basal ganglia stroke 
Basilar artery occlusion 
Basilar artery stenosis 
Basilar artery thrombosis 
Brachiocephalic arteriosclerosis 
Brachiocephalic artery occlusion 
Brachiocephalic artery stenosis 
Brain hypoxia 
Brain stem embolism 
Brain stem infarction 
Brain stem ischaemia 
Brain stem stroke 
Brain stem thrombosis 
Capsular warning syndrome 
Carotid angioplasty 
Carotid arterial embolus 
Carotid arteriosclerosis 
Carotid artery bypass 
Carotid artery disease 
Carotid artery insufficiency 
Carotid artery occlusion 


 
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Carotid artery restenosis 
Carotid artery stenosis 
Carotid artery stent insertion 
Carotid artery stent removal 
Carotid artery thrombosis 
Carotid endarterectomy 
Carotid revascularisation 
Cerebellar artery occlusion 
Cerebellar artery thrombosis 
Cerebellar embolism 
Cerebellar infarction 
Cerebellar ischaemia 
Cerebral arteriosclerosis 
Cerebral artery embolism 
Cerebral artery occlusion 
Cerebral artery restenosis 
Cerebral artery stenosis 
Cerebral artery thrombosis 
Cerebral gas embolism 
Cerebral infarction 
Cerebral infarction foetal 
Cerebral ischaemia 
Cerebral revascularisation 
Cerebral septic infarct 
Cerebral small vessel ischaemic disease 
Cerebral thrombosis 
Cerebral vasoconstriction 
Cerebral venous thrombosis 
Cerebrovascular accident 
Cerebrovascular disorder 
Cerebrovascular insufficiency 
Cerebrovascular stenosis 
Embolic cerebral infarction 
Embolic stroke 
Hypoxic-ischaemic encephalopathy 
Inner ear infarction 
Ischaemic cerebral infarction 
Ischaemic stroke 
Lacunar infarction 
Lateral medullary syndrome 
Migrainous infarction 
Millard-Gubler syndrome 
Moyamoya disease 
Perinatal stroke 
Post procedural stroke 


 
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Precerebral artery occlusion 
Reversible ischaemic neurological deficit 
Spinal artery embolism 
Spinal artery thrombosis 
Stroke in evolution 
Subclavian steal syndrome 
Thalamic infarction 
Thrombotic cerebral infarction 
Thrombotic stroke 
Transient ischaemic attack 
Vascular encephalopathy 
Vertebral artery occlusion 
Vertebral artery stenosis 
Vertebral artery thrombosis 
Vertebrobasilar insufficiency 
 
Carotid artery calcification 
 
Cerebral microembolism 
 
Cerebral vascular occlusion 
 
Delayed ischaemic neurological deficit 
 
Lacunar stroke 
 
Post cardiac arrest syndrome 
 
Precerebral arteriosclerosis 
 
Reversible cerebral vasoconstriction syndrome 
 
Vascular stent occlusion 
 
Vascular stent restenosis 
 
Vascular stent stenosis 
 
Cardiac failure (SMQ) 
Narrow 
Acute left ventricular failure 
Acute pulmonary oedema 
Acute right ventricular failure 
Cardiac asthma 
Cardiac failure 
Cardiac failure acute 
Cardiac failure chronic 
Cardiac failure congestive 
Cardiac failure high output 
Cardiogenic shock 
Cardiopulmonary failure 
Cardiorenal syndrome 
Chronic left ventricular failure 
Chronic right ventricular failure 
Cor pulmonale 
Cor pulmonale acute 
Cor pulmonale chronic 


 
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Ejection fraction decreased 
Hepatic congestion 
Hepatojugular reflux 
Left ventricular failure 
Low cardiac output syndrome 
Neonatal cardiac failure 
Obstructive shock 
Pulmonary oedema 
Pulmonary oedema neonatal 
Right ventricular failure 
Ventricular failure 
 
Radiation associated cardiac failure 
 
Right ventricular ejection fraction decreased 
 
Ischaemic Heart Disease (SMQ) 
Myocardial infarction (SMQ) 
Narrow 
Acute coronary syndrome 
Acute myocardial infarction 
Angina unstable 
Blood creatine phosphokinase MB abnormal 
Blood creatine phosphokinase MB increased 
Coronary artery embolism 
Coronary artery occlusion 
Coronary artery reocclusion 
Coronary artery thrombosis 
Coronary bypass thrombosis 
Kounis syndrome 
Myocardial infarction 
Myocardial necrosis 
Myocardial reperfusion injury 
Myocardial stunning 
Papillary muscle infarction 
Post procedural myocardial infarction 
Postinfarction angina 
Silent myocardial infarction 
Troponin I increased 
Troponin increased 
Troponin T increased 
 
Coronary vascular graft occlusion 
 
Other ischaemic heart disease (SMQ) 
Narrow 
Angina pectoris 
Angina unstable 
Arteriosclerosis coronary artery 
Arteriospasm coronary 


 
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Coronary angioplasty 
Coronary arterial stent insertion 
Coronary artery bypass 
Coronary artery disease 
Coronary artery dissection 
Coronary artery insufficiency 
Coronary artery restenosis 
Coronary artery stenosis 
Coronary endarterectomy 
Coronary no-reflow phenomenon 
Coronary ostial stenosis 
Coronary revascularisation 
Dissecting coronary artery aneurysm 
ECG signs of myocardial ischaemia 
External counterpulsation 
Haemorrhage coronary artery 
Ischaemic cardiomyopathy 
Microvascular coronary artery disease 
Myocardial ischaemia 
Percutaneous coronary intervention 
Prinzmetal angina 
Stress cardiomyopathy 
Subclavian coronary steal syndrome 
Subendocardial ischaemia 
 
Coronary brachytherapy 
 
Coronary bypass stenosis 
 
Coronary vascular graft stenosis 
 
Ischaemic mitral regurgitation 
 
Cardiac arrhythmias (SMQ) 
Cardiac Arrhythmia Terms (incl bradyarrhythmias and tachyarrhythmias) (SMQ) 
Bradyarrhythmias (including conduction defects and disorders of sinus node function) (SMQ) 
Bradyarrhythmia terms, nonspecific (SMQ) 
Narrow 
Bradyarrhythmia 
Ventricular asystole 
 
Conduction defects (SMQ) 
Narrow 
Accessory cardiac pathway 
Adams-Stokes syndrome 
Agonal rhythm 
Atrial conduction time prolongation 
Atrioventricular block 
Atrioventricular block complete 
Atrioventricular block first degree 
Atrioventricular block second degree 


 
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Atrioventricular conduction time shortened 
Atrioventricular dissociation 
Bifascicular block 
Brugada syndrome 
Bundle branch block 
Bundle branch block bilateral 
Bundle branch block left 
Bundle branch block right 
Conduction disorder 
Defect conduction intraventricular 
Electrocardiogram delta waves abnormal 
Electrocardiogram PQ interval prolonged 
Electrocardiogram PQ interval shortened 
Electrocardiogram PR prolongation 
Electrocardiogram PR shortened 
Electrocardiogram QRS complex prolonged 
Electrocardiogram QT prolonged 
Electrocardiogram repolarisation abnormality 
Lenegre's disease 
Long QT syndrome 
Sinoatrial block 
Trifascicular block 
Ventricular dyssynchrony 
Wolff-Parkinson-White syndrome 
 
Paroxysmal atrioventricular block 
 
Disorders of sinus node function (SMQ) 
Narrow 
Nodal arrhythmia 
Nodal rhythm 
Sick sinus syndrome 
Sinus arrest 
Sinus arrhythmia 
Sinus bradycardia 
Wandering pacemaker 
 
Cardiac arrhythmia terms, nonspecific (SMQ) 
Narrow 
Arrhythmia 
Heart alternation 
Heart rate irregular 
Pacemaker generated arrhythmia 
Pacemaker syndrome 
Paroxysmal arrhythmia 
Pulseless electrical activity 
Reperfusion arrhythmia 
Withdrawal arrhythmia 


 
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Tachyarrhythmias (including supraventricular and ventricular tachyarrhythmias) (SMQ) 
Supraventricular tachyarrhythmias (SMQ) 
Narrow 
Arrhythmia supraventricular 
Atrial fibrillation 
Atrial flutter 
Atrial parasystole 
Atrial tachycardia 
Junctional ectopic tachycardia 
Sinus tachycardia 
Supraventricular extrasystoles 
Supraventricular tachyarrhythmia 
Supraventricular tachycardia 
 
Tachyarrhythmia terms, nonspecific (SMQ) 
Narrow 
Anomalous atrioventricular excitation 
Cardiac flutter 
Extrasystoles 
Tachyarrhythmia 
 
Cardiac fibrillation 
 
 
Ventricular tachyarrhythmias (SMQ) 
Narrow 
Accelerated idioventricular rhythm 
Cardiac fibrillation 
Parasystole 
Rhythm idioventricular 
Torsade de pointes 
Ventricular arrhythmia 
Ventricular extrasystoles 
Ventricular fibrillation 
Ventricular flutter 
Ventricular parasystole 
Ventricular pre-excitation 
Ventricular tachyarrhythmia 
Ventricular tachycardia 
Arrhythmia related investigations, signs and symptoms (SMQ) [selected PTs] 
 
Bradycardia 
 
Central bradycardia 
 
Heart rate abnormal 
 
Heart rate decreased 
 
Heart rate increased 
 
Rebound tachycardia 
 
Tachycardia 
 
Tachycardia paroxysmal 
 


 
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Torsade de pointes/QT prolongation (SMQ) 
Narrow 
Electrocardiogram QT interval abnormal 
Electrocardiogram QT prolonged 
Long QT syndrome 
Long QT syndrome congenital 
Torsade de pointes 
Ventricular tachycardia 
 
Ventricular flutter 
 
Ventricular tachyarrhythmia 
 
Death  
Suddent Death 
Brain death 
Death 
Sudden cardiac death 
cardiac arrest 
Cardio-respiratory arrest 
cardiac death 
 
Sudden Death 
 
Sudden unexplained death in epilepsy 
 
Accidental death 
 
Apparent death 
 
Maternal death during child birth 
 
Cardio-respiratory arrest 
 
Anticholinergic syndrome (SMQ) 
Narrow 
Anticholinergic syndrome 
 
Dry mouth 
Broad 
Ataxia 
Autonomic nervous system imbalance 
Balance disorder 
Coordination abnormal 
Depressed level of consciousness 
Dizziness 
Hyporesponsive to stimuli 
Loss of consciousness 
Presyncope 
Sedation 
Slow response to stimuli 
Somnolence 
Stupor 
Agitation 
Confusional state 
Delirium 
Disorientation 


 
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Hallucination 
Hallucination, auditory 
Hallucination, gustatory 
Hallucination, olfactory 
Hallucination, synaesthetic 
Hallucination, tactile 
Hallucination, visual 
Hallucinations, mixed 
Restlessness 
Thinking abnormal 
Abasia 
Accommodation disorder 
Anhidrosis 
Blindness transient 
Cycloplegia 
Dry eye 
Dysphagia 
Gait disturbance 
Hyperaemia 
Hyperpyrexia 
Hypohidrosis 
Mydriasis 
Pyrexia 
Tachycardia 
Thirst 
Toxicity to various agents 
Urinary retention 
Vision blurred 
Visual acuity reduced 
Visual acuity reduced transiently 
 
Hemifacial anhidrosis 
 
Gastrointestinal perforation, ulceration, haemorrhage or obstruction (SMQ) 
Gastrointestinal obstruction (SMQ) 
Narrow 
Anal dilation procedure 
Anal stenosis 
Anastomotic stenosis 
Anastomotic ulcer, obstructive 
Anorectal stenosis 
Appendicolith 
Barium impaction 
Distal intestinal obstruction syndrome 
Duodenal obstruction 
Duodenal stenosis 
Duodenal ulcer perforation, obstructive 


 
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Duodenal ulcer, obstructive 
Fibrosing colonopathy 
Fixed bowel loop 
Gallstone ileus 
Gastric ileus 
Gastric stenosis 
Gastric ulcer haemorrhage, obstructive 
Gastric ulcer perforation, obstructive 
Gastric ulcer, obstructive 
Gastric volvulus 
Gastrointestinal anastomotic leak 
Gastrointestinal dilation procedure 
Gastrointestinal motility disorder 
Gastrointestinal obstruction 
Gastrointestinal stenosis 
Ileal stenosis 
Ileus 
Ileus paralytic 
Ileus spastic 
Impaired gastric emptying 
Intestinal fibrosis 
Intestinal malrotation repair 
Intestinal obstruction 
Intestinal scarring 
Intestinal stenosis 
Intussusception 
Jejunal stenosis 
Large intestinal obstruction 
Large intestinal obstruction reduction 
Large intestinal stenosis 
Mechanical ileus 
Necrotising colitis 
Necrotising gastritis 
Necrotising oesophagitis 
Neonatal intestinal obstruction 
Obstruction gastric 
Oesophageal compression 
Oesophageal dilation procedure 
Oesophageal obstruction 
Oesophageal stenosis 
Peptic ulcer perforation, obstructive 
Peptic ulcer, obstructive 
Postoperative ileus 
Prepyloric stenosis 
Pylorus dilation procedure 


 
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Rectal obstruction 
Rectal stenosis 
Small intestinal bacterial overgrowth 
Small intestinal obstruction 
Small intestinal stenosis 
 
Stomach dilation procedure 
 
Stricturoplasty 
 
Subileus 
 
Volvulus 
 
HLGT Urinary Tract signs and symptoms  
HLT Bladder and Urethral symptoms 
Bladder discomfort 
Bladder irritation 
Bladder pain 
Bladder spasm 
Bladder tamponade 
Dysuria 
Enuresis 
Fowler's syndrome 
Incontinence 
Lower urinary tract symptoms 
Micturition disorder 
Micturition frequency decreased 
Micturition urgency 
Mixed incontinence 
Paruresis 
Pollakiuria 
Psychogenic dysuria 
Strangury 
Stress urinary incontinence 
Terminal dribbling 
Urethral pain 
Urethral syndrome 
Urge incontinence 
Urinary hesitation 
Urinary incontinence 
Urinary retention 
Urinary retention postoperative 
Urinary straining 
Urine flow decreased 
HLT Urinary Abnormalities  
Acquired aminoaciduria 
Albuminuria 
Alkaptonuria 


 
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Aminoaciduria 
Ammoniuria 
Aspartylglucosaminuria 
Asymptomatic bacteriuria 
Bacteriuria 
Bacteriuria in pregnancy 
Bence Jones proteinuria 
Bilirubinuria 
Candiduria 
Choluria 
Chromaturia 
Chyluria 
Cryoglobulinuria 
Crystalluria 
Cylindruria 
Cystinuria 
Essential fructosuria 
Faecaluria 
Globulinuria 
Glycosuria 
Glycosuria during pregnancy 
Haematinuria 
Haematuria 
Haematuria traumatic 
Haemoglobinuria 
Haemosiderinuria 
Homocystinuria 
Hydroxyprolinuria 
Hypercalciuria 
Hyperchloruria 
Hyperkaliuria 
Hypermagnesuria 
Hypermethioniuria 
Hyperoxaluria 
Hyperphosphaturia 
Hypersthenuria 
Hyperuricosuria 
Hypocalciuria 
Hypocitraturia 
Hyposthenuria 
Isosthenuria 
Ketonuria 
Leukocyturia 
Lipiduria 
Loin pain haematuria syndrome 


 
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March haemoglobinuria 
Methaemoglobinuria 
Methylmalonic aciduria 
Microalbuminuria 
Myoglobinuria 
Nitrituria 
Oroticaciduria 
Oroticaciduria congenital 
Orthostatic proteinuria 
Paroxysmal nocturnal haemoglobinuria 
Pentosuria 
Phenylketonuria 
Pneumaturia 
Porphyrinuria 
Post procedural haematuria 
Proteinuria 
Pyuria 
Semenuria 
 
Sterile pyuria 
Urine abnormality 
Urine odour abnormal 
Urobilinuria 
 
Funguria 
 
Hypernatriuria 
 
Hyponatriuria 
 
HLT Urinary tract signs and symptoms NEC 
Costovertebral angle tenderness 
Cystitis-like symptom 
Extravasation of urine 
Flank pain 
Haemorrhage urinary tract 
Nocturia 
Pelvic discomfort 
Pelvic pain 
Perinephric collection 
Periureteral collection 
Polyuria 
Prostatism 
Renal colic 
Renal lymphocele 
Renal pain 
Transurethral resection syndrome 
Urinary tract pain 
 
Bladder hyperaemia 


 
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Kidney congestion 
 
Postoperative pathological diuresis 
 
Urinary tract discomfort 
 
Urothelium erosion 
 
HLT Tremor (excl congenital) 
Action tremor 
Asterixis 
Essential tremor 
Head titubation 
Holmes tremor 
Intention tremor 
Orthostatic tremor 
Postural tremor 
Psychogenic tremor 
Resting tremor 
Tremor 
Tremor neonatal 
 
HLT Visual Disorders NEC  
Charles Bonnet syndrome 
Computer vision syndrome 
Diplopia 
Dysmetropsia 
Eccentric fixation 
Glare 
Halo vision 
 
Irlen syndrome 
Loss of visual contrast sensitivity 
Metamorphopsia 
Oscillopsia 
Photopsia 
Retinal migraine 
Scintillating scotoma 
Subacute myelo-opticoneuropathy 
Vision abnormal neonatal 
Vision blurred 
Visual brightness 
Visual impairment 
Visual perseveration 
 
Cortical visual impairment 
 
Delayed dark adaptation 
 
Delayed visual maturation 
 
Heteronymous diplopia 


 
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Homonymous diplopia 
 
Neurologic neglect syndrome 
 
Psychogenic visual disorder 
 
Glaucoma (SMQ) 
Narrow 
Angle closure glaucoma 
Borderline glaucoma 
Developmental glaucoma 
Diabetic glaucoma 
Exfoliation glaucoma 
Fundoscopy abnormal 
Glaucoma 
Glaucoma drug therapy 
Glaucoma surgery 
Glaucoma traumatic 
Glaucomatocyclitic crises 
Glaucomatous optic disc atrophy 
Gonioscopy abnormal 
Halo vision 
Intraocular pressure fluctuation 
Intraocular pressure increased 
Intraocular pressure test abnormal 
Iridotomy 
Loss of visual contrast sensitivity 
Normal tension glaucoma 
Ocular hypertension 
Open angle glaucoma 
Ophthalmic fluid drainage 
Optic discs blurred 
Optic nerve cup/disc ratio increased 
Optic nerve cupping 
Phacolytic glaucoma 
Phacotrabeculectomy 
Pigmentary glaucoma 
Pupillary light reflex tests abnormal 
Slit-lamp tests abnormal 
Trabeculectomy 
Trabeculoplasty 
Uveitic glaucoma 
Uveitis-glaucoma-hyphaema syndrome 
Visual field tests abnormal 
 
Ocular stent placement 
 
Pseudophakic glaucoma 
 
Viscocanalostomy 
 


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APPENDIX 6 
MOCK-UP TABLES, LISTINGS, AND FIGURES 
__________________________________________________________________ 
 
Study Number: 
PT003014 
Investigational Drug and Drug 
Number: 
Glycopyrronium and Formoterol Fumarate Inhalation 
Aerosol (GFF MDI); PT003 
Glycopyrronium Inhalation Aerosol (GP MDI); PT005 
Formoterol Fumarate Inhalation Aerosol (FF MDI); 
PT001 
Indication: 
COPD 
Dosage Form/Strength: 
GFF MDI 14.4/9.6 μg ex-actuator BID 
GP MDI 14.4 μg ex-actuator BID 
FF MDI 9.6 μg ex-actuator BID 
 
PT003014 Protocol 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 
 
 
 


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General Instructions for End-of-Text TFLs 
 
Following are the specifications for end of text standard tables, listings, and figures (TFLs). 
 
Header 
 
The following header should appear at the very top of each page of a table, a listing, or a figure (TLF): 
Protocol PT003014 
 
 
 
 
                  GFF MDI/GP MDI/FF MDI  
 
 
Footer 
 
The following footer should appear at the bottom of each page of a TLF generated in SAS: 
 
Report generated by program:/sasdir/PGNAME.sas  Version YYYY-mm-dd hh:mm (Page n of N) 
 
where: PGNAME = SAS program name. Version will be replaced by “Draft” or “Final”.  Page number 
will be right-justified. 
 
Title 
 
At least two (2) lines should be reserved for the whole title. The first line of the title is for the TLF 
number (i.e., title index #) and the actual title (title); a longer title may continue onto subsequent lines. 
The analysis population descriptor (Population) will be specified on the line following the title line(s). All 
titles should be centered, as shown in the following example:  
 
Table 1.5.3 Demographics 
Analysis Set: Safety Population 
 
Footnotes 
 
x 
In general, a footnote serves as a brief explanation/clarification/definition/concept of a flag symbol 
or a character, an abbreviation, a terminology, etc., that appears in or related directly to the displayed 
content of a TLF. Detailed/technical elaboration of, for example, a mathematical/statistical formula, 
a statistical term/test, or an algorithm for deriving a parameter value, should be addressed in the text 
of the statistical analysis plan (SAP). 
x 
All footnotes should follow immediately after a horizontal solid line. There should be one and only 
one space between the last footnote and the footer.  
x 
Each line of a complete footnote should end with a period. When a footnote needs more than 1 line, 
one (1) period is needed. 
x 
Footnotes should be in the format shown in the following example:   
 
Row Labels/Column Labels: The mockups will reflect the preferred style of capitalization. 
 
 


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Page Layout  
 
x 
All output should be in landscape orientation. A margin of 1.5, 1, 1, and 1 inch should be on the top, 
right, left, and bottom, respectively.  
x 
All efforts should be made to present all Treatment groups in one page. 
x 
When 3 or more Treatment groups are designed for a study and if it is not possible to fit all of them 
in one page, the 4th and 5th treatment groups should be displayed on the 2nd page, etc. The Study 
Biostatistician will pre-determine the order for the display of the treatment groups.  
 
Page Format 
 
x 
There should be a solid line at the top of the tables and listings just below the title. 
x 
There should be a solid line just below the column headings that runs completely across the width of 
the tables and listings. 
x 
There should be a solid line at the bottom of the tables and listings just above the footnote(s) on 
every page. 
 
Font 
 
x 
The default font to be used in the actual study tables/listings should be Courier New 8 point which is 
approximately equivalent to the acceptable font size of Times New Roman 9-10 in accordance with 
the FDA’s guidance on Electronic Common Technical Document Specification.  
x 
The use of Courier New 7 point is optional for some tables/listings and will be determined at the 
study level by the Study Biostatistician and Study Programmer. However, it is recommended that 
this option be used primarily for data listings. 
 
Descriptive Statistics 
 
By default, descriptive statistics in this template covers: n, Mean, Median, Standard Deviation (SD), 
Minimum (Min), and Maximum (Max). Unless otherwise specified in the actual table shells, the mean, 
standard deviation, standard error of the mean, and median should be displayed to one more decimal place 
than the original data. The standard error of the mean will be displayed with at least 2 significant digits 
for efficacy tables. 
 
Rounding for Percentage 
 
Unless specified in the actual table shells for a study, all percentages will be rounded to 1 decimal place in 
all TLFs. 
 
Unless specified in the actual table shells for a study, p-values will be presented with 4 decimal places. 
 
 


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Alignment of Decimals 
 
x 
It is recommended that all the decimal places be aligned in summary tables, as shown in the 
following example: 
 
 
Decimal Align 
n 
xxx 
Mean 
xx.xx 
SD 
xx.xx xx.xxx 
Median 
xx.xx 
Minimum, Maximum 
xx.x, xx.x 
 
x 
When numbers with decimal points are included in brackets (e.g., percentages), have the brackets 
aligned to the right and then padded to allow for all possible percentages and then the left brackets 
will also be aligned. For example: 
 
Brackets Align 
( 99.9) 
( xx.x) 
(  9.9) 
(  x.x) 
 
 
x 
It is recommended that all column entries in a summary tables and listings are aligned to the center. 
x 
Columns for text fields are all left justified. Columns with whole numbers are all right justified. 
x 
For graphs, the lines are distinguishable and that the symbols for each line are appropriate. Legend is 
consistent across output for Treatment names and abbreviations. 
  
Use of N Versus n 
 
x 
N = total number of subjects in the defined analysis set. 
x 
n = total number of subjects in the specific category. 
x 
If N is specified in the column heading then any reference to the number of subjects in the body 
should be small n, as shown in the following example:  
 
Demographic Parameter 
Treatment Group A 
(N=XXX) 
Treatment  
Group B 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
Age (years) 
 
 
 
n 
        xxx 
        xxx 
        xxx 
Mean 
        xx.x 
        xx.x 
        xx.x 
SD 
        x.xx 
        x.xx 
        x.xx 
Median 
        xx.x 
        xx.x 
        xx.x 
Minimum, Maximum   
        xx, xx 
        xx, xx 
        xx, xx 
 
 


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A Note for Subject Data Listings 
 
x 
Observed Dates/AE Severity/Relationship to investigational product are used in subject data listings. 
x 
Observed values or raw assessment scores are used in data listings along with their derived values 
used in analyses, e.g., raw assessment scores and derived total scores. 
 
 


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TABLE OF CONTENTS FOR END-OF-TEXT TLFs 
 
1. 
SUBJECT DISPOSITION, DEMOGRAPHIC, BASELINE, AND OTHER SUMMARY 
TABLES ........................................................................................................................................... 32 
Table 1.1.1 
Subject Disposition ........................................................................................................... 32 
Analysis Set: All Subjects Randomized 
Table 1.1.2 
Distribution of Subjects by Country/Region and Treatment ............................................. 33 
Analysis Set: All Subjects Randomized 
Table 1.1.3 
Distribution of Subjects in Analysis Populations, by Country, Center, and 
Treatment.......................................................................................................................... 34 
Analysis Set: All Subjects Randomized 
Table 1.1.4 
Reasons for Subjects Not Randomized ............................................................................. 35 
Analysis Set: Non-Randomized Analysis Set 
Table 1.1.5 
Subjects Excluded From ITT, PP, Symptomatic, Rescue Ventolin User, and Safety 
Populations ....................................................................................................................... 36 
Analysis Set: All Subjects Randomized 
Table 1.2.1 
Reason for Early Discontinuation ..................................................................................... 37 
Analysis Set: All Subjects Randomized 
Table 1.2.2 
Reason for Early Discontinuation Overall and by CAT Score Subpopulation ................. 38 
Analysis Set: ITT Population 
Table 1.2.3 
Reason for Early Discontinuation ..................................................................................... 38 
Analysis Set: PP Population 
Table 1.2.4 
Reason for Early Discontinuation ..................................................................................... 38 
Analysis Set: Safety Population 
Table 1.3 
Reason for Exclusion From the PP Population ................................................................. 39 
Analysis Set: ITT Population 
Table 1.4.1 
Demographics and Baseline Characteristics Overall and by CAT Subpopulation ........... 40 
Analysis Set: ITT Population 
Table 1.4.2 
Demographics and Baseline Characteristics ..................................................................... 44 
Analysis Set: PP Population 
Table 1.4.3 
Demographics and Baseline Characteristics ..................................................................... 44 
Analysis Set: Rescue Ventolin User Population 
Table 1.4.4 
Demographics and Baseline Characteristics ..................................................................... 44 
Analysis Set: Safety Population 
Table 1.4.5 
Demographics and Baseline Characteristics ..................................................................... 44 
Analysis Set: Non-Randomized Analysis Set 
Table 1.5.1 
Severity and Duration of COPD Overall and by CAT Score Subpopulation.................... 45 
Analysis Set: ITT Population 
Table 1.5.2 
Severity and Duration of COPD ....................................................................................... 46 
Analysis Set: PP Population 
Table 1.5.3 
Severity and Duration of COPD ....................................................................................... 46 
Analysis Set: Rescue Ventolin User Population 


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Table 1.5.4 
Severity and Duration of COPD ....................................................................................... 46 
Analysis Set: Safety Population 
Table 1.6.1 
Screening Pre- and Post-Bronchodilator and Baseline Spirometry Parameters 
Overall and by CAT Score Subpopulation ....................................................................... 47 
Analysis Set: ITT Population 
Table 1.6.2 
Screening Pre- and Post-Bronchodilator and Baseline Spirometry Parameters ................ 48 
Analysis Set: PP Population 
Table 1.6.3 
Screening Pre- and Post-Bronchodilator and Baseline Spirometry Parameters ................ 48 
Analysis Set: Rescue Ventolin User Population 
Table 1.7.1 
Reversibility to Ventolin HFA Overall and by CAT Score Subpopulation ...................... 49 
Analysis Set: ITT Population 
Table 1.7.2 
Reversibility to Ventolin HFA .......................................................................................... 50 
Analysis Set: PP Population 
Table 1.7.3 
Reversibility to Ventolin HFA .......................................................................................... 50 
Analysis Set: Rescue Ventolin User Population 
Table 1.8.1 
Reversibility to Atrovent HFA Overall and by CAT Score Subpopulation ...................... 50 
Analysis Set: ITT Population 
Table 1.8.2 
Reversibility to Atrovent HFA ......................................................................................... 50 
Analysis Set: PP Population 
Table 1.8.3 
Reversibility to Atrovent HFA ......................................................................................... 50 
Analysis Set: Rescue Ventolin User Population 
Table 1.8.4 
Reversibility to Ventolin HFA and/or Atrovent HFA ....................................................... 51 
Analysis Set: ITT Population 
Table 1.9.1 
Medical/Surgical History .................................................................................................. 52 
Analysis Set: Safety Population 
Table 1.9.2 
Cardiovascular Risk Factors of Interest ............................................................................ 53 
Analysis Set: Safety Population 
Table 1.9.3 
History of Moderate or Severe COPD Exacerbations Within Past 12 Months ................. 54 
Analysis Set: ITT Population 
Table 1.10.1 
Prior Medications - COPD-Related .................................................................................. 56 
Analysis Set: Safety Population 
Table 1.10.2 
Prior Medications - Non-COPD-Related .......................................................................... 56 
Analysis Set: Safety Population 
Table 1.11.1 
Concomitant Medications - COPD Related ...................................................................... 57 
Analysis Set: Safety Population 
Table 1.11.2 
Concomitant Medications - Non-COPD Related .............................................................. 57 
Analysis Set: Safety Population 
Table 1.12 
Study Treatment Exposure and Compliance ..................................................................... 58 
Analysis Set: Safety Population 
Table 1.13 
Changes in Smoking Status After Start of Treatment ....................................................... 60 
Analysis Set: Safety Population 


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2. 
EFFICACY DATA SUMMARY TABLES AND FIGURES, INCLUDING HCRU 
TABLES ........................................................................................................................................... 61 
CHANGE FROM BASELINE IN MORNING PRE-DOSE TROUGH FEV1 ........................................... 61 
Table 2.1.1 
Morning Pre-dose Trough FEV1 (L) ................................................................................. 62 
Analysis Set: ITT Population 
Figure 2.1.1.1 
Adjusted Mean Change From Baseline in Morning Pre-dose Trough FEV1 (L) ± 
SE Over Time ................................................................................................................... 64 
Analysis Set: ITT Population 
Figure 2.1.1.2 
Treatment Differences From Placebo MDI*: Adjusted Mean Change From 
Baseline (95% CI) in Morning Pre-dose Trough FEV1 (L) Over Time ............................ 65 
Analysis Set: ITT Population 
Table 2.1.2 
Morning Pre-dose Trough FEV1 (L) ................................................................................. 66 
Analysis Set: PP Population 
Figure 2.1.2 
Adjusted Mean Change From Baseline in Morning Pre-dose Trough FEV1 (L) ± 
SE Over Time ................................................................................................................... 66 
Analysis Set: PP Population 
Table 2.1.3.1 
Missing Data for Change From Baseline in Morning Pre-dose Trough FEV1 by 
Visit and Reason ............................................................................................................... 67 
Analysis Set: ITT Population 
Table 2.1.3.2 
Unique Patterns of Missing Visits for Change From Baseline in Morning Pre-dose 
Trough FEV1 .................................................................................................................... 72 
Analysis Set: ITT Population 
Table 2.1.4.1 
Sensitivity Analysis: Treatment Comparisons for Change From Baseline in 
Morning Pre-dose Trough FEV1 (L) at Week 24 ............................................................. 73 
Analysis Set: ITT Population 
Figure 2.1.4.1 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. Placebo MDI for 
Change From Baseline in Morning Pre-dose Trough FEV1 (L) at Week 24 .................... 74 
Analysis Set: ITT Population 
Figure 2.1.4.2 
Sensitivity Analysis: Comparison of FF MDI 9.6 μg vs. Placebo MDI for Change 
From Baseline in Morning Pre-dose Trough FEV1 (L) at Week 24 ................................. 75 
Analysis Set: ITT Population 
Figure 2.1.4.3 
Sensitivity Analysis: Comparison of GP MDI 14.4 μg vs. Placebo MDI for Change 
From Baseline in Morning Pre-dose Trough FEV1 (L) at Week 24 ................................. 75 
Analysis Set: ITT Population 
Figure 2.1.4.4 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. FF MDI 9.6 μg for 
Change From Baseline in Morning Pre-dose Trough FEV1 (L) at Week 24 .................... 75 
Analysis Set: ITT Population 
Figure 2.1.4.5 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. GP MDI 14.4 μg 
for Change From Baseline in Morning Pre-dose Trough FEV1 (L) at Week 24 .............. 75 
Analysis Set: ITT Population 
Table 2.1.4.2 
Sensitivity Analysis: Treatment Comparisons for Change From Baseline in 
Morning Pre-dose Trough FEV1 (L) Over 24 Weeks ....................................................... 75 
Analysis Set: ITT Population 


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Figure 2.1.4.6 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. Placebo MDI for 
Change From Baseline in Morning Pre-dose Trough FEV1 (L) Over 24 Weeks ............. 75 
Analysis Set: ITT Population 
Figure 2.1.4.7 
Sensitivity Analysis: Comparison of FF MDI 9.6 μg vs. Placebo MDI for Change 
From Baseline in Morning Pre-dose Trough FEV1 (L) Over 24 Weeks .......................... 75 
Analysis Set: ITT Population 
Figure 2.1.4.8 
Sensitivity Analysis: Comparison of GP MDI 14.4 μg vs. Placebo MDI for Change 
From Baseline in Morning Pre-dose Trough FEV1 (L) Over 24 Weeks .......................... 75 
Analysis Set: ITT Population 
Figure 2.1.4.9 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. FF MDI 9.6 μg for 
Change From Baseline in Morning Pre-dose Trough FEV1 (L) Over 24 Weeks .............. 76 
Analysis Set: ITT Population 
Figure 2.1.4.10 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. GP MDI 14.4 μg 
for Change From Baseline in Morning Pre-dose Trough FEV1 (L) Over 24 Weeks ........ 76 
Analysis Set: ITT Population 
Table 2.1.4.3 
Sensitivity Analysis: Treatment Comparisons for Change From Baseline in 
Morning Pre-dose Trough FEV1 (L) Over Weeks 12-24 .................................................. 76 
Analysis Set: ITT Population 
Figure 2.1.4.11 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. Placebo MDI for 
Change From Baseline in Morning Pre-dose Trough FEV1 (L) Over Weeks 12-24 ........ 76 
Analysis Set: ITT Population 
Figure 2.1.4.12 
Sensitivity Analysis: Comparison of FF MDI 9.6 μg vs. Placebo MDI for Change 
From Baseline in Morning Pre-dose Trough FEV1 (L) Over Weeks 12-24 ..................... 76 
Analysis Set: ITT Population 
Figure 2.1.4.13 
Sensitivity Analysis: Comparison of GP MDI 14.4 μg vs. Placebo MDI for Change 
From Baseline in Morning Pre-dose Trough FEV1 (L) Over Weeks 12-24 ..................... 76 
Analysis Set: ITT Population 
Figure 2.1.4.14 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. FF MDI 9.6 μg for 
Change From Baseline in Morning Pre-dose Trough FEV1 (L) Over Weeks 12-24 ........ 76 
Analysis Set: ITT Population 
Figure 2.1.4.15 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. GP MDI 14.4 μg 
for Change From Baseline in Morning Pre-dose Trough FEV1 (L) Over Weeks 12-
24 ...................................................................................................................................... 76 
Analysis Set: ITT Population 
Figure 2.1.4.16 
Comparison of GFF MDI 14.4/9.6 μg vs. Placebo MDI for Change From Baseline 
in Morning Pre-dose Trough FEV1 (L) at Week 24 Using Imputed Estimates at 
Various Deltas .................................................................................................................. 77 
Analysis Set: ITT Population 
Figure 2.1.4.17 
Comparison of FF MDI 9.6 μg vs. Placebo MDI for Change From Baseline in 
Morning Pre-dose Trough FEV1 at Week 24 Using Imputed Estimates at Various 
Deltas ................................................................................................................................ 77 
Analysis Set: ITT Population 
Figure 2.1.4.18 
Comparison of GP MDI 14.4 μg vs. Placebo MDI for Change From Baseline in 
Morning Pre-dose Trough FEV1 at Week 24 Using Imputed Estimates at Various 
Deltas ................................................................................................................................ 77 
Analysis Set: ITT Population 


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Figure 2.1.4.19 
Comparison of GFF MDI 14.4/9.6 μg vs. FF MDI 9.6 μg for Change From 
Baseline in Morning Pre-dose Trough FEV1 at Week 24 Using Imputed Estimates 
at Various Deltas .............................................................................................................. 77 
Analysis Set: ITT Population 
Figure 2.1.4.20 
Comparison of GFF MDI 14.4/9.6 μg vs. GP MDI 14.4 μg for Change From 
Baseline in Morning Pre-dose Trough FEV1 at Week 24 Using Imputed Estimates 
at Various Deltas .............................................................................................................. 77 
Analysis Set: ITT Population 
Figure 2.1.4.21 
Comparison of GFF MDI 14.4/9.6 μg vs. Placebo MDI for Change From Baseline 
in Morning Pre-dose Trough FEV1 Over 24 Weeks Using Imputed Estimates at 
Various Deltas .................................................................................................................. 77 
Analysis Set: ITT Population 
Figure 2.1.4.22 
Comparison of FF MDI 9.6 μg  vs. Placebo MDI for Change From Baseline in 
Morning Pre-dose Trough FEV1 Over 24 Weeks Using Imputed Estimates at 
Various Deltas .................................................................................................................. 78 
Analysis Set: ITT Population 
Figure 2.1.4.23 
Comparison of GP MDI 14.4 μg vs. Placebo MDI for Change From Baseline in 
Morning Pre-dose Trough FEV1 Over 24 Weeks Using Imputed Estimates at 
Various Deltas .................................................................................................................. 78 
Analysis Set: ITT Population 
Figure 2.1.4.24 
Comparison of GFF MDI 14.4/9.6 μg vs. FF MDI 9.6 μg for Change From 
Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks Using Imputed 
Estimates at Various Deltas .............................................................................................. 78 
Analysis Set: ITT Population 
Figure 2.1.4.25 
Comparison of GFF MDI 14.4/9.6 μg vs. GP MDI 14.4 μg for Change From 
Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks Using Imputed 
Estimates at Various Deltas .............................................................................................. 78 
Analysis Set: ITT Population 
Figure 2.1.4.26 
Comparison of GFF MDI 14.4/9.6 μg vs. Placebo MDI for Change From Baseline 
in Morning Pre-dose Trough FEV1 Over Weeks 12-24Using Imputed Estimates at 
Various Deltas .................................................................................................................. 78 
Analysis Set: ITT Population 
Figure 2.1.4.27 
Comparison of FF MDI 9.6 μg  vs. Placebo MDI for Change From Baseline in 
Morning Pre-dose Trough FEV1 Over Weeks 12-24 Using Imputed Estimates at 
Various Deltas .................................................................................................................. 78 
Analysis Set: ITT Population 
Figure 2.1.4.28 
Comparison of GP MDI 14.4 μg vs. Placebo MDI for Change From Baseline in 
Morning Pre-dose Trough FEV1 Over Weeks 12-24Using Imputed Estimates at 
Various Deltas .................................................................................................................. 78 
Analysis Set: ITT Population 
Figure 2.1.4.29 
Comparison of GFF MDI 14.4/9.6 μg vs. FF MDI 9.6 μg for Change From 
Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24 Using Imputed 
Estimates at Various Deltas .............................................................................................. 78 
Analysis Set: ITT Population 


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Figure 2.1.4.30 
Comparison of GFF MDI 14.4/9.6 μg vs. GP MDI 14.4 μg for Change From 
Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24 Using Imputed 
Estimates at Various Deltas .............................................................................................. 79 
Analysis Set: ITT Population 
Table 2.1.4.4 
 Cumulative Proportion of Responders Based on Change From Baseline in 
Morning Pre-dose Trough FEV1 at Week 24.................................................................... 80 
Analysis Set: ITT Population 
Figure 2.1.4.31 
Cumulative Proportion of Responders Based on Change From Baseline in 
Morning Pre-dose Trough FEV1 at Week 24.................................................................... 81 
Analysis Set: ITT Population 
Table 2.1.4.5 
Cumulative Proportion of Responders Based on Change From Baseline in 
Morning Pre-dose Trough FEV1 Over 24 Weeks ............................................................. 82 
Analysis Set: ITT Population 
Figure 2.1.4.32 
Cumulative Proportion of Responders Based on Change From Baseline in 
Morning Pre-dose Trough FEV1 Over 24 Weeks ............................................................. 82 
Analysis Set: ITT Population 
Table 2.1.4.6 
 Cumulative Proportion of Responders Based on Change From Baseline in 
Morning Pre-dose Trough FEV1 Over Weeks 12-24 ........................................................ 82 
Analysis Set: ITT Population 
Figure 2.1.4.33 
Cumulative Proportion of Responders Based on Change From Baseline in 
Morning Pre-dose Trough FEV1 Over Weeks 12-24 ........................................................ 82 
Analysis Set: ITT Population 
TRANSITION DYSPNEA INDEX (TDI) ................................................................................................. 83 
Table 2.2.1 
TDI Focal Score Overall and by CAT Score Subpopulation ............................................ 83 
Analysis Set: ITT Population 
Figure 2.2.1.1.1 
Adjusted Mean TDI Focal Score ± SE Over Time ........................................................... 85 
Analysis Set: ITT Population 
Figure 2.2.1.1.2 
Treatment Differences From Placebo MDI*: Adjusted Mean TDI Focal Score 
(95% CI) Over Time ......................................................................................................... 85 
Analysis Set: ITT Population 
Figure 2.2.1.2.1 
Adjusted Mean TDI Focal Score ± SE Over Time: CAT Score Subpopulation of 
>= 10 ................................................................................................................................ 85 
Analysis Set: ITT Population 
Figure 2.2.1.2.2 
Adjusted Mean TDI Focal Score ± SE Over Time: Symptomatic Population (CAT 
Score ≥15), ....................................................................................................................... 85 
Analysis Set: ITT Population 
Figure 2.2.1.2.3 
Adjusted Mean TDI Focal Score ± SE Over Time: CAT Score Subpopulation of 
>= 20 ................................................................................................................................ 85 
Analysis Set: ITT Population 
Table 2.2.2.1 
TDI Component Scores for Functional Impairment, Magnitude of Task, and 
Magnitude of Effort Overall and by CAT Score Subpopulation ...................................... 85 
Analysis Set: ITT Population 
Figure 2.2.2.1.x 
Adjusted Mean TDI Functional Impairment Component Score ± SE Over Time 
Overall and by CAT Score Subpopulation ....................................................................... 85 
Analysis Set: ITT Population 


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Figure 2.2.2.2.x 
Adjusted Mean TDI Magnitude of Task Component Score ± SE Over Time 
Overall and by CAT Score Subpopulation ....................................................................... 85 
Analysis Set: ITT Population 
Figure 2.2.2.3.x 
Adjusted Mean TDI Magnitude of Effort Component Score ± SE Over Time 
Overall and by CAT Score Subpopulation ....................................................................... 85 
Analysis Set: ITT Population 
Table 2.2.3 
Response in TDI Focal Score (Achievment of a Minimum Clinically Important 
Difference Threshold of ≥1 Unit on Average) Over 24 Weeks and Over Weeks 12-
24 Overall and by CAT Score Subpopulation .................................................................. 86 
Analysis Set: ITT Population 
PEAK CHANGE FROM BASELINE IN FEV1 ......................................................................................... 88 
Table 2.3.1 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-dose .............................. 88 
Analysis Set: ITT Population 
Figure 2.3.1 
Adjusted Mean Peak Change From Baseline in FEV1 (L) ± SE Within 2 Hours 
Post-dose .......................................................................................................................... 88 
Analysis Set: ITT Population 
ST. GEORGE RESPIRATORY QUESTIONNAIRE (SGRQ) .................................................................. 88 
Table 2.4.1 
SGRQ Total Score (units) Overall and by CAT Score Subpopulation ............................. 88 
Analysis Set: ITT Population 
Figure 2.4.1.1 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over 
Time ................................................................................................................................. 89 
Analysis Set: ITT Population 
Figure 2.4.1.2 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over 
Time: CAT Score Subpopulation of >= 10 ...................................................................... 89 
Analysis Set: ITT Population 
Figure 2.4.1.3 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over 
Time: Symptomatic Population (CAT Score ≥15), .......................................................... 89 
Analysis Set: ITT Population 
Figure 2.4.1.4 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over 
Time: CAT Score Subpopulation of >= 20 ...................................................................... 89 
Analysis Set: ITT Population 
Table 2.4.2 
Total Score (units) of Each SGRQ Domain Overall and by CAT Score 
Subpopulation ................................................................................................................... 89 
Analysis Set: ITT Population 
Table 2.4.3 
Response in SGRQ Total Score (Achievment of a Minimum Clinically Important 
Difference Threshold of ≥4 Units on Average) Overall and by CAT Score 
Subpopulation ................................................................................................................... 90 
Analysis Set: ITT Population 
NUMBER OF PUFFS OF RESCUE VENTOLIN HFA ............................................................................ 91 
Table 2.5.1 
Mean Daily, Daytime, and Nighttime Number of Puffs of Rescue Ventolin HFA ........... 91 
Analysis Set: Rescue Ventolin User Population 
Figure 2.5.1.1 
Adjusted Mean Change From Baseline in Mean Daily Number of Puffs of Rescue 
Ventolin HFA ± SE Over Time ........................................................................................ 91 
Analysis Set: Rescue Ventolin User Population 


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Figure 2.5.1.2 
Adjusted Mean Change From Baseline in Mean Daytime Number of Puffs of 
Rescue Ventolin HFA ± SE Over Time ........................................................................... 91 
Analysis Set: Rescue Ventolin User Population 
Figure 2.5.1.3 
Adjusted Mean Change From Baseline in Mean Nighttime Number of Puffs of 
Rescue Ventolin HFA± SE Over Time ............................................................................ 91 
Analysis Set: Rescue Ventolin User Population 
Table 2.5.2 
Percentage of Days With No Rescue Ventolin HFA Use Over 24 Weeks ....................... 92 
Analysis Set: Rescue Ventolin User Population 
TIME TO ONSET OF ACTION ASSESSED USING FEV1 ON DAY 1 .................................................. 93 
Table 2.6.1 
FEV1 (L) by Post-dose Timepoint on Day 1 ..................................................................... 93 
Analysis Set: ITT Population 
Figure 2.6.1 
Adjusted Mean Change From Baseline in FEV1 (L) ± SE Over the 2 Hour Post-
dose Interval on Day 1 ...................................................................................................... 94 
Analysis Set: ITT Population 
OTHER SPIROMETRY MEASURES INCLUDING PERCENT RESPONDERS ANALYSES 
FOR DAY 1 ...................................................................................................................................... 95 
Table 2.7 
FEV1 AUC0-2 (L) .............................................................................................................. 95 
Analysis Set: ITT Population 
Figure 2.7 
Adjusted Mean FEV1 AUC0-2 (L) ± SE Over Time .......................................................... 95 
Analysis Set: ITT Population 
Table 2.8 
FVC AUC0-2 (L)................................................................................................................ 95 
Analysis Set: ITT Population 
Figure 2.8 
Adjusted Mean FVC AUC0-2 (L) ± SE Over Time ........................................................... 95 
Analysis Set: ITT Population 
Table 2.9 
Peak Change From Baseline in FVC (L) Within 2 Hours Post-dose ................................ 95 
Analysis Set: ITT Population 
Figure 2.9 
Adjusted Mean Peak Change From Baseline in FVC (L) ± SE Within 2 Hours 
Post-dose .......................................................................................................................... 95 
Analysis Set: ITT Population 
Table 2.10 
Morning Pre-dose Trough FVC (L) .................................................................................. 95 
Analysis Set: ITT Population 
Figure 2.10 
Adjusted Mean Change From Baseline in Morning Pre-dose Trough FVC (L) ± SE ...... 95 
Analysis Set: ITT Population 
Table 2.11.1 
Percentage of Subjects With ≥10% Improvement From Baseline in FEV1 During 2 
Hour Post-dose Interval and by Post-dose Timepoint on Day 1 ....................................... 96 
Analysis Set: ITT Population 
Table 2.11.2 
Percentage of Subjects With ≥12% Improvement From Baseline in FEV1 During 2 
Hour Post-dose Interval and by Post-dose Timepoint on Day 1 ....................................... 96 
Analysis Set: ITT Population 
Table 2.11.3 
Percentage of Subjects With ≥100 mL Improvement From Baseline in FEV1 
During 2 Hour Post-dose Interval and by Post-dose Timepoint on Day 1........................ 96 
Analysis Set: ITT Population 


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Table 2.11.4 
Percentage of Subjects With ≥200 mL Improvement From Baseline in FEV1 
During 2 Hour Post-dose Interval and by Post-dose Timepoint on Day 1........................ 96 
Analysis Set: ITT Population 
Table 2.11.5 
Percentage of Subjects With Improvement From Baseline in FEV1 of Both ≥12% 
and ≥200 mL During 2 Hour Post-dose Interval and by Post-dose Timepoint on 
Day 1 ................................................................................................................................ 96 
Analysis Set: ITT Population 
Table 2.12 
FVC (L) Over the 2 Hour Post-dose Interval on Day 1 .................................................... 97 
Analysis Set: ITT Population 
Figure 2.12 
Adjusted Mean Change From Baseline in FVC (L) ± SE Over the 2 Hour Post-
dose Interval on Day 1 ...................................................................................................... 97 
Analysis Set: ITT Population 
EXACERBATIONS ................................................................................................................................... 98 
Table 2.13.1 
Rate of COPD Exacerbations Overall and by CAT Score Subpopulation ........................ 98 
Analysis Set: ITT Population 
Table 2.13.2 
Rate of COPD Exacerbations With Imputation Overall and by CAT Score 
Subpopulation ................................................................................................................. 100 
Analysis Set: ITT Population 
Table 2.14 
Time to First COPD Exacerbation of Any Severity and Time to First Moderate or 
Severe COPD Exacerbation Overall and by CAT Score Subpopulation ........................ 101 
Analysis Set: ITT Population 
Figure 2.14.1.x 
Kaplan-Meier Curves for Time to First COPD Exacerbation of Any Severity 
Overall and by CAT Score Subpopulation ..................................................................... 102 
Analysis Set: ITT Population 
Figure 2.14.2.x 
Kaplan-Meier Curves for Time to First Moderate or Severe COPD Exacerbation 
Overall and by CAT Score Subpopulation ..................................................................... 102 
Analysis Set: ITT Population 
Table 2.15 
Time to Treatment Failure Overall and by CAT Score Subpopulation .......................... 103 
Analysis Set: ITT Population 
Figure 2.15.x 
Kaplan-Meier Curves for Time to Treatment Failure Overall and by CAT Score 
Subpopulation ................................................................................................................. 104 
Analysis Set: ITT Population 
Table 2.16.1 
Time to First Clinically Important Deterioration (CID) Overall and by CAT Score 
Subpopulation ................................................................................................................. 105 
Analysis Set: ITT Population 
Figure 2.16.1.x 
Kaplan-Meier Curves for Time to First CID Overall and by CAT Score 
Subpopulation ................................................................................................................. 106 
Analysis Set: ITT Population 
Table 2.16.2 
Time to First Clinically Important Deterioration (CID) With Death and Time to  
First Occurrence of Each Component of CID with Death Overall and by CAT 
Score Subpopulation ....................................................................................................... 106 
Analysis Set: ITT Population 
Figure 2.16.2.x 
Kaplan-Meier Curves for Time to First CID With Death and Time to First 
Occurrence of Each Component of CID With Death Overall and by CAT Score 
Subpopulation ................................................................................................................. 107 
Analysis Set: ITT Population 


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Table 2.17 
Time to First Sustained Clinically Important Deterioration (CID) and Time to First 
Occurrence of Each Component of Sustained CID Overall and by CAT Score 
Subpopulation ................................................................................................................. 108 
Analysis Set: ITT Population 
Figure 2.17.x 
Kaplan-Meier Curves for Time to First Sustained CID and Time to First 
Occurrence of Each Component of Sustained CID Overall and by CAT Score 
Subpopulation ................................................................................................................. 109 
Analysis Set: ITT Population 
SYMPTOMS............................................................................................................................................. 110 
Table 2.18.1 
Mean Daily, Daytime, and Nighttime Total Symptom Scores ....................................... 110 
Analysis Set: ITT Population 
Table 2.18.2 
Mean Daily, Daytime, and Nighttime Cough Symptom Scores ..................................... 110 
Analysis Set: ITT Population 
Table 2.18.3 
Mean Daily, Daytime, and Nighttime Shortness of Breath Symptom Scores ................ 110 
Analysis Set: ITT Population 
Table 2.18.4 
Mean Daily, Daytime, and Nighttime Sputum Volume Symptom Scores ...................... 110 
Analysis Set: ITT Population 
Table 2.18.5 
Mean Number of Nighttime Awakenings ....................................................................... 110 
Analysis Set: ITT Population 
CORRELATIONS .................................................................................................................................... 111 
Figure 2.19.1 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 at Week 
24 With Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 
Weeks ............................................................................................................................. 111 
Analysis Set: All Available Data 
Figure 2.19.2 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 at Week 
24 With Peak Change From Baseline in FEV1 at Week 24 ............................................ 112 
Analysis Set: All Available Data 
Figure 2.19.3 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 at Week 
24 With Change From Baseline in SGRQ Total Score at Week 24 ............................... 112 
Analysis Set: All Available Data 
Figure 2.19.4 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 at Week 
24 With Change From Baseline in Rescue Ventolin HFA Usage Over 24 Weeks ......... 112 
Analysis Set: All Available Data 
Figure 2.19.5 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 at Week 
24 With TDI Focal Score Over 24 Weeks ...................................................................... 112 
Analysis Set: All Available Data 
Figure 2.19.6 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 at Week 
24 With Peak Change From Baseline in FEV1 Over 24 Weeks ..................................... 112 
Analysis Set: All Available Data 
Figure 2.19.7 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 
Weeks With Peak Change From Baseline in FEV1 at Week 24 ..................................... 112 
Analysis Set: All Available Data 
Figure 2.19.8 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 
Weeks With Change From Baseline in SGRQ Total Score at Week 24 ......................... 113 
Analysis Set: All Available Data 


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Figure 2.19.9 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 
Weeks With Change From Baseline in Rescue Ventolin HFA Usage Over 24 
Weeks ............................................................................................................................. 113 
Analysis Set: All Available Data 
Figure 2.19.10 
Correlation of Peak Change From Baseline in FEV1 at Week 24 With Change 
From Baseline in SGRQ Total Score at Week 24 .......................................................... 113 
Analysis Set: All Available Data 
Figure 2.19.11 
Correlation of Peak Change From Baseline in FEV1 at Week 24 With Change 
From Baseline in Rescue Ventolin HFA Usage Over 24 Weeks .................................... 113 
Analysis Set: All Available Data 
Figure 2.19.12 
Correlation of Peak Change From Baseline in FEV1 at Week 24 With TDI Focal 
Score Over 24 Weeks ..................................................................................................... 113 
Analysis Set: All Available Data 
Figure 2.19.13 
Correlation of Peak Change From Baseline in FEV1 at Week 24 With Peak 
Change From Baseline in FEV1 Over 24 Weeks ............................................................ 113 
Analysis Set: All Available Data 
Figure 2.19.14 
Correlation of Change From Baseline in SGRQ Total Score at Week 24 With 
Change From Baseline in Rescue Ventolin HFA Usage Over 24 Weeks....................... 113 
Analysis Set: All Available Data 
Figure 2.19.15 
Correlation of Change From Baseline in SGRQ Total Score at Week 24 With TDI 
Focal Score Over 24 Weeks ........................................................................................... 113 
Analysis Set: All Available Data 
Figure 2.19.16 
Correlation of Change From Baseline in SGRQ Total Score at Week 24 With Peak 
Change From Baseline in FEV1 Over 24 Weeks ............................................................ 113 
Analysis Set: All Available Data 
Figure 2.19.17 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 
Weeks With TDI Focal Score Over 24 Weeks ............................................................... 113 
Analysis Set: All Available Data 
Figure 2.19.18 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 
Weeks With Peak Change From Baseline in FEV1 Over 24 Weeks .............................. 114 
Analysis Set: All Available Data 
Figure 2.19.19 
Correlation of TDI Focal Score Over 24 Weeks With Peak Change From Baseline 
in FEV1 Over 24 Weeks ................................................................................................. 114 
Analysis Set: All Available Data 
Figure 2.19.20 
Correlation of TDI Focal Score Over 24 Weeks With Change From Baseline in 
Rescue Ventolin HFA Usage Over 24 Weeks ................................................................ 114 
Analysis Set: All Available Data 
Figure 2.19.21 
Correlation of Peak Change From Baseline in FEV1 Over 24 Weeks With Change 
From Baseline in Rescue Ventolin HFA Usage Over 24 Weeks .................................... 114 
Analysis Set: All Available Data 
Figure 2.19.22 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 at 
Week 24 With Morning Pre-dose Trough FEV1 Over Weeks 12-24 ............................. 114 
Analysis Set: All Available Data 
Figure 2.19.23 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 at 
Week 24 With TDI Focal Score Over Weeks 12-24 ...................................................... 114 
Analysis Set: All Available Data 


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Figure 2.19.24 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 at 
Week 24 With Peak Change from Baseline in FEV1 Over Weeks 12-24 ....................... 114 
Analysis Set: All Available Data 
Figure 2.19.25 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 at 
Week 24 With SGRQ Total Score Over Weeks 12-24 ................................................... 114 
Analysis Set: All Available Data 
Figure 2.19.26 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over 
Week 24 With Morning Pre-dose Trough FEV1 Over Weeks 12-24 ............................. 114 
Analysis Set: All Available Data 
Figure 2.19.27 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over 
Week 24 With TDI Focal Score Over Weeks 12-24 ...................................................... 114 
Analysis Set: All Available Data 
Figure 2.19.28 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over 
Week 24 With Peak Change from Baseline in FEV1 Over Weeks 12-24 ....................... 115 
Analysis Set: All Available Data 
Figure 2.19.29 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over 
Week 24 With SGRQ Total Score Over Weeks 12-24 ................................................... 115 
Analysis Set: All Available Data 
Figure 2.19.30 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over 
Weeks 12-24 With TDI Focal Score Over Weeks 12-24 ............................................... 115 
Analysis Set: All Available Data 
Figure 2.19.31 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over 
Weeks 12-24 With Peak Change from Baseline in FEV1 Over Weeks 12-24 ................ 115 
Analysis Set: All Available Data 
Figure 2.19.32 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over 
Weeks 12-24 With SGRQ Total Score Over Weeks 12-24 ............................................ 115 
Analysis Set: All Available Data 
Figure 2.19.33 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over 
Weeks 12-24 With Rescue Ventolin Use Over 24 Weeks .............................................. 115 
Analysis Set: All Available Data 
Figure 2.19.34 
Correlation of TDI Focal Score Over 24 Weeks With Morning Pre-dose Trough 
FEV1 Over Weeks 12-24 ................................................................................................ 115 
Analysis Set: All Available Data 
Figure 2.19.35 
Correlation of TDI Focal Score Over 24 Weeks  With TDI Focal Score Over 
Weeks 12-24 ................................................................................................................... 115 
Analysis Set: All Available Data 
Figure 2.19.36 
Correlation of TDI Focal Score Over 24 Weeks With Peak Change from Baseline 
in FEV1 Over Weeks 12-24 ............................................................................................ 115 
Analysis Set: All Available Data 
Figure 2.19.37 
Correlation of TDI Focal Score Over 24 Weeks With SGRQ Total Score Over 
Weeks 12-24 ................................................................................................................... 115 
Analysis Set: All Available Data 
Figure 2.19.38 
Correlation of TDI Focal Score Over Weeks 12-24 With Peak Change from 
Baseline in FEV1 Over Weeks 12-24 ............................................................................. 115 
Analysis Set: All Available Data 


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Figure 2.19.39 
Correlation of TDI Focal Score Over Weeks 12-24 With SGRQ Total Score Over 
Weeks 12-24 ................................................................................................................... 116 
Analysis Set: All Available Data 
Figure 2.19.40 
Correlation of TDI Focal Score Over Weeks 12-24 With Rescue Ventolin Use 
Over 24 Weeks ............................................................................................................... 116 
Analysis Set: All Available Data 
Figure 2.19.41 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose at 
Week 24 With Morning Pre-dose Trough FEV1 Over Weeks 12-24 ............................. 116 
Analysis Set: All Available Data 
Figure 2.19.42 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose at 
Week 24 With TDI Focal Score Over Weeks 12-24 ...................................................... 116 
Analysis Set: All Available Data 
Figure 2.19.43 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose at 
Week 24 With Peak Change from Baseline in FEV1 Over Weeks 12-24 ....................... 116 
Analysis Set: All Available Data 
Figure 2.19.44 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose at 
Week 24 With SGRQ Total Score Over Weeks 12-24 ................................................... 116 
Analysis Set: All Available Data 
Figure 2.19.45 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose 
Over 24 Weeks  With Morning Pre-dose Trough FEV1 Over Weeks 12-24 .................. 116 
Analysis Set: All Available Data 
Figure 2.19.46 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose 
Over 24 Weeks  With TDI Focal Score Over Weeks 12-24 ........................................... 116 
Analysis Set: All Available Data 
Figure 2.19.47 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose 
Over 24 Weeks  With Peak Change from Baseline in FEV1 Over Weeks 12-24 ........... 116 
Analysis Set: All Available Data 
Figure 2.19.48 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose 
Over 24 Weeks  With SGRQ Total Score Over Weeks 12-24 ....................................... 116 
Analysis Set: All Available Data 
Figure 2.19.49 
Correlation of Peak Change from Baseline Within 2 Hours Post-dose Over Weeks 
12-24 With SGRQ Total Score Over Weeks 12-24 ........................................................ 117 
Analysis Set: All Available Data 
Figure 2.19.50 
Correlation of Peak Change from Baseline Within 2 Hours Post-dose Over Weeks 
12-24 With Rescue Ventolin Use Over 24 Weeks ......................................................... 117 
Analysis Set: All Available Data 
Figure 2.19.51 
Correlation of Change from Baseline in SGRQ Total Score at Week 24 With 
Morning Pre-dose Trough FEV1 Over Weeks 12-24 ...................................................... 117 
Analysis Set: All Available Data 
Figure 2.19.52 
Correlation of Change from Baseline in SGRQ Total Score at Week 24 With TDI 
Focal Score Over Weeks 12-24 ...................................................................................... 117 
Analysis Set: All Available Data 
Figure 2.19.53 
Correlation of Change from Baseline in SGRQ Total Score at Week 24 With Peak 
Change from Baseline in FEV1 Over Weeks 12-24........................................................ 117 
Analysis Set: All Available Data 


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Figure 2.19.54 
Correlation of Change from Baseline in SGRQ Total Score at Week 24 With 
SGRQ Total Score Over Weeks 12-24 ........................................................................... 117 
Analysis Set: All Available Data 
Figure 2.19.55 
Correlation of Change from Baseline in SGRQ Total Score Over Weeks 12-24 
With Rescue Ventolin Use Over 24 Weeks .................................................................... 117 
Analysis Set: All Available Data 
Table 2.19.1 
Pearson Correlation Matrix of Key Efficacy Endpoints (Excluding Correlations 
with Efficacy Endpoints Over Weeks 12-24) ................................................................. 118 
Analysis Set: All Available Data 
Table 2.19.2 
Pearson Correlation Matrix of Key Efficacy Endpoints Over Weeks 12-24 With 
Other Key Efficacy Endpoints and With Each Other ..................................................... 120 
Analysis Set: All Available Data 
SUBGROUP ANALYSES ....................................................................................................................... 122 
Table 2.20.x 
Subject Disposition by Region and Country: <Region Subgroup or Country> .............. 122 
Analysis Set: All Subjects Randomized 
Table 2.21.x 
Reason for Early Discontinuation by Region and Country: <Region Subgroup or 
Country> ......................................................................................................................... 124 
Analysis Set: All Subjects Randomized 
Table 2.22.1.x 
Demographics and Baseline Characteristics by Region and Country: <Region 
Subgroup or Country> .................................................................................................... 126 
Analysis Set: ITT Population 
Table 2.22.2 
Demographics and Baseline Characteristics by GOLD Category................................... 130 
Analysis Set: ITT Population 
Table 2.22.2 
Demographics and Baseline Characteristics by GOLD Severity .................................... 130 
Analysis Set: ITT Population 
Table 2.23.x 
Screening Pre- and Post-Bronchodilator and Baseline Spirometry Parameters by 
Region and Country: <Region Subgroup or Country> ................................................... 131 
Analysis Set: ITT Population 
Table 2.24.1.x 
Severity and Duration of COPD by Region and Country: <Region Subgroup or 
Country> ......................................................................................................................... 133 
Analysis Set: ITT Population 
Table 2.24.2 
Severity and Duration of COPD by GOLD Category ..................................................... 134 
Analysis Set: ITT Population 
Table 2.24.3 
Severity and Duration of COPD by GOLD Severity ...................................................... 135 
Table 2.25.1.x 
Reversibility to Ventolin HFA by Region and Country: <Region Subgroup or 
Country> ......................................................................................................................... 135 
Analysis Set: ITT Population 
Table 2.25.2 
Reversibility to Ventolin HFA by GOLD Category ....................................................... 135 
Analysis Set: ITT Population 
Table 2.25.3 
Reversibility to Ventolin HFA by GOLD Severity......................................................... 135 
Analysis Set: ITT Population 
Table 2.26.1.x 
Reversibility to Atrovent HFA by Region and Country: <Region Subgroup or 
Country> ......................................................................................................................... 135 
Analysis Set: ITT Population 


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Table 2.26.2 
Reversibility to Atrovent HFA by GOLD Category ....................................................... 135 
Analysis Set: ITT Population 
Table 2.26.3 
Reversibility to Atrovent HFA by GOLD Severity ........................................................ 135 
Analysis Set: ITT Population 
Table 2.27.1.x 
Study Treatment Exposure and Compliance by Region and Country: <Region 
Subgroup or Country> .................................................................................................... 136 
Analysis Set: Safety Population 
Table 2.27.2 
Study Treatment Exposure and Compliance by GOLD Category .................................. 137 
Analysis Set: Safety Population 
Table 2.27.3 
Study Treatment Exposure and Compliance by GOLD Severity ................................... 137 
Analysis Set: Safety Population 
Table 2.28.1.x 
Morning Pre-dose Trough FEV1 (L) by Region and Country:  <Region Subgroup 
or Country> .................................................................................................................... 138 
Analysis Set: ITT Population 
Figure 2.28.1.1 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE (Regions/Countries) ............. 140 
Analysis Set: ITT Population 
Figure 2.28.1.2.1 
Galbraith Plot for Adjusted Mean Change From Baseline in Morning Pre-dose 
Trough FEV1 (L) ± SE at Week 24 (All Countries) ....................................................... 141 
Analysis Set: ITT Population 
Figure 2.28.1.2.2 
Galbraith Plot for Adjusted Mean Change From Baseline in Morning Pre-dose 
Trough FEV1 (L) ± SE Over 24 Weeks (All Countries) ................................................. 141 
Analysis Set: ITT Population 
Figure 2.28.1.2.3 
Galbraith Plot for Adjusted Mean Change From Baseline in Morning Pre-dose 
Trough FEV1 (L) ± SE Over Weeks 12-24 (All Countries) ........................................... 141 
Analysis Set: ITT Population 
Figure 2.28.1.3.1 
Q-Q Plot for Adjusted Mean Change From Baseline in Morning Pre-dose Trough 
FEV1 (L) ± SE at Week 24 (All Countries) .................................................................... 142 
Analysis Set: ITT Population 
Figure 2.28.1.3.2 
Q-Q Plot for Adjusted Mean Change From Baseline in Morning Pre-dose Trough 
FEV1 (L) ± SE Over 24 Weeks (All Countries) ............................................................. 142 
Analysis Set: ITT Population 
Figure 2.28.1.3.3 
Q-Q Plot for Adjusted Mean Change From Baseline in Morning Pre-dose Trough 
FEV1 (L) ± SE Over Weeks 12-24 (All Countries) ........................................................ 142 
Analysis Set: ITT Population 
Table 2.28.2 
Morning Pre-dose Trough FEV1 (L) by GOLD Category .............................................. 143 
Analysis Set: ITT Population 
Figure 2.28.2.1 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE at Week 24 by GOLD 
Category ......................................................................................................................... 143 
Analysis Set: ITT Population 
Figure 2.28.2.2 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE Over 24 Weeks by 
GOLD Category ............................................................................................................. 144 
Analysis Set: ITT Population 
Figure 2.28.2.3 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE Over Weeks 12-24 by 
GOLD Category ............................................................................................................. 144 
Analysis Set: ITT Population 


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Table 2.28.3 
Morning Pre-dose Trough FEV1 (L) by GOLD Severity ................................................ 144 
Analysis Set: ITT Population 
Figure 2.28.3.1 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE at Week 24 by GOLD 
Severity ........................................................................................................................... 144 
Analysis Set: ITT Population 
Figure 2.28.3.2 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE Over 24 Weeks by 
GOLD Severity ............................................................................................................... 144 
Analysis Set: ITT Population 
Figure 2.28.3.3 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE Over Weeks 12-24 by 
GOLD Severity ............................................................................................................... 144 
Analysis Set: ITT Population 
Table 2.29.x 
TDI Focal Score by Region and Country: <Region Subgroup or Country> ................... 145 
Analysis Set: ITT Population 
Figure 2.29.1 
Forest Plot for TDI Focal Score ± SE (Regions/Countries) ............................................ 146 
Analysis Set: ITT Population 
Figure 2.29.2.1 
Galbraith Plot for Adjusted Mean TDI Focal Score ± SE Over 24 Weeks (All 
Countries) ....................................................................................................................... 146 
Analysis Set: ITT Population 
Figure 2.29.2.2 
Galbraith Plot for Adjusted Mean TDI Focal Score ± SE Over Weeks 12- 24 (All 
Countries) ....................................................................................................................... 146 
Analysis Set: ITT Population 
Figure 2.29.3.1 
Q-Q Plot for Adjusted Mean TDI Focal Score ± SE Over 24 Weeks (All 
Countries) ....................................................................................................................... 147 
Analysis Set: ITT Population 
Figure 2.29.3.2 
Q-Q Plot for Adjusted Mean TDI Focal Score ± SE Over Weeks 12-24 (All 
Countries) ....................................................................................................................... 147 
Analysis Set: ITT Population 
Table 2.30.1.1.x 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-dose by Region and 
Country: <Region Subgroup or Country> ...................................................................... 147 
Analysis Set: ITT Population 
Figure 2.30.1.1 
Forest Plot for Peak Change from Baseline in FEV1 (L) ± SE Within 2 Hours Post-
dose (Regions/Countries) ............................................................................................... 147 
Analysis Set: ITT Population 
Figure 2.30.1.2.1 
Galbraith Plot for Adjusted Mean Peak Change from Baseline in FEV1 (L) ± SE at 
Week 24 (All Countries) ................................................................................................ 147 
Analysis Set: ITT Population 
Figure 2.30.1.2.2 
Galbraith Plot for Adjusted Mean Peak Change from Baseline in FEV1 (L) ± SE 
Over 24 Weeks (All Countries) ...................................................................................... 147 
Analysis Set: ITT Population 
Figure 2.30.1.2.3 
Galbraith Plot for Adjusted Mean Peak Change from Baseline in FEV1 (L) ± SE 
Over Weeks 12-24 (All Countries) ................................................................................. 147 
Analysis Set: ITT Population 
Figure 2.30.1.3.1 
Q-Q Plot for Adjusted Mean Peak Change from Baseline in FEV1 (L) ± SE at 
Week 24 (All Countries) ................................................................................................ 147 
Analysis Set: ITT Population 


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Figure 2.30.1.3.2 
Q-Q Plot for Adjusted Mean Peak Change from Baseline in FEV1 (L) ± SE Over 
24 Weeks (All Countries) ............................................................................................... 147 
Analysis Set: ITT Population 
Figure 2.30.1.3.3 
Q-Q Plot for Adjusted Mean Peak Change from Baseline in FEV1 (L) ± SE Over 
Weeks 12-24 (All Countries) .......................................................................................... 147 
Analysis Set: ITT Population 
Table 2.30.2 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-dose by GOLD 
Category ......................................................................................................................... 147 
Analysis Set: ITT Population 
Figure 2.30.2.1 
Forest Plot for Mean Peak Change from Baseline in FEV1 (L) ± SE Within 2 
Hours Post-dose by GOLD Category ............................................................................. 148 
Analysis Set: ITT Population 
Table 2.30.3 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-dose by GOLD 
Severity ........................................................................................................................... 148 
Analysis Set: ITT Population 
Figure 2.30.3.1 
Forest Plot for Mean Peak Change from Baseline in FEV1 (L) ± SE Within 2 
Hours Post-dose at Week 24 by GOLD Severity ........................................................... 148 
Analysis Set: ITT Population 
Figure 2.30.3.2 
Forest Plot for Mean Peak Change from Baseline in FEV1 (L) ± SE Within 2 
Hours Post-dose Over 24 Weeks by GOLD Severity ..................................................... 148 
Analysis Set: ITT Population 
Figure 2.30.3.3 
Forest Plot for Mean Peak Change from Baseline in FEV1 (L) ± SE Within 2 
Hours Post-dose Over Weeks 12-24 by GOLD Severity................................................ 148 
Analysis Set: ITT Population 
Table 2.31.1.x 
SGRQ Total Score (units) by Region and Country: < Region Subgroup or 
Country> ......................................................................................................................... 149 
Analysis Set: ITT Population 
Figure 2.31.1.1 
Forest Plot for SGRQ Total Score (units)  ± SE at Week 24 by Region and 
Country ........................................................................................................................... 149 
Analysis Set: ITT Population 
Figure 2.31.2.1 
Galbraith Plot for Adjusted Mean Change from Baseline in SGRQ Total Score 
(units) ± SE at Week 24 (All Countries) ........................................................................ 149 
Analysis Set: ITT Population 
Figure 2.31.2.2 
Galbraith Plot for Adjusted Mean Change from Baseline in SGRQ Total Score 
(units) ± SE Over Weeks 12-24 (All Countries) ............................................................. 149 
Analysis Set: ITT Population 
Figure 2.31.3.1 
Q-Q Plot for Adjusted Mean Change from Baseline in SGRQ Total Score (units) ± 
SE at Week 24 (All Countries) ....................................................................................... 149 
Analysis Set: ITT Population 
Figure 2.31.3.2 
Q-Q Plot for Adjusted Mean Change from Baseline in SGRQ Total Score (units) ± 
SE Over Weeks 12-24 (All Countries) ........................................................................... 149 
Analysis Set: ITT Population 
Table 2.32.x 
Response in SGRQ Total Score (Achievment of a Minimum Clinically Important 
Difference Threshold of ≥4 Units on Average) by Region and Country: <Region 
Subgroup or Country> .................................................................................................... 150 
Analysis Set: ITT Population 


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Figure 2.32 
Forest Plot for Response in SGRQ Total Score ± 95% CI (Regions/Countries) ............ 150 
Analysis Set: ITT Population 
Table 2.33.1.x 
Mean Daily Number of Puffs of Rescue Ventolin by Region and Country: 
<Region Subgroup or Country> ..................................................................................... 151 
Analysis Set: ITT Population 
Figure 2.33.1.1 
Forest Plot for Change from Baseline in Daily Number of Puffs of Rescue 
Ventolin ± SE Over 24 Weeks (Regions/Countries) ...................................................... 151 
Analysis Set: ITT Population 
Figure 2.33.1.2 
Galbraith Plot for Adjusted Mean Change from Baseline in Daily Number of Puffs 
of Rescue Ventolin ± SE Over 24 Weeks (All Countries).............................................. 151 
Analysis Set: ITT Population 
Figure 2.33.1.3 
Q-Q Plot for Adjusted Mean Change from Baseline in Daily Number of Puffs of 
Rescue Ventolin ± SE Over 24 Weeks (All Countries) .................................................. 151 
Analysis Set: ITT Population 
Table 2.33.2.x 
Mean Daily Number of Puffs of Rescue Ventolin by Region and Country: 
<Region Subgroup or Country> ..................................................................................... 151 
Analysis Set: Rescue Ventolin User Population 
Figure 2.33.2.1 
Forest Plot for Change from Baseline in Daily Number of Puffs of Rescue 
Ventolin ± SE (Regions/Countries) ................................................................................ 151 
Analysis Set: Rescue Ventolin User Population 
Figure 2.33.2.2 
Galbraith Plot for Adjusted Mean Change from Baseline in Daily Number of Puffs 
of Rescue Ventolin ± SE Over 24 Weeks (All Countries).............................................. 151 
Analysis Set: Rescue Ventolin User Population 
Figure 2.33.2.3 
Q-Q Plot for Adjusted Mean Change from Baseline in Daily Number of Puffs of 
Rescue Ventolin ± SE Over 24 Weeks (All Countries) .................................................. 151 
Analysis Set: Rescue Ventolin User Population 
Table 2.34 
Change from Baseline in FEV1 at 5 Min Post-dose on Day 1 by Region and 
Country: <Region Subgroup or Country> ...................................................................... 152 
Analysis Set: ITT Population 
Figure 2.34.1 
Forest Plot for FEV1 at 5 Min Post-dose on Day 1 (Regions/Countries) ........................ 152 
Analysis Set: ITT Population 
Figure 2.34.2 
Galbraith Plot for Adjusted Mean Change from Baseline in FEV1 at 5 Min Post-
dose ± SE on Day 1 (All Countries) ............................................................................... 152 
Analysis Set: ITT Population 
Figure 2.34.3 
Q-Q Plot for Adjusted Mean Change from Baseline in FEV1 at 5 Min Post-dose ± 
SE on Day 1 (All Countries)........................................................................................... 152 
Analysis Set: ITT Population 
Table 2.35 
Change from Baseline in FEV1 at 15 Min Post-dose on Day 1 by Region and 
Country: <Region Subgroup or Country> ...................................................................... 152 
Analysis Set: ITT Population 
Figure 2.35.1 
Forest Plot for FEV1 at 15 Min Post-dose on Day 1 (Regions/Countries) ...................... 152 
Analysis Set: ITT Population 
Figure 2.35.2 
Galbraith Plot for Adjusted Mean Change from Baseline in FEV1 at 15 Min Post-
dose ± SE on Day 1 (All Countries) ............................................................................... 152 
Analysis Set: ITT Population 


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Figure 2.35.3 
Q-Q Plot for Adjusted Mean Change from Baseline in FEV1 at 15 Min Post-dose ± 
SE (All Countries) .......................................................................................................... 152 
Analysis Set: ITT Population 
Table 2.36 
Interaction of Treatment and Subgroup for Each Subgroup Analysis ............................ 153 
Analysis Set: ITT Population 
HEALTHCARE RESOURCE UTILIZATION ........................................................................................ 154 
Table 2.37.1 
Healthcare Resource Utilization: Number of Days Missed From Work......................... 154 
Analysis Set: Safety Population 
Table 2.37.2 
Healthcare Resource Utilization by Relationship to COPD and Treatment ................... 156 
Analysis Set: Safety Population 
3. 
SAFETY .......................................................................................................................................... 158 
ADVERSE EVENTS ................................................................................................................................ 159 
Table 3.1.1 
Overall Summary of Adverse Events ............................................................................. 159 
Analysis Set: Safety Population 
Table 3.1.2.x 
Overall Summary of Adverse Events by Region and Country: <Region Subgroup 
or Country> .................................................................................................................... 161 
Analysis Set: Safety Population 
Table 3.2.1.1.1 
Adverse Events by MedDRA Primary System Organ Class and Preferred Term .......... 162 
Analysis Set: Safety Population 
Table 3.2.1.1.x 
Adverse Events by Region and Country, MedDRA Primary System Organ Class 
and Preferred Term: <Region Subgroup or Country> .................................................... 163 
Analysis Set: Safety Population 
Table 3.2.1.2.1 
Adverse Events With Onset After the Last Date of Treatment by MedDRA 
Primary System Organ Class and Preferred Term .......................................................... 163 
Analysis Set: Safety Population 
Table 3.2.1.2.x 
Adverse Events With Onset After the Last Date of Treatment by Region and 
Country, MedDRA Primary System Organ Class, and Preferred Term: <Region 
Subgroup or Country> .................................................................................................... 163 
Analysis Set: Safety Population 
Table 3.2.2.1 
Adverse Events Occurring in >=2% of Subjects in a Treatment by Descending 
Frequency ....................................................................................................................... 164 
Analysis Set: Safety Population 
Table 3.2.2.x 
Adverse Events Occurring in >=2% of Subjects in a Treatment by Descending 
Frequency by Region and Country: <Region Subgroup or Country> ............................ 164 
Analysis Set: Safety Population 
Table 3.2.3.1 
Adverse Events in MedDRA SMQs/Groupings of Interest by Term .............................. 164 
Analysis Set: Safety Population 
Table 3.2.3.x 
Adverse Events in MedDRA SMQs/Groupings of Interest by Term by Region and 
Country:  <Region Subgroup or Country> ..................................................................... 164 
Analysis Set: Safety Population 
Table 3.2.4.1 
Non-serious Adverse Events Occurring in ≥5% of Subjects in a Treatment by 
MedDRA Primary System Organ Class and Preferred Term ......................................... 165 
Analysis Set: Safety Population 


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Table 3.2.4.x 
Non-serious Adverse Events Occurring in ≥5% of Subjects in a Treatment by 
Region and Country. MedDRA Primary System Organ Class, and Preferred Term: 
<Region Subgroup or Country> ..................................................................................... 165 
Analysis Set: Safety Population 
Table 3.3.1 
Rate of Adverse Events Adjusted for Exposure by MedDRA Primary System 
Organ Class and Preferred Term .................................................................................... 166 
Analysis Set: Safety Population 
Table 3.3.x 
Rate of Adverse Events Adjusted for Exposure by Region and Country, MedDRA 
Primary System Organ Class, and Preferred Term: : <Region Subgroup or 
Country> ......................................................................................................................... 166 
Analysis Set: Safety Population 
Table 3.4.1 
Adverse Events Suspected to be Drug-Related by MedDRA Primary System 
Organ Class and Preferred Term .................................................................................... 167 
Analysis Set: Safety Population 
Table 3.4.x 
Adverse Events Suspected to be Drug-Related by Region and Country:, MedDRA 
Primary System Organ Class, and Preferred Term: <Region Subgroup or 
Country> ......................................................................................................................... 167 
Analysis Set: Safety Population 
Table 3.5.1 
Adverse Events Causing Study Drug Discontinuation by MedDRA Primary 
System Organ Class and Preferred Term ........................................................................ 167 
Analysis Set: Safety Population 
Table 3.5.x 
Adverse Events Causing Study Drug Discontinuation by Region and Country, 
MedDRA Primary System Organ Class and Preferred Term: <Region Subgroup or 
Country> ......................................................................................................................... 167 
Analysis Set: Safety Population 
Table 3.6 
Listing of Adverse Events Leading to Permanent Discontinuation of Study 
Treatment........................................................................................................................ 168 
Analysis Set: All Subjects Randomized 
Table 3.7.1.1 
Serious Adverse Events by MedDRA Primary System Organ Class and Preferred 
Term ............................................................................................................................... 169 
Analysis Set: Safety Population 
Table 3.7.1.x 
Serious Adverse Events by Region Subgroup or Country, MedDRA Primary 
System Organ Class, and Preferred Term ....................................................................... 169 
Analysis Set: Safety Population 
Table 3.7.2.1 
Serious Adverse Events With Onset After the Last Date of Treatment by MedDRA 
Primary System Organ Class and Preferred Term .......................................................... 169 
Analysis Set: Safety Population 
Table 3.7.2.x 
Serious Adverse Events With Onset After the Last Date of Treatment by Region 
and Country, MedDRA Primary System Organ Class and Preferred Term: 
<Region Subgroup or Country> ..................................................................................... 169 
Analysis Set: Safety Population 
Table 3.8.1 
Listing of Serious Adverse Events (SAEs) ..................................................................... 170 
Analysis Set: All Subjects Screened 
Table 3.8.2 
Listing of SAE-Specific Report Information .................................................................. 171 
Analysis Set: All Subjects Screened 


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Table 3.9.1 
Rate of Serious Adverse Events Adjusted for Exposure, by MedDRA Primary 
System Organ Class and Preferred Term ........................................................................ 172 
Analysis Set: Safety Population 
Table 3.9.x 
Rate of Serious Adverse Events Adjusted for Exposure, by Region and Country,  
MedDRA Primary System Organ Class and Preferred Term: <Region Subgroup or 
Country> ......................................................................................................................... 172 
Analysis Set: Safety Population 
Table 3.10.1 
Serious Adverse Events Suspected to be Drug-Related by MedDRA Primary 
System Organ Class and Preferred Term ........................................................................ 173 
Analysis Set: Safety Population 
Table 3.10.x 
Serious Adverse Events Suspected to be Drug-Related by Region and Country,  
MedDRA Primary System Organ Class and Preferred Term: <Region Subgroup or 
Country> ......................................................................................................................... 173 
Analysis Set: Safety Population 
Table 3.11.1.1 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – 
GFF MDI 14.4/9.6 μg ..................................................................................................... 174 
Analysis Set: Safety Population 
Table 3.11.1.x 
TEAEs by Region and Country, Primary System Organ Class, Preferred Term, and 
Highest Severity – GFF MDI 14.4/9.6 μg: <Region Subgroup or Country> ................. 174 
Analysis Set: Safety Population 
Table 3.11.2.1 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – 
FF MDI 9.6 μg ................................................................................................................ 175 
Analysis Set: Safety Population 
Table 3.11.2.x 
TEAEs by TEAEs by Region and Country, Primary System Organ Class, 
Preferred Term, and Highest Severity – FF MDI 9.6 μg: <Region Subgroup or 
Country> ......................................................................................................................... 175 
Analysis Set: Safety Population 
Table 3.11.3.1 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – 
GP MDI 14.4 μg ............................................................................................................. 175 
Analysis Set: Safety Population 
Table 3.11.3.x 
TEAEs by TEAEs by Region and Country, Primary System Organ Class, 
Preferred Term, and Highest Severity – GP MDI 14.4 μg: <Region Subgroup or 
Country> ......................................................................................................................... 175 
Analysis Set: Safety Population 
Table 3.11.4.1 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – 
Placebo MDI................................................................................................................... 175 
Analysis Set: Safety Population 
Table 3.11.4.x 
TEAEs by TEAEs by Region and Country, Primary System Organ Class, 
Preferred Term, and Highest Severity Placebo MDI: <Region Subgroup or 
Country> ......................................................................................................................... 175 
Analysis Set: Safety Population 
Table 3.12.1 
Death Events, by MedDRA Primary System Organ Class and Preferred Term ............. 176 
Analysis Set: Safety Population 
Table 3.12.x 
Death Events, by Region and Country, MedDRA Primary System Organ Class and 
Preferred Term: <Region Subgroup or Country> ........................................................... 176 
Table 3.13 
Listing of Deaths............................................................................................................. 177 
Analysis Set: All Subjects Screened 


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LABORATORY PARAMETERS ............................................................................................................ 179 
Table 3.14.1 
Laboratory Parameters by Visit and Time of Assessment – Hematology Panel ............. 179 
Analysis Set: Safety Population 
Table 3.14.2 
Laboratory Parameters by Visit and Time of Assessment – Blood Chemistry Panel ..... 180 
Analysis Set: Safety Population 
Table 3.14.3 
Laboratory Parameters by Visit and Time of Assessment – Kidney Function ............... 181 
Analysis Set: Safety Population 
Table 3.14.4 
Laboratory Parameters by Visit and Time of Assessment – Urinalysis pH and 
Specific Gravity .............................................................................................................. 181 
Analysis Set: Safety Population 
Table 3.14.5 
Shift Table for Laboratory Hematology Data: NCI-CTC Grading ................................. 182 
Analysis Set: Safety Population 
Table 3.14.6 
Shift Table for Laboratory Chemistry Data: NCI-CTC Grading .................................... 183 
Analysis Set: Safety Population 
Table 3.14.7 
Shift Table for Kidney Function: NCI-CTC Grading ..................................................... 183 
Analysis Set: Safety Population 
Table 3.14.8 
Post-Baseline Newly Occurring or Worsening Potentially Clinically Significant 
Laboratory Values Based on CTCAE 4.03 and Other Criteria ....................................... 184 
Analysis Set: Safety Population 
Table 3.14.9 
All Potassium Records for Subjects With Newly Occurring or Worsening 
Potentially Clinically Significant Potassium Values Post-Baseline ............................... 186 
Analysis Set: Safety Population 
Table 3.14.10 
All Glucose Records for Subjects With Newly Occurring or Worsening Potentially 
Clinically Significant Glucose Values Post-Baseline ..................................................... 186 
Analysis Set: Safety Population 
Table 3.14.11 
All Records for Subjects With Newly Occurring or Worsening Potentially 
Clinically Significant Values Post-Baseline Other Than Those for Glucose and 
Potassium ....................................................................................................................... 186 
Analysis Set: Safety Population 
VITAL SIGNS .......................................................................................................................................... 187 
Table 3.15.1 
Vital Sign Measurements by Visit and Time of Assessment .......................................... 187 
Analysis Set: Safety Population 
Table 3.15.2 
Post-Baseline Potentially Clinically Significant Vital Sign Values ................................ 189 
Analysis Set: Safety Population 
Table 3.15.3 
Listing of Potentially Clinically Significant Systolic and Diastolic Blood Pressure 
Increases and Decreases ................................................................................................. 190 
Analysis Set: Safety Population 
Table 3.15.4 
Listing of Potentially Clinically Significant Tachycardia and Bradycardia Events ........ 190 
Analysis Set: All Subjects Randomized 
12-LEAD ELECTROCARDIOGRAM (ECG) ......................................................................................... 191 
Table 3.16.1 
ECG Parameters by Visit and Time of Assessment ........................................................ 191 
Analysis Set: Safety Population 
Figure 3.16.1a 
Mean Change From Baseline for QTcF (ms) ± SE Over Time During Treatment ......... 193 
Analysis Set: Safety Population 


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Figure 3.16.1b 
Mean Change From Baseline for QTcF (ms) ± SE Over 2 Hours Post-dose on Day 
1 ...................................................................................................................................... 194 
Analysis Set: Safety Population 
Figure 3.16.1c 
Mean Change From Baseline for Heart Rate (bpm) ± SE Over Time During 
Treatment........................................................................................................................ 194 
Analysis Set: Safety Population 
Figure 3.16.1d 
Mean Change From Baseline for Heart Rate (bpm) ± SE Over 2 Hours Post-dose 
on Day 1 ......................................................................................................................... 194 
Analysis Set: Safety Population 
Table 3.16.2 
Post-Baseline Potentially Clinically Significant (PCS) ECG Values ............................. 195 
Analysis Set: Safety Population 
Table 3.16.3 
Listing of ECG's Meeting QTcF Interval Prolongation Criteria ..................................... 197 
Analysis Set: All Subjects Randomized 
Table 3.16.4 
Listing of PR Interval Increases: Post-Baseline Increases of >50 ms From Baseline..... 197 
Analysis Set: All Subjects Randomized 
Table 3.16.5 
Listing of QRS Prolongations: Post-Baseline Prolongations of >40 ms From 
Baseline .......................................................................................................................... 197 
Analysis Set: All Subjects Randomized 
4. 
SUBJECT DATA LISTINGS ......................................................................................................... 198 
4.1 
SUBJECT DISCONTINUATIONS/COMPLETIONS ................................................................... 199 
Listing 1.1 
Study Centers .................................................................................................................. 199 
Analysis Set: All Subjects Screened 
Listing 1.2 
Subject Disposition and Demographic Data ................................................................... 200 
Analysis Set: All Subjects Screened 
Listing 1.3 
Randomized Treatment, Actual Treatment, and Duration of Treatment ........................ 202 
Analysis Set: All Subjects Randomized 
Listing 1.4 
Reasons Subjects Were Not Randomized ....................................................................... 203 
Analysis Set: Non-Randomized Analysis Set 
Listing 1.5 
Changes in Smoking Status During Study ...................................................................... 204 
Analysis Set: All Subjects Randomized 
4.2 
PROTOCOL DEVIATIONS .......................................................................................................... 205 
Listing 2.1 
Violation of Inclusion/Exclusion Criteria and Waivers .................................................. 205 
Analysis Set: All Subjects Randomized 
Listing 2.2 
Screening Lung Function and Ventolin HFA and Atrovent HFA Reversibility ............. 206 
Analysis Set: All Subjects Randomized 
4.3 
SUBJECTS EXCLUDED FROM THE ITT, PP, SYMPTOMATIC, AND SAFETY 
POPULATIONS ............................................................................................................................. 207 
4.4 
BASELINE CHARACTERISTICS ................................................................................................ 208 
Listing 4.1 
COPD Diagnosis ............................................................................................................. 208 
Analysis Set: All Subjects Randomized 
Listing 4.2 
Screening CAT Assessment ............................................................................................ 209 
Analysis Set: All Subjects Randomized 


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Listing 4.3 
Screening MMRC Scale ................................................................................................. 210 
Analysis Set: All Subjects Randomized 
Listing 4.4 
History of Moderate or Severe COPD Exacerbations ..................................................... 211 
Analysis Set: All Subjects Randomized 
Listing 4.5.1 
Relevant Medical and Surgical History .......................................................................... 212 
Analysis Set: All Subjects Randomized 
Listing 4.5.2 
Cardiovascular Risk Factors of Interest .......................................................................... 213 
Analysis Set: All Subjects Randomized 
Listing 4.6 
Screening Reproductive Status and Pregnancy Test Results .......................................... 214 
Analysis Set: All Subjects Randomized 
Listing 4.7 
Prior, Concomitant, and Post-Treatment COPD Medications ........................................ 215 
Analysis Set: All Subjects Randomized 
Listing 4.8 
Prior, Concomitant, and Post-Treatment Non-COPD-Related Medications ................... 216 
Analysis Set: All Subjects Randomized 
Listing 4.9 
Suspect Drug Assessment for SAEs ............................................................................... 217 
Analysis Set: All Subjects Randomized 
4.5 
DOSING AND COMPLIANCE ..................................................................................................... 218 
Listing 5.1.1 
Study Drug Dosing, Dispensing, and Return .................................................................. 219 
Analysis Set: All Subjects Randomized 
Listing 5.1.2 
Atrovent HFA and Ventolin HFA Dispensing ................................................................ 221 
Analysis Set: All Subjects Randomized 
Listing 5.2 
Compliance and Exposure to Study Treatment ............................................................... 222 
Analysis Set: All Subjects Randomized 
4.6 
INDIVIDUAL EFFICACY DATA AND HCRU DATA ............................................................... 223 
4.6.1 EFFICACY ..................................................................................................................................... 223 
Listing 6.1.1 
Subjects Who Failed Restrictions Prior to Spirometry Assessment ............................... 224 
Analysis Set: All Subjects Randomized 
Listing 6.1.2 
Reason for Missingness Overall and by Visit ................................................................. 225 
Analysis Set: All Subjects Randomized 
Listing 6.1.3 
Spirometry Measurements .............................................................................................. 226 
Analysis Set: All Subjects Randomized 
Listing 6.1.4 
FEV1 (L) at Each Post-dose Timepoint Through 2 Hours on a Test Day ....................... 227 
Analysis Set: ITT Population 
Listing 6.1.5 
FVC (L) at Each Post-dose Timepoint Through 2 Hours on a Test Day ........................ 228 
Analysis Set: ITT Population 
Listing 6.1.6 
Subject Dosing and Symptoms Diary, Including Rescue Ventolin Use ......................... 229 
Analysis Set: All Subjects Randomized 
Listing 6.1.7 
COPD Exacerbations ...................................................................................................... 231 
Analysis Set: All Subjects Randomized 
Listing 6.1.8 
Baseline Dyspnea Index (BDI) /Transition Dyspnea Index (TDI) ................................. 232 
Analysis Set: All Subjects Randomized 
Listing 6.1.9 
St. George Respiratory Questionnaire (SGRQ) .............................................................. 233 
Analysis Set: All Subjects Randomized 


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Listing 6.1.10 
Individual Items of the St. George Respiratory Questionnaire (SGRQ) ......................... 234 
Analysis Set: All Subjects Randomized 
4.6.2 HEALTHCARE RESOURCE UTILIZATION .............................................................................. 235 
Listing 6.2 
Healthcare Resource Utilization ..................................................................................... 235 
Analysis Set: Safety Population 
4.7 
ADVERSE EVENT LISTINGS...................................................................................................... 236 
Listing 7.1 
Adverse Events by Primary System Organ Class, Preferred Term, Treatment, 
Country, Center, Subject ID, and Onset Day .................................................................. 236 
Analysis Set: All Subjects Randomized 
Listing 7.2 
Glossary of Adverse Event Preferred Terms vs. Investigator’s Verbatim ...................... 238 
Listing 7.3 
Adverse Events by Treatment, Country, Center, Subject ID, and Onset Day ................. 239 
Analysis Set: All Subjects Randomized 
4.8 
LABORATORY VALUES ............................................................................................................. 241 
Listing 8.1 
Laboratory Test Results (Hematology Panel) ................................................................. 241 
Analysis Set: All Subjects Randomized 
Listing 8.2 
Laboratory Test Results (Morphology) .......................................................................... 242 
Analysis Set: All Subjects Randomized 
Listing 8.3 
Laboratory Test Results (Chemistry Panel and Kidney Function) ................................. 242 
Analysis Set: All Subjects Randomized 
Listing 8.4 
Laboratory Test Results (Urinalysis Panel) .................................................................... 242 
Analysis Set: All Subjects Randomized 
Listing 8.5 
Laboratory Test Comments ............................................................................................ 243 
Analysis Set: All Subjects Randomized 
4.9 
OTHER CLINICAL OBSERVATIONS AND MEASUREMENTS ............................................. 244 
Listing 9.1 
Vital Signs, Weight, and Height ..................................................................................... 244 
Analysis Set: All Subjects Randomized 
Listing 9.2 
12-Lead Electrocardiogram (ECG) ................................................................................. 246 
Analysis Set: All Subjects Randomized 
Listing 9.3 
Pregnancy Testing After Start of Treatment in the Study ............................................... 248 
Analysis Set: All Subjects Randomized 
Listing 9.4 
Comments ....................................................................................................................... 249 
Analysis Set: All Subjects Randomized 


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SHELLS FOR END-OF-TEXT TLFS 
 


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1. Subject Disposition, Demographic, Baseline, and Other Summary Tables 
 
Table 1.1.1 
Subject Disposition 
Analysis Set: All Subjects Randomized 
 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo  
MDI 
 (N=xxx) 
All Subjects 
(N=xxxx) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Not Treated 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Treated 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Completed Week 12 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Completed Week 24 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Completed Follow-up Telephone Call 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Early Discontinuation [a] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
ITT Population [b] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PP Population [c] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Symptomatic Population [d] 
 
 
 
 
 
Rescue Ventolin User Population [e] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Safety Population [f] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
[a]  Early discontinuation was defined as failure to complete both the final visit and the Follow-up Telephone Call. 
[b]  The Intent-To-Treat (ITT) Population was defined as all subjects who were randomized to treatment and received at least one 
    dose  of study treatment. 
[c]  The Per Protocol (PP) Population was a subset of the ITT Population defined as all subjects with post-randomization data 
    obtained prior to a major protocol deviation. Data obtained after any major protocol deviation were excluded.  Since  
    receiving the wrong treatment is a major protocol deviation, subjects in the PP Population were analyzed according to the 
    treatment they received. Post-randomization visits will be excluded from the per protocol set if there is no evidence in the  
    diary that study medication was used the evening prior to the scheduled visit. 
[d]  The Symptomatic Population was defined as all subjects in the ITT Population with CAT scores of >=15 at Visit 4. 
[e]  The Rescue Ventolin User Population was defined as all subjects in the ITT Population with average baseline rescue Ventolin  
    use of ≥1 puff/day. 
[f]  The Safety Population was defined as all subjects who were randomized to treatment and received at least one dose of the study  
    treatment.  
 
 
 


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Table 1.1.2 
Distribution of Subjects by Country/Region and Treatment 
Analysis Set: All Subjects Randomized 
 
Country/Region Subgroup 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
  GP MDI  
14.4 μg 
(N=xxx) 
Placebo  
MDI 
 (N=xxx) 
All Subjects 
(N=xxxx) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Country 
 
 
 
 
 
 <Country 1> 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 <Country 2> 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 <Country 3> 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 <Country 4> 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Regional Subgroup 
 
 
 
 
 
  Non-Japan 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Asia 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Europe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  North America 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Asia includes subjects from China, Japan, South Korea and Taiwan; Asian subjects from other regions/countries 
are excluded. 
Report generated by program: pt003014/sasdir/statout/t010102.sas   Version    YYYY-MM-DD xx:xx    (Page n of N) 
 
 
 
 
 
 
Notes to Programmer: Repeat for each country and center within country.  


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Table 1.1.3 
Distribution of Subjects in Analysis Populations, by Country, Center, and Treatment 
Analysis Set: All Subjects Randomized 
 
Country / Center # 
(Investigator) 
Analysis Population 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
  GP MDI  
14.4 μg 
(N=xxx) 
Placebo  
MDI 
 (N=xxx) 
All Subjects 
(N=xxxx) 
 
 
 
 
 
 
 <Country> 
Total Randomized 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ITT Population  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PP Population  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Symptomatic Population 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Rescue Ventolin User Population 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Safety Population 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
     <Center 1 
     (Investigator)> 
Total Randomized 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ITT Population  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PP Population  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Symptomatic Population 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Rescue Ventolin User Population 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Safety Population 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
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Notes to Programmer: Repeat for each country and center within country.  


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Table 1.1.4 
Reasons for Subjects Not Randomized 
Analysis Set: Non-Randomized Analysis Set 
 
Reason Not Randomized 
All Subjects Not Randomized 
(N=xxx) 
            n (%) 
Any Inclusion/Exclusion Criterion  
          xxx (xx.x) 
Exclusion Criterion #x: xxxx xxxx xx xxxxx xxxxx xxxx 
          xxx (xx.x) 
Exclusion Criterion 3h(c): Not Reproducible at Visit 4 
          xxx (xx.x) 
Inclusion Criterion #x: xx x x xxx xxxx xxxx xxxxxxxxxxxx  
          xxx (xx.x) 
Inclusion Criterion #x: xxxx xxxx xx xxxxx xxxxx xxxx 
          xxx (xx.x) 
 
Administrative Reasons 
          xxx (xx.x) 
Additional Protocol-Specified Criteria 
          xxx (xx.x) 
  Heart Rate Increase  
          xxx (xx.x) 
  SBP Increase   
          xxx (xx.x) 
  Prescription of Any Prohibited Medications 
          xxx (xx.x) 
  Decrease in Creatinine Clearance    
          xxx (xx.x) 
  Hepatic Impairment 
          xxx (xx.x) 
  QTcF Increase 
          xxx (xx.x) 
  COPD Exacerbations  
          xxx (xx.x) 
  eDiary Non-Compliance 
          xxx (xx.x) 
  Other 
          xxx (xx.x) 
Note: Reasons of Other are listed by subject in Listing 1.2. 
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Notes to Programmer: Order by frequency within each category (Screen Failure and Protocol-Specified Criteria). 


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Table 1.1.5 
Subjects Excluded From ITT, PP, Symptomatic, Rescue Ventolin User, and Safety Populations 
Analysis Set: All Subjects Randomized 
 
Subject 
ID 
Analysis Population 
Population 
Excluded 
Visit 
Excluded 
Reason for Exclusion 
Randomized 
ITT 
PP 
Symptomatic 
Rescue 
Ventolin 
User 
Safety 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4 μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
Yes 
No 
No 
No 
No 
No 
ITT 
All 
Did not receive at least one dose of 
the study treatment. 
PP 
All 
Did not receive at least one dose of 
the study treatment. 
Symptomatic 
All 
Screening CAT Score was not >=15. 
Rescue 
Ventolin 
User 
All 
Did not have an average baseline 
rescue Ventolin use of ≥1 puff/day. 
 
Safety 
All 
Did not receive at least one dose of 
the study treatment. 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
Yes 
No 
No 
Yes 
Yes 
No 
ITT 
All 
Did not receive at least one dose of 
the study treatment 
PP 
All 
xxxxxxxxxxxxxxxxxxxxxxxxx 
Safety 
ALL 
Did not receive at least one dose of 
the study treatment 
 
 
 
 
 
 
xxxxxx 
Yes 
No 
No 
Yes 
Yes 
No 
PP 
Week xx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxx 
 
 
 
 
 
 
 
 
 
 
Note: A subject may be included in an analysis population as a whole, but may have period or timepoint data excluded. 
 
Report generated by program: pt003014/sasdir/programs/statout/ t010105.sas   Version YYYY-MM-DD xx:xx      (Page n of N) 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, Country, Center, and Subject ID within Center. List records 
per subject, population excluded, and visits excluded.  


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Table 1.2.1 
Reason for Early Discontinuation 
Analysis Set: All Subjects Randomized 
 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo  
MDI 
 (N=xxx) 
All Subjects 
(N=xxxx) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Early Discontinuation 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Reason for Early Discontinuation 
 
 
 
 
 
 
 
 
 
 
  Adverse Event(s) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Administrative Reasons  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Lack of Efficacy 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Subject Discretion 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
     Withdrawal of Consent 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
     COPD 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
     Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Investigator  
  Considers It to Be 
  in the Best Interest of  
  Subject 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
     <Specified Reason> 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Subject Lost to Follow-up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      On or Before Week 24 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      After Week 24 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Major Protocol Violation 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
     <Specified Reason> 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Protocol-specified Discontinuation  
  Criteria [a] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Heart Rate Increase  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Systolic Blood Pressure Increase   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Prescription of Any  
      Prohibited Medications 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Decrease in Creatinine Clearance   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Hepatic Impairment 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      QTcF Increase 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      COPD Exacerbations  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      eDiary Non-Compliance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


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  Screen Failure (subject randomized in  
  error) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: Reasons of Other are listed by subject in Listing 1.2. 
[a] As per Protocol Section 5.7, except for eDiary non-compliance which is per Protocol Section 7.1.3. 
  
Report generated by program: pt003014/sasdir/programs/statout/t010201.sas Version  YYYY-MM-DD xx:xx (Page n of N)   
 
 
 
 
 
 
 
Table 1.2.2 
Reason for Early Discontinuation Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
Table 1.2.3 
Reason for Early Discontinuation 
Analysis Set: PP Population 
 
Table 1.2.4 
Reason for Early Discontinuation 
Analysis Set: Safety Population 
 
 
 
Notes to Programmers; Sort by descending frequency of 
major category using All Subjects column. Within major 
category, sort by descending frequency of subcategory 
using All Subjects column. 
Notes to Programmer:  
Display the following at top of summary as follows:  
<CAT Score Subpopulation> 
 
Note to Programmer: Do for category “CAT Score Overall” and then repeat tabulation below for CAT Score ≥10, Symptomatic Population 
(CAT Score ≥15), and CAT Score ≥20. 


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Table 1.3 
Reason for Exclusion From the PP Population 
Analysis Set: ITT Population 
 
Reason for 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
Exclusion from PP Population  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Reason 1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Reason 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
… 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Subjects may have multiple reasons for exclusion; therefore, counts for individual reasons may not add up to the 
total number of subjects excluded from the population. 
 
Report generated by program: pt003014/sasdir/programs/statout/t0103.sas  Version   YYYY-MM-DD xx:xx  (Page n of N) 
 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 40 of 249 
 
 
 
 
Table 1.4.1 
Demographics and Baseline Characteristics Overall and by CAT Subpopulation 
Analysis Set: ITT Population 
 
<CAT Score Subpopulation> 
 
Note to Programmer: Do for category “CAT Score Overall” and then repeat tabulation below for CAT Score ≥10, Symptomatic Population 
(CAT Score ≥15), and CAT Score ≥20. 
 
Parameter 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
 
 
 
 
 
 
Age (Years)[a] 
 
 
 
 
 
  n 
xxx 
xxx 
xxx 
xxx 
xxxx 
  Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
xx 
xx 
xx 
xx 
xx 
  Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Age Group, n (%) 
 
 
 
 
 
   Age < 65 years 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Age >= 65 years 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Missing 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
 
 
 
 
 
 
Gender, n (%) 
 
 
 
 
 
  Male 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Female 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
Race, n (%) 
 
 
 
 
 
  American Indian or Alaska   
  Native 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   Asian 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
  Australia or New Zealand  
  (Indigenous) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
  Black or African  
  American 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
  Native Hawaiian or 
  Other Pacific     
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 41 of 249 
 
 
 
 
<CAT Score Subpopulation> 
 
Note to Programmer: Do for category “CAT Score Overall” and then repeat tabulation below for CAT Score ≥10, Symptomatic Population 
(CAT Score ≥15), and CAT Score ≥20. 
 
Parameter 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
  Islander 
  White 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Other 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
Ethnicity, n (%) 
 
 
 
 
 
   Hispanic 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Non-Hispanic 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Missing 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
 
 
Total CAT Score [b] 
 
 
 
 
 
  n 
xxx 
xxx 
xxx 
xxx 
xxxx 
  Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
  Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
   < 10, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   >=10, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   < 15, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   >=15, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   < 20, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   >=20, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   Missing 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 
 
 
 
 
 
MMRC Grade [c] 
 
 
 
 
 
  n 
xxx 
xxx 
xxx 
xxx 
xxx 
  Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
  Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 42 of 249 
 
 
 
 
<CAT Score Subpopulation> 
 
Note to Programmer: Do for category “CAT Score Overall” and then repeat tabulation below for CAT Score ≥10, Symptomatic Population 
(CAT Score ≥15), and CAT Score ≥20. 
 
Parameter 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
   < 2, n (%) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   >=2, n (%) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Missing, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 
 
 
 
 
 
Used Inhaled Corticosteroids at 
Baseline [d], n (%)  
 
 
 
 
 
  Yes 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  No 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 
 
 
 
 
 
Smoking Status [e], n (%)  
 
 
 
 
 
  Current Smoker 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Former Smoker 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 
 
 
 
 
 
Number of Years Smoked 
 
 
 
 
 
  n 
xxx 
xxx 
xxx 
xxx 
xxx 
  Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
  Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Average Number of Cigarettes 
Smoked Per Day 
 
 
 
 
 
 n 
xxx 
xxx 
xxx 
xxx 
xxx 
 Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
 SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 Minimum 
 Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Number of Pack Years Smoked [f] 
 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 43 of 249 
 
 
 
 
<CAT Score Subpopulation> 
 
Note to Programmer: Do for category “CAT Score Overall” and then repeat tabulation below for CAT Score ≥10, Symptomatic Population 
(CAT Score ≥15), and CAT Score ≥20. 
 
Parameter 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
  n 
xxx 
xxx 
xxx 
xxx 
xxx 
  Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
  Maximum 
xx.x  
xx.x 
xx.x 
xx.x 
xx.x  
xx.x 
xx.x  
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
  n 
xxx 
xxx 
xxx 
xxx 
xxx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 Minimum 
  Maximum 
xx.x  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Height (cm) 
 
 
 
 
 
  n 
Xxx 
xxx 
xxx 
xxx 
xxx 
  Mean  
xxx.x  
xxx.x  
xxx.x 
xxx.x 
xxx.x  
  SD 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
  Median 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
  Minimum 
  Maximum 
xxx.x  
xxx.x 
xxx.x  
xxx.x 
xxx.x  
xxx.x 
xxx.x  
xxx.x 
xxx.x  
xxx.x 
 
 
 
 
 
 
BMI (kg/m2) 
 
 
 
 
 
  n 
Xxx 
xxx 
xxx 
xxx 
xxx 
  Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
  Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x  
xx.x 
xx.x  
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
[a]  Age is age at Visit 1.  The remaining characteristics were based on data from Screening visits prior to the start of the study. 
[b]  CAT = COPD Assessment Test. The total score is the sum of eight CAT item scores (Range: 0-40) 
[c]  MMRC = Modified Medical Research Council Scale, grades range between 0 and 4, where 4 represents the highest level of    


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 44 of 249 
 
 
 
 
<CAT Score Subpopulation> 
 
Note to Programmer: Do for category “CAT Score Overall” and then repeat tabulation below for CAT Score ≥10, Symptomatic Population 
(CAT Score ≥15), and CAT Score ≥20. 
 
Parameter 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
     breathlessness. 
[d] ‘At baseline’ means that the medication was taken on the day of the first dose of study medication. 
[e]  Former Smoker was defined as those who have stopped smoking for at least 6 weeks prior to first Screening Visit. 
[f]  Number of pack years smoked = (number of cigarettes per day / 20) x number of years smoked. 
 
      
Report generated by program: pt003014/sasdir/programs/statout/t010401.sas Version   YYYY-MM-DD xx:xx  (Page n of N) 
 
 
 
 
 
 
 
 
Table 1.4.2 
Demographics and Baseline Characteristics  
Analysis Set: PP Population 
 
Table 1.4.3 
Demographics and Baseline Characteristics 
Analysis Set: Rescue Ventolin User Population 
 
Table 1.4.4 
Demographics and Baseline Characteristics 
Analysis Set: Safety Population 
 
Table 1.4.5 
Demographics and Baseline Characteristics 
Analysis Set: Non-Randomized Analysis Set 
 
 
 
Notes to Programmer: Calculate BMI using Height at Visit 1. BMI = weight (kg)/height (m)2.  
Keep the summary for a parameter in the same page when breaking the table into multiple pages. Repeat titles, column headers and 
footnotes on each page. The race/ethnicities of Native Hawaiian or other Pacific Islander OR American Indian or Alaska Native OR 
Australia or New Zealand (indigenous) can be removed from this table if they do not exist in the database.  
Please delete Missing row when there are no missing values. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 45 of 249 
 
 
 
 
Table 1.5.1 
Severity and Duration of COPD Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
<CAT Score Subpopulation> 
 
Note to Programmer: Do for category “CAT Score Overall” and then repeat tabulation below for CAT Score ≥10, Symptomatic Population (CAT Score ≥15), and CAT Score ≥20.  
 
   
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
 
   
 
 
 
 
 
 
COPD Severity [a], n (%)  
 
 
 
 
 
   Moderate (GOLD 2)  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Severe (GOLD 3) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Very Severe (GOLD 4) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx(xx.x) 
 
 
 
 
 
 
Duration of COPD (yrs) [b] 
   n 
   Mean  
   SD 
 
xxx 
xx.x  
xx.x 
 
xxx 
xx.x  
xx.x 
 
xxx 
xx.x  
xx.x 
 
xxx 
xx.x  
xx.x 
 
xxxx 
xx.x  
xx.x 
   25th Percentile  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   75th Percentile  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Minimum  
   Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
GOLD Category, n (%) 
 
 
 
 
 
A 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
B 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
C 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx(xx.x) 
D 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
[a]  Severity of COPD defined in Appendix 3 of the protocol was based on the non-missing post-Ventolin HFA assessment at Screening  
     Visit 2 (or if the assessment was missing, the  non-missing post-Atrovent assessment at Screening Visit 3).  
[b]  The duration of COPD is calculated relative to the start of study treatment Day 1 (Visit 4). 
 
Report generated by program: pt003014/sasdir/programs/statout/t010501.sas Version  YYYY-MM-DD xx:xx    (Page n of N)  
 
 
 
Notes to Programmer: Duration of COPD = (First Dose date of Study Treatment - Date COPD First Diagnosed)/365.25, where day of COPD 
diagnosed is assumed to be the 1st of the month. Add a footnote noting how many missing values there are for severity if this is true for the final 
data. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 46 of 249 
 
 
 
 
Table 1.5.2 
Severity and Duration of COPD  
Analysis Set: PP Population 
 
Table 1.5.3 
Severity and Duration of COPD 
Analysis Set: Rescue Ventolin User Population 
 
Table 1.5.4 
Severity and Duration of COPD 
Analysis Set: Safety Population 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 47 of 249 
 
 
 
 
Table 1.6.1 
Screening Pre- and Post-Bronchodilator and Baseline Spirometry Parameters Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
<CAT Score Subpopulation> 
 
Note to Programmer: Do for category “CAT Score Overall” and then repeat tabulation below for CAT Score ≥10, Symptomatic Population 
(CAT Score ≥15), and CAT Score ≥20.  
 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
 
 
 
 
 
 
Screening FEV1 (% predicted) 
 
 
 
 
 
 
Pre-Ventolin HFA: 
      n 
      Mean  
      SD 
 
xx 
xx.xxx   
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx 
xx.xxx 
      25th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Median  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      75th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Minimum  
      Maximum 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
Post-Ventolin HFA: 
      n 
      Mean   
      SD 
 
xx 
xx.xxx   
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx 
xx.xxx 
      25th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Median  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      75th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
     Minimum  
      Maximum 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
Pre-Atrovent HFA: 
      n 
      Mean  
      SD 
 
xx 
xx.xxx   
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx 
xx.xxx 
      25th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Median  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      75th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Minimum  
      Maximum 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 48 of 249 
 
 
 
 
 
 
 
 
 
 
Post-Atrovent HFA: 
      n 
      Mean   
      SD 
 
xx 
xx.xxx   
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx 
xx.xxx 
      25th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Median  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      75th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Minimum  
      Maximum 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline is defined as the mean of all evaluable 60 and 30 minute pre-dose values on Day 1 (Visit 4). 
 
Report generated by program: pt003014/sasdir/programs/statout/t010601.sas Version YYYY-MM-DD xx:xx (Page n of N)  
 
Table 1.6.2 
Screening Pre- and Post-Bronchodilator and Baseline Spirometry Parameters 
Analysis Set: PP Population 
 
Table 1.6.3 
Screening Pre- and Post-Bronchodilator and Baseline Spirometry Parameters 
Analysis Set: Rescue Ventolin User Population 
 
 
Notes to Programmer: 
 
Repeat above for these Screening parameters: 
Screening FEV1 (L) Pre-Bronchodilator 
Screening FEV1 (L) Post-Bronchodilator 
Screening FVC (% predicted) Pre-Bronchodilator 
Screening FVC (% predicted) Post-Bronchodilator 
Screening FVC (L) Pre-Bronchodilator 
Screening FVC (L) Post-Bronchodilator 
 
Also, provide for the following Baseline parameters: 
Baseline FEV1 (% predicted) 
Baseline FEV1 (L)  
Baseline FVC (% predicted) 
Baseline FVC (L)  
 
Show only 2 significant digits for the % predicted statistics. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 49 of 249 
 
 
 
 
Table 1.7.1 
Reversibility to Ventolin HFA Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
<CAT Score Subpopulation> 
 
Note to Programmer: Do for category “CAT Score Overall” and then repeat tabulation below for CAT Score ≥10, Symptomatic Population 
(CAT Score ≥15), and CAT Score ≥20.  
 
  
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects  
(N=xxxx) 
Post-Ventolin HFA  FEV1 - Pre-Ventolin HFA FEV1 (mL) 
 n  
 Mean 
 SD 
 Median 
 Minimum 
 Maximum 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Reversibility (%) Post-Ventolin HFA for FEV1 [a] 
 n 
 Mean 
 SD 
 Median 
 Minimum  
 Maximum 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 Reversible [b], n (%)  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
≥12% Improvement in FEV1 from Pre-Ventolin HFA 
at Post-Ventolin HFA, 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
≥ 150 mL Improvement in FEV1 from Pre-Ventolin 
HFA at Post-Ventolin HFA, 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
≥ 200 mL Improvement in FEV1 from Pre-Ventolin 
HFA at Post-Ventolin HFA, 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
If a subject was missing a Post-Ventolin or Pre-Ventolin FEV1 value at Screening Visit 2, these values were replaced by the Pre-
Atrovent and Post-Atrovent values from Screening Visit 3  


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 50 of 249 
 
 
 
 
[a]  Reversibility (%) is defined as 100 x (the change from pre-Ventolin HFA to post for FEV1)/pre-Ventolin HFA FEV1. 
[b]  Reversible is defined as Improvement in FEV1 post-Ventolin HFA administration compared to pre-Ventolin HFA of >=12% and >=200 mL.  
 
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Table 1.7.2 
Reversibility to Ventolin HFA  
Analysis Set: PP Population 
 
Table 1.7.3 
Reversibility to Ventolin HFA  
Analysis Set: Rescue Ventolin User Population 
 
 
Table 1.8.1 
Reversibility to Atrovent HFA Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 1.8.2 
Reversibility to Atrovent HFA 
Analysis Set: PP Population 
 
Table 1.8.3 
Reversibility to Atrovent HFA 
Analysis Set: Rescue Ventolin User Population 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 51 of 249 
 
 
 
 
Table 1.8.4 
Reversibility to Ventolin HFA and/or Atrovent HFA 
Analysis Set: ITT Population 
 
 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
n  (%)  
n  (%) 
n  (%) 
n  (%) 
n  (%) 
Reversible to neither Ventolin HFA nor Atrovent HFA 
 xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Reversible to Ventolin HFA only 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Reversible to Atrovent HFA only 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Reversible to Both Ventolin HFA and Atrovent HFA 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Reversible to Atrovent HFA, Reversibility to 
Ventolin HFA is missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Reversible to Ventolin HFA, Reversibility to 
Atrovent HFA is missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Reversibility to Ventolin HFA and Atrovent HFA are 
missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Reversibility to Ventolin HFA missing, Not 
Reversible to Atrovent HFA 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Not Reversible to Ventolin HFA, Reversibility to 
Atrovent HFA is missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
Report generated by program: pt003014/sasdir/programs/statout/t0108004.sas Version YYYY-MM-DD xx:xx      (Page n of N)         
 
 
 
 
 
 
 
 
 
Note to Programmer: add last 2 rows into the table if there is at  least one subject in the study included in these rows, ie, n greater than 0 for at least one 
treatment. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 52 of 249 
 
 
 
 
Table 1.9.1 
Medical/Surgical History  
Analysis Set: Safety Population 
 
 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
n  (%)  
n  (%) 
n  (%) 
n  (%) 
n  (%) 
 
Subject Had Medical /Surgical 
History 
 
 
 
 
 
No 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Yes 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
Cardiovascular 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
CNS/Neurological 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Dermatologic 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Drug Allergy 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
EENT 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Endocrine/Metabolic 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
High Total Cholesterol 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Diabetes 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Type I 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Type II 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Gastrointestinal 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Genitourinary 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Hepatic 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Hematologic 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Immunological 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Malignancy 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Musculoskeletal 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Psychiatric 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Respiratory 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Renal 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Other 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
 
Report generated by program: pt003014/sasdir/programs/statout/t010901.sas Version YYYY-MM-DD xx:xx      (Page n of N)         
 
 
 
Note to Programmer: Please sort by descending frequency of occurrence in All Subjects. Denominator should be N 
from the column header for a treatment. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 53 of 249 
 
 
 
 
Table 1.9.2 
Cardiovascular Risk Factors of Interest 
Analysis Set: Safety Population 
 
 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
n  (%)  
n  (%) 
n  (%) 
n  (%) 
n  (%) 
 
Subject Had Cardiovascular Risk 
Factor of Interest 
 
 
 
 
 
No 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Yes 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
Hypertension 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
High Total Cholesterol 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Transient Ischemic Attack 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Stroke 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Atrial Fibrillation 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Peripheral Vascular Disease 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Diabetes 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Type I 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Type II 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Angina 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Angioplasty 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Stents 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  CABG 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  No Surgery 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Myocardial Infarction 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Angioplasty 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Stents 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  CABG 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  No Surgery 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
Report generated by program: pt003014/sasdir/programs/statout/t010902.sas Version YYYY-MM-DD xx:xx      (Page n of N)           
 
 
 
 
 
 
Notes to Programmer: Please sort risk factors  in descending frequency of occurrence in All Subjects, then 
within diabetes, angina, and myocardial infarction subcategories, sort by descending frequency. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 54 of 249 
 
 
 
 
Table 1.9.3 
History of Moderate or Severe COPD Exacerbations Within Past 12 Months 
Analysis Set: ITT Population 
 
 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
 
 
 
 
 
 
 Subject treated for an  
 exacerbation with  
 systemic (oral or IV)  
 corticosteroids and/or  
 antibiotics, n(%) [Events] 
xxx (xx.x) 
[xx] 
xxx (xx.x) 
[xx] 
xxx (xx.x) 
[xx] 
xxx (xx.x) 
[xx] 
xxx (xx.x) 
[xx] 
 
 
 
 
 
 
 Number of exacerbations per subject 
 
 
 
 
 
  Mean 
  SD 
  Median 
  Minimum  
  Maximum 
xx.xx 
xx.xxx 
xx.xx 
xx 
xx 
xx.xx 
xx.xxx 
xx.xx 
xx 
xx 
xx.xx 
xx.xxx 
xx.xx 
xx 
xx 
xx.xx 
xx.xxx 
xx.xx 
xx 
xx 
xx.xx 
xx.xxx 
xx.xx 
xx 
xx 
 
 
 
 
 
 
 Subject admitted to           
 hospital or received   
 emergency room (urgent   
 care center) treatment, 
 n(%) [Events}  
xxx (xx.x) 
[xx] 
 
xxx (xx.x) 
[xx] 
 
xxx (xx.x) 
[xx] 
 
xxx (xx.x) 
[xx] 
 
xxx (xx.x) 
[xx] 
 
 
 
 
 
 
 
 Number of           
 hospitalizations/ 
 emergency room (urgent   
 care center) visits per 
 subject 
 
 
 
 
 
  Mean 
  SD 
  Median 
xx.xx 
xx.xxx 
xx.xx 
xx.xx 
xx.xxx 
xx.xx 
xx.xx 
xx.xxx 
xx.xx 
xx.xx 
xx.xxx 
xx.xx 
xx.xx 
xx.xxx 
xx.xx 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 55 of 249 
 
 
 
 
 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
  Minimum  
  Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
The number of exacerbations and number of hospitalizations/emergency room (urgent care center) visits for subjects without an  
exacerbation, hospitalization, or emergency room (urgent care center) visit was 0. 
 
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GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 56 of 249 
 
 
 
 
Table 1.10.1 
Prior Medications - COPD-Related 
Analysis Set: Safety Population 
 
Preferred Term/Active Ingredients 
(COPD Medications only) 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
     n (%) 
     n (%) 
     n (%) 
     n (%) 
     n (%) 
Any Prior COPD Medication 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
Medication 1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Medication 2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
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Table 1.10.2 
Prior Medications - Non-COPD-Related 
Analysis Set: Safety Population 
 
 
 
 
 
 
Notes to Programmer: Sort Medications by 
descending frequency of use in All Subjects 
Notes to Programmer: Sort Medications by descending frequency of use in All Subjects 
Add a row for “Any Prior Non-COPD Medication”. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 57 of 249 
 
 
 
 
Table 1.11.1 
Concomitant Medications - COPD Related 
Analysis Set: Safety Population 
 
Preferred Term/Active Ingredients 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
     n(%) 
     n(%) 
     n(%) 
     n(%) 
     n(%) 
Any Concomitant COPD Medication 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
Medication 1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Medication 2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
All subjects were allowed sponsor provided Ventolin HFA which was reported on the Concomitant Medications CRF.   
See Listing 6.1.1 for any subject(s) who took Ventolin HFA within 6 hours of pre-dose assessments during the treatment. See Listing 
6.1.3 for any subjects who took Ventolin HFA for rescue pre-dose or post-dose during the course of the test day measurements. Table 
2.8.1 summarizes the mean number of puffs of rescue Ventolin during treatment. 
 
Report generated by program: pt003014/sasdir/programs/statout/t011101.sas            Version YYYY-MM-DD xx:xx    (Page n of N) 
 
 
 
 
 
 
 
Table 1.11.2 
Concomitant Medications - Non-COPD Related 
Analysis Set: Safety Population 
 
 
 
 
Notes to Programmer: Sort Medications by descending 
frequency of use in All Subjects 
Notes to Programmer: Sort Medications by 
descending frequency of use in All Subjects 
Add a row for “Any Non-COPD Medication”. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 58 of 249 
 
 
 
 
Table 1.12 
Study Treatment Exposure and Compliance 
Analysis Set: Safety Population 
 
 
 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
 
 
 
 
 
 
 
Exposure [a] 
n 
Mean  
SD 
Median 
Minimum 
Maximum 
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
 xxx   
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
 xxx   
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
 xxx   
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
 xxx   
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
 xxx   
 
 
 
 
 
 
 
Total  
Person-Years of 
Exposure [b] 
 
  xx.xx 
  xx.xx 
  xx.xx 
 
  xx.xx 
  xx.xx 
 
 
 
 
 
 
 
Total Number of 
Puffs of Study 
Medication 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
 xxx    
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
xxx   
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
xxx   
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
xxx   
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
xxx   
 
 
 
 
 
 
 
Percent 
Compliance [c], 
n (%)  
  0 – <  20% 
 20 – <  40% 
 40 – <  60%  
 60 – <  80%  
 80 –   100%  
 >100 - 120% 
 >120% 
 Missing 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 x(xx.x) 
x(xx.x) 
   xx     
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 x(xx.x) 
       x(xx.x) 
        xx 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
  x(xx.x) 
       x(xx.x) 
     xx 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 x(xx.x) 
       x(xx.x) 
        xx 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 x(xx.x) 
       x(xx.x) 
        xx 
 
 n 
 Mean 
 SD 
 Median 
 Minimum 
 Maximum 
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
    xxx   
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
xxx 
   
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
   xxx  
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
   xxx  
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
   xxx   


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 59 of 249 
 
 
 
 
[a] Exposure (days) = (End date of treatment – Date of first dose of treatment) + 1. 
[b] Total person-years of exposure for a treatment group is the total exposure in the study across all subjects in the treatment. 
[c] Percent compliance is defined as (total number of puffs of study treatment taken on a study day/total expected puffs taken on a 
    study day) averaged across all days of a subject’s dosing between start of study treatment and last day on study treatment x 100. 
    The expected number of puffs on dates prior to the last date of treatment was 4.  
    The expected number of puffs for a test day which was the last date of treatment was 2. 
    The expected number of puffs for the last date of treatment which was not a test day was 4 when a PM dose was taken and 2 
    otherwise. 
 
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GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 60 of 249 
 
 
 
 
Table 1.13 
Changes in Smoking Status After Start of Treatment 
Analysis Set: Safety Population 
 
Change in Smoking Status 
Relative to Screening Smoking 
Status 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
n  (%)  
n  (%) 
n  (%) 
n  (%) 
n  (%) 
 
 
 
 
 
 
Former Smoker Switched to 
Current Smoker at Any Point During  
Treatment 
xxx  (xx.x) 
xxx  (xx.x) 
xxx  (xx.x) 
xxx  (xx.x) 
xxx  (xx.x) 
Current Smoker Switched to  
Former Smoker at Any Point During 
Treatment 
xxx  (xx.x) 
xxx  (xx.x) 
xxx  (xx.x) 
xxx  (xx.x) 
xxx  (xx.x) 
 
 
 
 
 
 
 
Report generated by program: pt003014/sasdir/programs/statout/t0113.sas  Version    YYYY-MM-DD xx:xx      (Page n of N)                  
 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer: Put a row for ‘Non-smoker Switched to Smoker’ only if this data case is present in the data. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 61 of 249 
 
 
 
 
2. Efficacy Data Summary Tables and Figures, Including HCRU Tables 
 
Change From Baseline in Morning Pre-dose Trough FEV1 
 
   
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 62 of 249 
 
 
 
 
Table 2.1.1 Morning Pre-dose Trough FEV1 (L) 
Analysis Set: ITT Population 
 
Treatment 
Baseline FEV1 
Change From Baseline 
LS Mean Differences Between Treatments  
Placebo MDI 
FF MDI  
9.6 μg 
GP MDI  
14.4 μg 
 
Over 24 Weeks 
 
GFF MDI 14.4/9.6 μg 
  n 
xx 
 
 
 
 
  Mean  
x.xxx 
 
 
 
 
  SD 
x.xxx 
 
 
 
 
  Median 
x.xxx 
 
 
 
 
  Min-Max 
x.xxx-x.xxx 
 
 
 
 
  LS Mean (SE) 
 
  x.xxx (x.xxxx)        x.xxx (x.xxxx) 
  x.xxx (x.xxxx) 
  x.xxx (x.xxxx) 
  95% CI 
 
( x.xxx, x.xxx) 
( x.xxx, x.xxx) 
( x.xxx, x.xxx) 
( x.xxx, x.xxx) 
  P-value 
 
 
  x.xxxx  
  x.xxxx  
  x.xxxx  
 
 
 
 
 
 
FF MDI 9.6 μg 
  n 
xx 
 
 
 
 
  Mean  
x.xxx 
 
 
 
 
  SD 
x.xxx 
 
 
 
 
  Median 
x.xxx 
 
 
 
 
  Min-Max 
x.xxx-x.xxx 
 
 
 
 
  LS Mean (SE) 
 
  x.xxx (x.xxxx) 
  x.xxx (x.xxxx) 
Not Applicable 
  x.xxx (x.xxxx) 
  95% CI 
 
( x.xxx, x.xxx) 
( x.xxx, x.xxx) 
 
( x.xxx, x.xxx) 
  P-value 
 
 
  x.xxxx  
 
  x.xxxx  
 
 
 
 
 
 
GP MDI 14.4 μg 
  n 
xx 
 
 
 
 
  Mean  
x.xxx 
 
 
 
 
  SD 
x.xxx 
 
 
 
 
  Median 
x.xxx 
 
 
 
 
  Min-Max 
x.xxx-x.xxx 
 
 
 
 
  LS Mean (SE) 
 
  x.xxx (x.xxxx) 
  x.xxx (x.xxxx) 
Shown Above 
Not Applicable 
  95% CI 
 
( x.xxx, x.xxx) 
( x.xxx, x.xxx) 
 
 
  P-value 
 
 
  x.xxxx 
 
 
   
 
 
 
 
 
Placebo 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 63 of 249 
 
 
 
 
Treatment 
Baseline FEV1 
Change From Baseline 
LS Mean Differences Between Treatments  
Placebo MDI 
FF MDI  
9.6 μg 
GP MDI  
14.4 μg 
  n 
xx 
 
 
 
 
  Mean  
x.xxx 
 
 
 
 
  SD 
x.xxx 
 
 
 
 
  Median 
x.xxx 
 
 
 
 
  Min-Max  
x.xxx-x.xxx 
 
 
 
 
  LS Mean (SE) 
 
  x.xxx (x.xxxx) 
 Not Applicable 
Shown Above 
Shown Above 
  95% CI 
 
( x.xxx, x.xxx) 
 
 
 
 
 
 
 
 
 
 
 
Baseline is defined as the mean of evaluable 60 and 30 minute pre-dose values on Day 1 (Visit 4).                                        
 
LS Mean = least squares mean from the linear repeated measures model which included the following covariates: baseline FEV1, percent 
reversibility to Ventolin HFA, treatment, visit, and treatment by visit interaction.  
                                                                                                                                         
Report generated by program: pt003014/sasdir/programs/statout/t020101.sas Version YYYY-MM-DD hh:mm (Page n of N)                                                
 
 
 
 
Note to Programmer: Repeat for “Over Weeks 12-24” and for each post-baseline visit from Week 2 to Week 
24. The raw change from baseline will be added for each individual visit, but not for 0-24 weeks or 12-
24 weeks. Do not split a treatment across a page. The baseline summary statistics are based on subjects 
who were included in the model used for analysis. (.e.g., subjects who had at least one data point post-
baseline from Week 2 to Week 24 and had non-missing data for all covariates used for the analysis). 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 64 of 249 
 
 
 
 
Figure 2.1.1.1 
Adjusted Mean Change From Baseline in Morning Pre-dose Trough FEV1 (L) ± SE Over Time 
Analysis Set: ITT Population 
 
Source: Table 2.1.1 
      Report generated by program: pt003014/sasdir/programs/statout/f020101.sas  Version YYYY-MM-DD xx:xx     (Page n of N) 
 
Number of Weeks Post-Dose
Adjusted Mean Change from Baseline in FEV1
Morning Pre-Dose Trough (L) ± SE
0
2
4
8
12
16
20
24
12-24
0-24
-0.04
-0.02
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
0.22
0.24
  Treatment Group:
GFF MDI 14.4/9.6 μg
GP MDI 14.4 μg
FF MDI 9.6 μg
Spiriva 18 μg
Placebo MDI
Source: Table 14.2.1.1
Program: /pt003006/dryrun1/programs/graphs/f14_2_1_1.sas   Draft   2013-09-13 15:16 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 65 of 249 
 
 
 
 
Figure 2.1.1.2 
Treatment Differences From Placebo MDI*: Adjusted Mean Change From Baseline (95% CI) in Morning Pre-dose Trough FEV1 (L) Over 
Time 
Analysis Set: ITT Population 
 
 
*Superiority of test treatments vs. Placebo MDI. 
 
Source: Table 2.1.1 
 
Program generated by program:pt003014/dryrun1/programs/statout/f02010102.sas  Version YYYY-MM-DD xx:xx (Page n of N) 
 
 
 
Notes to Programmer: Add “Adjusted Mean” in front of “Difference” in the y axis label. Update treatment names for 
treatments in this study. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 66 of 249 
 
 
 
 
Table 2.1.2 
Morning Pre-dose Trough FEV1 (L)  
Analysis Set: PP Population 
 
Figure 2.1.2 
Adjusted Mean Change From Baseline in Morning Pre-dose Trough FEV1 (L) ± SE Over Time 
Analysis Set: PP Population 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 67 of 249 
 
 
 
 
Table 2.1.3.1 
Missing Data for Change From Baseline in Morning Pre-dose Trough FEV1 by Visit and Reason 
Analysis Set: ITT Population 
 
Week 2 
 
Week 4 
 
Week 8 
 
 
Week 12 
 
Week 16 
 
Week 20 
Week 24 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
GFF MDI 14.4/9.6 μg: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total Missing 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing Baseline (Day 1) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing value due to unacceptable grade (MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing value since subject did not complete FEV1 
spirometry (MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit missed due to COPD? 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Yes (MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  No (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Unknown (MNAR)  
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reason for early discontinuation at the visit or in the 
interval between visit and previous visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 68 of 249 
 
 
 
 
Week 2 
 
Week 4 
 
Week 8 
 
 
Week 12 
 
Week 16 
 
Week 20 
Week 24 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
  Adverse Event (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Adverse Event (MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Administrative Reasons (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Lack of Efficacy (MAR/MCAR)  
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Lack of Efficacy (MNAR)  
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Subject Discretion (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Other  (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Subject Discretion (MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Withdrawal of Consent (MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
     COPD Related (MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Other (MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 69 of 249 
 
 
 
 
Week 2 
 
Week 4 
 
Week 8 
 
 
Week 12 
 
Week 16 
 
Week 20 
Week 24 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
  Investigator’s decision in the best    
  interest of subject (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Investigator’s decision in the best    
  interest of subject (MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Subject Lost to Follow-up (MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Major Protocol Violation 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
     <Specified Reason> (MAR/MCAR or MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
     <Specified Reason> (MAR/MCAR or MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Discontinuation Due to Protocol  
  Specified Criteria  
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Heart rate increase as per protocol (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     SBP increase as per protocol (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Prescription of any prohibited medications  
     (MAR/MCAR or MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Decrease in creatinine clearance as per protocol  
     (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 70 of 249 
 
 
 
 
Week 2 
 
Week 4 
 
Week 8 
 
 
Week 12 
 
Week 16 
 
Week 20 
Week 24 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
 
n  
(%) 
     Hepatic impairment as per protocol (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     QTcF increase as per protocol (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     COPD exacerbations as per protocol (MAR/MCAR)  
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     COPD exacerbations as per protocol (MNAR)  
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     eDiary non-compliance as per protocol (MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Pregnancy as per protocol (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Other (MAR/MCAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Other (MNAR) 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
xx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MAR = missing at random.  MCAR = missing completely at random.  MNAR = Missing not at random. 
Report generated by program: pt003014/sasdir/programs/statout/t02010301.sas         Version YYYY-MM-DD xx:xx     (Page n of N)  
 
Notes to Programmer: Repeat above 
for each remaining Treatment. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 71 of 249 
 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer: When  <Other Specify> OR <Specify Reason> reasons are to be collapsed and can be either 
MAR/MCAR or MNAR, a category was create above for MAR/MCAR and one collapsed category for MNAR. For example, this 
was done for “Subject Discretion” and “Investigator’s Decision in the best interest of subject”. 
For empty cells, show a count of 0 without a percentage. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 72 of 249 
 
 
 
 
Table 2.1.3.2 
Unique Patterns of Missing Visits for Change From Baseline in Morning Pre-dose Trough FEV1  
Analysis Set: ITT Population 
 
Pattern of Missing Data 
Week 2  Week 4  Week 8  
 
Week 12  Week 16  Week 20  
Week 24 
All Treatments (N=xxxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pattern 1 (n=xxx) 
M 
 
M 
 
M 
 
M 
 
M 
 
M 
 
M 
Pattern 2 (n=xxx) 
M 
 
M 
 
M 
 
M 
 
M 
 
M 
 
M 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P = Present. M = Missing. 
Report generated by Program: pt003014/final/programs/statout/t02010302.sas         Version YYYY-MM-DD xx:xx     (Page n of 
N) 





 
 
Notes to Programmer: Repeat for each Treatment.  


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 73 of 249 
 
 
 
 
Table 2.1.4.1 
Sensitivity Analysis: Treatment Comparisons for Change From Baseline in Morning Pre-dose Trough FEV1 (L) at Week 24 
Analysis Set: ITT Population 
 
Key Pairwise Comparison 
Delta [L] [a] 
Estimated 
Difference and 95% 
CI [b] 
P-value [b] 
Relative Increase 
in Variance [c] 
Fraction of 
Missing 
Information [d] 
Relative 
Efficiency [e] 
GFF MDI 14.4/9.6 μg vs. 
Placebo MDI 
x.xxxx 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
Repeat for Each of the 4 
Remaining Key Comparisons 
(treatment vs. control) in 
the following order: 
FF MDI 9.6 μg vs Placebo 
GP MDI 14.4 μg vs Placebo 
GFF MDI 14.4/9.6 μg vs. FF 
MDI 9.6 μg 
GFF MDI 14.4/9.6 μg vs. GP 
MDI 14.4 μg 
 
 
 
 
 
 
 
 
 
 
 
 
[a] Delta is defined as the amount on average by which the first unobserved trough value at dropout in the non-control treatment is  
   worsened compared to the observed trough value of subjects who continue in the study.  
[b] The estimated difference is the least squares (LS) mean difference at Week 24. This estimated difference is from the linear  
   repeated measures model which included the following covariates: baseline FEV1, percent reversibility to Ventolin HFA, treatment,  
    visit, and treatment by visit interaction.    
[c] Relative increase in variance is the ratio of between-imputation variance to within-imputation variance.                           
[d] Fraction of missing information: the relative loss of efficiency in estimation of the treatment difference due to missing data.     
[e] Relative efficiency of using the finite number of imputations vs. infinite number of imputations.                                   
 
 
 
 
 
Notes to Programmer: in the footnote, please replace “At Week 24” with “Over 24 Weeks” when using this mockup for the 
change in Morning Pre-dose Trough FEV1 Over 24 Weeks and TDI summary tables below. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 74 of 249 
 
 
 
 
Figure 2.1.4.1 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 (L) 
at Week 24 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                         Delta varies from 0 to the estimated treatment difference.  
                           Report generated by program: pt003014/sasdir/programs/graphs/f02_01_04_01.sas   Version YYYY-MM-DD xx:xx  (Page n of N)      
 
 
 
 
Sensitivity Analysis
0
0.05
0.1
0.15
0.2
0
0.2
0.4
0.6
0.8
1
Delta
p-value
Notes to Programmer: Remove ‘Sensitivity Analysis’ from the plot area. Delta values plotted will be replaced and will be 
specified at analysis time. Delta values will be based on the estimated treatment difference from comparator from the primary 
analysis in the ITT population where values will vary from 0 to the estimated difference. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 75 of 249 
 
 
 
 
THIS GRAPH WILL BE REPEATED FOR EACH OF THE 5 PRIMARY COMPARISONS (GFF, FF, and GP vs. Placebo and GFF vs. FF and GFF vs. GP) for 
the following 3 endpoints: change from baseline in morning pre-dose trough FEV1 at Week 24, change from baseline in morning pre-dose trough FEV1 over 24 
weeks, and TDI over 24 weeks.   
 
Figure 2.1.4.2 
Sensitivity Analysis: Comparison of FF MDI 9.6 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 (L) at 
Week 24 
Analysis Set: ITT Population 
 
Figure 2.1.4.3 
Sensitivity Analysis: Comparison of GP MDI 14.4 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 (L) at 
Week 24 
Analysis Set: ITT Population 
 
Figure 2.1.4.4 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. FF MDI 9.6 μg for Change From Baseline in Morning Pre-dose Trough FEV1 
(L) at Week 24 
Analysis Set: ITT Population 
 
Figure 2.1.4.5 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. GP MDI 14.4 μg for Change From Baseline in Morning Pre-dose Trough FEV1 
(L) at Week 24 
Analysis Set: ITT Population 
 
Table 2.1.4.2 
Sensitivity Analysis: Treatment Comparisons for Change From Baseline in Morning Pre-dose Trough FEV1 (L) Over 24 Weeks 
Analysis Set: ITT Population 
 
Figure 2.1.4.6 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 (L) 
Over 24 Weeks 
Analysis Set: ITT Population 
 
Figure 2.1.4.7 
Sensitivity Analysis: Comparison of FF MDI 9.6 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 (L) Over 
24 Weeks 
Analysis Set: ITT Population 
 
Figure 2.1.4.8 
Sensitivity Analysis: Comparison of GP MDI 14.4 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 (L) Over 
24 Weeks 
Analysis Set: ITT Population 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 76 of 249 
 
 
 
 
Figure 2.1.4.9 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. FF MDI 9.6 μg for Change From Baseline in Morning Pre-dose Trough FEV1 
(L) Over 24 Weeks 
Analysis Set: ITT Population 
 
Figure 2.1.4.10 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. GP MDI 14.4 μg for Change From Baseline in Morning Pre-dose Trough FEV1 
(L) Over 24 Weeks 
Analysis Set: ITT Population 
 
Table 2.1.4.3 
Sensitivity Analysis: Treatment Comparisons for Change From Baseline in Morning Pre-dose Trough FEV1 (L) Over Weeks 12-24 
Analysis Set: ITT Population 
 
Figure 2.1.4.11 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 (L) 
Over Weeks 12-24 
Analysis Set: ITT Population 
 
Figure 2.1.4.12 
Sensitivity Analysis: Comparison of FF MDI 9.6 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 (L) Over 
Weeks 12-24 
Analysis Set: ITT Population 
 
Figure 2.1.4.13 
Sensitivity Analysis: Comparison of GP MDI 14.4 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 (L) Over 
Weeks 12-24 
Analysis Set: ITT Population 
 
Figure 2.1.4.14 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. FF MDI 9.6 μg for Change From Baseline in Morning Pre-dose Trough FEV1 
(L) Over Weeks 12-24 
Analysis Set: ITT Population 
 
Figure 2.1.4.15 
Sensitivity Analysis: Comparison of GFF MDI 14.4/9.6 μg vs. GP MDI 14.4 μg for Change From Baseline in Morning Pre-dose Trough FEV1 
(L) Over Weeks 12-24 
Analysis Set: ITT Population 
 
 


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Figure 2.1.4.16 
Comparison of GFF MDI 14.4/9.6 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 (L) at Week 24 Using 
Imputed Estimates at Various Deltas 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
 
Figure 2.1.4.17 
Comparison of FF MDI 9.6 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 Using Imputed 
Estimates at Various Deltas 
Analysis Set: ITT Population 
 
Figure 2.1.4.18 
Comparison of GP MDI 14.4 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 Using Imputed 
Estimates at Various Deltas 
Analysis Set: ITT Population 
 
Figure 2.1.4.19 
Comparison of GFF MDI 14.4/9.6 μg vs. FF MDI 9.6 μg for Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 Using 
Imputed Estimates at Various Deltas 
Analysis Set: ITT Population 
 
Figure 2.1.4.20 
Comparison of GFF MDI 14.4/9.6 μg vs. GP MDI 14.4 μg for Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 Using 
Imputed Estimates at Various Deltas 
Analysis Set: ITT Population 
 
Figure 2.1.4.21 
Comparison of GFF MDI 14.4/9.6 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks Using 
Imputed Estimates at Various Deltas 
Analysis Set: ITT Population 
Notes to Programmer: Plot mean adjusted estimates for all weeks post-baseline (using 
imputed values).  5 Groups would be plotted: Treatment Completers, Comparator 
Completers, Treatment Dropouts MAR/MCAR, Treatment Dropouts MNAR, and 
<Comparator Dropouts or Placebo Dropouts---no MAR/MCAR or MNAR for these.>.  
Legend symbols should match the line symbols. At the top of each page of the figure, put 
“Delta =xx mL (y treatment effect)” where y = 0, 1/3, 2/3, and 1 x”. 


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Figure 2.1.4.22 
Comparison of FF MDI 9.6 μg  vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks Using Imputed 
Estimates at Various Deltas 
Analysis Set: ITT Population 
 
Figure 2.1.4.23 
Comparison of GP MDI 14.4 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks Using 
Imputed Estimates at Various Deltas 
Analysis Set: ITT Population 
 
Figure 2.1.4.24 
Comparison of GFF MDI 14.4/9.6 μg vs. FF MDI 9.6 μg for Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks Using 
Imputed Estimates at Various Deltas 
Analysis Set: ITT Population 
 
Figure 2.1.4.25 
Comparison of GFF MDI 14.4/9.6 μg vs. GP MDI 14.4 μg for Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks Using 
Imputed Estimates at Various Deltas 
Analysis Set: ITT Population 
 
Figure 2.1.4.26 
Comparison of GFF MDI 14.4/9.6 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24Using 
Imputed Estimates at Various Deltas 
Analysis Set: ITT Population 
 
Figure 2.1.4.27 
Comparison of FF MDI 9.6 μg  vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24 Using 
Imputed Estimates at Various Deltas 
Analysis Set: ITT Population 
 
Figure 2.1.4.28 
Comparison of GP MDI 14.4 μg vs. Placebo MDI for Change From Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24Using 
Imputed Estimates at Various Deltas 
Analysis Set: ITT Population 
 
Figure 2.1.4.29 
Comparison of GFF MDI 14.4/9.6 μg vs. FF MDI 9.6 μg for Change From Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24 
Using Imputed Estimates at Various Deltas 
Analysis Set: ITT Population 
 


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Figure 2.1.4.30 
Comparison of GFF MDI 14.4/9.6 μg vs. GP MDI 14.4 μg for Change From Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24 
Using Imputed Estimates at Various Deltas 
Analysis Set: ITT Population 
 
 


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Table 2.1.4.4 
 Cumulative Proportion of Responders Based on Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 
Analysis Set: ITT Population 
 
Response 
Criteria 
Change 
from 
Baseline 
in FEV1 
(L)≥  
Cumulative Response (%) 
Treatment Difference vs. 
Placebo MDI 
Treatment Difference for GFF 
MDI 14.4/9.6 vs. Components 
GFF MDI 
14.4/9.6 μg 
 (N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
GFF MDI 
14.4/9.6 
μg 
(p-value) 
FF MDI 
9.6 μg 
(p-value) 
GP MDI 
14.4 μg 
(p-value) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
P-value 
 
 
 
 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxxx 
 
 
 
 
 
 
 
 
 
x.xxx 
 xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
x.xxx 
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xx.x 
The cumulative response is defined as the percentage of subjects with a change from baseline in FEV1 meeting or exceeding the  
criteria.  Subjects with missing data at Week 24 were considered non-responders.  The p-value shown is from a  
Kolmogorov-Smirnov Test comparing test treatments with Placebo MDI (or components) on the distribution of cumulative response  
rates across all values of the change from baseline in FEV1 at Week 24. 
 
 


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Figure 2.1.4.31 
Cumulative Proportion of Responders Based on Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
 
This is just an example plot.  “Percent Pain Intensity Difference” shown above will be replaced with values of change from baseline in 
morning pre-dose trough FEV1 representing values from the 1st to the 99 percentile (irrespective of treatment order). All treatments will be 
plotted. Subjects with missing data will be considered non-responders for the analysis and this figure. 


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Table 2.1.4.5 
Cumulative Proportion of Responders Based on Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks 
Analysis Set: ITT Population 
 
Figure 2.1.4.32 
Cumulative Proportion of Responders Based on Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks 
Analysis Set: ITT Population 
 
Table 2.1.4.6 
 Cumulative Proportion of Responders Based on Change From Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24 
Analysis Set: ITT Population 
 
Figure 2.1.4.33 
Cumulative Proportion of Responders Based on Change From Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24 
Analysis Set: ITT Population 
 
 
 


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Transition Dyspnea Index (TDI) 
 
 
Table 2.2.1 
TDI Focal Score Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
<CAT Score Subpopulation> 
 
Note to Programmer: Do for category “CAT Score Overall” which will include subjects with missing TDI score and 
then repeat tabulation below for CAT Score ≥10, Symptomatic Population (CAT Score ≥15), and CAT Score ≥20. The 
model will be run separately for each category. 
 
Treatment 
BDI Focal Score 
TDI Focal Score 
LS Mean Differences Between Treatments 
Placebo MDI 
FF MDI  
9.6 μg 
GP MDI  
14.4 μg 
Over 24 Weeks 
 
GFF MDI 14.4/9.6 μg 
  n 
xx 
 
 
 
 
  Mean  
x.x 
 
 
 
 
  SD 
x.x 
 
 
 
 
  Median 
x.x 
 
 
 
 
  Min-Max 
x.x-x.x 
 
 
 
 
  LS Mean (SE) 
 
  x.x (x.xx)        x.xx (x.xxx) 
  x.xx (x.xxx) 
  x.xx (x.xxx) 
  95% CI 
 
( x.x, x.x) 
( x.xx, x.xx) 
( x.xx, x.xx) 
( x.xx, x.xx) 
  P-value 
 
 
  x.xxxx  
  x.xxxx  
  x.xxxx  
 
 
 
 
 
 
FF MDI 9.6 μg 
  n 
xx 
 
 
 
 
  Mean  
x.x 
 
 
 
 
  SD 
x.x 
 
 
 
 
  Median 
x.x 
 
 
 
 
  Min-Max 
x.x-x.x 
 
 
 
 
  LS Mean (SE) 
 
  x.x (x.xx)        x.xx (x.xxx) 
Not Applicable 
  x.xx (x.xxx) 
  95% CI 
 
( x.x, x.x) 
( x.xx, x.xx) 
 
( x.xx, x.xx) 
  P-value 
 
 
  x.xxxx  
 
  x.xxxx  
 
 
 
 
 
 
GP MDI 14.4 μg 
  n 
xx 
 
 
 
 
  Mean  
x.x 
 
 
 
 


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<CAT Score Subpopulation> 
 
Note to Programmer: Do for category “CAT Score Overall” which will include subjects with missing TDI score and 
then repeat tabulation below for CAT Score ≥10, Symptomatic Population (CAT Score ≥15), and CAT Score ≥20. The 
model will be run separately for each category. 
 
Treatment 
BDI Focal Score 
TDI Focal Score 
LS Mean Differences Between Treatments 
Placebo MDI 
FF MDI  
9.6 μg 
GP MDI  
14.4 μg 
  SD 
x.x 
 
 
 
 
  Median 
x.x 
 
 
 
 
  Min-Max 
x.x-x.x 
 
 
 
 
  LS Mean (SE) 
 
  x.x (x.xx)        x.xx (x.xxx) 
Shown Above 
Not Applicable 
  95% CI 
 
( x.x, x.x) 
( x.xx, x.xx) 
 
 
  P-value 
 
 
  x.xxxx  
 
 
   
 
 
 
 
 
Placebo 
  n 
xx 
 
 
 
 
  Mean  
x.x 
 
 
 
 
  SD 
x.x 
 
 
 
 
  Median 
x.x 
 
 
 
 
  Min-Max  
x.x-x.x 
 
 
 
 
  LS Mean (SE) 
 
  x.x (x.xx) 
 Not Applicable 
Shown Above 
Shown Above 
  95% CI 
 
( x.x, x.x) 
 
 
 
 
 
 
 
 
 
LS Mean = least squares means are from the linear repeated measures model which included the following 
covariates: BDI focal score, percent reversibility to Ventolin HFA, treatment, visit, and treatment by visit 
interaction.  
 
Report generated by program: pt003014/sasdir/programs/statout/t020201.sas Version YYYY-MM-DD hh:mm  (Page n of N)        
 
 
 
Note to Programmer: Repeat for Over Weeks 12-24 and for each post-baseline visit from Week 4 to Week 
24. Descriptive statistics for the raw TDI focal score will be added for each individual visit, but not 
for 0-24 weeks or for Over Weeks 12-24. Do not split a treatment across a page. 


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Figure 2.2.1.1.1 Adjusted Mean TDI Focal Score ± SE Over Time  
Analysis Set: ITT Population 
 
 
 
 
Figure 2.2.1.1.2 Treatment Differences From Placebo MDI*: Adjusted Mean TDI Focal Score (95% CI) Over Time 
Analysis Set: ITT Population 
 
Figure 2.2.1.2.1 Adjusted Mean TDI Focal Score ± SE Over Time: CAT Score Subpopulation of >= 10 
Analysis Set: ITT Population 
 
Figure 2.2.1.2.2 Adjusted Mean TDI Focal Score ± SE Over Time: Symptomatic Population (CAT Score ≥15),  
Analysis Set: ITT Population 
 
Figure 2.2.1.2.3 Adjusted Mean TDI Focal Score ± SE Over Time: CAT Score Subpopulation of >= 20 
Analysis Set: ITT Population 
 
Table 2.2.2.1 
TDI Component Scores for Functional Impairment, Magnitude of Task, and Magnitude of Effort Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Figure 2.2.2.1.x Adjusted Mean TDI Functional Impairment Component Score ± SE Over Time Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Figure 2.2.2.2.x Adjusted Mean TDI Magnitude of Task Component Score ± SE Over Time Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Figure 2.2.2.3.x Adjusted Mean TDI Magnitude of Effort Component Score ± SE Over Time Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
Note to Programmer: show by visit and also 4-24 value as a single point.  Do not start  x axis at 0. 


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Table 2.2.3 
Response in TDI Focal Score (Achievment of a Minimum Clinically Important Difference Threshold of ≥1 Unit on Average) Over 24 Weeks 
and Over Weeks 12-24 Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
<CAT Score Subpopulation> 
 
Note to Programmer: Do for “CAT Score Overall” population which will include subjects with missing CAT score and then repeat 
tabulation below for subpopulations of CAT Score ≥10, Symptomatic Population (CAT Score ≥15),and CAT Score ≥20. The model will be run 
separately for each category. 
 
Percentage of Subjects 
Achieving TDI Focal 
Score of at Least 1.0 
Unit On Average Over 24 
Weeks 
 
Observed % (n/N) 
 
Model-Based Percentages [a] 
 
Comparator  
Placebo MDI 
FF MDI  
9.6 μg 
GP MDI  
14.4 μg 
 
Over 24 Weeks 
 
GFF MDI 
14.4/9.6 μg 
xx.xx% (xxx/xxx) 
 
Treatment 
Comparator 
Difference 
95% CI 
 
Odds Ratio 
95% CI 
P-value 
xx.xx 
xx.xx 
xx.xx 
(x.xx, xx.xx) 
 
x.xxxx 
(x.xxxx, x.xxxx) 
x.xxxx 
xx.xx 
xx.xx 
xx.xx 
(x.xx, xx.xx) 
 
x.xxxx 
(x.xxxx, x.xxxx) 
x.xxxx 
xx.xx 
xx.xx 
xx.xx 
(x.xx, xx.xx) 
 
x.xxxx 
(x.xxxx, x.xxxx) 
x.xxxx 
 
 
 
 
 
FF MDI 9.6 μg 
xx.xx% (xxx/xxx) 
 
Treatment 
Comparator 
Difference 
95% CI 
 
Odds Ratio 
95% CI 
P-value 
xx.xx 
xx.xx 
xx.xx 
(x.xx, xx.xx) 
 
x.xxxx 
(x.xxxx, x.xxxx) 
x.xxxx 
Not Applicable 
xx.xx 
xx.xx 
xx.xx 
(x.xx, xx.xx) 
 
x.xxxx 
(x.xxxx, x.xxxx) 
x.xxxx 
 
 
 
 
 
GP MDI 14.4 μg 
xx.xx% (xxx/xxx) 
 
Treatment 
Comparator 
Difference 
xx.xx 
xx.xx 
xx.xx 
Shown Above 
 
Not Applicable 


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<CAT Score Subpopulation> 
 
Note to Programmer: Do for “CAT Score Overall” population which will include subjects with missing CAT score and then repeat 
tabulation below for subpopulations of CAT Score ≥10, Symptomatic Population (CAT Score ≥15),and CAT Score ≥20. The model will be run 
separately for each category. 
 
Percentage of Subjects 
Achieving TDI Focal 
Score of at Least 1.0 
Unit On Average Over 24 
Weeks 
 
Observed % (n/N) 
 
Model-Based Percentages [a] 
 
Comparator  
Placebo MDI 
FF MDI  
9.6 μg 
GP MDI  
14.4 μg 
95% CI 
 
Odds Ratio 
95% CI 
P-value 
(x.xx, xx.xx) 
 
x.xxxx 
(x.xxxx, x.xxxx) 
x.xxxx 
 
 
 
 
 
Placebo MDI 
xx.xx% (xxx/xxx) 
 
 
Not Applicable 
Shown Above 
 
Shown Above 
 
REPEAT for Over Weeks 
12-24 
 
 
 
 
[a] Estimated percentages, differences between percentages and p-values are based on a logistic regression model with TDI response as 
    a binary response and the following covariates in the model: BDI Focal Score, percent reversibility to Ventolin HFA, and  
    treatment. The p-value is associated with the test of whether the  odds ratio is equal to 1.0.  A significant p-value for the test 
    of the odds ratio indicates that the odds of a treatment effect in  the  treatment is not equal to that for the comparator (either 
    significantly higher or significantly lower than 1.0). 
 
Report generated by program:  pt003014/sasdir/programs/statout/t020203.sas  Version  YYYY-MM-DD xx:xx   (Page n of N) 
 
 
 
 
 
 
 
 
 
Notes to Programmer:  
 
USE THIS TABLE FORMAT FOR ALL RESPONSE TABLES IN THIS DOCUMENT (SGRQ AND PERCENT RESPONSE TABLES). 


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07 Mar 2017 
Page 88 of 249 
 
 
 
 
Peak Change From Baseline in FEV1 
 
 
Table 2.3.1 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-dose 
Analysis Set: ITT Population 
 
Figure 2.3.1 
Adjusted Mean Peak Change From Baseline in FEV1 (L) ± SE Within 2 Hours Post-dose 
Analysis Set: ITT Population 
 
 
St. George Respiratory Questionnaire (SGRQ) 
 
Table 2.4.1 
SGRQ Total Score (units) Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
Note to Programmer: Similar to Table 2.2.1, use all ITT data and then repeat tabulation below for CAT Score ≥10, Symptomatic 
Population (CAT Score ≥15), and CAT Score ≥20. The model will be run separately for each category. 
 
The following will be the first footnote in the table: 
 
A 1 unit change in the SGRQ total score corresponds to a change of 1% per the SGRQ scoring manual.


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Figure 2.4.1.1 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over Time 
Analysis Set: ITT Population  
 
 
 
 
 
Figure 2.4.1.2 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over Time: CAT Score Subpopulation of >= 10 
Analysis Set: ITT Population 
 
Figure 2.4.1.3 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over Time: Symptomatic Population (CAT Score ≥15),  
Analysis Set: ITT Population 
 
Figure 2.4.1.4 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over Time: CAT Score Subpopulation of >= 20 
Analysis Set: ITT Population 
 
Table 2.4.2 
Total Score (units) of Each SGRQ Domain Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
Note to Programmer; show by visit and also 4-24 
and 12-24 value as a single point. 


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Final Version 
07 Mar 2017 
Page 90 of 249 
 
 
 
 
Table 2.4.3 
Response in SGRQ Total Score (Achievment of a Minimum Clinically Important Difference Threshold of ≥4 Units on Average) Overall and by 
CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
Notes to the Programmer: please use the format of Table 2.2.4.1. Replace the covariate of BDI with baseline SGRQ total 
score. Do for at Week 24 and for over Weeks 12-24. 
 
The following will be the first footnote in the table: 
 
A 1 unit change in the SGRQ total score corresponds to a change of 1% per the SGRQ scoring manual. 


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Page 91 of 249 
 
 
 
 
Number of Puffs of Rescue Ventolin HFA 
 
Table 2.5.1 
Mean Daily, Daytime, and Nighttime Number of Puffs of Rescue Ventolin HFA 
Analysis Set: Rescue Ventolin User Population 
 
 
 
 
 
Figure 2.5.1.1 
Adjusted Mean Change From Baseline in Mean Daily Number of Puffs of Rescue Ventolin HFA ± SE Over Time  
Analysis Set: Rescue Ventolin User Population 
 
 
 
 
 
 
 
Figure 2.5.1.2 
Adjusted Mean Change From Baseline in Mean Daytime Number of Puffs of Rescue Ventolin HFA ± SE Over Time  
Analysis Set: Rescue Ventolin User Population 
 
Figure 2.5.1.3 
Adjusted Mean Change From Baseline in Mean Nighttime Number of Puffs of Rescue Ventolin HFA± SE Over Time  
Analysis Set: Rescue Ventolin User Population 
 
 
 
Notes to Programmer: Show each 4-week interval, 
and Over Weeks 12-24 and over 24 weeks as single 
points (1-24 and 12-24). Label the 4-week 
intervals as “1-4, 5-8, 9-12, 13-16, 17-20, and 
21-24”.  Connect all treatment lines to 0. 
Note to Programmer: Similar to Table 2.2.1. 


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Page 92 of 249 
 
 
 
 
Table 2.5.2 
Percentage of Days With No Rescue Ventolin HFA Use Over 24 Weeks 
Analysis Set: Rescue Ventolin User Population 
 
 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer: A ‘Day with no rescue use’ is 
defined, using rescue Ventolin usage data from 
days where rescue Ventolin usage data is non-
missing, as any day where the subject reported no 
puffs of rescue Ventolin. The percentage of days 
with ‘no rescue use’ will be summarized by 
treatment and analyzed using ANCOVA with baseline 
average daily rescue Ventolin use and percent 
reversibility to Ventolin HFA as continuous  
covariates. 


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Final Version 
07 Mar 2017 
Page 93 of 249 
 
 
 
 
Time to Onset of Action Assessed Using FEV1 on Day 1 
 
 
Table 2.6.1 
FEV1 (L) by Post-dose Timepoint on Day 1 
Analysis Set: ITT Population 
 
 
 
 
 
 
Notes to Programmer: Please use the format of 
Table 2.1.1 and within this table, sort by 2 hour 
post-dose assessment. 


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07 Mar 2017 
Page 94 of 249 
 
 
 
 
Figure 2.6.1 
Adjusted Mean Change From Baseline in FEV1 (L) ± SE Over the 2 Hour Post-dose Interval on Day 1  
Analysis Set: ITT Population 
 
 
 
Source: Table 2.6.1. 
 
Report generated by program: pt003014/sasdir/programs/statout/f021801.sas     Version YYYY-MM-DD hh:mm   (Page n of N)  
 
 
 
 
 
Notes to Programmer: Timepoints up to and including 2 hours post dose are shown, including the 5 min timepoint. Replace 
treatments shown with the 5 treatments used in this study. Replace the x axis label with “Time Post-dose”.  Add +/- SE to 
end of the y axis label. 


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Other Spirometry Measures Including Percent Responders Analyses for Day 1 
 
 
Table 2.7 
FEV1 AUC0-2 (L)  
Analysis Set: ITT Population 
 
 
 
 
 
 
Figure 2.7 
Adjusted Mean FEV1 AUC0-2 (L) ± SE Over Time 
Analysis Set: ITT Population 
 
Table 2.8 
FVC AUC0-2 (L) 
Analysis Set: ITT Population 
 
Figure 2.8 
Adjusted Mean FVC AUC0-2 (L) ± SE Over Time 
Analysis Set: ITT Population 
 
Table 2.9 
Peak Change From Baseline in FVC (L) Within 2 Hours Post-dose  
Analysis Set: ITT Population 
 
Figure 2.9 
Adjusted Mean Peak Change From Baseline in FVC (L) ± SE Within 2 Hours Post-dose 
Analysis Set: ITT Population 
 
Table 2.10 
Morning Pre-dose Trough FVC (L)  
Analysis Set: ITT Population 
 
Figure 2.10 
Adjusted Mean Change From Baseline in Morning Pre-dose Trough FVC (L) ± SE 
Analysis Set: ITT Population 
 
Note to Programmer: tabulate for over 24 weeks, over 12-24 weeks, and for each post-baseline 
visit. This variable is based on change from baseline in FEV1. 


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Table 2.11.1 
Percentage of Subjects With ≥10% Improvement From Baseline in FEV1 During 2 Hour Post-dose Interval and by Post-dose Timepoint on Day 
1 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2.11.2 
Percentage of Subjects With ≥12% Improvement From Baseline in FEV1 During 2 Hour Post-dose Interval and by Post-dose Timepoint on Day 
1 
Analysis Set: ITT Population 
 
Table 2.11.3 
Percentage of Subjects With ≥100 mL Improvement From Baseline in FEV1 During 2 Hour Post-dose Interval and by Post-dose Timepoint on 
Day 1 
Analysis Set: ITT Population 
 
Table 2.11.4 
Percentage of Subjects With ≥200 mL Improvement From Baseline in FEV1 During 2 Hour Post-dose Interval and by Post-dose Timepoint on 
Day 1 
Analysis Set: ITT Population 
 
Table 2.11.5 
Percentage of Subjects With Improvement From Baseline in FEV1 of Both ≥12% and ≥200 mL During 2 Hour Post-dose Interval and by Post-
dose Timepoint on Day 1 
Analysis Set: ITT Population 
 
 
 
Notes to the Programmer: please use the format of Table 2.2.8.1. Do for Over 2 Hour Post-dose Interval and also for each Post-
dose timepoint.  
 
Footnote: 
[a]  Estimated percentages, differences between percentages and p-values are based on a logistic regression model with ≥10% 
improvement From baseline in FEV1 during 2 hour post-dose interval as a binary response and the following covariates in the 
model: baseline FEV1, percent reversibility to Ventolin HFA, and treatment. The p-value is associated with the test of 
whether the odds ratio is equal to 1.0. A significant p-value for the test of the odds ratio indicates that the odds of a 
treatment effect in the treatment is not equal to that for the comparator (either significantly higher or significantly 
lower than 1.0). 
 


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Table 2.12 
FVC (L) Over the 2 Hour Post-dose Interval on Day 1  
Analysis Set: ITT Population 
 
Figure 2.12 
Adjusted Mean Change From Baseline in FVC (L) ± SE Over the 2 Hour Post-dose Interval on Day 1 
Analysis Set: ITT Population 
 
 
 


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Exacerbations 
 
Table 2.13.1 
Rate of COPD Exacerbations Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
<CAT Score Subpopulation> 
Note to Programmer: Do for “CAT Score Overall” population which will include subjects with missing CAT score and then repeat 
tabulation below for subpopulations of CAT Score ≥10, Symptomatic Population (CAT Score ≥15),and CAT Score ≥20. The model will be run 
separately for each category. 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI  
9.6 μg  
(N=xxx) 
GP MDI  
14.4 μg  
(N=xxx) 
Placebo MDI 
(N=xxx) 
Subjects with COPD Exacerbations [a], n(%) 
[Events]  
xx (xx.x) 
[x] 
xx (xx.x) 
[x] 
xx (xx.x) 
[x] 
xx (xx.x) 
[x] 
Mild 
xx (xx.x) 
[x] 
xx (xx.x) 
[x] 
xx (xx.x) 
[x] 
xx (xx.x) 
[x] 
 Moderate  
xx (xx.x) 
[x] 
xx (xx.x) 
[x] 
xx (xx.x) 
[x] 
xx (xx.x) 
[x] 
Severe  
xx (xx.x) 
   [x] 
xx (xx.x) 
   [x] 
xx (xx.x) 
   [x] 
xx (xx.x) 
   [x] 
Moderate or Severe  
xx (xx.x) 
   [x] 
xx (xx.x) 
      [x] 
xx (xx.x) 
      [x] 
xx (xx.x) 
      [x] 
Any Severity 
xx (xx.x) 
   [x] 
xx (xx.x) 
   [x] 
xx (xx.x) 
   [x] 
xx (xx.x) 
   [x] 
 
 
 
 
COPD Exacerbation of Any Severity 
 
 
 
 
Rate (per year) of COPD Exacerbation [b] 
x.xx 
x.xx 
x.xx 
x.xx 
Adjusted Rate of COPD Exacerbation (c) 
x.xx 
x.xx 
x.xx 
x.xx 
 
 
 
 
Treatment Incidence Rate Ratio (P-value) 
(95% CI) [c][e] 
 
 
 
 
GFF MDI 14.4/9.6 μg (n=xxx) 
Not Applicable 
x.xx (x.xxxx) 
(x.xx, x.xx) 
x.xx (x.xxxx) 
(x.xx, x.xx) 
x.xx (x.xxxx) 
(x.xx, x.xx) 
FF MDI 9.6 μg (n=xxx) 
 
Not Applicable 
x.xx (x.xxxx) 
(x.xx, x.xx) 
x.xx (x.xxxx) 
(x.xx, x.xx) 
GP MDI 14.4 μg (n=xxx) 
 
 
Not Applicable 
x.xx (x.xxxx) 


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(x.xx, x.xx) 
Placebo MDI (n=xxx) 
 
 
 
Not Applicable 
 
 
 
 
Treatment Difference in Rates 
(95% CI) [c] [d] 
 
 
 
 
GFF MDI 14.4/9.6 μg (n=xxx) 
Not 
Applicable 
x.xx 
(x.xx, x.xxxx) 
x.xx 
(x.xx, xxxx) 
x.xx 
(x.xx, x.xx) 
FF MDI 9.6 μg (n=xxx) 
 
Not Applicable 
xxxx 
(xxxx, x.xx) 
xxxx 
(x.xx, x.xx) 
GP MDI 14.4 μg (n=xxx) 
 
 
Not Applicable 
x.xx 
(x.xx, x.xx) 
Placebo MDI (n=xxx) 
 
 
 
Not Applicable 
[a]   COPD exacerbations were considered separate events provided that 7 or more days were between the recorded stop date of  
     the earlier event and start date of the later.  
[b]   The rate of exacerbations per year = Total number of exacerbations / Total years of exposure  across all subjects for the 
     treatment.  Time during an exacerbation or in the 7 days following an exacerbation was not included in the calculation of 
     exposure.  
[c]   Treatments were compared adjusting for baseline percent predicted FEV1, baseline CAT score, baseline COPD exacerbation 
     history (yes/no), smoking status at baseline (former smoker/current smoker), baseline continuous eosinophil count, and inhaled  
     corticosteroid use at baseline (yes/no) using negative binomial regression. Treatment exposure was used as an offset variable. 
[d]   Row Treatment minus Column Treatment. 
[e]   Row Treatment / Column Treatment. 
Report generated by program: pt003014/sasdir/programs/statout/t021301.sas    Version       YYYY-MM-DD xx:xx (Page n of N)   
Notes to Programmer: Repeat above for Rate of Moderate or Severe COPD exacerbation except for the 1st 6 rows of the table. If n is not sufficient, 
only relevant statistics will be provided. Replace ‘COPD Exacerbation of Any Severity’ with ‘Moderate or Severe COPD Exacerbation’. Repeat 
these labels when starting a new page and put ‘(Continued)’ at the end of the phrase. 
Notes to Programmers: put a blank line after each treatment row. 


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Table 2.13.2 
Rate of COPD Exacerbations With Imputation Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
Notes to Programmer: Repeat above for Rate of Moderate or Severe COPD exacerbation except for the 1st 6 rows of the table.  Add a footnote: Analyses 
include the 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. 


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Table 2.14 
Time to First COPD Exacerbation of Any Severity and Time to First Moderate or Severe COPD Exacerbation Overall and by CAT Score 
Subpopulation 
Analysis Set: ITT Population 
 
<CAT Score Subpopulation> 
Note to Programmer: Do for “CAT Score Overall” population which will include subjects with missing CAT score and then repeat 
tabulation below for subpopulations of CAT Score ≥10, Symptomatic Population (CAT Score ≥15),and CAT Score ≥20. The model will be run 
separately for each category. 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI  
9.6 μg 
 (N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo  
MDI 
 (N=xxx) 
Subjects with COPD Exacerbation of Any Severity, n(%) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Time to First COPD Exacerbation of Any Severity 
 
 
 
 
Hazard Ratio (Relative to Comparator) 
  95% CI 
  P-value 
GFF MDI 14.4/9.6 μg (n=xxx) 
Not Applicable 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
FF MDI 9.6 μg (n=xxx) 
 
Not Applicable 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
GP MDI 14.4 μg (n=xxx) 
 
 
Not Applicable 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
Placebo MDI (n=xxx) 
 
 
 
Not Applicable 
Time to COPD Exacerbation (weeks) = (date of first COPD exacerbation – first treatment administration date + 1)/7. Treatment 
comparisons were performed using the Cox regression model, adjusting for baseline percent predicted FEV1, baseline COPD exacerbation 
history (yes/no), baseline CAT score, smoking status at baseline (former smoker/current smoker), baseline continuous eosinophil count, 
and inhaled corticosteroid use at baseline (yes/no). 
Report generated by program: pt003014/sasdir/programs/statout/t0214.sas    Version       YYYY-MM-DD xx:xx (Page n of N)    
Notes to Programmer: Use  “Time to First COPD Exacerbation of Any Severity  (Continued)” if starting a new page.  
Repeat above for time to first moderate or severe COPD exacerbation.  Replace “Time to First COPD Exacerbation of Any Severity” with “Time to First 
Moderate or Severe COPD Exacerbation”. Use data up to the last visit date (if on or after the last date of treatment) or up to the 
date of last treatment if this occurred after the last visit), as long as on or prior to Day 183. 


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Figure 2.14.1.x 
Kaplan-Meier Curves for Time to First COPD Exacerbation of Any Severity Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
 
 
 
Figure 2.14.2.x 
Kaplan-Meier Curves for Time to First Moderate or Severe COPD Exacerbation Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
Notes to Programmer: Use data up to the last visit date (if on or after the last date of 
treatment) or up to the date of last treatment if this occurred after the last visit), as 
long as on or prior to Day 183. 
Notes to Programmer: Use data up to the last visit date (if on or after the last date of 
treatment) or up to the date of last treatment if this occurred after the last visit), as 
long as on or prior to Day 183. 


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Table 2.15 
Time to Treatment Failure Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
<CAT Score Subpopulation> 
Note to Programmer: Do for “CAT Score Overall” population which will include subjects with missing CAT score and then repeat 
tabulation below for subpopulations of CAT Score ≥10, Symptomatic Population (CAT Score ≥15),and CAT Score ≥20. The model will be run 
separately for each category. 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI  
9.6 μg 
 (N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo MDI 
(N=xxx) 
Subjects with Treatment Failure, n(%) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Hazard Ratio (Relative to Comparator) 
  95% CI 
  P-value 
GFF MDI 14.4/9.6 μg (n=xxx) 
Not Applicable 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
FF MDI 9.6 μg (n=xxx) 
 
Not Applicable 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
GP MDI 14.4 μg (n=xxx) 
 
 
Not Applicable 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
Placebo MDI (n=xxx) 
 
 
 
Not Applicable 
Treatment failure is defined as occurrence of a moderate/severe COPD exacerbation or early discontinuation for any reason.  Time to 
treatment failure (weeks) = (date of treatment failure – first treatment administration date + 1)/7.  Treatment comparisons were 
performed using the Cox regression model, adjusting for baseline percent predicted FEV1, baseline COPD exacerbation history (yes/no), 
baseline CAT score, smoking status at baseline (former smoker/current smoker), baseline continuous eosinophil count, and inhaled 
corticosteroid use at baseline (yes/no). 
Report generated by program: pt003014/sasdir/programs/statout/t0215.sas    Version       YYYY-MM-DD xx:xx (Page n of N) 
Notes to Programmer: If n is not sufficient, only relevant statistics will be provided. 
Notes to Programmer: Use data up to the last visit date (if on or after the last date of treatment) or up to the date of last 
treatment if this occurred after the last visit), as long as on or prior to Day 183. 


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Figure 2.15.x 
Kaplan-Meier Curves for Time to Treatment Failure Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
 
 
 
Notes to Programmer: Use data up to the last visit date (if on or after the last date of treatment) or up to the date of last 
treatment if this occurred after the last visit), as long as on or prior to Day 183. 


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Table 2.16.1 
Time to First Clinically Important Deterioration (CID) Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
<CAT Score Subpopulation> 
Note to Programmer: Do for the “CAT Score Overall” population which will include subjects with missing CAT score and then repeat 
tabulation below for subpopulations of CAT Score ≥10, CAT Score ≥15,and CAT Score ≥20. The model will be run separately for each 
category. 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI  
9.6 μg 
 (N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo MDI 
(N=xxx) 
Subjects with first CID, n(%) [a] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Median time to CID (weeks) [b] 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
Hazard Ratio (Relative to Comparator) 
  95% CI 
  P-value 
GFF MDI 14.4/9.6 μg (n=xxx) 
Not Applicable 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
FF MDI 9.6 μg (n=xxx) 
 
Not Applicable 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
GP MDI 14.4 μg (n=xxx) 
 
 
Not Applicable 
x.xxx 
(x.xxx, x.xxx) 
x.xxxx 
Placebo MDI (n=xxx) 
 
 
 
Not Applicable 
 
[a] CID is defined as the first occurrence of one of the following events: 1) >= 100 mL decline in trough FEV1; 2) a treatment 
   emergent moderate/severe COPD exacerbation; or 3) increase of >= 4 units on the SGRQ. 
[b] Time to CID (weeks) = (date of CID - first treatment administration date + 1)/7. Treatment comparisons were performed using the  
   Cox regression model, adjusting for baseline percent predicted FEV1, baseline CAT score, baseline COPD exacerbation history  
   (yes/no), smoking status at baseline (former smoker/current smoker), and inhaled corticosteroid use at baseline (yes/no). 
Report generated by program: pt003014/sasdir/programs/statout/t021601.sas    Version       YYYY-MM-DD xx:xx (Page n of N)    
 
 
Notes to Programmer: If n is not sufficient, only relevant statistics will be provided. 
Note to Programmers: Time to a CID event will be based on the time of the component event which occurred first. Subjects who did 
not have a CID event will be censored at the earliest censoring day among the component censoring times. COPD exacerbations 
occurring past day 183 will not be counted as CID events. 


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Figure 2.16.1.x 
Kaplan-Meier Curves for Time to First CID Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
Table 2.16.2 
Time to First Clinically Important Deterioration (CID) With Death and Time to  First Occurrence of Each Component of CID with Death 
Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer:  
 
Time to a CID event will be based on the time of the component event which occurred first. Subjects who did not have a CID event 
will be censored at the earliest censoring day among the component censoring times. COPD exacerbations occurring past day 183 
will not be counted as CID event (use data up to the last visit date (if on or after the last date of treatment) or up to the 
date of last treatment if this occurred after the last visit), as long as on or prior to Day 183). 
Notes to Programmer: 
 
Follow the format of Table 2.6.1.  Do not display the Median time to CID row in this table.  
Time to first CID event will be based on the time of the component event which occurred first.  COPD exacerbations occurring 
past day 183 will not be counted as CID events. 


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Figure 2.16.2.x 
Kaplan-Meier Curves for Time to First CID With Death and Time to First Occurrence of Each Component of CID With Death Overall and by 
CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer:  
 
Time to first CID event will be based on the time of the component event which occurred first. Subjects who did not have a CID 
event will be censored at the earliest censoring day among the component censoring times. COPD exacerbations occurring past Day 
183 will not be counted as CID event (use data up to the last visit date (if on or after the last date of treatment) or up to 
the date of last treatment if this occurred after the last visit), as long as on or prior to Day 183). 


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Table 2.17 
Time to First Sustained Clinically Important Deterioration (CID) and Time to First Occurrence of Each Component of Sustained CID Overall 
and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer:  
First sustained CID will be defined as the first occurrence of one of the following events: 1) a sustained 
decline in trough FEV1; 2) a sustained SGRQ increase; or 3) a treatment emergent moderate/severe COPD 
exacerbation.  
Component Definitions:  
A sustained decline in trough FEV1 will be defined as ≥100 mL decline in trough FEV1 on 2 consecutive 
analysis visits or for ≥50% of all subsequent analysis visits with available trough FEV1. 
A sustained SGRQ increase will be defined as ≥4 points increase in SGRQ on 2 consecutive analysis visits 
or for ≥50% of all subsequent analysis visits with available SGRQ. 
For the COX regression, subjects who did not experience a component event will be censored at the Week 24 
visit or Day 183, whichever was earlier. The basic assumptions of the model including the proportional 
hazards assumption will be checked. 
Time to first trough FEV1 event will be the study day of the post-baseline analysis visit when change from 
baseline in trough FEV1 was ≤ -100 mL. If this event did not occur, the observation will be censored at the 
last analysis visit where trough FEV1 was evaluated. Time to first sustained decline in trough FEV1 will be 
the study day of the initial decline, satisfying the sustained definition. If the subject did not 
experience a sustained trough FEV1 decline, censoring will occur at the second-last analysis visit where 
trough FEV1 was evaluated. 
Similar considerations apply to time to first SGRQ event and first sustained SGRQ event. 
Time to a sustained CID event will be based on the time of the component event which occurred first. COPD 
exacerbations occurring past Day 183 will not be counted as sustained CID events. 
 


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Figure 2.17.x 
Kaplan-Meier Curves for Time to First Sustained CID and Time to First Occurrence of Each Component of Sustained CID Overall and by CAT 
Score Subpopulation 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer:  
 
Time to first sustained CID event will be based on the time of the component event which occurred first. Subjects who did not 
have a sustained CID event will be censored at the earliest censoring day among the component censoring times. COPD exacerbations 
occurring past Day 183 will not be counted as CID event (use data up to the last visit date (if on or after the last date of 
treatment) or up to the date of last treatment if this occurred after the last visit), as long as on or prior to Day 183). 


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Symptoms 
 
 
Table 2.18.1 
Mean Daily, Daytime, and Nighttime Total Symptom Scores 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2.18.2 
Mean Daily, Daytime, and Nighttime Cough Symptom Scores 
Analysis Set: ITT Population 
 
Table 2.18.3 
Mean Daily, Daytime, and Nighttime Shortness of Breath Symptom Scores 
Analysis Set: ITT Population 
 
Table 2.18.4 
Mean Daily, Daytime, and Nighttime Sputum Volume Symptom Scores 
Analysis Set: ITT Population 
 
Table 2.18.5 
Mean Number of Nighttime Awakenings 
Analysis Set: ITT Population 
 
 Notes to the Programmer: ‘Baseline’ column header should be “Baseline Average Awakenings (per night)”.  Add a footnote to the 
table: “Nighttime awakenings are coded 0 to 6 ….”. (See Table 8 of the SAP).” 
Notes to the Programmer:  
Add the following footnote for the total daily symptom score tabulation: 
Calculation of the mean daily total symptom score was based on scaled Ventolin HFA use over 24 hours with the 
following categories: 0 = No Ventolin HFA use, 1 = 1-2 puffs, 2 = 3-4 puffs, 3 = 5-6 puffs, 4 = 7-8 puffs, 5 = 9-10 
puffs, and 6 = >10 puffs. 
 
Add the following footnote for the daytime symptom score tabulation: 
Calculation of the mean daily daytime symptom score was based on scaled Ventolin HFA use with the following 
categories: 0 = No Ventolin HFA use, 1 = 1-2 puffs, 2 = 3-4 puffs, 3 = 5-6 puffs, and 4 = >6 puffs. 
 
Add the following footnote for the nighttime symptom score tabulation: 
Calculation of the mean daily nighttime symptom score was based on scaled Ventolin HFA use with the following 
categories: 0 = No Ventolin HFA use, 1 = 1-2 puffs, 2 = 3-4 puffs, 3 = 5-6 puffs, and 4 = >6 puffs. 
 


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Correlations 
(Note to Programmer:  For all correlation plots below, show the Pearson r correlation coefficient (r) and the Spearman correlation coefficient (rs). Do not show 
R2.  The Spearman correlation coefficient may be shown as “Rho”  or the symbol for Rho if subscripts are not possible). 
Figure 2.19.1 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 With Change From Baseline in Morning Pre-dose Trough 
FEV1 Over 24 Weeks 
Analysis Set: All Available Data 
 
 
Endpoint A (unit of measurement) 
Variable Endpoint B (unit of measurement) 
r = 0.9924, R² = 0.9848
GFF 18/9.6 
GFF 9/9.6
GFF 4.6/9.6
GFF 2.4/9.6
GFF 1.2/9.6
GP 18 
FF 9.6
Spiriva 18 
 
 


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Treatment plotted is treatment received. 
 
Source: Table 2.27 
 
Report generated by program: pt003014/sasdir/programs/statout/f022801.sas     Version YYYY-MM-DD hh:mm   (Page n of N) 
 
 
 
 
 
 
 
Figure 2.19.2 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 With Peak Change From Baseline in FEV1 at Week 24 
Analysis Set: All Available Data 
 
Figure 2.19.3 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 With Change From Baseline in SGRQ Total Score at 
Week 24 
Analysis Set: All Available Data 
 
Figure 2.19.4 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 With Change From Baseline in Rescue Ventolin HFA 
Usage Over 24 Weeks  
Analysis Set: All Available Data 
 
Figure 2.19.5 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 With TDI Focal Score Over 24 Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.6 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 With Peak Change From Baseline in FEV1 Over 24 
Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.7 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks With Peak Change From Baseline in FEV1 at Week 
24 
Analysis Set: All Available Data 
 
Notes to Programmer: Please redo figures with all treatments, replacing the x and y axis above 
with the two variables names identified in the title for this figure---the first of the 2 
names in the table will be used for the y axis and the 2nd name in the title for the y axis.   


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Figure 2.19.8 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks With Change From Baseline in SGRQ Total Score at 
Week 24 
Analysis Set: All Available Data 
 
Figure 2.19.9 
Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks With Change From Baseline in Rescue Ventolin HFA 
Usage Over 24 Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.10 
Correlation of Peak Change From Baseline in FEV1 at Week 24 With Change From Baseline in SGRQ Total Score at Week 24 
Analysis Set: All Available Data 
 
Figure 2.19.11 
Correlation of Peak Change From Baseline in FEV1 at Week 24 With Change From Baseline in Rescue Ventolin HFA Usage Over 24 Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.12 
Correlation of Peak Change From Baseline in FEV1 at Week 24 With TDI Focal Score Over 24 Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.13 
Correlation of Peak Change From Baseline in FEV1 at Week 24 With Peak Change From Baseline in FEV1 Over 24 Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.14 
Correlation of Change From Baseline in SGRQ Total Score at Week 24 With Change From Baseline in Rescue Ventolin HFA Usage Over 24 
Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.15 
Correlation of Change From Baseline in SGRQ Total Score at Week 24 With TDI Focal Score Over 24 Weeks  
Analysis Set: All Available Data 
 
Figure 2.19.16 
Correlation of Change From Baseline in SGRQ Total Score at Week 24 With Peak Change From Baseline in FEV1 Over 24 Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.17 Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks With TDI Focal Score Over 24 Weeks 
Analysis Set: All Available Data 
 


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Figure 2.19.18 Correlation of Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks With Peak Change From Baseline in FEV1 Over 24 
Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.19 Correlation of TDI Focal Score Over 24 Weeks With Peak Change From Baseline in FEV1 Over 24 Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.20 Correlation of TDI Focal Score Over 24 Weeks With Change From Baseline in Rescue Ventolin HFA Usage Over 24 Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.21 Correlation of Peak Change From Baseline in FEV1 Over 24 Weeks With Change From Baseline in Rescue Ventolin HFA Usage Over 24 
Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.22 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 at Week 24 With Morning Pre-dose Trough FEV1 Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.23 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 at Week 24 With TDI Focal Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.24 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 at Week 24 With Peak Change from Baseline in FEV1 Over Weeks 
12-24 
Analysis Set: All Available Data 
 
Figure 2.19.25 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 at Week 24 With SGRQ Total Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.26 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over Week 24 With Morning Pre-dose Trough FEV1 Over Weeks 12-
24 
Analysis Set: All Available Data 
 
Figure 2.19.27 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over Week 24 With TDI Focal Score Over Weeks 12-24 
Analysis Set: All Available Data 
 


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Figure 2.19.28 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over Week 24 With Peak Change from Baseline in FEV1 Over Weeks 
12-24 
Analysis Set: All Available Data 
 
Figure 2.19.29 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over Week 24 With SGRQ Total Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.30 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24 With TDI Focal Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.31 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24 With Peak Change from Baseline in FEV1 Over 
Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.32 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24 With SGRQ Total Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.33 
Correlation of Change from Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24 With Rescue Ventolin Use Over 24 Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.34 
Correlation of TDI Focal Score Over 24 Weeks With Morning Pre-dose Trough FEV1 Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.35 
Correlation of TDI Focal Score Over 24 Weeks  With TDI Focal Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.36 
Correlation of TDI Focal Score Over 24 Weeks With Peak Change from Baseline in FEV1 Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.37 
Correlation of TDI Focal Score Over 24 Weeks With SGRQ Total Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.38 
Correlation of TDI Focal Score Over Weeks 12-24 With Peak Change from Baseline in FEV1 Over Weeks 12-24 
Analysis Set: All Available Data 


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Figure 2.19.39 
Correlation of TDI Focal Score Over Weeks 12-24 With SGRQ Total Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.40 
Correlation of TDI Focal Score Over Weeks 12-24 With Rescue Ventolin Use Over 24 Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.41 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose at Week 24 With Morning Pre-dose Trough FEV1 Over Weeks 
12-24 
Analysis Set: All Available Data 
 
Figure 2.19.42 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose at Week 24 With TDI Focal Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.43 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose at Week 24 With Peak Change from Baseline in FEV1 Over 
Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.44 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose at Week 24 With SGRQ Total Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.45 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose Over 24 Weeks  With Morning Pre-dose Trough FEV1 Over 
Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.46 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose Over 24 Weeks  With TDI Focal Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.47 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose Over 24 Weeks  With Peak Change from Baseline in FEV1 Over 
Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.48 
Correlation of Peak Change from Baseline in FEV1 Within 2 Hours Post-dose Over 24 Weeks  With SGRQ Total Score Over Weeks 12-24 
Analysis Set: All Available Data 


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Figure 2.19.49 
Correlation of Peak Change from Baseline Within 2 Hours Post-dose Over Weeks 12-24 With SGRQ Total Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.50 
Correlation of Peak Change from Baseline Within 2 Hours Post-dose Over Weeks 12-24 With Rescue Ventolin Use Over 24 Weeks 
Analysis Set: All Available Data 
 
Figure 2.19.51 
Correlation of Change from Baseline in SGRQ Total Score at Week 24 With Morning Pre-dose Trough FEV1 Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.52 
Correlation of Change from Baseline in SGRQ Total Score at Week 24 With TDI Focal Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.53 
Correlation of Change from Baseline in SGRQ Total Score at Week 24 With Peak Change from Baseline in FEV1 Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.54 
Correlation of Change from Baseline in SGRQ Total Score at Week 24 With SGRQ Total Score Over Weeks 12-24 
Analysis Set: All Available Data 
 
Figure 2.19.55 
Correlation of Change from Baseline in SGRQ Total Score Over Weeks 12-24 With Rescue Ventolin Use Over 24 Weeks 
Analysis Set: All Available Data 
 
 
 
 


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Table 2.19.1 
Pearson Correlation Matrix of Key Efficacy Endpoints (Excluding Correlations with Efficacy Endpoints Over Weeks 12-24) 
Analysis Set: All Available Data 
 
GFF MDI, GP MDI, FF MDI, 
and Placebo MDI Treatments 
Combined (N=xxxx) 
Morning Pre-dose Trough 
FEV1 
 
 Peak Change from Baseline 
in FEV1 
 SGRQ Total Score 
Rescue Ventolin HFA 
Use Over 24 Weeks 
At Week 24 
Over 24 
Weeks 
TDI Focal 
Score Over 24 
Weeks 
At Week 24 
Over 24 
Weeks 
At Week 24 
Change from Baseline in 
Morning Pre-dose Trough FEV1 
at Week 24 
NA 
0.xxx 
 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
Change from Baseline in 
Morning Pre-dose Trough FEV1 
Over Week 24 
 
NA 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
TDI Focal Score Over 
24 Weeks 
 
 
NA 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
Peak Change from Baseline in 
FEV1 Within 2 Hours Post-dose 
at Week 24 
 
 
 
NA 
0.xxx 
0.xxx 
0.xxx 
Peak Change from Baseline in 
FEV1 Within 2 Hours Post-dose 
Over 24 Weeks 
 
 
 
 
NA 
0.xxx 
0.xxx 
Change from Baseline in SGRQ 
Total Score at Week 24 
 
 
 
 
 
NA 
0.xxx 
Change from Baseline in 
Rescue Ventolin HFA Use Over 
24 Weeks 
 
 
 
 
 
 
NA 


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GFF MDI, GP MDI, FF MDI, 
and Placebo MDI Treatments 
Combined (N=xxxx) 
Morning Pre-dose Trough 
FEV1 
 
 Peak Change from Baseline 
in FEV1 
 SGRQ Total Score 
Rescue Ventolin HFA 
Use Over 24 Weeks 
At Week 24 
Over 24 
Weeks 
TDI Focal 
Score Over 24 
Weeks 
At Week 24 
Over 24 
Weeks 
At Week 24 
Abbreviations:  FEV1=forced expiratory volume in 1 second; FF=formoterol fumarate; GFF=glycopyrronium and formoterol fumarate; GP=glycopyrronium; 
HFA = hydrofluoroalkane; MDI=metered dose inhaler; NA=not applicable; SGRQ=St. George’s Respiratory Questionnaire; TDI=Transition Dyspnea Index. 
Note:  All column headings represent change from baseline with the exception of TDI focal score. 
 
Report generated by program: pt003014/sasdir/programs/statout/t021901.sas    Version       YYYY-MM-DD xx:xx (Page n of N)    
 
 
 
 
 
 
 
Notes to Programmer: Also repeat for each treatment (GFF, GP, FF, and Placebo). 


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Table 2.19.2 
Pearson Correlation Matrix of Key Efficacy Endpoints Over Weeks 12-24 With Other Key Efficacy Endpoints and With Each Other 
Analysis Set: All Available Data 
 
 
 Morning Pre-dose Trough 
FEV1  
Over Weeks 12-24 
TDI Focal 
Score Over 
Weeks 12-24  
Peak Change from Baseline in 
FEV1 Over Weeks 12-24 
 SGRQ Total Score 
Over Weeks 12-24 
Rescue Ventolin HFA 
Use Over 24 Weeks 
Change from Baseline in 
Morning Pre-dose Trough FEV1 
at Week 24 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
See Table 2.19.1 
Change from Baseline in 
Morning Pre-dose Trough FEV1 
Over Week 24 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
See Table 2.19.1 
Change from Baseline in 
Morning Pre-dose Trough FEV1 
Over Weeks 12-24 
NA 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
TDI Focal Score Over 
24 Weeks 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
See Table 2.19.1 
TDI Focal Score Over Weeks 
12-24 
See above 
NA 
0.xxx 
0.xxx 
0.xxx 
Peak Change from Baseline in 
FEV1 Within 2 Hours Post-dose 
at Week 24 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
See Table 2.19.1 
Peak Change from Baseline in 
FEV1 Within 2 Hours Post-dose 
Over 24 Weeks 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
See Table 2.19.1 
Peak Change from Baseline 
Within 2 Hours Post-dose Over 
Weeks 12-24 
See above 
See above 
NA 
0.xxx 
0.xxx 


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 Morning Pre-dose Trough 
FEV1  
Over Weeks 12-24 
TDI Focal 
Score Over 
Weeks 12-24  
Peak Change from Baseline in 
FEV1 Over Weeks 12-24 
 SGRQ Total Score 
Over Weeks 12-24 
Rescue Ventolin HFA 
Use Over 24 Weeks 
Change from Baseline in SGRQ 
Total Score at Week 24 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
See Table 2.19.1 
Change from Baseline in SGRQ 
Total Score Over Weeks 12-24 
See above 
See above 
See above 
NA 
0.xxx 
Change from Baseline in Rescue 
Ventolin HFA Use Over 24 
Weeks 
See above 
See above 
See above 
See above 
NA 
Abbreviations:  FEV1=forced expiratory volume in 1 second; FF=formoterol fumarate; GFF=glycopyrronium and formoterol fumarate; GP=glycopyrronium; 
HFA = hydrofluoroalkane; MDI=metered dose inhaler; NA=not applicable; SGRQ=St. George’s Respiratory Questionnaire; TDI=Transition Dyspnea Index. 
Note:  All column headings represent change from baseline with the exception of TDI focal score. 
 
Report generated by program: pt003014/sasdir/programs/statout/t021902.sas    Version       YYYY-MM-DD xx:xx (Page n of N)    
 
 
 
 
 
 
 
Notes to Programmer: Also repeat for each treatment (GFF, GP, FF, and Placebo). 


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Subgroup Analyses 
 
Table 2.20.x 
Subject Disposition by Region and Country: <Region Subgroup or Country> 
Analysis Set: All Subjects Randomized 
 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo  
MDI 
 (N=xxx) 
All Subjects 
(N=xxxx) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Not Treated 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Treated 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Completed Week 12 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Completed Week 24 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Completed Follow-up Telephone Call 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Early Discontinuation [a] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
ITT Population [b] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PP Population [c] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Symptomatic Population [d] 
 
 
 
 
 
Rescue Ventolin User Population [e] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Safety Population [f] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
[a]  Early discontinuation was defined as failure to complete both the final visit and the Follow-up Telephone Call. 
[b]  The Intent-To-Treat (ITT) Population was defined as all subjects who were randomized to treatment and received at least one 
    dose  of study treatment. 
[c]  The Per Protocol (PP) Population was a subset of the ITT Population defined as all subjects with post-randomization data 
    obtained prior to a major protocol deviation. Data obtained after any major protocol deviation were excluded.  Since  
    receiving the wrong treatment is a major protocol deviation, subjects in the PP Population were analyzed according to the 
    treatment they received. Post-randomization visits will be excluded from the per protocol set if there is no evidence in the  
    diary that study medication was used the evening prior to the scheduled visit. 
[d]  The Symptomatic Population was defined as all subjects in the ITT Population with CAT scores of >=15 at Visit 4. 
[e]  The Rescue Ventolin User Population was defined as all subjects in the ITT Population with average baseline rescue Ventolin  
    use of ≥1 puff/day. 
[f]  The Safety Population was defined as all subjects who were randomized to treatment and received at least one dose of the study  
    treatment.  
Region Subgroup/Country Category includes the following: 
Table 2.20..1 
Japan vs. Non-Japan, 


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Table 2.20.2 
China 
Table 2.20.3 
Asia 
Table 2.20.4 
EU 
Table 2.20.5 
US 
Table 2.20.6 
Czech Republic 
Table 2.20.7 
Germany 
Table 2.20.8 
Hungary 
Table 2.20.9 
Poland 
Table 2.20.10 
Russia 
Table 2.20.11 
South Korea 
Table 2.20.12 
Taiwan 
Table 2.20.13 
U.K.) 
Report generated by program: pt003014/sasdir/programs/statout/t0220.sas Version  YYYY-MM-DD xx:xx (Page n of N)   
 
 
 


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Table 2.21.x 
Reason for Early Discontinuation by Region and Country: <Region Subgroup or Country> 
Analysis Set: All Subjects Randomized 
 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo  
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
Early Discontinuation 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Reason for Early Discontinuation 
 
 
 
 
 
 
 
 
 
 
  Adverse Event(s) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Administrative Reasons  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Lack of Efficacy 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Subject Discretion 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
     Withdrawal of Consent 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
     COPD 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
     Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Investigator  
  Considers It to Be 
  in the Best Interest of  
  Subject 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
     <Specified Reason> 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Subject Lost to Follow-up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      On or Before Week 24 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      After Week 24 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Major Protocol Violation 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
     <Specified Reason> 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Protocol-specified Discontinuation  
  Criteria [a] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Heart Rate Increase  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Systolic Blood Pressure Increase   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Prescription of Any  
      Prohibited Medications 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Decrease in Creatinine Clearance   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Hepatic Impairment 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      QTcF Increase 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      COPD Exacerbations  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      eDiary Non-Compliance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


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      Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Screen Failure (subject randomized in  
  error) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: Reasons of Other are listed by subject in Listing 1.2. 
[a] As per Protocol Section 5.7, except for eDiary non-compliance which is per Protocol Section 7.1.3. 
Report generated by program: pt003014/sasdir/programs/statout/t0221.sas Version  YYYY-MM-DD xx:xx (Page n of N)   
 
 
 
 
 
 
 
 
Notes to Programmers; Sort by descending frequency of 
major category using All Subjects column. Within major 
category, sort by descending frequency of subcategory 
using All Subjects column. 


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Table 2.22.1.x 
Demographics and Baseline Characteristics by Region and Country: <Region Subgroup or Country> 
Analysis Set: ITT Population 
 
Parameter 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
 
n (%) [a] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
Age (Years)[b] 
 
 
 
 
 
  N 
xxx 
xxx 
xxx 
xxx 
xxxx 
  Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
xx 
xx 
xx 
xx 
xx 
  Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Age Group, n (%) 
 
 
 
 
 
   Age < 65 years 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Age >= 65 years 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Missing 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
 
 
 
 
 
 
Gender, n (%) 
 
 
 
 
 
  Male 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Female 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
Race, n (%) 
 
 
 
 
 
  Black or African  
  American 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
  White 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Native Hawaiian or 
  Other Pacific     
  Islander 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
  American Indian or    
  Alaska Native 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
  Asian 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
  Australia or New    
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 


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Parameter 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
  Zealand (Indigenous) 
  Other 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
  Missing 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 
 
 
 
 
 
Ethnicity, n (%) 
 
 
 
 
 
   Hispanic 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Non-Hispanic 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Missing 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
  x (xx.x) 
 
 
Total CAT Score [c] 
 
 
 
 
 
  N 
xxx 
xxx 
xxx 
xxx 
xxxx 
  Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
  Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   < 10, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   >=10, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   < 15, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   >=15, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   < 20, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   >=20, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
   Missing, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 
 
 
 
 
 
MMRC Grade [d] 
 
 
 
 
 
  N 
xxx 
xxx 
xxx 
xxx 
xxx 
  Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
  Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   < 2, n (%) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   >=2, n (%) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Missing, n (%) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 
 
 
 
 
 
Used Inhaled Corticosteroids at 
Baseline [e], n (%)  
 
 
 
 
 
  Yes 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 


GFF MDI/GP MDI/FF MDI 
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Final Version 
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Parameter 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
  No 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 
 
 
 
 
 
Smoking Status [f], n (%) 
 
 
 
 
 
  Current Smoker 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Former Smoker 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Missing 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 xx (xx.x) 
 
 
 
 
 
 
Number of Years Smoked 
 
 
 
 
 
  n 
xxx 
xxx 
xxx 
xxx 
xxx 
  Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
  Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Average Number of Cigarettes 
Smoked Per Day 
 
 
 
 
 
 n 
xxx 
xxx 
xxx 
xxx 
xxx 
 Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
 SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 Minimum 
 Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Number of Pack Years Smoked [g] 
 
 
 
 
 
  n 
xxx 
xxx 
xxx 
xxx 
xxx 
  Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
  Maximum 
xx.x  
xx.x 
xx.x 
xx.x 
xx.x  
xx.x 
xx.x  
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
  n 
xxx 
xxx 
xxx 
xxx 
xxx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 129 of 249 
 
 
 
 
Parameter 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 Minimum 
  Maximum 
xx.x  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Height (cm) 
 
 
 
 
 
  n 
xxx 
xxx 
xxx 
xxx 
xxx 
  Mean  
xxx.x  
xxx.x  
xxx.x 
xxx.x 
xxx.x  
  SD 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
  Median 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
  Minimum 
  Maximum 
xxx.x  
xxx.x 
xxx.x  
xxx.x 
xxx.x  
xxx.x 
xxx.x  
xxx.x 
xxx.x  
xxx.x 
 
 
 
 
 
 
BMI (kg/m2) 
 
 
 
 
 
  n 
xxx 
xxx 
xxx 
xxx 
xxx 
  Mean  
xx.x  
xx.x  
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
  Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x  
xx.x 
xx.x  
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
[a]  N refers to overall ITT and n is n within in the category; % refers to percentage of overall population. “ 
[b]  Age is age at Visit 4.  The remaining characteristics were based on data from Screening visits prior to the start of the study. 
[c]  CAT = COPD Assessment Test. The total score is the sum of eight CAT item scores (Range: 0-40) 
[d]  MMRC = Modified Medical Research Council Scale, grades range between 0 and 4, where 4 represents the highest level of    
     breathlessness. 
[e] ‘At baseline’ means that the medication was taken on the day of the first dose of study medication. 
[f]  Former Smoker was defined as those who have stopped smoking for at least 6 weeks prior to first Screening Visit. 
[g]  Number of pack years smoked = (number of cigarettes per day / 20) x number of years smoked. 
      
Report generated by program: pt003014/sasdir/programs/statout/t022201xx.sas Version   YYYY-MM-DD xx:xx  (Page n of N) 
 
 
 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
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Page 130 of 249 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2.22.2 
Demographics and Baseline Characteristics by GOLD Category 
Analysis Set: ITT Population 
 
 
 
 
 
Table 2.22.2 
Demographics and Baseline Characteristics by GOLD Severity 
Analysis Set: ITT Population 
 
 
 
Notes to Programmer: Calculate BMI using Height at Visit 1. BMI = weight (kg)/height (m)2.  
Keep the summary for a parameter in the same page when breaking the table into multiple pages. Repeat titles, column 
headers and footnotes on each page. The race/ethnicities of Native Hawaiian or other Pacific Islander OR American 
Indian or Alaska Native OR Australia or New Zealand (indigenous) can be removed from this table if they do not exist 
in the database.  
 
Region Subgroup/Country Category includes the following: 
Table 2.22.1 
Japan vs. Non-Japan, 
Table 2.22.2 
China 
Table 2.22.3 
Asia 
Table 2.22.4 
EU 
Table 2.22.5 
US 
Table 2.22.6 
Czech Republic 
Table 2.22.7 
Germany 
Table 2.22.8 
Hungary 
Table 2.22.9 
Poland 
Table 2.22.10 
Russia 
Table 2.22.11 
South Korea 
Table 2.22.12 
Taiwan 
Table 2.22.13 
U.K.) 
Notes to Programmer: repeat table for each category; put row label at top of each iteration of the table above the columns headers: GOLD 
Category: <A or B or C or D>. Remove last row of table (GOLD Category).  
Note to Programmer: GOLD Severity is defined as GOLD 2, 3, and 4. 


GFF MDI/GP MDI/FF MDI 
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Final Version 
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Page 131 of 249 
 
 
 
 
Table 2.23.x 
Screening Pre- and Post-Bronchodilator and Baseline Spirometry Parameters by Region and Country: <Region Subgroup or Country> 
Analysis Set: ITT Population 
 
 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
 
 
 
 
 
 
Screening FEV1 (% predicted) 
 
 
 
 
 
 
Pre-Ventolin HFA: 
      n 
      Mean  
      SD 
 
xx 
xx.xxx   
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx 
xx.xxx 
      25th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Median  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      75th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Minimum  
      Maximum 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
Post-Ventolin HFA: 
      n 
      Mean   
      SD 
 
xx 
xx.xxx   
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx 
xx.xxx 
      25th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Median  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      75th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
     Minimum  
      Maximum 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
Pre-Atrovent HFA: 
      n 
      Mean  
      SD 
 
xx 
xx.xxx   
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx  
xx.xxx 
 
xx 
xx.xxx 
xx.xxx 
      25th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Median  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      75th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Minimum  
      Maximum 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
Post-Atrovent HFA: 
      n 
 
xx 
 
xx 
 
xx 
 
xx 
 
xx 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 132 of 249 
 
 
 
 
      Mean   
      SD 
xx.xxx   
xx.xxx 
xx.xxx  
xx.xxx 
xx.xxx  
xx.xxx 
xx.xxx  
xx.xxx 
xx.xxx 
xx.xxx 
      25th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Median  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      75th Percentile  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
      Minimum  
      Maximum 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline is defined as the mean of all evaluable 60 and 30 minute pre-dose values on Day 1 (Visit 4).    
 
Report generated by program: pt003014/sasdir/programs/statout/t022301.sas Version YYYY-MM-DD xx:xx (Page n of N)  
 
 
 
 
Notes to Programmer: 
 
Repeat above for these Screening parameters: 
Screening FEV1 (L) Pre-Bronchodilator 
Screening FEV1 (L) Post-Bronchodilator 
Screening FVC (% predicted) Pre-Bronchodilator 
Screening FVC (% predicted) Post-Bronchodilator 
Screening FVC (L) Pre-Bronchodilator 
Screening FVC (L) Post-Bronchodilator 
 
Also, provide for the following Baseline parameters: 
Baseline FEV1 (% predicted) 
Baseline FEV1 (L)  
Baseline FVC (% predicted) 
Baseline FVC (L)  
 
Show only 2 significant digits for the % predicted statistics. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 133 of 249 
 
 
 
 
 
Table 2.24.1.x 
Severity and Duration of COPD by Region and Country: <Region Subgroup or Country> 
Analysis Set: ITT Population 
 
 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
 
 
 
 
 
COPD Severity [a], n (%)  
 
 
 
 
   Moderate (GOLD 2)  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Severe (GOLD 3) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Very Severe (GOLD 4) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
Duration of COPD (yrs) [b] 
   n 
   Mean  
   SD 
 
xxx 
xx.x  
xx.x 
 
xxx 
xx.x  
xx.x 
 
xxx 
xx.x  
xx.x 
 
xxx 
xx.x  
xx.x 
   25th Percentile  
xx.x 
xx.x 
xx.x 
xx.x 
   Median  
xx.x 
xx.x 
xx.x 
xx.x 
   75th Percentile  
xx.x 
xx.x 
xx.x 
xx.x 
   Minimum  
   Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
GOLD Category, n (%) 
 
 
 
 
A 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
B 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
C 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
D 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
[a]  Severity of COPD defined in Appendix 3 of the protocol was based on the non-missing post-Ventolin HFA assessment at Screening  
     Visit 2 (or if the assessment was missing, the  non-missing post-Atrovent assessment at Screening Visit 3).  
[b]  The duration of COPD is calculated relative to the start of study treatment Day 1 (Visit 4). 
 
Report generated by program: pt003014/sasdir/programs/statout/t022401.sas Version  YYYY-MM-DD xx:xx    (Page n of N)  
 
 
 
 
 
Notes to Programmer: Duration of COPD = (First Dose date of Study Treatment - Date COPD First Diagnosed)/365.25, where day of COPD diagnosed 
is assumed to be the 1st of the month. Add a footnote noting how many missing values there are for severity if this is true for the final data. 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 134 of 249 
 
 
 
 
Table 2.24.2 
Severity and Duration of COPD by GOLD Category 
Analysis Set: ITT Population 
 
<GOLD Category> 
 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
 
 
 
 
 
 
n (%) [a] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
COPD Severity [a], n (%)  
 
 
 
 
 
   Moderate (GOLD 2)  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Severe (GOLD 3) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Very Severe (GOLD 4) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx(xx.x) 
 
 
 
 
 
 
Duration of COPD (yrs) [b] 
   n 
   Mean  
   SD 
 
xxx 
xx.x  
xx.x 
 
xxx 
xx.x  
xx.x 
 
xxx 
xx.x  
xx.x 
 
xxx 
xx.x  
xx.x 
 
xxxx 
xx.x  
xx.x 
   25th Percentile  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   75th Percentile  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Minimum  
   Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
[a]  Severity of COPD defined in Appendix 3 of the protocol was based on the non-missing post-Ventolin HFA assessment at Screening  
     Visit 2 (or if the assessment was missing, the  non-missing post-Atrovent assessment at Screening Visit 3). 
[b]  The duration of COPD is calculated relative to the start of study treatment Day 1 (Visit 4). 
 
Report generated by program: PT003014/sasdir/programs/statout/t022402.sas Version  YYYY-MM-DD xx:xx    (Page n of N)  
 
 
 
Notes to Programmer: Duration of COPD = (First Dose date of Study Treatment - Date COPD First Diagnosed)/365.25, where day of COPD diagnosed is 
assumed to be the 1st of the month. Add a footnote noting how many missing values there are for severity if this is true for the final data. 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 135 of 249 
 
 
 
 
Table 2.24.3 
Severity and Duration of COPD by GOLD Severity 
Analysis Set: ITT Population 
 
 
Table 2.25.1.x 
Reversibility to Ventolin HFA by Region and Country: <Region Subgroup or Country> 
Analysis Set: ITT Population 
 
Table 2.25.2 
Reversibility to Ventolin HFA by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.25.3 
Reversibility to Ventolin HFA by GOLD Severity 
Analysis Set: ITT Population 
 
 
Table 2.26.1.x 
Reversibility to Atrovent HFA by Region and Country: <Region Subgroup or Country> 
Analysis Set: ITT Population 
 
Table 2.26.2 
Reversibility to Atrovent HFA by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.26.3 
Reversibility to Atrovent HFA by GOLD Severity 
Analysis Set: ITT Population 
 
 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 136 of 249 
 
 
 
 
Table 2.27.1.x 
Study Treatment Exposure and Compliance by Region and Country: <Region Subgroup or Country> 
Analysis Set: Safety Population 
 
<Region Subgroup: <subcategory>> 
 
Note that this does not apply when tabulation is for an individual country. 
 
 
 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
Exposure [a] 
n 
Mean  
SD 
Median 
Minimum 
Maximum 
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
 xxx   
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
 xxx   
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
 xxx   
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
 xxx   
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
 xxx   
 
 
 
 
 
 
 
Total  
Person-Years 
of Exposure 
[b] 
 
  xx.xx 
  xx.xx 
  xx.xx 
 
  xx.xx 
  xx.xx 
 
 
 
 
 
 
 
Number of 
Puffs of Study 
Medication 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
 xxx    
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
xxx   
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
xxx   
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
xxx   
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
xxx   
 
 
 
 
 
 
 
Percent 
Compliance 
[c], n (%)  
  0 – <  20% 
 20 – <  40% 
 40 – <  60%  
 60 – <  80%  
 80 –   100%  
 >100 - 120% 
 >120% 
 Missing 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 x(xx.x) 
x(xx.x) 
  xx(xx.x)    
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 x(xx.x) 
x(xx.x) 
  xx(xx.x)    
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 x(xx.x) 
x(xx.x) 
  xx(xx.x)    
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 x(xx.x) 
x(xx.x) 
  xx(xx.x)    
 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 x(xx.x) 
x(xx.x) 
  xx(xx.x)    
 


GFF MDI/GP MDI/FF MDI 
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Final Version 
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 n 
 Mean 
 SD 
 Median 
 Minimum 
 Maximum 
 xxx 
 xxx.x  
  xx.x  
 xxx.x 
 xxx 
    xxx   
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
xxx 
   
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
   xxx  
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
   xxx  
xxx 
xxx.x  
 xx.x  
xxx.x 
xxx 
   xxx   
[a] Exposure (days) = (End date of treatment – Date of first dose of treatment) + 1. 
[b] Total person-years of exposure for a treatment group is the total exposure in the study across all subjects in the treatment. 
[c] Percent compliance is defined as (total number of puffs of study treatment taken on a study day/total expected puffs taken on a 
    study day) averaged across all days of a subject’s dosing between start of study treatment and last day on study treatment x 100. 
    The expected number of puffs on dates prior to the last date of treatment was 4.  
    The expected number of puffs for a test day which was the last date of treatment was 2. 
    The expected number of puffs for the last date of treatment which was not a test day was 4 when a PM dose was taken and then 2 
    otherwise.  
 
Report generated by program: pt003014/sasdir/programs/statout/t022701.sas         Version   YYYY-MM-DD xx:xx      (Page n of N)  
 
 
Table 2.27.2 
Study Treatment Exposure and Compliance by GOLD Category 
Analysis Set: Safety Population 
 
Table 2.27.3 
Study Treatment Exposure and Compliance by GOLD Severity 
Analysis Set: Safety Population 
 
 
 


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Table 2.28.1.x 
Morning Pre-dose Trough FEV1 (L) by Region and Country:  <Region Subgroup or Country> 
Analysis Set: ITT Population 
 
<Region Subgroup: <subcategory>>   
 
Note that this does not apply when tabulation is for an individual country. 
Treatment 
Baseline FEV1 
 
 
Change From Baseline 
LS Mean Differences Between Treatments 
Placebo MDI 
FF MDI 
9.6 μg 
GP MDI 
14.4 μg 
Over 24 Weeks 
 
GFF MDI 14.4/9.6 μg 
  n 
Xx 
 
 
 
 
  Mean  
x.xxx 
 
 
 
 
  SD 
x.xxx 
 
 
 
 
  Median 
x.xxx 
 
 
 
 
  Min-Max 
x.xxx-x.xxx 
 
 
 
 
  LS Mean (SE) 
 
  x.xxx (x.xxxx)  
  x.xxx (x.xxxx) 
  x.xxx (x.xxxx) 
  x.xxx (x.xxxx) 
  95% CI 
 
( x.xxx, x.xxx) 
( x.xxx, x.xxx) 
( x.xxx, x.xxx) 
( x.xxx, x.xxx) 
  P-value 
 
 
  x.xxxx  
  x.xxxx  
  x.xxxx  
 
 
 
 
 
 
FF MDI 9.6 μg 
  n 
xx 
 
 
 
 
  Mean  
x.xxx 
 
 
 
 
  SD 
x.xxx 
 
 
 
 
  Median 
x.xxx 
 
 
 
 
 Min-Max 
x.xxx-x.xxx 
 
 
 
 
  LS Mean (SE) 
 
  x.xxx (x.xxxx) 
  x.xxx (x.xxxx) 
Not Applicable 
  x.xxx (x.xxxx) 
  95% CI 
 
( x.xxx, x.xxx) 
( x.xxx, x.xxx) 
 
( x.xxx, x.xxx) 
  P-value 
 
 
  x.xxxx  
 
  x.xxxx  
 
 
 
 
 
 
GP MDI 14.4 μg 
  n 
xx 
 
 
 
 
  Mean  
x.xxx 
 
 
 
 
  SD 
x.xxx 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
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<Region Subgroup: <subcategory>>   
 
Note that this does not apply when tabulation is for an individual country. 
Treatment 
Baseline FEV1 
 
 
Change From Baseline 
LS Mean Differences Between Treatments 
Placebo MDI 
FF MDI 
9.6 μg 
GP MDI 
14.4 μg 
  Median 
x.xxx 
 
 
 
 
  Min-Max 
x.xxx-x.xxx 
 
 
 
 
  LS Mean (SE) 
 
  x.xxx (x.xxxx) 
  x.xxx (x.xxxx) 
Shown Above 
Not Applicable 
  95% CI 
 
( x.xxx, x.xxx) 
( x.xxx, x.xxx) 
 
 
  P-value 
 
 
  x.xxxx 
 
 
   
 
 
 
 
 
Placebo 
  n 
xx 
 
 
 
 
  Mean  
x.xxx 
 
 
 
 
  SD 
x.xxx 
 
 
 
 
  Median 
x.xxx 
 
 
 
 
  Min-Max  
x.xxx-x.xxx 
 
 
 
 
  LS Mean (SE) 
 
  x.xxx (x.xxxx) 
Not Applicable 
Shown Above 
Shown Above 
  95% CI 
 
( x.xxx, x.xxx) 
 
 
 
 
 
 
 
 
 
 
LS Mean = least squares mean from the linear repeated measures model which included the following covariates: baseline FEV1, percent 
reversibility to Ventolin HFA, treatment, visit, and treatment by visit interaction. 
 
Report generated by program: pt003014/sasdir/programs/statout/t022801.sas Version YYYY-MM-DD hh:mm  (Page n of N)   
 
 
 
Note to Programmer: Repeat for 12-24 Weeks and for each post-baseline visit from Week 2 to Week 24. The raw change 
from baseline will be added for each individual visit, but not for 4-24 weeks or 12-24 weeks. Do not split a 
treatment across a page. The baseline summary statistics are based on subjects who were included in the model used 
for analysis. (.e.g., subjects who had at least one data point post-baseline from Week 2 to Week 24 and had non-
missing data for all covariates used for the analysis). Repeat for each subgroup category. 


GFF MDI/GP MDI/FF MDI 
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Figure 2.28.1.1 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE (Regions/Countries) 
Analysis Set: ITT Population 
 
 
 
 
 
 
(Programmers: This is Page 1 with Comparisons of GFF MDI to Placebo, FF MDI, and GP MDI). 
 
(Programmers: This is Page 2 with Comparisons of FF MDI and GP MDI to Placebo.)
 
 
 
Notes to Programmer:  Use the example 2-page portrait-orientation forest plot below. Replace PT003006, PT003007, and Integrated 
with the regional subgroups and countries. USE THIS EXAMPLE FOR ALL REGIONS/COUNTRIES FOREST PLOTS. 
Replace Trough FEV1 row label with ‘Morning Trough FEV1 at Week 24’. 
Replace Peak FEV1 row label with ‘Morning Trough FEV1 Over 24 Weeks’. 
Replace FEV1 AUC 0-12 row label with ‘Morning Pre-dose Trough FEV1 over Weeks 12-24. 


GFF MDI/GP MDI/FF MDI 
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Figure 2.28.1.2.1 Galbraith Plot for Adjusted Mean Change From Baseline in Morning Pre-dose Trough FEV1 (L) ± SE at Week 24 (All Countries) 
Analysis Set: ITT Population 
 
 
 
 
Figure 2.28.1.2.2 Galbraith Plot for Adjusted Mean Change From Baseline in Morning Pre-dose Trough FEV1 (L) ± SE Over 24 Weeks (All Countries) 
Analysis Set: ITT Population  
 
Figure 2.28.1.2.3 Galbraith Plot for Adjusted Mean Change From Baseline in Morning Pre-dose Trough FEV1 (L) ± SE Over Weeks 12-24 (All Countries) 
Analysis Set: ITT Population 
  
 
Notes to Programmer: y axis with “Effect Estimate/SE”. 
Replace ‘HR’ with “Estimate”. 
 


GFF MDI/GP MDI/FF MDI 
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07 Mar 2017 
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Figure 2.28.1.3.1 Q-Q Plot for Adjusted Mean Change From Baseline in Morning Pre-dose Trough FEV1 (L) ± SE at Week 24 (All Countries) 
Analysis Set: ITT Population 
 
 
 
Figure 2.28.1.3.2 Q-Q Plot for Adjusted Mean Change From Baseline in Morning Pre-dose Trough FEV1 (L) ± SE Over 24 Weeks (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.28.1.3.3 Q-Q Plot for Adjusted Mean Change From Baseline in Morning Pre-dose Trough FEV1 (L) ± SE Over Weeks 12-24 (All Countries) 
Analysis Set: ITT Population 
 
 
 


GFF MDI/GP MDI/FF MDI 
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07 Mar 2017 
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Table 2.28.2 
Morning Pre-dose Trough FEV1 (L) by GOLD Category 
Analysis Set: ITT Population 
 
Figure 2.28.2.1 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE at Week 24 by GOLD Category 
Analysis Set: ITT Population 
 
 
Notes to Programmer: Please replace GOLD Severity in the example below with GOLD Category. USE THIS EXAMPLE FOR 
ALL GOLD FOREST PLOTS. 


GFF MDI/GP MDI/FF MDI 
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07 Mar 2017 
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Figure 2.28.2.2 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE Over 24 Weeks by GOLD Category 
Analysis Set: ITT Population 
 
Figure 2.28.2.3 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE Over Weeks 12-24 by GOLD Category 
Analysis Set: ITT Population 
 
 
Table 2.28.3 
Morning Pre-dose Trough FEV1 (L) by GOLD Severity 
Analysis Set: ITT Population 
 
Figure 2.28.3.1 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE at Week 24 by GOLD Severity 
Analysis Set: ITT Population 
 
Figure 2.28.3.2 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE Over 24 Weeks by GOLD Severity 
Analysis Set: ITT Population 
 
Figure 2.28.3.3 
Forest Plot for Morning Pre-dose Trough FEV1 (L) ± SE Over Weeks 12-24 by GOLD Severity 
Analysis Set: ITT Population 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
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07 Mar 2017 
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Table 2.29.x 
TDI Focal Score by Region and Country: <Region Subgroup or Country> 
Analysis Set: ITT Population 
 
Treatment 
BDI Focal Score 
TDI Focal Score 
LS Mean Differences Between Treatments 
Placebo MDI 
FF MDI  
9.6 μg  
 GP MDI  
14.4 μg 
 
Over 24 Weeks 
 
GFF MDI 14.4/9.6 μg 
  n 
xx 
 
 
 
 
  Mean  
x.x 
 
 
 
 
  SD 
x.x 
 
 
 
 
  Median 
x.x 
 
 
 
 
  Min-Max 
x.x-x.x 
 
 
 
 
  LS Mean (SE) 
 
  x.x (x.xx)        
  x.xx (x.xxx) 
  x.xx (x.xxx) 
  x.xx (x.xxx) 
  95% CI 
 
( x.x, x.x) 
( x.xx, x.xx) 
( x.xx, x.xx) 
( x.xx, x.xxx) 
  P-value 
 
 
  x.xxxx  
  x.xxxx  
  x.xxxx  
 
 
 
 
 
 
FF MDI 9.6 μg 
  n 
xx 
 
 
 
 
  Mean  
x.x 
 
 
 
 
  SD 
x.x 
 
 
 
 
  Median 
x.x 
 
 
 
 
  Min-Max 
x.x-x.x 
 
 
 
 
  LS Mean (SE) 
 
  x.x (x.xx)        
  x.xx (x.xxx) 
Not Applicable 
  x.xx (x.xxx) 
  95% CI 
 
( x.x, x.x) 
( x.xx, x.xx) 
 
( x.xx, x.xx) 
  P-value 
 
 
  x.xxxx  
 
  x.xxxx  
 
 
 
 
 
 
GP MDI 14.4 μg  
  n 
xx 
 
 
 
 
  Mean  
x.x 
 
 
 
 
  SD 
x.x 
 
 
 
 
  Median 
x.x 
 
 
 
 
  Min-Max 
x.x-x.x 
 
 
 
 
  LS Mean (SE) 
 
  x.x (x.xx)        
  x.xx (x.xxx) 
Shown Above 
Not Applicable 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 146 of 249 
 
 
 
 
Treatment 
BDI Focal Score 
TDI Focal Score 
LS Mean Differences Between Treatments 
Placebo MDI 
FF MDI  
9.6 μg  
 GP MDI  
14.4 μg 
  95% CI 
 
( x.x, x.x) 
( x.xx, x.xx) 
 
 
  P-value 
 
 
  x.xxxx  
 
 
   
 
 
 
 
 
Placebo 
  n 
xx 
 
 
 
 
  Mean  
x.x 
 
 
 
 
  SD 
x.x 
 
 
 
 
  Median 
x.x 
 
 
 
 
  Min-Max  
x.x-x.x 
 
 
 
 
  LS Mean (SE) 
 
  x.x (x.xx) 
 Not Applicable 
Shown Above 
Shown Above 
  95% CI 
 
( x.x, x.x) 
 
 
 
 
 
 
LS Mean = least squares mean from the linear repeated measures model which included the following covariates: BDI focal score, percent 
reversibility to Ventolin HFA, visit, and treatment by visit interaction. 
 
Report generated by program: pt003014/sasdir/programs/statout/t0229.sas   Version YYYY-MM-DD hh:mm  (Page n of N) 
 
 
Figure 2.29.1 
Forest Plot for TDI Focal Score ± SE (Regions/Countries) 
Analysis Set: ITT Population 
 
 
 
 
Figure 2.29.2.1 
Galbraith Plot for Adjusted Mean TDI Focal Score ± SE Over 24 Weeks (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.29.2.2 
Galbraith Plot for Adjusted Mean TDI Focal Score ± SE Over Weeks 12- 24 (All Countries) 
Analysis Set: ITT Population 
 
Note to Programmer: Repeat for over Weeks 12-24 and for each post-baseline visit from Week 4 to Week 24. Descriptive 
statistics for the raw TDI will be added for each individual visit, but not for 0-24 weeks or Over Weeks 12-24. Do not 
split a treatment across a page. Repeat for each subgroup category. 
Notes to Programmer: show for Over 24 Weeks and for Over Weeks 12-24 (use the format of Figure 
2.28.1.1). 


GFF MDI/GP MDI/FF MDI 
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07 Mar 2017 
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Figure 2.29.3.1 
Q-Q Plot for Adjusted Mean TDI Focal Score ± SE Over 24 Weeks (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.29.3.2 
Q-Q Plot for Adjusted Mean TDI Focal Score ± SE Over Weeks 12-24 (All Countries) 
Analysis Set: ITT Population 
 
Table 2.30.1.1.x Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-dose by Region and Country: <Region Subgroup or Country> 
Analysis Set: ITT Population 
 
Figure 2.30.1.1 
Forest Plot for Peak Change from Baseline in FEV1 (L) ± SE Within 2 Hours Post-dose (Regions/Countries) 
Analysis Set: ITT Population 
 
Figure 2.30.1.2.1 Galbraith Plot for Adjusted Mean Peak Change from Baseline in FEV1 (L) ± SE at Week 24 (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.30.1.2.2 Galbraith Plot for Adjusted Mean Peak Change from Baseline in FEV1 (L) ± SE Over 24 Weeks (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.30.1.2.3 Galbraith Plot for Adjusted Mean Peak Change from Baseline in FEV1 (L) ± SE Over Weeks 12-24 (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.30.1.3.1 Q-Q Plot for Adjusted Mean Peak Change from Baseline in FEV1 (L) ± SE at Week 24 (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.30.1.3.2 Q-Q Plot for Adjusted Mean Peak Change from Baseline in FEV1 (L) ± SE Over 24 Weeks (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.30.1.3.3 Q-Q Plot for Adjusted Mean Peak Change from Baseline in FEV1 (L) ± SE Over Weeks 12-24 (All Countries) 
Analysis Set: ITT Population 
 
 
Table 2.30.2 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-dose by GOLD Category 
Analysis Set: ITT Population 
 


GFF MDI/GP MDI/FF MDI 
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07 Mar 2017 
Page 148 of 249 
 
 
 
 
Figure 2.30.2.1 
Forest Plot for Mean Peak Change from Baseline in FEV1 (L) ± SE Within 2 Hours Post-dose by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.30.3 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-dose by GOLD Severity 
Analysis Set: ITT Population 
 
Figure 2.30.3.1 
Forest Plot for Mean Peak Change from Baseline in FEV1 (L) ± SE Within 2 Hours Post-dose at Week 24 by GOLD Severity 
Analysis Set: ITT Population 
 
Figure 2.30.3.2 
Forest Plot for Mean Peak Change from Baseline in FEV1 (L) ± SE Within 2 Hours Post-dose Over 24 Weeks by GOLD Severity 
Analysis Set: ITT Population 
 
Figure 2.30.3.3 
Forest Plot for Mean Peak Change from Baseline in FEV1 (L) ± SE Within 2 Hours Post-dose Over Weeks 12-24 by GOLD Severity 
Analysis Set: ITT Population 
 
 


GFF MDI/GP MDI/FF MDI 
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07 Mar 2017 
Page 149 of 249 
 
 
 
 
Table 2.31.1.x 
SGRQ Total Score (units) by Region and Country: < Region Subgroup or Country> 
Analysis Set: ITT Population 
 
 
 
 
 
Figure 2.31.1.1 
Forest Plot for SGRQ Total Score (units)  ± SE at Week 24 by Region and Country 
Analysis Set: ITT Population 
 
 
 
 
Figure 2.31.2.1 
Galbraith Plot for Adjusted Mean Change from Baseline in SGRQ Total Score (units) ± SE at Week 24 (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.31.2.2 
Galbraith Plot for Adjusted Mean Change from Baseline in SGRQ Total Score (units) ± SE Over Weeks 12-24 (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.31.3.1 
Q-Q Plot for Adjusted Mean Change from Baseline in SGRQ Total Score (units) ± SE at Week 24 (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.31.3.2 
Q-Q Plot for Adjusted Mean Change from Baseline in SGRQ Total Score (units) ± SE Over Weeks 12-24 (All Countries) 
Analysis Set: ITT Population 
 
Notes to Programmer: display descriptive statistics only, 
without model-based estimates. Remove the model footnote. 
Notes to Programmer: show for At Week 24 and for Over Weeks 12-24 (use the format of Figure 
2.28.1.1). 


GFF MDI/GP MDI/FF MDI 
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Table 2.32.x 
Response in SGRQ Total Score (Achievment of a Minimum Clinically Important Difference Threshold of ≥4 Units on Average) by Region and 
Country: <Region Subgroup or Country> 
Analysis Set: ITT Population 
 
 
 
 
 
 
Figure 2.32 
Forest Plot for Response in SGRQ Total Score ± 95% CI (Regions/Countries) 
Analysis Set: ITT Population 
 
 
 
 
 
 
 
Notes to Programmer: Display descriptive statistics only, without model-based estimates. Remove the model footnote. Forest plots will show percentage 
with a response for Week 24 and also Over Weeks 12-24 for all regional subgroups and countries. Similar to Figure 2.28.1.1. 
Notes to Programmer: Forest plots will show percentage with a response for Week 24 and also Over Weeks 12-24 for all regional subgroups and countries 
(use the format of Figure 2.28.1.1). 


GFF MDI/GP MDI/FF MDI 
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Table 2.33.1.x 
Mean Daily Number of Puffs of Rescue Ventolin by Region and Country: <Region Subgroup or Country> 
Analysis Set: ITT Population 
 
Figure 2.33.1.1 
Forest Plot for Change from Baseline in Daily Number of Puffs of Rescue Ventolin ± SE Over 24 Weeks (Regions/Countries) 
Analysis Set: ITT Population 
 
 
 
 
Figure 2.33.1.2 
Galbraith Plot for Adjusted Mean Change from Baseline in Daily Number of Puffs of Rescue Ventolin ± SE Over 24 Weeks (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.33.1.3 
Q-Q Plot for Adjusted Mean Change from Baseline in Daily Number of Puffs of Rescue Ventolin ± SE Over 24 Weeks (All Countries) 
Analysis Set: ITT Population 
 
 
Table 2.33.2.x 
Mean Daily Number of Puffs of Rescue Ventolin by Region and Country: <Region Subgroup or Country> 
Analysis Set: Rescue Ventolin User Population 
 
Figure 2.33.2.1 
Forest Plot for Change from Baseline in Daily Number of Puffs of Rescue Ventolin ± SE (Regions/Countries) 
Analysis Set: Rescue Ventolin User Population 
 
Figure 2.33.2.2 
Galbraith Plot for Adjusted Mean Change from Baseline in Daily Number of Puffs of Rescue Ventolin ± SE Over 24 Weeks (All Countries) 
Analysis Set: Rescue Ventolin User Population 
 
Figure 2.33.2.3 
Q-Q Plot for Adjusted Mean Change from Baseline in Daily Number of Puffs of Rescue Ventolin ± SE Over 24 Weeks (All Countries) 
Analysis Set: Rescue Ventolin User Population 
 
 
 
 
 
 
 
Notes to Programmer: show for Over 24 Weeks and for Over Weeks 12-24 (use the format of Figure 2.28.1.1). 


GFF MDI/GP MDI/FF MDI 
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07 Mar 2017 
Page 152 of 249 
 
 
 
 
Table 2.34 
Change from Baseline in FEV1 at 5 Min Post-dose on Day 1 by Region and Country: <Region Subgroup or Country> 
Analysis Set: ITT Population 
 
Figure 2.34.1 
Forest Plot for FEV1 at 5 Min Post-dose on Day 1 (Regions/Countries) 
Analysis Set: ITT Population 
 
Figure 2.34.2 
Galbraith Plot for Adjusted Mean Change from Baseline in FEV1 at 5 Min Post-dose ± SE on Day 1 (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.34.3 
Q-Q Plot for Adjusted Mean Change from Baseline in FEV1 at 5 Min Post-dose ± SE on Day 1 (All Countries) 
Analysis Set: ITT Population 
 
 
Table 2.35 
Change from Baseline in FEV1 at 15 Min Post-dose on Day 1 by Region and Country: <Region Subgroup or Country> 
Analysis Set: ITT Population 
 
Figure 2.35.1 
Forest Plot for FEV1 at 15 Min Post-dose on Day 1 (Regions/Countries) 
Analysis Set: ITT Population 
 
Figure 2.35.2 
Galbraith Plot for Adjusted Mean Change from Baseline in FEV1 at 15 Min Post-dose ± SE on Day 1 (All Countries) 
Analysis Set: ITT Population 
 
Figure 2.35.3 
Q-Q Plot for Adjusted Mean Change from Baseline in FEV1 at 15 Min Post-dose ± SE (All Countries) 
Analysis Set: ITT Population 
 
 


GFF MDI/GP MDI/FF MDI 
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Table 2.36 
Interaction of Treatment and Subgroup for Each Subgroup Analysis 
Analysis Set: ITT Population 
 
Subgroup Analysis 
Treatment-by-Subgroup Interaction P-value 
(Subgroup Main Effect P-value) 
Change from 
baseline in pre-
dose trough FEV` 
TDI Focal 
Score 
Peak change 
from baseline 
in FEV1 within 
2 hours post-
dose 
Change from 
baseline in 
SGRQ total 
score  
Change from 
baseline in 
mean daily 
number of 
puffs of 
rescue 
Ventolin HFA 
Time to Onset 
at 5 min 
post-dose on 
Day 1 (change 
from baseline 
in FEV1 at 5 
min post-
dose) 
Time to Onset 
at 15 min 
post-dose on 
Day 1 (change 
from baseline 
in FEV1 at 15 
min post-
dose) 
Region Subgroup (Japan vs Non-Japan) 
0.xxxx 
(x.xxxx) 
0.xxxx 
(x.xxxx) 
0.xxxx 
(x.xxxx) 
Not 
Applicable 
0.xxxx 
(x.xxxx) 
0.xxxx 
(x.xxxx) 
0.xxxx 
(x.xxxx) 
Country 
0.xxxx 
(x.xxxx) 
0.xxxx 
(x.xxxx) 
0.xxxx 
(x.xxxx) 
Not 
Applicable 
0.xxxx 
(x.xxxx) 
0.xxxx 
(x.xxxx) 
0.xxxx 
(x.xxxx) 
GOLD Category A, B, C, and D 
0.xxxx 
(x.xxxx) 
Not 
Applicable 
0.xxxx 
(x.xxxx) 
Not 
Applicable 
Not 
Applicable 
Not 
Applicable 
Not 
Applicable 
GOLD Category 2, 3, and 4 
0.xxxx 
(x.xxxx) 
Not 
Applicable 
0.xxxx 
(x.xxxx) 
Not 
Applicable 
Not 
Applicable 
Not 
Applicable 
Not 
Applicable 
For each subgroup analysis, treatment-by-subgroup interaction was tested using the following model: baseline, percent reversibility to 
Ventolin HFA, treatment, visit, treatment, treatment-by-visit interaction, subgroup, and the treatment-by-subgroup interaction. 
Report generated by program: pt003014/sasdir/programs/statout/t0237.sas    Version       YYYY-MM-DD xx:xx (Page n of N)   
 
 
 
 
 
 
 
 
Notes to Programmer: Baseline in the model is baseline FEV1 for the change in trough FEV1 analyses and BDI for 
the TDI analyses.  


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Healthcare Resource Utilization 
 
 
Table 2.37.1 
Healthcare Resource Utilization: Number of Days Missed From Work 
Analysis Set: Safety Population 
 
Number of Days Missed From 
Work Per Subject 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
 
 
 
 
 
 
By Subject 
 
 
 
 
 
 
 
 
 
 
 
 Unadjusted 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
xx 
xx 
xx 
xx 
xx 
  Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 Adjusted (per year) 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
xx 
xx 
xx 
xx 
xx 
  Maximum 
xx 
xx 
xx 
xx 
xx 
 
By Family Members of 
Subject 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
  Unadjusted 
 
 
 
 
 
  n 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x  
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx 
xx 
xx 
xx 
xx 
  Minimum 
   Maximum 
 
 
 
 
 


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Number of Days Missed From 
Work Per Subject 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
REPEAT FOR ‘Adjusted (per 
year)’ 
 
 
 
 
 
Subjects with ‘Not applicable’ for number of days missed from work are excluded. 
Adjusted (per year) summary statistics are those obtained when the number of days are extrapolated out to a 52 week period, based on 
the number of days observed during the subject’s participation in Study PT003014.  
 
Report generated by program: pt003014/sasdir/programs/statout/t023801.sas  Version  YYYY-MM-DD xx:xx  Page n of N) 
 
 
 
 
 
 
 
 
 
Notes to Programmer: For ‘Adjusted (per year)’, convert data to 52 weeks 
using the following formula: 
52 x (weeks missed/xx weeks actually completed in study) 


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Table 2.37.2 
Healthcare Resource Utilization by Relationship to COPD and Treatment 
Analysis Set: Safety Population 
 
COPD Related 
Utilization Parameter 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
 
 
 
 
 
 
Telephone Calls to Health 
Care Provider  
 
 
 
 
 
 
 
 
 
 
 
 Unadjusted 
 
 
 
 
 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 Adjusted (per year) 
 
 
 
 
 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  
 
 
 
 
 
n of Subjects (%) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
For the Telephone calls to HCP 
and Visits to HCP row header, 
show “Telephone Calls to 
Healthcare Provider, n of 
Subjects (%)” and “Visits to 
Healthcare Provider”, n of 
Subjects (%). Same for ER Visits. 
For Hospitalizations row header, 
use “Hospitalizations, n of 
Subjects (%)”. 
For Intubations row header, use 
“Intubations During 
 
 
 
 
 


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Hospitalization, n of Subjects (% 
of Subjects Hospitalized” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adjusted (per year) summary statistics were those obtained when the number of utilization events were extrapolated out to a 52 week 
period, based on the number of utilization events observed during the subject’s participation in Study PT003014.  
If it was unknown whether a subject stayed in the ICU (CCU), the number of days in the ICU (CCU) was imputed as 0 days.  If the 
subject reported a stay in the ICU (CCU), but the number of days was missing, then the number of days was imputed as the average of 
the number of days that subjects with non-missing data in the treatment group reported. 
Report generated by program: pt003014/sasdir/programs/statout/t023802.sas   Version   YYYY-MM-DD xx:xx    (Page n of N)               
Notes to Programmer:  
 
Put “COPD Related’ at the top of each page of this output. 
 
Repeat for the following: 
x 
COPD Related Visits to Health Care Providers 
x 
COPD Related ER Visits 
 
Repeat for Non-COPD Related. Put “Non-COPD Related’ at the top of each page of this output. 
Repeat for Combined which is defined as COPD Related and Non-COPD Related combined. Put ‘COPD Related and 
Non-COPD Related’ at the top of each page. 
Then repeat format for the following items for hospitalizations: 
x 
COPD Related Hospitalizations 
x 
COPD Related Number of Days in the Hospital 
x 
COPD Related Number of Days in Intensive Care Unit (ICU) 
x 
COPD Related Number of Days in Coronary Care Unit (CCU) 
x 
COPD Related Intubations During Hospitalization. 
 
For Intubations During Hospitalization, do not show Mean, SD, Median, Minimum, or Maximum. N1 for this 
category is the number of subjects hospitalized in the treatment. 
 
Repeat the hospitalization items for Drug-Related. 
Repeat these for Non-COPD Related. 
Repeat these for Combined which is defined as COPD Related and Non-COPD Related combined. 
 
For Adjusted (per year) summary statistics, convert the Median, Minimum, and Maximum for each parameter to 
52 weeks using the following formula: 52 x (weeks missed/xx weeks actually completed in study) 


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3. Safety 
 
 


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Adverse Events 
 
Table 3.1.1 
Overall Summary of Adverse Events 
Analysis Set: Safety Population 
 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
n (%) 
[Events] 
n (%) 
[Events] 
n (%) 
[Events]] 
n (%) 
[Events] 
n (%) 
[Events] 
Subjects With at Least One TEAE [a] 
 
xx (xx.x) 
[xxx] 
 
 
xx (xx.x) 
[xxx] 
 
xx (xx.x) 
[xxx] 
 
xx (xx.x) 
[xxx] 
 
xx (xx.x) 
[xx.x] 
Subjects With TEAEs Related to Study 
Treatment [b] 
xx (xx.x) 
[xxx] 
xx (xx.x) 
[xxx] 
xx (xx.x) 
[xxx] 
xx (xx.x) 
[xxx] 
xx (xx.x) 
[xx.x] 
Subjects With Serious TEAEs 
xx (xx.x) 
[xx.x] 
 
xx (xx.x) 
[xx.x] 
xx (xx.x) 
[xx.x] 
xx (xx.x) 
[xx.x] 
xx (xx.x) 
[xx.x] 
Subjects With Serious TEAEs Related to 
Study Treatment [b] 
xx (xx.x) 
[xx.x] 
xx (xx.x) 
[xx.x] 
xx (xx.x) 
[xx.x] 
xx (xx.x) 
[xx.x] 
xx (xx.x) 
[xx.x] 
Subjects With TEAEs Leading to Early 
Discontinuation 
xx (xx.x) 
[xx.x] 
xx (xx.x) 
[xx.x] 
xx (xx.x) 
[xx.x] 
xx (xx.x) 
[xx.x] 
xx (xx.x) 
[xx.x] 
Deaths – All Causes 
 
 
 
 
 
   During Treatment Period [c] 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
   During Treatment Period  
   + 14 Days [c] 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
Deaths – Probable Cardiovascular Cause 
 
 
 
 
 
   During Treatment Period [c] 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
   During Treatment Period 
   + 14 Days [c] 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 


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Deaths – Probable Respiratory Cause 
 
 
 
 
 
   During Treatment Period [c] 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
   During Treatment Period 
   + 14 Days [c] 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
Deaths – Probable Cause Other than 
Cardiovascular or Respiratory 
 
 
 
 
 
   During Treatment Period [c] 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
   During Treatment Period 
   + 14 Days [c] 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
 
[a]   TEAE = Treatment-Emergent Adverse Event 
[b]   Related = Possibly, Probably, or Definitely.  
[c]   For the purpose of determining that a death occurred during the Treatment Period, the end of the Treatment Period was defined as  
     the date of Visit 11 or the last date of treatment, the date of the Discontinuation Visit or the last date of treatment  
     whichever was later, or if these dates were missing, the date of the last data collection (i.e., date of death).                  
                                                                                                                                       
Report generated by program: pt003014/sasdir/programs/statout/t030101.sas   Version  YYYY-MM-DD  xx:xx             (Page n of N) 
 
 
 
 
 
 
 
Notes to Programmer: For deaths tabulations, 
Cardiovascular and Respiratory Deaths are those indicated 
on the Adjudications CRF. 


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Table 3.1.2.x 
Overall Summary of Adverse Events by Region and Country: <Region Subgroup or Country> 
Analysis Set: Safety Population 
 
 
 
 
 
 
 
 
Notes to Programmer: follow numbering used for Subgroup efficacy tables, starting with 3.1.2. 


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Table 3.2.1.1.1 
Adverse Events by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
 
System Organ Class 
  Preferred Term 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo  
MDI 
 (N=xxx) 
All Subjects 
(N=xxxx) 
n (%) 
[Events] 
n (%) 
[Events] 
n (%) 
[Events] 
n (%) 
[Events] 
n (%) 
[Events] 
 
 
 
 
 
 
At Least One TEAE [a]  
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
 System Organ Class 1 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
   Preferred Term 1 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
   Preferred Term 2 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
 System Organ Class 2 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
   Preferred Term 1 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
   Preferred Term 2 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
xx ( xx.x) 
[xx] 
 Etc… 
 
 
 
 
 
[a]   TEAE = Treatment-Emergent Adverse Event  
Report generated by program: pt003014/sasdir/programs/statout/t030201.sas   Version YYYY-MM-DD xx:xx    (Page n of N) 
 
 
 
 


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Table 3.2.1.1.x 
Adverse Events by Region and Country, MedDRA Primary System Organ Class and Preferred Term: <Region Subgroup or Country> 
Analysis Set: Safety Population 
 
 
 
 
 
Table 3.2.1.2.1 
Adverse Events With Onset After the Last Date of Treatment by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
 
 
Table 3.2.1.2.x 
Adverse Events With Onset After the Last Date of Treatment by Region and Country, MedDRA Primary System Organ Class, and Preferred 
Term: <Region Subgroup or Country> 
Analysis Set: Safety Population 
 
 
Notes to Programmer: Instead of ‘At Least One TEAE”, use “At Least One Post-Treatment AE”.  
Notes to Programmer: follow numbering used for Subgroup efficacy tables, starting with 3.2.1.1.2. 


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Table 3.2.2.1 
Adverse Events Occurring in >=2% of Subjects in a Treatment by Descending Frequency 
Analysis Set: Safety Population 
 
 
 
 
 
Table 3.2.2.x 
Adverse Events Occurring in >=2% of Subjects in a Treatment by Descending Frequency by Region and Country: <Region Subgroup or 
Country> 
Analysis Set: Safety Population 
 
Table 3.2.3.1 
Adverse Events in MedDRA SMQs/Groupings of Interest by Term 
Analysis Set: Safety Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3.2.3.x 
Adverse Events in MedDRA SMQs/Groupings of Interest by Term by Region and Country:  <Region Subgroup or Country> 
Analysis Set: Safety Population 
 
 
Notes to Programmer:  
 
Replace the columns for SOC and Preferred Term 
with the following 2 columns as found in Appendix 
5 of the SAP: 
1. SMQ / Grouping 
2. Preferred Term (or Lower Level Term).  
Start a new page for each new SMQ and insert the 
SMQ label and MedDRA number for the SMQ underneath 
the column headers at the start of each new page. 
 
There will be a footnote to flag when an LLT is 
summarized instead of a Preferred Term. 
 
Notes to Programmer: Sort preferred terms by descending frequency of subjects, then by number of events for 
Total column, and then in alphabetical order. Use the format of Table 3.2.1, but delete the “At Least One” row 
from this table. SOCs will not be used in this table. Only include AEs with incidence of 2.0% or greater (prior 
to rounding). 


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Table 3.2.4.1 
Non-serious Adverse Events Occurring in ≥5% of Subjects in a Treatment by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
 
 
 
 
 
 
Table 3.2.4.x 
Non-serious Adverse Events Occurring in ≥5% of Subjects in a Treatment by Region and Country. MedDRA Primary System Organ Class, and 
Preferred Term: <Region Subgroup or Country> 
Analysis Set: Safety Population 
 
 
 
Notes  to Programmer: Do not provide n(%) summary statistics for the SOC rows, but show the label for each SOC. The n 
and % for the “At Least One Non-Serious TEAE [a]“ row should be calculated using all subjects in the treatment group as 
the denominator and all subjects with non-serious AEs as the numerator. Add a footnote “[a]   TEAE = Treatment-
Emergent Adverse Event”. 


GFF MDI/GP MDI/FF MDI 
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07 Mar 2017 
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Table 3.3.1 
Rate of Adverse Events Adjusted for Exposure by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
 
System Organ Class 
  Preferred Term 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo  
MDI 
 (N=xxx) 
All Subjects 
(N=xxxx) 
 Events (Rate) 
Events (Rate) 
Events (Rate) 
Events (Rate) 
Events (Rate) 
 
 
 
 
 
Total Person-Years of Exposure 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
Total AEs 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 System Organ Class 1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Preferred Term 1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Preferred Term 2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 System Organ Class 2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Preferred Term 1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Preferred Term 2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 … 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
Rate = the rate of AEs per 1000 Person-Years = 1000 x (Total number of AEs / Total years of exposure across all subjects for the 
treatment).  Total person-years of exposure for a treatment group is the total exposure (years) in the study across all subjects in 
the treatment group. 
Report generated by program: pt003014/sasdir/programs/statout/t0303.sas       Version YYYY-MM-DD xx:xx (Page n of N)   
 
Table 3.3.x 
Rate of Adverse Events Adjusted for Exposure by Region and Country, MedDRA Primary System Organ Class, and Preferred Term: : <Region 
Subgroup or Country> 
Analysis Set: Safety Population 
 


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Table 3.4.1 
Adverse Events Suspected to be Drug-Related by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
[a]   TEAE = Treatment-Emergent Adverse Event 
[b]   Suspected to be drug-related = possibly, probably, or definitely. 
 
Report generated by program: pt003014/sasdir/programs/statout/t0304.sas    Version YYYY-MM-DD xx:xx   (Page n of N) 
 
 
 
 
 
Table 3.4.x 
Adverse Events Suspected to be Drug-Related by Region and Country:, MedDRA Primary System Organ Class, and Preferred Term: <Region 
Subgroup or Country> 
Analysis Set: Safety Population 
 
 
Table 3.5.1 
Adverse Events Causing Study Drug Discontinuation by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
[a]  TEAE = Treatment-Emergent Adverse Event  
[b]  An AE leading to treatment discontinuation is an AE with ‘Action Taken’ = ‘Permanently Discontinued’, or ‘Outcome’ = ‘Fatal’,  
     or ‘Death’ as reason for Seriousness on Adverse Event’ CRF.  
 
 
Report generated by program: pt003014/sasdir/programs/statout/t0305.sas  Version  YYYY-MM-DD xx:xx   (Page n of N) 
 
 
 
 
 
 
Table 3.5.x 
Adverse Events Causing Study Drug Discontinuation by Region and Country, MedDRA Primary System Organ Class and Preferred Term: 
<Region Subgroup or Country> 
Analysis Set: Safety Population 
 
 
Notes to Programmer: Instead of ‘At Least One TEAE’, use 
“At Least One Drug-Related TEAE [a] [b]”. 
Notes to Programmer: Instead of ‘At Least One TEAE”, use 
“At Least One TEAE Leading to Discontinuation [a] [b]”. 
 


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Table 3.6 
Listing of Adverse Events Leading to Permanent Discontinuation of Study Treatment 
Analysis Set: All Subjects Randomized 
 
Subject 
ID 
(Age 
(yrs)/ 
Gender/ 
Race) 
Primary System 
Organ Class 
AE Verbatim 
(Preferred Term)  
Treat. 
Emerg. 
Event 
Serious 
Onset 
Date 
(Study  
Day) 
[a] 
Duration 
of Event Severity  
Relation
-ship 
Action  
AE 
Treated 
Outcome 
(Death) 
Study Day 
Resolved/ 
Death [a] 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4 μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
xxxxxx 
(54/F/W) 
xxx xxx xxxxx 
AE 1 
(xxxxxxxxxx) 
Yes 
No 
YYYY-MM-
DD 
(2) 
  
Moderate  Not 
Related 
None 
No 
Ongoing 
(No) 
xxx xxx xxxx 
AE 2  
(xxxxxxxxxx) 
Yes 
Yes 
YYYY-MM-
DD 
(P1) 
xx 
Moderate Possibly Interru
pted  
Yes 
Resolved 
(Yes) 
P3 
… 
… 
 
 
 
 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia  
     or New Zealand (indigenous), A=Asian, O=Other. 
[a]   A negative number for study day denotes the number of days prior to the start of study treatment.  Pxx = Days after last dose.   
                                                                                                             
Report generated by program: pt003014/sasdir/programs/statout/t0306.sas   Version    YYYY-MM-DD xx:xx   (Page n of N) 
 
                                              
                                                                                               
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, Country, Center, Subject ID, Primary System Organ Class, and Onset Day of AE. 
Page by treatment and not by Treatment and Center. 


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Table 3.7.1.1 
Serious Adverse Events by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
 
 
 
 
 
Table 3.7.1.x 
Serious Adverse Events by Region Subgroup or Country, MedDRA Primary System Organ Class, and Preferred Term 
Analysis Set: Safety Population 
 
 
 
 
Table 3.7.2.1 
Serious Adverse Events With Onset After the Last Date of Treatment by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.7.2.x 
Serious Adverse Events With Onset After the Last Date of Treatment by Region and Country, MedDRA Primary System Organ Class and 
Preferred Term: <Region Subgroup or Country> 
Analysis Set: Safety Population 
 
 
 
Notes to Programmer: Instead of “At Least One TEAE”, 
use “At Least One Serious TEAE [a]”. Add the footnote: 
[a]   TEAE = Treatment-Emergent Adverse Event 
Notes to Programmer: follow numbering used for Subgroup efficacy tables, starting with 3.7.1.2. 


GFF MDI/GP MDI/FF MDI 
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07 Mar 2017 
Page 170 of 249 
 
 
 
 
Table 3.8.1 
Listing of Serious Adverse Events (SAEs) 
Analysis Set: All Subjects Screened 
 
Subject 
ID 
Age 
(yrs)/
Gender
/Race 
Primary 
System Organ 
Class 
SAE Verbatim 
(Preferred Term) 
Reason for Being Serious 
(Day) [a] 
Treat. 
Emerg. 
Onset 
Day 
[a] 
Day of 
Most 
Recent 
Dose 
Duration 
of Event 
Severity/ 
Relation-
ship 
Action/ 
(Outcome)  
(AE 
Treated) 
Study 
Day 
Resolved
[a] 
Treatment: Subjects Not Randomized, GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4 μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
xxxxxx 
70/F/W xxxx xxx xx 
xxxx 
xxx xxx xxxxx xxxxxxx 
(xxxxxxxxxxxxxxxxxxx) 
Hospitalization / 
prolongation of existing 
Hospitalization  (Day 5-
Day 8) 
Yes 
5 
(4) 
4 
Moderate / 
Not 
Related 
None/ 
(Resolved) 
(Yes) 
8 
 
 
 
 
Interrupted
, Date 
Stopped: 
YYYY-12-07; 
AE abated: 
Yes; Date 
restarted: 
YYYY_12_08: 
AE reoccur? 
Yes 
 
 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia  
     or New Zealand (indigenous), A=Asian, O=Other. 
[a]   A negative number for study day denotes the number of days prior to the start of study treatment.  Pxx = Days after last dose.    
                                                                                                                                        
Report generated by program: pt003014/sasdir/programs/statout/t030801.sas     Version YYYY-MM-DD xx:xx     (Page n of N)                 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, Country, Center, Subject ID, Primary System Organ Class Preferred Term, and Onset 
Day.  If Reason for Seriousness is Hospitalization or Prolongation of Existing Hospitalization, also present in parentheses the 
days subject admitted into and discharged from Hospital “(Day xx – Day xx)”. If the Reason for Seriousness is death, also present 
the day of death. 


GFF MDI/GP MDI/FF MDI 
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07 Mar 2017 
Page 171 of 249 
 
 
 
 
Table 3.8.2 
Listing of SAE-Specific Report Information 
Analysis Set: All Subjects Screened 
 
Subject  
ID  
Diagnosis, Details and Relevant 
Diagnostic Tests 
Last 
Treatment and 
Date   
(YYYY-MM-DD) 
Date of SAE 
Onset (YYYY-
MM-DD) 
Serious Reason 
(YYYY-MM-DD) 
Action Taken with 
Study Drug 
Severity/ 
Relationship/ 
(Outcome YYYY-
MM-DD) 
SAE 
Treated 
Treatment: Subjects Not Randomized, GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4 μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
xxxxxx 
Diagnosis: xxxxxxxxxxxxxxxxxxxxxxx 
Details: signs, symptoms, time 
course, and relevant medical 
history.  
Relevant Diagnostic Tests: 
Confirmatory procedures and 
Results, if any. 
xxxx MDI  
YYYY-MM-DD 
YYYY-MM-DD Death (YYYY-MM-DD) 
Autopsy: yes or no 
 
Life-threatening 
 
Hospitalization or 
prolongation of 
existing 
hospitalization  
(YYYY-MM-DD-YYYY-MM-
DD) 
 
A persistent or 
significant 
disability/incapacit
y 
 
Congenital 
anomaly/birth defect 
 
A significant 
medical event that 
requires medical or 
surgical 
intervention to 
prevent one of the 
serious outcomes 
listed above. 
None 
Interrupted (Stopped: 
YYYY-MM-DD 
SAE Abated: Yes/No 
Treatment Restarted: 
YYYY-MM-DD 
SAE Reoccur: Yes/no) 
Permanently 
Discontinued 
Moderate / 
Possibly / 
(Resolved 
YYYY-07-27) 
Yes/No 
Report generated by program: pt003014/sasdir/programs/statout/t030802.sas  Version   YYYY-MM-DD xx:xx  (Page n of N)                    
Notes TO Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID, and Onset Day of 
SAE. 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 172 of 249 
 
 
 
 
Table 3.9.1 
Rate of Serious Adverse Events Adjusted for Exposure, by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
System Organ Class 
  Preferred Term 
GFF MDI  
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo  
MDI 
 (N=xxx) 
All Subjects 
(N=xxxx) 
 Events (Rate) 
Events (Rate) 
Events (Rate) 
Events (Rate) 
Events (Rate) 
 
 
 
 
 
Total Person-Years of 
Exposure 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Total SAEs[a] 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 System Organ Class 1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Preferred Term 1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Preferred Term 2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 System Organ Class 2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Preferred Term 1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Preferred Term 2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 … 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
[a] SAE = Serious Adverse Event. 
Rate = the rate of SAEs per 1000 Person-Years = 1000 x (Total number SAEs / Total years of exposure across all subjects for the 
treatment). Total person-years of exposure for a treatment group is the total exposure (years) in the study across all subjects in the 
treatment group. 
0 
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Table 3.9.x 
Rate of Serious Adverse Events Adjusted for Exposure, by Region and Country,  MedDRA Primary System Organ Class and Preferred Term: 
<Region Subgroup or Country> 
Analysis Set: Safety Population 
 
 
 


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Table 3.10.1 
Serious Adverse Events Suspected to be Drug-Related by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
[a] TEAE = Treatment-Emergent Adverse Event[b] Suspected to be drug-related = possibly, probably, or definitely. 
 
 
 
 
 
Table 3.10.x 
Serious Adverse Events Suspected to be Drug-Related by Region and Country,  MedDRA Primary System Organ Class and Preferred Term: 
<Region Subgroup or Country> 
Analysis Set: Safety Population 
 
 
 
Notes to Programmer: Instead of ‘At Least One TEAE’, use 
“At Least one Serious Related TEAE [a][b]”. 


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Table 3.11.1.1 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – GFF MDI 14.4/9.6 μg 
Analysis Set: Safety Population 
 
 
Primary System Organ Class 
   Preferred Term 
GFF MDI 14.4/9.6 μg (N=xxx) 
Mild 
n (%) 
Moderate 
 n (%) 
Severe 
 n (%) 
Any Severity 
n (%) 
 
 
 
 
 
At Least One TEAE [a] 
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
 
 
 
 
 
System Organ Class 1  
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
Preferred Term 1 
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
Preferred Term 2 
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
System Organ Class 2  
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
Preferred Term 1 
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
Preferred Term 2 
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
xxx (xxx.x) 
 
 
 
 
 
…. 
 
 
 
 
     [a]   TEAE = Treatment-Emergent Adverse Event  
Only the highest severity is counted for multiple occurrences of the same adverse event in one individual. 
 
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Table 3.11.1.x 
TEAEs by Region and Country, Primary System Organ Class, Preferred Term, and Highest Severity – GFF MDI 14.4/9.6 μg: <Region 
Subgroup or Country> 
Analysis Set: Safety Population 
 
 
 


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Table 3.11.2.1 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – FF MDI 9.6 μg 
Analysis Set: Safety Population 
 
Table 3.11.2.x 
TEAEs by TEAEs by Region and Country, Primary System Organ Class, Preferred Term, and Highest Severity – FF MDI 9.6 μg: <Region 
Subgroup or Country> 
Analysis Set: Safety Population 
 
 
Table 3.11.3.1 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – GP MDI 14.4 μg  
Analysis Set: Safety Population 
 
Table 3.11.3.x 
TEAEs by TEAEs by Region and Country, Primary System Organ Class, Preferred Term, and Highest Severity – GP MDI 14.4 μg: <Region 
Subgroup or Country> 
Analysis Set: Safety Population 
 
Table 3.11.4.1 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – Placebo MDI 
Analysis Set: Safety Population 
 
 
Table 3.11.4.x 
TEAEs by TEAEs by Region and Country, Primary System Organ Class, Preferred Term, and Highest Severity Placebo MDI: <Region 
Subgroup or Country> 
Analysis Set: Safety Population 
 
 
 


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Table 3.12.1 
Death Events, by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
[a] TEAE = Treatment-Emergent Adverse Event 
 
 
 
 
Table 3.12.x 
Death Events, by Region and Country, MedDRA Primary System Organ Class and Preferred Term: <Region Subgroup or Country> 
Analysis Set: Safety Population 
 
 
Notes to Programmer: Use ‘At Least One TEAE [a]”. 


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Table 3.13 
Listing of Deaths 
Analysis Set: All Subjects Screened 
 
Subject ID 
Number of 
Days on 
Treatment 
(Treatment 
Start and 
End Dates) 
[a] 
Date (YYYY-
MM-DD) of 
Death 
Days Since 
Last Dose 
at Time of 
Death 
Adverse Event 
Cause of Death 
Category 
Relationship to Study 
Drug 
 
Subjects Not Randomized, During Treatment or Within 14 Days Post-Treatment, or After 14 Days Post-Treatment 
 
Treatment: Subjects Not Randomized, GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4 μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
xxx 
(YYYY-MM-DD 
– YYYY-MM-
DD) 
YYYY-MM-DD 
 
x 
AE verbatim 
Cardiovascular 
Possibly 
 
 
 
 
 
 
 
xxxxxx 
xxx 
(YYYY-MM-DD 
– YYYY-MM-
DD) 
YYYY-MM-DD 
 
x 
AE verbatim 
Respiratory 
Definitely 
 
 
 
 
 
 
 
xxxxxx 
xxx 
(YYYY-MM-DD 
– YYYY-MM-
DD) 
YYYY-MM-DD 
 
x 
AE verbatim 
Cancer 
Probably 
 
 
 
 
 
 
 
xxxxxx 
xxx 
(YYYY-MM-DD 
– YYYY-MM-
DD) 
YYYY-MM-DD 
 
x 
AE verbatim 
Unknown 
Definitely 
 
 
 
 
 
 
 
NA = Not applicable.[a] Study Day of Last Dose of study treatment = Study date of last dose for study treatment – 
Date of first dose of study treatment + 1.  
 
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NOTE TO PROGRAMMER: Sort by Time Period (Subjects Not Randomized, During Treatment or 
Within 14 Days Post-Treatment, OR After 14 Days Post-Treatment), Actual Treatment, 
Country, Center, and Subject ID within Center. Put NA in second and 4th columns if 
subject was not randomized. 


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Laboratory Parameters 
 
Table 3.14.1 
Laboratory Parameters by Visit and Time of Assessment – Hematology Panel 
Analysis Set: Safety Population 
 
Parameter (unit) 
Visit/Timepoint 
Statistic 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
Parameter 1 (unit) 
Baseline 
(Day 1 Pre-dose) 
Actual Value: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
 xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
 xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
 xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
 xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
 xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
Week xx Pre-dose 
Actual Value: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
    x.xx 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx  
  x.xx 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
   x.xx 
Change From Baseline: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx   
  x.xx 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
  
Baseline is defined as the last available measurement prior to the start of treatment on Day 1 (Visit 4). 
End of Treatment is defined as the last non-missing assessment during the treatment period.  
                                                                                                                                   
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Notes to Programmer: Repeat the parameter at the beginning of each page under column header. 
Notes to Programmer:  
Repeat for all remaining post-baseline visits and also for “End of Treatment” is defined as the last non-missing 
assessment during the treatment period. 


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Table 3.14.2 
Laboratory Parameters by Visit and Time of Assessment – Blood Chemistry Panel 
Analysis Set: Safety Population 
        
Parameter (unit) 
Visit/Timepoint 
Statistic 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
Parameter 1 (unit) 
Baseline 
(Day 1 Pre-dose) 
Actual Value: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
 xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
 xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
 xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
 xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
 xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
Week xx Pre-dose 
Actual Value: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
    x.xx 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx  
  x.xx 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
   x.xx 
Change From Baseline: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx   
  x.xx 
 
 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
 
xxx 
  x.xxx 
  x.xxx 
  x.xxx 
  x.xx 
  x.xx 
 
 
 
 
Baseline is defined as the last available measurement prior to the start of treatment on Day 1 (Visit 4). 
  End of Treatment is defined as the last non-missing assessment during the treatment period.                                                         
 
Report generated by program: pt003014/sasdir/programs/statout/t031402.sas Version  YYYY-MM-DD xx:xx     (Page n of N)  
 
 
 
Notes to Programmer: Repeat the parameter at the beginning of each page under column header.  


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Table 3.14.3 
Laboratory Parameters by Visit and Time of Assessment – Kidney Function 
Analysis Set: Safety Population 
 
 
Table 3.14.4 
Laboratory Parameters by Visit and Time of Assessment – Urinalysis pH and Specific Gravity 
Analysis Set: Safety Population 
 
 
 
 
 
 
 
 
Notes to Programmer: Repeat format of Table 3.14.2 
for pH and Specific Gravity.  


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Table 3.14.5 
Shift Table for Laboratory Hematology Data: NCI-CTC Grading 
Analysis Set: Safety Population 
 
Hemoglobin Increased  
 
Treatment 
Baseline Grade 
Post-Baseline Highest Grade 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Missing 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n 
GFF MDI 14.4/9.6 μg 
 
Grade 0   (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
Grade 1   (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
Grade 2   (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
Grade 3   (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
Grade 4   (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Any Grade (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Missing 
  x  
  x 
  x 
  x 
  x 
x 
 
 
 
 
 
 
 
 
FF MDI 9.6 μg 
Grade 0 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Grade 1 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Grade 2 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Grade 3 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Grade 4 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Any Grade (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Missing 
  x  
  x 
  x 
  x 
  x 
x 
 
 
 
 
 
 
 
 
GP MDI 14.4 μg 
Grade 0 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Grade 1 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Grade 2 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Grade 3 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Grade 4 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Any Grade (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Missing 
  x  
  x 
  x 
  x 
  x 
x 
 
 
 
 
 
 
 
 
Placebo MDI 
Grade 0 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Grade 1 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Grade 2 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Grade 3 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Grade 4 (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Any Grade (N=xxx) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x 
 
Missing 
  x  
  x 
  x 
  x 
  x 
x 
 
 
 
 
 
 
 
 
Baseline is defined as the last available measurement prior to the start of treatment on Day 1 (Visit 4).  
Grading criteria according to National Cancer Institute Common Toxicity Criteria (NCI-CTC, CTCAE) Version 4.03.                 


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Grade 0 = No Grade.                                                                                                             
N = number of subjects who received the treatment and had data in the baseline category with non-missing data Post-Baseline. 
n = number of subjects in baseline and post-baseline category.  % = 100 x n/N.                                
 
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Table 3.14.6 
Shift Table for Laboratory Chemistry Data: NCI-CTC Grading 
Analysis Set: Safety Population 
 
 
Table 3.14.7 
Shift Table for Kidney Function: NCI-CTC Grading 
Analysis Set: Safety Population 
 
 
 
Notes to Programmer: repeat for each laboratory 
test required within Hematology.  Add Grade 5 to 
post-baseline categories shown if there are any 
deaths for the parameter. 


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Table 3.14.8 
Post-Baseline Newly Occurring or Worsening Potentially Clinically Significant Laboratory Values Based on CTCAE 4.03 and Other Criteria 
Analysis Set: Safety Population 
 
CTCAE_4.03 and 
Other Criteria 
Threshold 
   [a] 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo  
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
n  (%) 
n  (%) 
n  (%) 
n  (%) 
n  (%) 
 
 
 
 
 
Hematology 
 
 
 
 
 
Hemoglobin  
<80 g/L 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
Increase >40 g/L to a 
value > ULN 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
White Blood Cell 
Count 
<2 x 109/L 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
>100 x 109/L 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
Platelet Count 
<50 x 109/L 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
>700  x 109/L 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
 
 
 
 
Chemistry 
 
 
 
 
 
GGT 
>2.5 x ULN [b] 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
AST 
>3 x ULN [b] 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
ALT 
>3 x ULN [b] 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
Alkaline 
Phosphatase 
>5 x ULN 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
Total Bilirubin 
>1.5 x ULN [b] 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
Triglycerides 
>5.65 mmol/L 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
Cholesterol  
>10.34 mmol/L 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
Albumin 
<20 g/L 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
 
 
 
 
 


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Potassium 
<3.0 mmol/L 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
>6.0 mmol/L 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
Glucose 
<2.2 mmol/L 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
>13.9 mmol/L 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
 
 
 
 
 
Kidney Function 
 
 
 
 
 
 eGFR – EPI [c] 
<30 mL/min/1.73 m2 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
n = number of subjects in the category. N1= number of subjects with data for the parameter. % = 100 x n/N1. 
Criteria for Platelet Count increase is not based on CTCAE 4.03 criteria. 
[a] CTCAE Threshold is Grade >=3 for all laboratory parameters except for GGT, AST, ALT, Total Bilirubin. 
[b] CTCAE Threshold is Grade >=2. 
[c] eGFR – EPI is estimated glomerular filtration rate using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula. 
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Table 3.14.9 
All Potassium Records for Subjects With Newly Occurring or Worsening Potentially Clinically Significant Potassium Values Post-Baseline  
Analysis Set: Safety Population  
 
 
 
 
 
 
 
 
 
Table 3.14.10 
All Glucose Records for Subjects With Newly Occurring or Worsening Potentially Clinically Significant Glucose Values Post-Baseline  
Analysis Set: Safety Population  
 
 
Table 3.14.11 
All Records for Subjects With Newly Occurring or Worsening Potentially Clinically Significant Values Post-Baseline Other Than Those for 
Glucose and Potassium 
Analysis Set: Safety Population 
 
 
 
Notes to Programmer: Please use Listing 8.1 and add a 
column after Subject ID identifying which criterion in Table 
3.14.8.1 is used for the PCS value. Put age, gender, and 
race underneath Subject ID in the first column. 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 187 of 249 
 
 
 
 
Vital Signs 
 
Table 3.15.1 
Vital Sign Measurements by Visit and Time of Assessment 
Analysis Set: Safety Population 
 
Parameter (Unit) 
Visit 
Timepoint 
Statistic 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
Heart Rate (beats/min) 
Day 1  
Baseline 
Actual Value: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
Post-dose  
30 Min 
Actual Value: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
Change From 
Baseline: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
Post-dose  
2 Hours 
Actual Value: 
n 
Mean 
SD 
Median 
Minimum 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 


GFF MDI/GP MDI/FF MDI 
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Parameter (Unit) 
Visit 
Timepoint 
Statistic 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
Maximum 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
Change From 
Baseline: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
  
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
  
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
  
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
  
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
Week xx 
 
 
 
 
 
End of Treatment 
<timepoint> 
 
 
 
 
 
 
 
  
 
     Baseline is defined as the average of the pre-dose measurements taken prior to the start of treatment at Day 1 (Visit 4). 
     End of Treatment for a timepoint is defined as the last non-missing on-treatment assessment available for the timepoint. 
 
     Report generated by program: pt003014/sasdir/programs/statout/t031501.sas Version YYYY-MM-DD xx:xx (Page n of N) 
 
 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer:  
 
Repeat the parameter at the beginning of each page under column header. 
Repeat for all parameters 
End of Treatment” will be provided for each scheduled post-baseline timepoint (pre-
dose, post-dose 30 minutes, and post-dose 2 hours).  End of Treatment for each of 
these assessment points is defined as the last non-missing on-treatment assessment 
available for the timepoint. 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 189 of 249 
 
 
 
 
Table 3.15.2 
Post-Baseline Potentially Clinically Significant Vital Sign Values 
Analysis Set: Safety Population 
 
Parameter 
Post-baseline  
Criteria 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo  
MDI  
(N=xxx) 
All Subjects 
(N=xxxx) 
n  (%) [%][a] 
n  (%) [%][a] 
n  (%) [%][a] 
n  (%) [%][a] 
n  (%) [%][a] 
 
 
 
 
 
Systolic Blood Pressure, 
increase 
≥180 mmHg and 
increase from 
Baseline ≥20 
mmHg  
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
Systolic Blood Pressure, 
decrease 
≤90 mmHg and 
decrease from 
Baseline ≥20 
mmHg  
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
Diastolic Blood 
Pressure, increase 
≥105 mmHg and 
increase from 
Baseline  
≥15 mmHg 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
Diastolic Blood 
Pressure, decrease 
≤50 mmHg and 
decrease from 
Baseline  
≥15 mmHg 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
Tachycardia Event 
≥110 bpm and 
increase ≥15% 
from Baseline 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
Bradycardia Event 
≤50 bpm and 
decrease ≥15% 
from Baseline 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
xx ( xx.x) 
   ( xx.x)  
 
 
 
 
 
 
Baseline is defined as the average of the pre-dose measurements taken prior to the start of treatment at Day 1 (Visit 4). 
n is the number of subjects meeting the Post-baseline Criteria at any time after the start of treatment. N1= number of subjects with 
data for the parameter. % = 100 x n/N1. 
[a] The second percentage provided for each treatment group is the percentage of all visits where a post-baseline value at the visit 
   was PCS. 
Report generated by program: pt003014/sasdir/programs/statout/t031502.sas   Version  YYYY-MM-DD xx:xx     (Page n of N) 
 
 


GFF MDI/GP MDI/FF MDI 
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Page 190 of 249 
 
 
 
 
Table 3.15.3 
Listing of Potentially Clinically Significant Systolic and Diastolic Blood Pressure Increases and Decreases 
Analysis Set: Safety Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3.15.4 
Listing of Potentially Clinically Significant Tachycardia and Bradycardia Events 
Analysis Set: All Subjects Randomized 
 
 
 
Notes to Programmer: please use these definitions for this data listing and the next 3 data listings. 
 
Systolic Blood Pressure, increase 
≥180 mmHg and increase from Baseline ≥20 mmHg 
Systolic Blood Pressure,  decrease ≤90 mmHg and decrease from Baseline ≥20 mmHg 
Diastolic Blood Pressure,  increase ≥105 mmHg and increase from Baseline ≥15 mmHg 
Diastolic Blood Pressure, decrease ≤50 mmHg and decrease from Baseline ≥15 mmHg 
Notes to Programmer: Please use Listing 9.1 and add 2 
columns after Subject ID identifying which  criteria of the in 
the table above is being displayed for a subject (criteria 
also shown in Table 3.15.2). Put age, gender, and race 
underneath Subject ID in the first column. In the last 
column display Visit 1 Height, weight, and BMI. 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 191 of 249 
 
 
 
 
12-Lead Electrocardiogram (ECG) 
 
Table 3.16.1 
ECG Parameters by Visit and Time of Assessment 
Analysis Set: Safety Population 
 
Parameter (Unit) 
Visit 
Timepoint 
Statistic 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
Heart Rate (beats/min) 
Day 1  
Baseline 
Actual Value: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
Post-dose  
30 Min 
Actual Value: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
Change From 
Baseline: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
Post-dose  
2 Hours 
Actual Value: 
n 
Mean 
SD 
Median 
Minimum 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 192 of 249 
 
 
 
 
Parameter (Unit) 
Visit 
Timepoint 
Statistic 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo 
MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
Maximum 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
Change From 
Baseline: 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
 
  
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
  
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
  
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
  
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
 
 
 xx 
  x.x 
  x.x 
  x.x 
  x.x 
  x.x 
Week xx 
 
 
 
 
 
End of Treatment 
<timepoint> 
 
 
 
 
 
 
 
  
 
     Baseline is defined as the average of the pre-dose measurements taken prior to the start of treatment at Day 1 (Visit 4). 
     End of Treatment for a timepoint is defined as the last non-missing on-treatment assessment available for the timepoint. 
 
     Report generated by program: pt003014/sasdir/programs/graph/f3_16_1.sas  Version YYYY-MM-DD HH:MM YYYY (Page n of N)  
 
 
 
 
 
 
Notes to Programmer:  
 
Repeat above assessments for each parameter (except for RR Interval). 
Include “Pre-dose Mean” for all visits after Visit 1. 
Repeat the parameter at the beginning of each page under column header. 
Repeat for all parameters. 
End of Treatment” will be provided for each scheduled post-baseline timepoint (pre-dose, post-
dose 30 minutes, and post-dose 2 hours).  End of Treatment for each of these assessment points 
is defined as the last non-missing on-treatment assessment available for the timepoint. 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 193 of 249 
 
 
 
 
Figure 3.16.1a 
Mean Change From Baseline for QTcF (ms) ± SE Over Time During Treatment 
Analysis Set: Safety Population 
 
 
 
 
The pre-dose mean value at each visit is plotted. 
Source: Table 3.16.1 
 
Report generated by program: pt003014/sasdir/programs/graph/f3_16_1.YYYYsas   Version YYYY-MM-DD HH:MM   (Page 1 of 1) 
 
 
 
Note to Programmer: The above legend will be replaced by GP MDI 14.4/9.6 μg, GP MDI 14.4 μg, FF MDI 9.6 μg, and Placebo MDI.  
The x axis label will be replaced by “Weeks Post-Baseline” and “Week 0 (Day 1)” and all subsequent weeks post-baseline will be plotted 
(“Week 2”, “Week 4”, “Week 8”, “Week 12”, “Week 16”, “Week 20”, and “Week 24”). 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 194 of 249 
 
 
 
 
Figure 3.16.1b 
Mean Change From Baseline for QTcF (ms) ± SE Over 2 Hours Post-dose on Day 1  
Analysis Set: Safety Population 
 
 
 
 
 
Figure 3.16.1c 
Mean Change From Baseline for Heart Rate (bpm) ± SE Over Time During Treatment 
Analysis Set: Safety Population 
 
 
 
 
 
 
Figure 3.16.1d 
Mean Change From Baseline for Heart Rate (bpm) ± SE Over 2 Hours Post-dose on Day 1  
Analysis Set: Safety Population 
 
 
 
 
 
 
 
Notes to Programmer: Plot 30 minutes and 2 hours post-dose. 
Notes to Programmer: Plot 30 minutes and 2 hours post-dose. 
Notes to Programmer: “Week 0 (Day 1)” and all subsequent weeks 
post-baseline will be plotted (“Week 2”, “Week 4”, “Week 8”, “Week 
12”, “Week 16”, “Week 20”, and “Week 24”. 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 195 of 249 
 
 
 
 
Table 3.16.2 
Post-Baseline Potentially Clinically Significant (PCS) ECG Values 
Analysis Set: Safety Population 
 
 
Parameter 
Post-baseline 
Criteria 
GFF MDI 
14.4/9.6 μg 
(N=xxx) 
FF MDI 
9.6 μg 
(N=xxx) 
GP MDI 
14.4 μg 
(N=xxx) 
Placebo MDI 
(N=xxx) 
All Subjects 
(N=xxxx) 
n  (%)  
n  (%)  
n  (%)  
n  (%)  
n  (%)  
 
 
 
 
 
QTcF 
Prolongation 
Value is >450 ms 
for a male subject 
or >470 ms for a 
female subject 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
 
 
 
 
Value is >500 ms  
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
 
 
 
 
Increase from 
baseline is >30 ms 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
 
 
 
 
Increase from 
baseline is >60 ms 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
 
 
 
 
Value is >500 ms 
and increase from 
baseline >30 ms  
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
 
 
 
 
Value is >500 ms 
and increase from 
baseline >60 ms  
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
 
 
 
 
PR Interval 
Increase 
Increase from 
baseline of >50 ms 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
 
 
 
 
QRS 
Prolongation 
Prolongation of  
>40 ms from 
baseline 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
xx ( xx.x) 
 
 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 196 of 249 
 
 
 
 
Baseline is defined as the average of the pre-dose measurements taken prior to the start of treatment at Day 1 (Visit 4). 
n is the number of subjects in the category. N1= number of subjects with data for the parameter. % = 100 x n/N1. 
 
Report generated by program: pt003014/sasdir/programs/statout/t031602.sas Version  YYYY-MM-DD xx:xx     (Page n of N) 
 
 
 
 
 
 
Notes to Programmer: Subject will be counted as meeting the criteria as long as there is one Post-
Baseline assessment meeting the criteria. 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 197 of 249 
 
 
 
 
Table 3.16.3 
Listing of ECG's Meeting QTcF Interval Prolongation Criteria 
Analysis Set: All Subjects Randomized 
 
 
 
 
 
 
 
 
 
Table 3.16.4 
Listing of PR Interval Increases: Post-Baseline Increases of >50 ms From Baseline 
Analysis Set: All Subjects Randomized 
 
Table 3.16.5 
Listing of QRS Prolongations: Post-Baseline Prolongations of >40 ms From Baseline 
Analysis Set: All Subjects Randomized 
 
Notes to Programmer: Please use Listing 9.2 and add a 
column after Subject ID identifying which QTcF criteria of 
the first 6 in the table above is being displayed (criteria 
shown in Table 3.16.2 above). Put age, gender, and race 
underneath Subject ID in the first column. 


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Final Version 
07 Mar 2017 
Page 198 of 249 
 
 
 
 
4. Subject Data Listings 
 
 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 199 of 249 
 
 
 
 
4.1 Subject Discontinuations/Completions 
 
Listing 1.1 
Study Centers 
Analysis Set: All Subjects Screened 
 
Center 
Investigator 
Location 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxx  City Country 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxx  City Country 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxx  City Country 
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l0101.sas       Version  YYYY-MM-DD xx:xx   (Page n of N) 
 
 
 


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Final Version 
07 Mar 2017 
Page 200 of 249 
 
 
 
 
Listing 1.2 
Subject Disposition and Demographic Data 
Analysis Set: All Subjects Screened 
 
Subject ID 
(Randomization 
Strata) 
Age 
(yrs)/ 
Gender 
(Race/
Ethni-
city) 
Height(cm
)/ Weight 
(kg) / 
BMI 
(kg/ 
m2) 
Smoking History 
Random-
ized? 
(Study 
Day) 
[c] 
Subject Study Status 
(Date of Discontinuation [Study Day)} 
(Follow-up Call?  Date) 
Date of Death 
[d] 
Smoking 
Status 
 [a] 
Number 
of 
Weeks 
Since 
Day 
Quit 
Number 
of 
Years 
Smoked 
Average 
Number 
of 
Ciga-
rettes 
Smoked 
Per Day 
Number 
of 
Pack 
Years 
Smoked 
 [b] 
 
Treatment: Subjects Not Randomized, GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
Xxxxxx 
Randomization 
Strata 
Description> 
 
Xx/M 
(x/xx) 
 
 
xxx.x/ 
xx.x/ 
xx.x 
Current 
Smoker 
xx.x 
xx 
xx 
xx.x 
Yes/No 
(xx) 
Completed Study 
(YYYY-MM-DD [xxx]) 
(Yes YYYY-DD-MM) 
NA 
 
 
 
 
 
 
 
 
 
 
Xxxxxx 
<Randomization 
Strata 
Description> 
 
Xx/M 
(x/xx) 
 
 
xxx.x/ 
xx.x/ 
xx.x 
Former 
Smoker 
xx.x 
xx 
xx 
xx.x 
Yes/No 
(xx) 
Discontinued 
Investigator’s Decision 
(YYYY-MM-DD [xxx]) 
(No) 
 
 
 
 
 
 
 
 
 
 
Xxxxxx 
<Randomization 
Strata 
Description> 
 
Xx/M 
(x/xx) 
 
 
xxx.x/ 
xx.x/ 
xx.x 
Current 
Smoker 
xx.x 
xx 
xx 
xx.x 
Yes/No 
(xx) 
Discontinued 
Subject Lost to Follow up 
(YYYY-MM-DD [xxx]) 
(No) 
 
 
 
 
 
 
 
 
 
 
Xxxxxx 
<Randomization 
Strata 
Description> 
 
Xx/M 
(x/xx) 
 
 
xxx.x/ 
xx.x/ 
xx.x 
Non-
Smoker 
xx.x 
xx 
xx 
xx.x 
No 
(NA) 
Discontinued 
Investigator’s Decision 
(YYYY-MM-DD [xxx]) 
(No) 
 
 
 
 
 
 
 
 
 
 
Xxxxxx 
<Randomization 
Xx/M 
(x/xx) 
xxx.x/ 
xx.x/ 
Current 
Smoker 
xx.x 
xx 
xx 
xx.x 
No 
(NA) 
Discontinued 
Adverse Event 


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 201 of 249 
 
 
 
 
Strata 
Description> 
 
 
 
xx.x 
(YYYY-MM-DD [xxx]) 
(No) 
Death: YYYY-MM-DD 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native,  
      ANZ=Australia or New Zealand (indigenous), A=Asian, O=Other. Ethnicity: H=Hispanic, NH=Non-Hispanic. 
NA = Not Applicable. 
[a]   Former Smoker is defined as those who have stopped smoking for at least 6 weeks prior to first Screening Visit. 
[b]   Number of pack years smoked = (number of cigarettes per day / 20) x number of years smoked. 
[c]   Study Day of randomization = date of randomization – first dose of study treatment + 1. 
[d]   The Date of Discontinuation is the later of the last visit date, the date of the last dose of study medication, or the date of  
      last contact for subjects lost-to-followup. For subjects not randomized, date of discontinuation Study Day is the last visit 
      date - date of Screening Visit 1;  for treated subjects, Study Day is the date of discontinuation - date of first dose of study  
      treatment+1.                                                                       
 
Source: xxxxxxx.sas7bdat 
 
Report generated by program: PT003014/sasdir/programs/statout/l0102.sas       Version  YYYY-MM-DD xx:xx   (Page n of N) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, and Subject ID within Center.  
Last Contact Date on the Study Completion/Early 
Discontinuation CRF is date of last contact. If 
Race = Other, concatenate the specified race after 
‘O’ within parenthesis, e.g., “O (specified)”.  


GFF MDI/GP MDI/FF MDI 
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Final Version 
07 Mar 2017 
Page 202 of 249 
 
 
 
 
Listing 1.3 
Randomized Treatment, Actual Treatment, and Duration of Treatment 
Analysis Set: All Subjects Randomized  
 
Subject ID 
Randomization 
Date 
Randomized 
Treatment 
Actual Treatment 
Start Date of 
Treatment 
(Study Day) 
and time 
(24 hr clock) 
End Date of 
Treatment 
(Study Day) 
and time 
(24 hr clock) 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
YYYY-MM-DD 
xxxxxxxxxx 
xxxxxxxxxx [a] 
YYYY-MM-DD 
(xxx) hh:mm 
YYYY-MM-DD 
(xxx) hh:mm 
xxxxxx 
YYYY-MM-DD 
xxxxxxxxxx 
xxxxxxxxxx 
YYYY-MM-DD 
(xxx) hh:mm 
YYYY-MM-DD 
(xxx) hh:mm 
xxxxxx 
YYYY-MM-DD 
xxxxxxxxxx 
xxxxxxxxxx 
YYYY-MM-DD 
(xxx) hh:mm 
YYYY-MM-DD 
(xxx) hh:mm 
[a] Subject received a treatment other than their randomized treatment. 
 
Source: xxxxxxx.sas7bdat  
 
Report generated by program: pt003014/sasdir/programs/statout/l0103.sas  Version  
YYYY-MM-DD xx:xx  (Page n of N) 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Country, Center, and 
Subject ID within Center. Start day and time will 
come from the Dosing CRF. End Study Day is the 
last dosing date, either from the diary data or 
from the Dosing CRF, whichever is the latest 
dosing date. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 203 of 249 
 
 
 
 
Listing 1.4 
Reasons Subjects Were Not Randomized 
Analysis Set: Non-Randomized Analysis Set 
 
Subject ID 
Date of Screening 
Age 
(yrs) 
Gender 
Race 
Reason Not Randomized 
 
 Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
YYYY-MM-DD 
xx 
Male 
W 
xxxxxxxxxxxxxxx (Inclusion Criterion #n) 
xxxxxx 
YYYY-MM-DD 
xx 
Female 
W 
xxxxxxxxxxxxxx (Inclusion Criterion #n) 
xxxxxx 
YYYY-MM-DD 
 
xx 
Male 
W 
xxxxxxxxxxxxxx (Inclusion Criterion #n) 
xxxxxx 
YYYY-MM-DD 
 
xx 
Male 
W 
xxxxxxxxxxxxxx (Inclusion Criterion #n) 
Xxxxxx 
YYYY-MM-DD 
Xx 
Female 
W 
<reason for discontinuation from the Discontinuation/Completion 
CRF> 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia or New 
Zealand (indigenous), A=Asian, O=Other.  
 
Source: xxxxxxx.sas7bdat  
 
Report generated by program: pt003014/sasdir/programs/statout/l0104.sas  Version YYYY-MM-DD xx:xx   (Page n of N) 
 
 
 
 
 
Notes to Programmer: Sort by Country, Center, and Subject ID within Center. If 
Race = Other (“O”), concatenate the specified race after ‘O’ within 
parenthesis, e.g., “e.g., “O: xxxxxx”. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 204 of 249 
 
 
 
 
Listing 1.5 
Changes in Smoking Status During Study 
Analysis Set: All Subjects Randomized 
 
Subject ID 
Age (yrs)/ 
Gender/ 
Race 
Visit 1 
Screening 
Smoking 
Status 
Did smoking status change since the last visit? 
Screening 
Visit 2 
Screening 
Visit 3 
Day 1 
(Visit 
4) 
Week 2 
Week 4 
Week 8 
Week 12  
Week 16 
Week 20 
Week 24 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
xx/F/W 
Former 
Smoker 
Yes 
No  
Yes 
No  
Yes 
No  
Yes 
No  
Yes 
No  
xxxxxx 
xx/F/W 
Current 
Smoker 
No 
No 
No 
No 
No 
No 
No 
No 
No 
No 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia or New  
      Zealand (indigenous), A=Asian, O=Other. 
 
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l0105.sas  Version YYYY-MM-DD xx:xx       (Page n of N) 
 
 
 
 
 
 
 
 
Notes to Programmer: If an unscheduled visit occurred between 
Visit X and Visit Y, please add a second row, showing change in 
status for a visit occurring after Visit X on the second line 
underneath the Visit x column.  Repeat if necessary If more than 
one line needed per subject, please add the following footnote 
to the table: Changes in status at an Unscheduled visit are 
shown on the additional line shown for a subject beneath the 
visit after which the unscheduled visit occurred. 
Sort by Randomized Treatment, Country, Center, and Subject ID 
within Center. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 205 of 249 
 
 
 
 
4.2 Protocol Deviations 
 
Listing 2.1 
Violation of Inclusion/Exclusion Criteria and Waivers 
Analysis Set: All Subjects Randomized 
 
Subject 
ID 
Age 
(yrs) 
Gender 
Race 
Informed 
Consent 
Signed 
Informed 
Consent 
Study 
Day [a] 
Eligibility 
Visit 
Study 
Day 
[a] 
Inclusion/ 
Exclusion 
Criteria 
Satisfied 
Type of 
Failed 
Criteria 
Failed 
Criteria 
Number 
Was Waiver 
Granted 
Reason for 
Waiver 
Granted 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
xx 
Male 
x 
Yes 
-xx 
Visit 1 
 -xx 
No 
Inclusion 
6 
Yes 
xxxx xxxxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia or  
      New Zealand (indigenous), A=Asian, O=Other.  
[a]          A negative number for study day denotes the number of days prior to the start of study treatment. 
 
Source:xxxxxxx.sas7bdat 
                     
Report generated by program: pt003014/sasdir/programs/statout/l0201.sas         Version YYYY-MM-DD xx:xx      (Page n of N) 
 
 
 
 
 
 
 
 
Notes to Programmer: If Race = Other (“O”), 
concatenate the specified race after ‘O’ within 
parenthesis, e.g., “O (specified)”. Sort by Actual 
Treatment, Country, Center, and Subject ID within 
Center. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 206 of 249 
 
 
 
 
Listing 2.2 
Screening Lung Function and Ventolin HFA and Atrovent HFA Reversibility                      
Analysis Set: All Subjects Randomized 
                                                                                                                                       
Subject 
ID 
Age 
(yrs) Gender 
Race 
Visit  
Effort Date 
(Nominal 
Time) 
Time of BD 
Dose  
(24 hr 
clock) 
Pre-dose 
Post-dose 
FEV1 
(L) 
FEV1 
Rank 
FVC 
(L) 
FVC 
Rank 
PEFR 
(L/min) 
FEV1 
(L) 
FEV1 
Rank 
FVC 
(L) 
FVC 
Rank 
PEFR 
(L/min
) 
 
Reversibili
ty % 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
xxxxxx 
xx Female 
W 
Visit 1 
YYYY-MM-DD 
(NA) 
xx:xx 
x.xxx 
x x.xxx 
x 
xxx.xxx x.xxx 
x 
x.xxx 
x 
xxx.xx
x 
     
Visit 2 
YYYY-MM-DD 
(-60 min.) 
xx:xx 
x.xxx 
x x.xxx 
x 
xxx.xxx x.xxx 
x 
x.xxx 
x 
xxx.xx
x 
     xx.x 
(V) 
Visit 2 
YYYY-MM-DD 
(-30 min.) 
 
x.xxx 
x x.xxx 
x 
xxx.xxx x.xxx 
x 
x.xxx 
x 
xxx.xx
x 
     xx.x 
(V) 
Visit 3 
YYYY-MM-DD 
(-60 min.) 
xx:xx 
x.xxx 
x x.xxx 
x 
xxx.xxx x.xxx 
x 
x.xxx 
x 
xxx.xx
x 
     xx.x 
(A) 
Visit 3 
YYYY-MM-DD 
(-30 min.) 
 
x.xxx x 
x.xxx x 
xxx.xxx x.xxx 
x 
x.xxx 
x 
xxx.xx
x 
     xx.x 
(V) 
  Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia or  
      New Zealand (indigenous), A=Asian, O=Other. 
  NA = Not Applicable. 
  BD = Bronchodilator. 
  (V) = Ventolin HFA. 
  (A) = Atrovent HFA. 
                                                                                                                                   
  Source: xxxxxxx.sas7bdat     
                                                                                                                                              
  Report generated by program: pt003014/sasdir/programs/statout/l0202.sas   Version YYYY-MM-DD xx:xx   (Page n of N) 
                                                                       
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, and Subject ID within Center. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 207 of 249 
 
 
 
 
4.3 Subjects Excluded From the ITT, PP, Symptomatic, and Safety Populations 
 
 
 
 
 
 
See Table 1.1.4 in Section 1. 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 208 of 249 
 
 
 
 
4.4 Baseline Characteristics 
 
Listing 4.1 
COPD Diagnosis  
Analysis Set: All Subjects Randomized 
 
Subject ID 
Age (yrs)/ Gender / Race 
Severity of COPD (Screening Visit 2) 
COPD First Diagnosed 
Date [a] 
Years Prior to First Dose 
[b] 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
 
xx / Male/ xxxx 
xx / Female / xxxx 
Mild 
YYYY-MM 
YYYY-06* 
x.x 
 xx.x 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native,  
      ANZ=Australia or New Zealand (indigenous), A=Asian, O=Other. 
[a]   Missing month of Date COPD First Diagnosed will be imputed as June, or the month in which 1st  will be the latest before informed 
      consent date; '*' indicates the month displayed was imputed.   
[b]   Years Prior to First Dose When COPD was First Diagnosed = (Date of First Dose of Study Treatment – Date COPD First  
      Diagnosed)/365.25. Day of Diagnosis will be imputed for all subjects as the 1st of the month. 
 
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l0401.sas  Version YYYY-MM-DD xx:xx   (Page n of N) 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, and Subject ID within Center. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 209 of 249 
 
 
 
 
Listing 4.2 
Screening CAT Assessment 
Analysis Set: All Subjects Randomized 
 
Subject ID 
CAT Analysis Score [a] 
1 [b] 
2 
3 
4 
5 
6 
7 
8 
Total 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxx 
3 
4 
0 
1 
5 
0 
2 
1 
16 
 
 
 
 
 
 
 
 
 
 
xxxxx 
 
 
 
 
 
 
 
 
ND 
ND =  Not Done 
[a]   The eight test items (1-8) correspond to cough, phlegm (mucus) in my chest, chest feels tight, walk up a hill or one flight  
      of stairs breathless, limited doing any activities at home, confident leaving my home despite my lung condition, sleep  
      soundly, and lots of energy, respectively. 
[b]   Scores are rated on 0-5 scale, anchored from no problem (0) to worst possible rating (5). 
 
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l0402.sas     Version YYYY-MM-DD xx:xx (Page n of N)                   
 
 
 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, and Subject ID. 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 210 of 249 
 
 
 
 
Listing 4.3 
Screening MMRC Scale 
Analysis Set: All Subjects Randomized 
 
Subject 
ID 
MMRC Scale Grade [a] 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
3 
xxxxxx 
ND 
ND =  Not Done 
[a]   Grades range between 0 and 4, where 4 represents the highest level of breathlessness. 
 
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l0403.sas  Version YYYY-MM-DD xx:xx (Page n of N)        
 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, and Subject ID. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 211 of 249 
 
 
 
 
Listing 4.4 
History of Moderate or Severe COPD Exacerbations 
Analysis Set: All Subjects Randomized 
 
Subject ID 
COPD exacerbation within the 
past 12 months prior to 
Screening [a] 
Number of Exacerbations 
Admitted to hospital or 
received ER Treatment in the 
past 12 months 
prior to Screening [b] 
Number of 
Hospitalizations 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
xxxxxx 
Yes 
2 
Yes 
1 
 
 
 
[a] Within the past 12 months, subject experienced a worsening in his/her respiratory symptoms (dyspnea, cough,  sputum 
   volume, sputum, purulence) beyond  normal day to day variation that led the treating physician to prescribe  
   treatment with systemic (oral or IV) corticosteroids and/or antibiotics for at least 3 days? 
[b] Subject been admitted to hospital (including intensive care unit) or received emergency room (including  urgent care 
   centers) treatment in  the past 12 months due to a worsening in his/her respiratory symptoms (dyspnea,  cough,  
   sputum volume, sputum purulence) beyond  normal day to day variation? 
Source: xxxxxxx.sas7bdat   
Report generated by program: pt003014/sasdir/programs/statout/l0404.sas     Version YYYY-MM-DD xx:xx (Page n of N)       
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, and Subject ID. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 212 of 249 
 
 
 
 
Listing 4.5.1 
Relevant Medical and Surgical History 
Analysis Set: All Subjects Randomized 
 
Subject 
ID 
Age/ 
Gender/ 
Race 
Category 
System Organ 
Class 
Diagnosis or 
Surgery/ 
(Preferred Term) 
Onset Date  
Onset 
Day [a] 
Still 
Present? 
End Date 
(Year/ 
Month) 
End 
Day [b] 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
xxxxxx 
xx/x/x 
Drug Allergy 
xxxxxxxx 
xxxxx/(xxxx) 
YYYY-MM 
-xxx 
No 
YYYY-MM 
xxx 
 
Malignancy 
xxxxxx 
xxxxx/(xxxx) 
YYYY-MM 
-xxx 
No 
YYYY-MM 
xxx 
 
 
 
 
 
 
 
xxxxxx 
xx/x/x 
CNS/Neurological 
xxxxxxxxxxxxxxxx xxxxx/(xxxx) 
YYYY-MM 
-xxx 
No 
YYYY-MM 
xxx 
 
Endocrine/Metabolic 
xxxxxxxxxx 
xxxxx/(xxxx) 
YYYY-MM 
-xxx 
Yes 
 
          
Ongoing 
 
 
 
 
 
 
 
xxxxxx 
xx/x/x 
Eyes/Ear/Nose/Throat 
xxxxxxxxxxxx 
xxxxx/(xxxx) 
YYYY-MM 
-xx 
No 
YYYY-MM 
xxx 
 
Hepatic 
xxxxxxxxxxxxxx 
xxxxx/(xxxx) 
YYYY-MM 
-xxx 
No 
YYYY-MM 
xxx 
 
 
 
 
 
 
 
xxxxxx 
xx/x/x 
Other 
xxxxxxxxxx 
xxxxx/(xxxx) 
YYYY-MM 
-xxx 
No 
YYYY-MM 
xxx 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia or  
     New Zealand (indigenous), A=Asian, O=Other.  
[a]   Onset Day=Onset date of condition – date of the first dose of study treatment. Day is imputed as 1st of the month. 
[b]   End Day=End date of condition – date of the first dose of study treatment. Day is imputed as 1st of the month. 
 
Source: xxxxxxx.sas7bdat   
Report generated by program: pt003014/sasdir/programs/statout/l040501.sas     Version YYYY-MM-DD xx:xx (Page n of N)                    
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID, and Onset Day. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 213 of 249 
 
 
 
 
Listing 4.5.2 
Cardiovascular Risk Factors of Interest 
Analysis Set: All Subjects Randomized 
 
Subject 
ID 
Age/ 
Gender/ 
Race 
Cardiovascular History Type of Diabetes Surgery 
Onset Date  
Onset 
Day [a] 
Treated? 
End Date 
(Year/ 
Month) 
End 
Day [b] 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
xxxxxx 
xx/x/x 
Diabetes 
Type II 
 
YYYY-MM 
-xxx 
No 
YYYY-MM 
xxx 
 
High Total Cholesterol 
 
 
YYYY-MM 
-xxx 
No 
YYYY-MM 
xxx 
 
 
 
 
 
 
 
 
xxxxxx 
xx/x/x 
Myocardial Infarction 
 
Angioplasty 
YYYY-MM 
-xxx 
No 
YYYY-MM 
xxx 
 
 
 
Stents 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xx/x/x 
Angina 
Type I 
No Surgery 
YYYY-MM 
-xx 
No 
YYYY-MM 
xxx 
 
 
 
 
 
 
 
 
xxxxxx 
xx/x/x 
Stroke 
 
 
YYYY-MM 
-xxx 
No 
YYYY-MM 
xxx 
 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia or  
     New Zealand (indigenous), A=Asian, O=Other.  
[a]   Onset Day=Onset date of condition – date of the first dose of study treatment. Day is imputed as 1st of the month. 
[b]   End Day=End date of condition – date of the first dose of study treatment. Day is imputed as 1st of the month. 
 
Source: xxxxxxx.sas7bdat   
Report generated by program: pt003014/sasdir/programs/statout/l040502.sas     Version YYYY-MM-DD xx:xx    (Page n of N)                 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID, and Onset Day. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 214 of 249 
 
 
 
 
Listing 4.6 
Screening Reproductive Status and Pregnancy Test Results 
Analysis Set: All Subjects Randomized 
 
Subject ID 
Age(yrs)/Gender  
/Race 
Screening Female 
Reproductive Status 
Pregnancy Test 
Visit 
Type of Pregnancy Test 
Study Day of 
Test [a] 
Result 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
xx/F/xxxx 
NA – Woman of non-
childbearing potential 
Visit 1 
Not Done  
NA 
NA 
 
 
 
 
 
 
 
xxxxxx 
xx/F/O(xxxx) 
Woman of childbearing 
potential  
Visit 1 
Serum Pregnancy Test 
xxx 
Positive 
Etc… 
 
 
 
 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native,  
      ANZ=Australia or New Zealand (indigenous), A=Asian, O=Other.  
a]    Study Day is defined as date of test – date of the first dose of study treatment. 
 
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l0406.sas     Version YYYY-MM-DD xx:xx (Page n of N)     
 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Investigator, Subject ID within 
Center, Visit, and Study Day of Pregnancy Test. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 215 of 249 
 
 
 
 
Listing 4.7 
Prior, Concomitant, and Post-Treatment COPD Medications 
Analysis Set: All Subjects Randomized 
 
Subject 
ID 
Medication 
Verbatim 
Term 
(Preferred 
Term) 
(ATC Term) 
Dose/ 
Unit/ 
Route/ 
Frequency 
Reason 
for 
Use 
Begin Date 
(YYYY-MM-DD) 
Stop Date 
(YYYY-MM-DD) 
Con-
tin- 
uing 
Duration 
(Days) 
Study Day 
Prior/ 
Concomitant/Post-
Treatment 
Begin 
Day 
[a] 
Stop 
Day 
[a] 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
1001 
xxxxxxxxxxxx 
(xxxxxx) 
(xxxxxx) 
90/ MCG/ 
IH/ PRN 
COPD 
2008-XX-XX 
 
Yes 
 
-22 
 
Yes/Yes/No 
 
 
 
 
 
 
 
 
 
 
 
All COPD-related medications taken within 30 days of Screening and while on study are listed.  
Medications were considered to be prior medications if taken prior to the start of study treatment. Medications were considered 
concomitant if they were reported as being taken at any point from the start of randomized study medication to the date of Visit 11a, 
the date of the Discontinuation Visit, or the last contact date (the date of the last in-clinic or last diary data collection or 
after). Medications with an onset date of the date of Visit 11a, the date of a Discontinuation Visit, or the last contact date or 
after were considered post-treatment medications. 
All subjects were allowed sponsor provided Ventolin HFA which was reported on the Concomitant Medications CRF.   
XX = Unknown month or day. 
[a]  A negative number for study day denotes the number of days prior to the start of study treatment. Pxx = Days after last dose. 
                                                                                                                                    
Sources: xxxxxxx.sas7bdat    
                                                                                                      
Report generated by program: pt003014/sasdir/programs/statout/l0407.sas    Version     YYYY-MM-DD xx:xx  (Page n of N)       
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, Country, Center, Subject ID, Preferred Term, and Begin Date of 
COPD medication. Show Anatomic and chemical portion of ATC code. Only medications with Reason for Use of COPD on 
eCRF will be listed here. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 216 of 249 
 
 
 
 
Listing 4.8 
Prior, Concomitant, and Post-Treatment Non-COPD-Related Medications 
Analysis Set: All Subjects Randomized 
 
 
 
 
 
 
 
 
Note to Programmer: Add the following footnote: All non-COPD-related medications taken within 30 days of Screening and while on study are listed.   Show Anatomic and 
chemical portion of ATC code. Only medications with Reason for Use of ‘Other’ on eCRF will be listed here.  Note that 
“Other: <Specify> will be provided in Reason for Use column. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 217 of 249 
 
 
 
 
Listing 4.9 
Suspect Drug Assessment for SAEs 
Analysis Set: All Subjects Randomized 
 
Subject ID 
SAE Verbatim Term/ 
Preferred Term/ 
Onset Date 
Medication 
Dose/ 
Unit/ 
Route/ 
Frequency 
Started 
Treatment/
Start Date 
of  
Study 
Treatment 
Begin Date/ 
Stop Date 
(YYYY-MM-DD) 
Con-
tin- 
uing 
Duration 
(Days) 
Begin Day/ 
Stop Day 
[a] 
SAE Causally 
Related to This 
Product/Does 
Principal 
Investigator 
feel that SAE 
may be related 
to other 
factor? 
(Specify) 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxx 
(x/x) 
 
Xxxxxxxxxxx/ 
Xxxxxxxxx/ 
YYYY-MM-DD 
Ventolin 
HFA 
90/μg/ 
IH/PRN 
Yes/ 
YYYY-MM-
DD/Blinded 
or Open-
Label 
2008-XX-XX 
 
Yes 
 
-22 
Yes / Yes 
(Pre-existing 
/Underlying 
disease or 
Prior or 
Concomitant 
Medication 
 xxxx 
(x/x) 
 
Xxxxxxxxxxx/ 
Xxxxxxxxx/ 
YYYY-MM-DD 
Atrovent 
HFA 
34/μg/ 
IH/QID 
No 
2008-XX-XX/ 
2008-XX-XX 
No 
5 
T1_P1/ 
T1_P5 
No 
 
 
 
 
 
 
 
 
 
 
XX = Unknown month or day. 
[a] A negative number for study day denotes the number of days prior to the start of study treatment. Otherwise, Study Day is Date – 
Date of first dose in the Period + 1. Tx_y = Treatment Period and Day within Treatment Pxx = Days after last dose in period. 
 
Sources: xxxxx.sas7bdat 
Report generated by program: PT003013/final/programs/statout/l0409.sas    Version    YYYY-MM-DD xx:xx    (Page x of y) 
 
 
 
 
 
 
Notes to Programmer: for last column, 2nd question, “Does Principal Investigator feel that SAE may be 
related to other factor? (Specify)”) is only listed on first line for each subject.  


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 218 of 249 
 
 
 
 
4.5 Dosing and Compliance 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 219 of 249 
 
 
 
 
Listing 5.1.1 
Study Drug Dosing, Dispensing, and Return 
Analysis Set: All Subjects Randomized 
 
Subject ID Visit 
Dispensed/ 
Dosing/ 
Returned 
Date  
Dispensed/ 
Returned 
Study Day [a] 
(Time of On-
Site Dose) 
 (24 hr clock) 
Primary/ 
Replacement 
Kit  
Study 
Medication 
Component ID 
Was 
Replacement 
Kit used? 
Dose Indicator 
Reading for 
Visit Dispensed/ 
Returned 
(Major discrepancy 
between eDiary and 
Dose Indicator 
reading as read by 
the site?) 
Week 2 
Dose Indicator 
Reading 
(Pre-dose / 
Post-dose) 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
xxxxxx 
 
Day 1 
Dispensed PD 
 
    1 (hh:mm) 
xxxxx  
 
 
 
Dispensed PD 
YYYY-MM-DD 
 
xxxxx  
 
 
 
Dispensed RD 
YYYY-MM-DD 
 
xxxxx  
 
 
Week 2 Dosing P 
 
15 (hh:mm) 
xxxxx 
(yes, subject error, 
site error, other: 
xxxxxxxx) 
xxx/xxx 
 
 
Dosing R 
xx (hh:mm) 
xxxxx  
(yes, subject error, 
site error, other: 
xxxxxxxx) 
xxx/xxx 
 
 
Dispensed R 
YYYY-MM-DD 
 
xxxxx  
xxx 
 
 
 
Returned  
YYYY-MM-DD 
 
xxxxx  
 
 
 
 
Week 4 Returned P 
YYYY-MM-DD 
xx (hh:mm) 
xxxxx  Yes 
xxx 
(yes, subject error, 
site error, other: 
xxxxxxxx) 
 
 
 
Returned R 
YYYY-MM-DD 
xx (hh:mm) 
xxxxx   
xxx 
(yes, subject error, 
site error, other: 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 220 of 249 
 
 
 
 
xxxxxxxx) 
 
Etc… 
 
 
 
 
 
PD = primary kit dispensed. 
RD = replacement kit dispensed. 
P = primary study drug dosing at visit. 
R = replacement kit used at the visit. 
Major discrepancy is defined as a >20 puff difference as per Protocol Section 7.1.5. 
[a]   Study Day = Date of on-site study medication dose – First dose of study treatment in the study + 1. 
Source: xxxxxxx.sas7bdat   
Report generated by program: pt003014/sasdir/programs/statout/l050101.sas     Version YYYY-MM-DD xx:xx  (Page n of N)                   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID within Center, Visit, 
Dispensed/Dosing/Returned. An asterisk will be 
placed next to a kit number where it is known that 
the kit did not contain the randomized assigned 
treatment. In the event that this happens, a 
footnote will be added to indicate ‘* = test kit 
did not contain the randomized assigned 
treatment’. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 221 of 249 
 
 
 
 
Listing 5.1.2 
Atrovent HFA and Ventolin HFA Dispensing 
Analysis Set: All Subjects Randomized 
 
Subject ID 
Atrovent HFA/Ventolin HFA 
Date Dispensed 
Component ID 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
xxxxxx 
 
Atrovent HFA 
YYYY-MM-DD 
Xxxxxx 
 
Ventolin HFA 
YYYY-MM-DD 
Xxxxxx 
 
 
 
Source: xxxxxxx.sas7bdat   
Report generated by program: pt003014/sasdir/programs/statout/l050102.sas     Version YYYY-MM-DD 
xx:xx  (Page n of N)                               
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID within Center, and 
Atrovent HFA/Ventolin HFA. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 222 of 249 
 
 
 
 
Listing 5.2 
Compliance and Exposure to Study Treatment 
Analysis Set: All Subjects Randomized 
 
Subject 
ID 
Age 
(yrs) 
Gender 
Race 
Treatment 
Day 
Number of Puffs 
Overall 
Compliance 
    [c] 
 (%) 
Exposure 
(days) 
[d] 
Taken 
Expected 
[a] 
Daily 
Compliance 
   [b] 
(%) 
Taken 
Overall 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
58 
Male 
W 
1 
4 
4 
xxx.x 
xx 
xx.xx 
xxx.x 
 
 
 
 
2 
4 
x 
xxx.x 
xx 
 
 
 
 
 
 
3 
x 
x 
xxx.x 
xx 
 
 
 
 
 
 
4 
x 
x 
xxx.x 
xx 
 
 
 
 
 
 
5 
x 
x 
xxx.x 
xx 
 
 
 
 
 
 
6 
x 
x 
xxx.x 
xx 
 
 
 
 
 
 
7 
x 
x 
xxx.x 
xx 
 
 
 
 
 
 
Etc... 
 
 
 
 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native,  
      ANZ=Australia or New Zealand (indigenous), A=Asian, O=Other.  
[a]   The expected number of puffs for a test day which was the last date of treatment was 2, the expected number of puffs for the  
      last date of treatment which was not a test day was 4 when a PM dose was taken and then 2 otherwise; the expected number of  
      puffs on dates prior to the last date of treatment was 4. 
[b]   Daily compliance = (# of puffs of study treatment taken / # of puffs of study treatment expected) x 100. 
[c]   Overall % Compliance = (total number of puffs of study treatment taken on a study day/total expected puffs taken on a study day) 
      averaged across all days of a subject’s dosing between start of study treatment and last day on study treatment x 100.  
[d]   Exposure = last date of study treatment – first date of study treatment + 1).  
 
Sources: xxxxxxx.sas7bdat 
 
Report generated by program: pt003014/sasdir/programs/statout/l0502.sas              Version YYYY-MM-DD xx:xx  (Page n of N)   
                                                                                                                                     
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID within Center, and 
Treatment Day. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 223 of 249 
 
 
 
 
4.6 Individual Efficacy Data and HCRU Data 
 
4.6.1 Efficacy 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 224 of 249 
 
 
 
 
Listing 6.1.1 
Subjects Who Failed Restrictions Prior to Spirometry Assessment 
Analysis Set: All Subjects Randomized 
                                                                                                                                       
Subject 
ID 
 
 
 
Visit 
Study Time 
Window of 
Assessment 
Effort 
Date 
Effort 
Time 
(24 hr 
clock) 
Prior to Study Visit, Subject has 
Not Smoked for 
at Least 4 
Hours  
Not Had Xanthine 
Containing 
Products for at 
Least 6 Hours  
Withheld COPD Medications 
Including Corticosteroids 
for at Least 6 Hours 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
Day 1 
Pre-dose  
60 Min 
YYYY-MM-DD 
8:14:57 
No 
No 
 
Note that subjects with missing data for any of the 3 restrictions are also listed. 
  
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l060101.sas         Version YYYY-MM-DD xx:xx           (Page n of N)        
 
 
 
 
 
 
Notes to Programmer: Sort by Randomized Treatment, Country, Center, Subject ID, and Effort Date. 
If Race is ‘O’ (other), concatenate it with the specified race.  Only subjects with ‘No’ or 
missing responses should be listed. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 225 of 249 
 
 
 
 
Listing 6.1.2 
Reason for Missingness Overall and by Visit 
Analysis Set: All Subjects Randomized 
 
Subject 
ID 
Visit (Study 
Day) 
Assessment Missed  
Reason Assessment Missed 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
Missing from 
Week xx 
Onward (xx) 
Change in Morning Pre-
dose Trough FEV1/TDI 
Reason for Early Discontinuation from CRF 
xxxxxx 
Day 1 (xx) 
TDI  
TDI not assessed at the visit. 
 
Week 12 (xx) 
Change in Morning Pre-
dose Trough FEV1 
Spirometry Grade 3 assessment is missing. 
 
Week 20 (xx) 
Change in Morning Pre-
dose Trough FEV1/TDI 
Visit missed for reasons of COPD-Related, Not COPD-Related, or Unknown. 
Source: xxxxxxx.sas7bdat  
 
Report generated by program: pt003014/sasdir/programs/statout/l060102.sas   Version YYYY-MM-DD xx:xx     (Page n of N) 
 
 
 
 
 
 
 
                                        
 
Notes to Programmer: Sort by Randomized Treatment, 
Country, Center, Subject ID within Center, and 
Overall/Visit. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 226 of 249 
 
 
 
 
Listing 6.1.3 
Spirometry Measurements 
Analysis Set: All Subjects Randomized 
 
 
Subject 
ID 
 
Age 
(yrs)/ 
Gender/ 
Race/ 
Height 
(cm) 
 Visit 
Treatment 
Date/Time 
(24 hr clock) 
Assessment 
Date 
Ventolin 
HFA used? 
(Time) 
Study Time 
Window  
(Actual Time 
of 
Assessment 
24 hr clock) 
Spirometry Assessments 
Raw Value 
[Predicted Value at Screening] 
(Percent of Predicted Value) 
(grade) [a]  
FEV1 (L) 
FEV6 
(L) 
FVC (L) 
FEV1/ 
FVC(%) 
FEF 
25-75 
(L/sec) 
 
PEFT (ms) 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 53/F/W/xx
x 
 Visit 1 
 
YYYY-MM-DD 
Yes 
(xx:xx 
AM/PM) 
 NA (xx:xx) 
x.xxx 
[x.xxx] 
(xx.x) 
(x) 
x.xxx 
x.xxx 
[x.xxx] 
(xx.x) 
(x) 
xx.x 
x.xxx 
[x.xxx] 
(xx.x) 
 
xxx 
 
 
Repeat for 
Visit 2, 
Visit 3,  
Day 1 and 
all  
other 
visits. 
YYYY-MM-DD 
hh:mm 
YYYY-MM-DD 
Yes 
(xxxxxx) 
Pre-dose xx 
Min (xx:xx) 
x.xxx 
(xx.x) 
(x) 
x.xxx 
x.xxx 
(xx.x) 
(x) 
xx.x 
x.xxx 
(xx.x) 
 
xxx 
NA = Not applicable. 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia or  
      New Zealand (indigenous), A=Asian, O=Other 
[a]  Grade is coded: 1=Acceptable   2=Borderline Acceptable  3=Unacceptable.  
 
Source: xxxxxxx.sas7bdat  
Report generated by program: pt003014/sasdir/programs/statout/l060103.sas   Version YYYY-MM-DD xx:xx                (Page n of N)  
 
 
 
 
                                                         
 
 
Notes to Programmer: Sort by Randomized Treatment, Country, Center, Subject ID, Assessment 
Date, and Nominal Time of Assessment. Show Predicted Value only for Screening Visits. 
Study Time Window is the SAP-specified derived time window. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 227 of 249 
 
 
 
 
Listing 6.1.4 
FEV1 (L) at Each Post-dose Timepoint Through 2 Hours on a Test Day 
Analysis Set: ITT Population 
 
Subject ID 
Age 
(yrs)/ 
Gender/ 
Race 
Visit 
FEV1 Pre-dose 
FEV1 Post-dose 
 
60 Min/ 
30 Min  
5 Min  
15 Min  
30 Min  
1 Hour 
 
2 Hours 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
 
xx/F/x 
Day 1 
x.xxx/ 
x.xxx 
 
x.xxx 
 
x.xxx 
 
 
x.xxx 
 
x.xxx 
 
x.xxx 
 
 
 
 
Week 
xx 
x.xxx/ 
x.xxx 
 
 
x.xxx 
 
x.xxx 
 
x.xxx 
 
x.xxx 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native,  
      ANZ=Australia or New Zealand (indigenous), A=Asian, O=Other. 
 
Source: xxxxxxx.sas7bdat 
 
Report generated by program: pt003014/sasdir/programs/statout/l060104.sas  Version YYYY-MM-DD xx:xx     (Page n of N) 
 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Randomized 
Treatment, Country, Center, Subject, and Visit.  


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 228 of 249 
 
 
 
 
Listing 6.1.5 
FVC (L) at Each Post-dose Timepoint Through 2 Hours on a Test Day 
Analysis Set: ITT Population 
 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 229 of 249 
 
 
 
 
Listing 6.1.6 
Subject Dosing and Symptoms Diary, Including Rescue Ventolin Use 
Analysis Set: All Subjects Randomized 
 
Subject 
ID 
Study Day 
[a] 
 
Morning 
or 
Evening 
Took study med? / Study med time 
Number of puffs of study med 
Did your dose indicator display a 
reading of 10 or 0? 
(Dose indicator reading) 
Do you have a clinic visit tomorrow? 
Did you open your drug replacement 
package? / How many times did you 
trigger the device after opening 
package or cleaning the device? 
Symptoms Questions 
Rescue 
Ventolin 
Use 
How 
often 
coughed 
last 
night 
(today) 
How much 
mucus 
(phlegm) 
did you 
cough up 
last 
night 
(today)? 
AM: How short 
of breath were 
you last 
night? 
PM: Did you 
feel short of 
breath today?  
When did 
you feel 
short of 
breath 
today? 
How many 
times did 
you wake 
up last 
night? 
 
Number of 
Puffs since 
last/ AM/PM 
study med 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
 
Screening 
 
AM 
PM 
N/A / N/A 
NA 
NA 
NA 
NA 
NA/NA 
Not at 
all, 
Rarely, 
Frequent
ly, 
Almost 
constant
ly 
 
<1 tsp 
1-2 tsp 
>2 tsp 
Not at all, 
Mild, 
Moderate, 
Severe, and 
Very Severe  
 
Yes No, active 
Or  
No, rested. 
Or  
During 
exercise 
xx 
xx 
 
 
Day 3 
 
   AM 
   PM 
(No, I have a clinic visit today, NA / 
Yes hh:mm)  
Xx 
Yes/no 
(xx) 
No 
Yes/No) / x 
Not at 
all, 
Rarely, 
Frequent
ly, 
Almost 
constant
ly 
 
<1 tsp 
1-2 tsp 
>2 tsp 
Not at all, 
Mild, 
Moderate, 
Severe, and 
Very Severe  
 
Yes No, active 
Or  
No, rested. 
Or  
 
During 
exercise 
xx 
xx 
 
 
 
 
 
 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 230 of 249 
 
 
 
 
 
NA = Not Applicable. 
[a]   Study Day = Diary card date - Date of first dose of study treatment + 1. 
How Often Coughed: not at all (0), rarely (1), frequently (2), almost constantly (3). 
How much mucus: none (0), <1 tsp (1), 1-2 tsp (2), >2 tsp (3). 
How short of breath were you last night? Not at all (0), mild (1), moderate (2), severe (3), or very severe (4). 
Did you feel short of breath Not at all, and I was active (0); not at all, and I rested today (1); 
When Short of Breath: During exercise (2); walking up stairs, uphill, or quickly (3); walking slowly or during light activity (4); 
washing or dressing (5); Sitting or resting (6). 
Times woke up last night: 0, 1, 2, 3, 4, 5 or more times, I was awake most or all of the night. 
 
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l060106.sas   Version   YYYY-MM-DD xx:xx           (Page n of N) 
 
 
 
 
 
 
 
 
 
 
 
 
Note to Programmer: Sort by Randomized Treatment, 
Country, Center, Subject ID within Center, Diary 
Day, and AM/PM. Number of puffs of study 
medication: 2 or Other.  


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 231 of 249 
 
 
 
 
Listing 6.1.7 
COPD Exacerbations 
Analysis Set: All Subjects Randomized 
 
Subject ID 
Age (yrs)/ 
Gender/ 
Race 
Study 
Day  
[a] 
Start Date 
End Date 
Ongoing 
Were 
antibiotics 
administered? 
(Number of 
Days Dosed) 
Severity 
Were injected 
or oral 
cortico-
steroids 
administered? 
(Number of 
Days Dosed) 
Was subject 
hospitalized? 
Did the 
Exacerbation 
Result in 
Death 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
Xxxxxx 
xx/F/W 
 -xx 
YYYY-MM-DD 
YYYY-MM-DD 
 
Yes 
(xx) 
 
No 
No 
No 
 
 1 
YYYY-MM-DD 
YYYY-MM-DD 
Yes 
No 
 
Moderate 
Yes 
(xx) 
Yes 
No 
 
xx 
YYYY-MM-DD 
YYYY-MM-DD 
No 
 
No 
 
Severe 
Yes 
(xx) 
Yes 
Yes 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native,  
      ANZ=Australia or New Zealand (indigenous), A=Asian, O=Other. 
 [a]  A negative number for study day denotes that the number of days prior to the start of study treatment Pxx = Days after the last  
      dose.                                             
                                                                                      
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l060107.sas  Version YYYY-MM-DD xx:xx       (Page n of N) 
 
 
 
 
 
 
Notes to Programmer: Severity is taken from the 
SAE CRF. Sort by Randomized Treatment, Country, 
Center, Subject ID within Center, Start Date and 
End Date/Ongoing. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 232 of 249 
 
 
 
 
Listing 6.1.8 
Baseline Dyspnea Index (BDI) /Transition Dyspnea Index (TDI) 
Analysis Set: All Subjects Randomized 
 
Subject 
ID 
Visit 
BDI/TDI 
Tiredness 
Score 
(practice) 
BDI/TDI Focal Score 
BDI/TDI Functional 
Impairment 
Component Score 
 
BDI / TDI Magnitude of 
Task 
Component Score 
BDI/TDI Magnitude of 
Effort 
Component Score 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
Week 
6 
x/x 
 
x/x 
x/x 
x/x 
x/x 
 
Week 
xx 
x/x 
 
x/x 
 
x/x 
x/x 
x/x 
NA = Not Applicable. 
Baseline is Day 1 (Visit 4). BDI scores range from 0 (very severe impairment) to 4 (no impairment); the BDI focal score, 
from 0 to 12, where the lower the score, the worse the severity of dyspnea.  The TDI Component scores range from -3 (major 
deterioration) to +3 (major improvement); the TDI focal score ranges from -9 to +9, where the lower the score, the more 
deterioration in the severity of dyspnea. 
 
Source: xxxxxxx.sas7bdat  
 
Report generated by program: PT003014/sasdir/programs/statout/l060108.sas  Version YYYY-MM-DD xx:xx       (Page n of N) 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID within Center, and 
Over 24 Weeks/Week xx. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 233 of 249 
 
 
 
 
Listing 6.1.9 
St. George Respiratory Questionnaire (SGRQ) 
Analysis Set: All Subjects Randomized 
 
Subject ID 
 
Visit 
Baseline/Weekly Visit Values 
SGRQ 
Total Score 
Symptoms 
Domain Score 
Activity 
Domain Score 
Impacts 
Domain Score 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
 
Week 
12 
x.xx/x.xx 
 
x.xx/x.xx 
 
x.xx/x.xx 
 
x.xx/x.xx 
 
 
Week 
xx 
x.xx/x.xx 
 
x.xx/x.xx 
 
x.xx/x.xx 
 
x.xx/x.xx 
 
NA = Not Applicable. 
Baseline is Day 1 (Visit 4). 
SGRQ total and domain scores are percentages ranging from 0 to 100, where higher values represent greater impairment of 
quality of life. 
 
Source: xxxxxxx.sas7bdat 
 
Report generated by program: pt003014/sasdir/programs/statout/l060109.sas  Version YYYY-MM-DD xx:xx       (Page n of N) 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID within Center, and Day 
1/Week xx.  


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 234 of 249 
 
 
 
 
Listing 6.1.10 
Individual Items of the St. George Respiratory Questionnaire (SGRQ) 
Analysis Set: All Subjects Randomized 
 
Subject ID 
Visit 
Individual Item on the Questionnaire 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
155 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
49 
51 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
Day 1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Week 
6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Week 
xx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
NA = Not Applicable. 
Please refer to Appendix 7 of the protocol for Individual item questions and response.  
 
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l060110.sas  Version YYYY-MM-DD xx:xx (Page n of N) 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID within Center, and 
Over 24 Weeks/Week xx. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 235 of 249 
 
 
 
 
4.6.2 Healthcare Resource Utilization 
 
Listing 6.2 
Healthcare Resource Utilization 
Analysis Set: Safety Population 
 
Subject ID 
 
 
Days Missed From 
Work 
 
Since the last visit? 
Hospitalizations 
Visit 
By 
Subject 
By 
Family 
Members 
of 
Subject 
COPD 
Related? 
Calls to 
Health 
Care 
Provider 
(Number) 
Visits to 
Health Care 
Provider 
(Number) 
ER 
Visits 
(Number) 
Hospitalized?
(Number of 
Days) 
ICU 
(Number  
of  
Days) 
CCU 
(Number 
Of 
 Days) 
Intubated? 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx 
 
Day 1 
x 
 
NA 
 
Yes 
Yes 
(x) 
Yes 
(x) 
Yes 
(x) 
Yes 
(x) 
 
Yes 
(x) 
No 
(NA) 
Yes 
Week 
xx 
x 
 
NA 
 
No 
Yes 
(x) 
Yes 
(x) 
Yes 
(x) 
Yes 
(x) 
 
Yes 
(x) 
Yes 
(x) 
No 
xxxxxx 
 
Day 1 
NA, 
 
x 
 
Yes 
Yes 
(x) 
Yes 
(x) 
Yes 
(x) 
No 
(NA) 
 
NA 
(NA) 
NA 
(NA) 
NA  
Week 
xx 
NA, 
 
x 
 
Yes 
Yes 
(x) 
Yes 
(x) 
Yes 
(x) 
No 
(NA) 
 
NA 
(NA) 
NA 
(NA) 
NA 
NA = Not Applicable.  
 
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l0602.sas  Version YYYY-MM-DD xx:xx  (Page n of N) 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 236 of 249 
 
 
 
 
4.7 Adverse Event Listings 
 
Listing 7.1 
Adverse Events by Primary System Organ Class, Preferred Term, Treatment, Country, Center, Subject ID, and Onset Day 
Analysis Set: All Subjects Randomized 
 
Primary System Organ Class:  xxxxxxxxxxxxxxxxx 
Preferred Term 
Treatment 
Country 
Center # 
(Investigator) 
Subject 
ID 
(Age / 
Gender/ 
Race) 
Treatment 
Emergent / 
Serious AE? 
Onset 
Date 
(Day) 
[a]/ Occur 
before or 
after 
start of a 
treatment 
On Day 1  
 
Dura-
tion 
of  
Event 
Severity / 
Relationship 
Action / Outcome  
(AE Treated ) 
Study Day 
Resolved 
/Death[a] 
 
 
 
xxxxxxxxxxxxxxxx 
xxxxxxxxx
xxxxxxx  
xxxxxxxxx ### 
(xxxxxxxxxx) 
xxxxxx 
(61/F/W) 
Yes / No 
YYYY-MM-DD 
(P1)/NA 
xx 
Moderate / 
Probably 
None/Resolved 
(Yes) 
P5 
xxxxxx 
(xx/x/x) 
Yes / No 
YYYY-MM-DD 
 (10)/NA 
xx 
Moderate/ 
Possibly 
Interrupted / 
Ongoing (Yes) 
 
 
 
 
 
 
 
 
xxxxxxxxx
xxxxxxx  
xxxxxxxxx 
### 
(xxxxxxxxxx) 
xxxxxx 
(xx/x/x) 
Yes / Yes 
YYYY-MM-DD 
(4)/NA 
xx 
xxxxxxxx/ 
xxxxxxxxx 
None/ 
Ongoing (No) 
 
xxxxxxxx 
### 
(xxxxxxxxxx) 
xxxxxx 
(xx/x/x) 
Yes / No 
YYYY-MM-DD 
(2)/NA 
xx 
xxxxxxxx/ 
xxxxxxxxx 
None/ 
Ongoing (No) 
 
… 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxxxxxxxx
xx 
xxxxxxxxx
xxxxxxx  
xxxxxxxxxx 
### 
(xxxxxxxxxx) 
xxxxxx 
(xx/x/x) 
No /No 
YYYY-MM-DD 
(1)/Before 
xx 
xxxxxxxx/ 
xxxxxxxxx 
None/ Resolved 
(Yes) 
 
xxxxxx 
(xx/x/x) 
Yes / Yes 
YYYY-MM-DD 
(3)/NA 
xx 
xxxxxxxx/ 
xxxxxxxxx 
Permanently 
Discontinued / 
Ongoing 
(Yes) 
 
 
 
 
 
 
 
 
xxxxxxxxxxxxxxxxxxx xxxxxxxxx
x 
### 
(xxxxxxxxxx) 
xxxxxx 
(xx/x/x) 
Yes / Yes 
YYYY-MM-DD 
(65) 
xx 
xxxxxxxx/ 
xxxxxxxxx 
None/ 
Resolved (No) 
 
 
 
 
 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia  
     or New Zealand (indigenous), A=Asian, O=Other. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 237 of 249 
 
 
 
 
[a]  A negative number for study day denotes the number of days prior to the start of study treatment. 
    Pxx = Days after last dose. 
Source: xxxx.sas7bdat 
generated by program: pt003014/sasdir/programs/statout/l0701.sas    Version YYYY-MM-DD xx:xx  (Page n of N)              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Primary System Organ 
Class, Preferred Term, Actual Treatment, Country, 
Center, Subject ID within Center, and Onset Day.  
Put a blank line after each Center. Present the 
preferred term, treatment, country, center 
(investigator name), Subject ID (Actual Treatment 
and Age/gender/Race only if start a new value or 
at the first line of each page. 
When a date of onset or date resolved is only 
partial, put full date in parenthesis under Study 
Day. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 238 of 249 
 
 
 
 
Listing 7.2 
Glossary of Adverse Event Preferred Terms vs. Investigator’s Verbatim 
 
MedDRA Adverse Event Coding Dictionary 
Investigator’s AE Verbatim 
Primary System Organ Class 
Preferred Term 
 
xxxxxxxxxxxxxxx 
 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
xxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
xxxxxxxxxxxx 
 
 
 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxx 
 
 
xxxxxxxxxx 
 
xxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
xxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxx 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
MedDra Version xx.x was used for coding. 
 
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l0702.sas     Version YYYY-MM-DD xx:xx    (Page n of N) 
 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Primary System Organ 
Class, Preferred Term, and Verbatim Term. List all 
unique investigators’ AE verbatim. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 239 of 249 
 
 
 
 
Listing 7.3 
Adverse Events by Treatment, Country, Center, Subject ID, and Onset Day 
Analysis Set: All Subjects Randomized 
 
Subject ID 
(Age/ 
Gender/ 
Race) 
Onset 
Date 
(Day) 
[a] 
Primary System 
Organ Class 
AE Verbatim  
(Preferred Term)  
Onset 
Date 
(Day) 
[a]/ Occur 
before or 
after start of 
a treatment 
On Day 1  
Duration 
of Event 
Sever-
ity 
Relation
-ship Action 
AE 
Treated? 
Outcome 
(Death?) 
Day 
Resolved
/ Death 
[b] 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
Xxxxxx 
(61/F/W) 
YYYY-
MM-DD 
(P1) 
xxx xxx xxxxx AE 1 
(xxxxxxxxxxxx) 
YYYY-MM-DD  
(P1)/NA 
xx 
Moderat
e 
 
Not 
related 
None 
No 
Ongoing 
xxx xxx xxxx 
AE 2  
(xxxxxxxxxx) 
YYYY-MM-DD  
 (10)/NA 
xx 
Moderat
e  
Possibly Interrup
ted  
Yes 
Resolved 
(Yes) 
P3 
… 
… 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia  
     or New Zealand (indigenous), A=Asian, O=Other. 
[a]   @ indicates that it could not be determined whether the AE had onset during study treatment.                                     
[b]   A negative number for study day denotes the number of days prior to the start of study treatment. Pxx = Days after last dose.    
                                                                                                                                       
Sources: adae.sas7bdat                                                                                                                 
                                                                                                                                       
Report generated by program: pt003014/sasdir/programs/statout/l0703.sas              Version YYYY-MM-DD xx:xx   (Page n of N) 
 
 
 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID, Primary System Organ 
Class, Preferred Term, and Onset Day. Put a blank 
line after each subject. Present the preferred 
term, latest treatment, country, center 
(investigator name), Subject ID, and 
Age/gender/Race when value changes start a new 
value or at the first line of each page.                             


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 240 of 249 
 
 
 
 
See Section 3 Tables 3.8.1 and 3.8.2 for Serious Adverse Events data listings. 
 
 
See Section 3 Table 3.6 for data listing of adverse events leading to permanent study discontinuation. 
 
 
See Section 3 Table 3.13 for data listing of deaths. 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 241 of 249 
 
 
 
 
4.8 Laboratory Values 
 
Listing 8.1 
Laboratory Test Results (Hematology Panel) 
Analysis Set: All Subjects Randomized 
 
Subject ID 
Age (yrs) 
/Gender /Race Visit 
Treatment 
Time (24 
hr clock) 
Collection 
Date 
(Study 
Day) 
[a] 
Nominal 
Time of 
Collection 
Study Time 
Window of 
Assessment/ 
(Actual  
Time of 
Collection 
[24 hour 
clock]) 
Lab Name  
Lab 
Parameter 
(Unit) 
Assay 
Value 
Reference 
Range 
Low-High 
Flag 
[b] 
Change 
From 
Baseline 
[c] 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
xxxxxx  
 
58/M/W 
Day 1 
 
10:13 
YYYY-MM-DD 
(1) 
PREDOSE  
Pre-dose 60 
Min (09:30) 
 
 
xxxxxx xxxxxxxxxx xxx 
xxx-xxx 
L/H 
x.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia  
     or New Zealand (indigenous), A=Asian, O=Other.                                          
[a]   A negative number for study day denotes the number of days prior to the start of study treatment. Pxx = Days after last dose. 
[b]   L = Low; H = High.                                                     
[c]   For change from baseline, baseline is defined as the last available measurement prior to the start of treatment on Day 1  
     (Visit 4). 
Source: adlb.sas7bdat    
                                                                                                                                      
Report generated by program: pt003014/sasdir/programs/statout/l0801.sas  Version YYYY-MM-DD xx:xx  (Page n of N)                       
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, Country, Center, Subject ID, Date of Visit, Nominal Time of 
Collection, and Lab Parameter.   Add ‘I = Indeterminate’ if the dataset contains an Indeterminate value.  Check the 
dataset for other flags that need to be added here. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 242 of 249 
 
 
 
 
Listing 8.2 
Laboratory Test Results (Morphology) 
Analysis Set: All Subjects Randomized 
 
 
Listing 8.3 
Laboratory Test Results (Chemistry Panel and Kidney Function) 
Analysis Set: All Subjects Randomized 
 
 
Listing 8.4 
Laboratory Test Results (Urinalysis Panel) 
Analysis Set: All Subjects Randomized 
 
 
 
 
 
 
 
 
Notes to Programmer: The change from baseline column is 
not needed for this data listing. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 243 of 249 
 
 
 
 
Listing 8.5 
Laboratory Test Comments 
Analysis Set: All Subjects Randomized 
                                                                                              
Subject ID 
Date 
(Study 
Day) [a] 
Study Time 
Window of 
Assessment 
Lab 
Name 
Lab Group 
Lab Parameter 
(Unit) 
Assay 
Value 
Reference 
Range 
Low-High 
 
Flag 
[b] 
Result Comments 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxxx  
 
YYYY-MM-
DD 
(P7) 
Pre-dose 60 
Min 
LabCorp 
Chemistry 
Bicarbonate 
(mmol/L) 
18.000 
19-34 
L 
xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[a]  A negative number for study day denotes the number of days prior to the start of study treatment. Pxx = Days after last dose. 
[b]  N = Normal: L = Low; H = High; Abn. = Abnormal.                                                     
                                                                                                                                       
Source: adlb.sas7bdat    
                                                                                                                                         
Report generated by program: pt003014/sasdir/programs/statout/l0805.sas  Version YYYY-MM-DD xx:xx  (Page n of N)   
 
 
 
 
 
 
 
See Section 3 Tables 3.14.9 to 3.14.11 for potentially clinically significant value listings. 
 
 
Notes to Programmer: Sort by Actual Treatment, Country, Center, Subject ID, Date of Visit, Nominal Time of 
Collection, and Lab Parameter.                  


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 244 of 249 
 
 
 
 
4.9 Other Clinical Observations and Measurements 
 
Listing 9.1 
Vital Signs, Weight, and Height 
Analysis Set: All Subjects Randomized 
 
 
Subject 
ID 
Age 
(yrs)/ 
Gender/ 
Race 
Visit 
Visit Date 
(Study Day) [a] 
Time of 
treatment 
(24 hr 
clock) 
Nominal 
Time of 
Assessment 
Study Time 
Window (Actual 
Time) of 
Assessment 
(24 hr 
clock) 
 
Temperature 
(Change from 
baseline) 
[b] 
(oC) 
Systolic BP 
(Change from 
baseline) 
[b] 
(mmHg) 
Diastolic BP 
(Change from 
baseline) 
[b] 
(mmHg) 
Heart Rate 
(Change from 
baseline) 
[b] 
(beats/min) 
Height 
(cm) 
Weight 
(kg) 
BMI 
(kg/m2)
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4 μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
Xxxxxx 
58/M/W 
Visit 1 
YYYY-MM-DD 
(-xx) 
NA 
NA (NA) 
xx.x 
xxx 
xxx 
xx 
xxx 
xxx.x 
xxx.x 
 
Visit 2 
YYYY-MM-DD 
(-xx) 
NA 
NA (NA) 
xx.x 
xxx 
xxx 
xx 
xxx 
xxx.x 
xxx.x 
 
Visit 3 
YYYY-MM-DD 
(-xx) 
NA 
NA (NA) 
xx.x 
xxx 
xxx 
xx 
xxx 
xxx.x 
xxx.x 
 
Day 1 
YYYY-MM-DD 
(1) 
 hh:mm 
Pre-dose 
xx Min.  
Pre-dose xx 
Min (xx:xx) 
(xx) 
xx.x (xx.x) 
or NA 
xxx  
xxx  
xx  
 
 
 
 
 
Post-dose 
x Hours 
Post-dose x 
Hours (xx:xx) 
(xx) 
xx.x (xx.x) 
or NA 
xxx (xx) 
xxx (xx) 
xx (xx) 
 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
Week xx 
YYYY-MM-DD 
(xx) 
 hh:mm 
Pre-dose 
xx Min. 
Pre-dose xx 
Min (xx:xx) 
(xx) 
xx.x (xx.x) 
or NA 
xxx (xx) 
xxx (xx) 
xx (xx) 
 
 
 
 
 
Post-dose 
x Hours 
Post-dose x 
Hours (xx:xx) 
(xx) 
xx.x (xx.x) 
or NA 
xxx (xx) 
xxx (xx) 
xx (xx) 
 
 
 
 
 
Etc… 
 
 
 
 
 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 245 of 249 
 
 
 
 
 
Unscheduled 
YYYY-MM-DD 
(Pxx) 
NA 
as appropriate xx.x (xx.x) 
or NA 
xxx (xx) 
xxx (xx) 
xx (xx) 
xxx 
xxx.x 
xxx.x 
 
Etc… 
 
 
 
 
 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia or  
     New Zealand (indigenous), A=Asian, O=Other. 
[a]   A negative number for study day denotes the number of days prior to the start of study treatment. Pxx = Days after last dose.     
[b]   For change from baseline, baseline is defined as the average of the pre-dose measurements taken prior to the start of treatment 
     at Day 1 (Visit 4). 
Source: advs.sas7bdat 
                                                                                                                                       
Report generated by program: pt003014/sasdir/programs/statout/l0901.sas  Version    YYYY-MM-DD xx:xx  (Page n of N)                     
 
 
 
 
 
                                                                                                          
 
 
 
See Section 3 Tables 3.15.3 and 3.15.4 for listing of potentially clinically significant systolic and 
diastolic blood pressure values, tachycardia and bradycardia. 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID, Date of Visit, and 
Nominal Time of Assessment.  Show Nominal 
Window of ‘Pre-dose’ from dataset as “Pre-dose 
60 Min.” here in this listing as indicated 
above. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 246 of 249 
 
 
 
 
Listing 9.2 
12-Lead Electrocardiogram (ECG) 
Analysis Set: All Subjects Randomized 
 
 
Subject 
ID 
Age 
(yrs)/ 
Gender/ 
Race 
Visit 
Visit Date 
(Study Day) [a] 
Treatment 
Time  
(24 hr 
clock) 
Nominal Time 
of Assessment 
Study Time 
Window (Actual 
Time) of 
Assessment 
(24 hr clock) 
Heart 
Rate 
(Change) 
 (BPM) 
Interval Raw Value  
(Change From Baseline) [b] 
Any 
Clinically 
Significant 
Abnormalities? 
RR 
(ms) 
PR 
(ms) 
QRS 
Axis 
(ms) 
QRS 
(ms) 
QT 
(ms) 
QTcF 
(ms) 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4 μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
Xxxxxx 
58/M/W 
Visit 1 
YYYY-MM-DD 
(-xx) 
NA 
NA (NA) 
xx.x 
xxx 
xxx 
xx 
xxx 
xxx 
xx 
No 
 
Visit 2 
YYYY-MM-DD 
(-xx) 
NA 
NA (NA) 
xx.x 
xxx 
xxx 
xx 
xxx 
xxx 
xx 
No 
 
Visit 3 
YYYY-MM-DD 
(-xx) 
NA 
NA (NA) 
xx.x 
xxx 
xxx 
xx 
xxx 
xxx 
xx 
No 
 
Day 1 
YYYY-MM-DD 
(1) 
NA 
NA (NA) 
xx.x 
xxx 
xxx 
xx 
xxx 
xxx 
xx 
No 
 
Week xx 
YYYY-MM-DD 
(xx) 
Hh:mm 
 
Pre-dose xx 
Min 
Pre-dose xx Min 
(xx:xx) 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
No 
 
 
 
Pre-dose xx 
Min 
Pre-dose xx Min 
(xx:xx) 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
No 
 
 
 
Etc…  
 
 
 
 
 
 
 
 
 
Week xx 
YYYY-MM-DD 
(xx) 
 
Post-dose x 
Hours 
Post-dose x 
Hours(xx:xx) 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
Yes 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
 
Unscheduled 
YYYY-MM-DD 
(Pxx) 
NA 
as appropriate 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.x) 
 
No 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 247 of 249 
 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia or  
     New Zealand (indigenous), A=Asian, O=Other.  
NA = Not Applicable. 
Abnormalities at Screening Visits 1 to 3 and Pre-dose on Day 1 (Visit 4) were noted on the Medical History CRF; abnormalities Post-
dose on Day 1 (Visit 4) or afterward were noted on the Adverse Events CRF.                                                              
[a]  A negative number for study day denotes the number of days prior to the start of study treatment.  Pxx = Days after last dose. 
[b]  For change from baseline, baseline is defined as the average of the pre-dose measurements taken prior to the start of treatment  
    at Day 1 (Visit 4). 
Source: eg.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l0902.sas      Version YYYY-MM-DD xx:xx  (Page n of N)  
 
 
 
 
 
 
 
 
 
 
See Section 3 Tables 3.16.3 and 3.16.5 for potentially clinically significant ECG values. 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID, Date, and Time of ECG 
Assessment. 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 248 of 249 
 
 
 
 
Listing 9.3 
Pregnancy Testing After Start of Treatment in the Study 
Analysis Set: All Subjects Randomized 
 
Subject ID 
Age (yrs) 
/Gender  
Screening 
Female Reproductive 
Status 
Visit 
Visit Date 
Pregnancy Test 
Type of Test 
Date 
Result 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
xxxxxx 
58/M 
NA 
Week 12 
YYYY-MM-DD 
Not Done 
 
 
 
Week 24 
YYYY-MM-DD 
Not Done 
 
 
 
 
 
 
xxxxxx 
76/F/W 
Woman of non-
childbearing potential  
Week 12 
YYYY-MM-DD 
Urine Pregnancy Test 
YYYY-MM-DD 
Negative 
 
Week 24 
YYYY-MM-DD 
Serum Pregnancy Test 
YYYY-MM-DD 
Negative  
Etc… 
 
 
 
 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska  
     Native, ANZ=Australia or New Zealand (indigenous), A=Asian, O=Other.   
                                                                                                                                    
Source: pg.sas7bdat         
                                                                                                                                       
Report generated by program: pt003014/sasdir/programs/statout/l0903.sas          Version YYYY-MM-DD xx:xx (Page n of N)                 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID, Visit Date, and 
Date of Pregnancy Test. 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 249 of 249 
 
 
 
 
Listing 9.4 
Comments 
Analysis Set: All Subjects Randomized 
 
Subject ID 
Age (yrs) 
Gender 
Race  
Visit 
Comment Applies To: 
Comments 
 
Treatment: GFF MDI 14.4/9.6 μg, FF MDI 9.6 μg, GP MDI 14.4  μg, or Placebo MDI 
 
Country Center # (Investigator): xxxxxxxxxxxxxxxxxx Center ### (xxxxxxxxxx) 
 
xxxxx 
63 
Male 
 
  W 
Visit 1 
Visit 2 
...  
Follow-up 
Unscheduled 
Subject Eligibility 
Study Medication 
Adverse Event 
Visit Scheduling 
Other: xxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxx 
Race: B=Black, W=White, NHPI=Native Hawaiian or other Pacific Islander, AIAN=American Indian or Alaska Native, ANZ=Australia or  
      New Zealand (indigenous), A=Asian, O=Other. 
 
Source: xxxxxxx.sas7bdat   
 
Report generated by program: pt003014/sasdir/programs/statout/l0904.sas    Version YYYY-MM-DD xx:xx    (Page n of N) 
 
 
 
 
 
 
 
 
 
Notes to Programmer: Sort by Actual Treatment, 
Country, Center, Subject ID, Visit, and category 
that comment applies to (Subject Eligibility, 
Study Medication, etc…). 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 1 of 48 
 
 
 
APPENDIX 7 
TABLE OF CONTENTS FOR POST-TEXT TLFs IN THE 
CHINA POPULATION 
__________________________________________________________________ 
 
 Number: 
PT003014 
Investigational Drug and Drug 
Number: 
Glycopyrronium and Formoterol Fumarate Inhalation 
Aerosol (GFF MDI); PT003 
Glycopyrronium Inhalation Aerosol (GP MDI); PT005 
Formoterol Fumarate Inhalation Aerosol (FF MDI); 
PT001 
Indication: 
COPD 
Dosage Form/Strength: 
GFF MDI 14.4/9.6 μg ex-actuator BID 
GP MDI 14.4 μg ex-actuator BID 
FF MDI 9.6 μg ex-actuator BID 
 
 
PT003014 Protocol 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 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 2 of 48 
 
  
 
General Instructions for End-of-Text TFLs 
 
The main study mock-ups document for PT003014 provides details regarding the presentation of TLFs 
(including titling, formatting, page layouts, content, etc.). 
 
 
 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 3 of 48 
 
  
 
TABLE OF CONTENTS FOR END-OF-TEXT TLFs 
 
1. 
SUBJECT DISPOSITION, DEMOGRAPHIC, BASELINE, AND OTHER SUMMARY 
TABLES ........................................................................................................................................... 16 
Table 1.1.1 
Subject Disposition ........................................................................................................... 16 
Analysis Set: All Subjects Randomized 
Table 1.1.3 
Distribution of Subjects in Analysis Populations, by Center and Treatment .................... 16 
Analysis Set: All Subjects Randomized 
Table 1.1.4 
Reasons for Subjects Not Randomized ............................................................................. 16 
Analysis Set: Non-Randomized Analysis Set 
Table 1.1.5 
Subjects Excluded From ITT, PP, Rescue Ventolin User, and Safety Populations .......... 16 
Analysis Set: All Subjects Randomized 
Table 1.2.2 
Reason for Early Discontinuation ..................................................................................... 16 
Analysis Set: ITT Population 
Table 1.3 
Reason for Exclusion From the PP Population ................................................................. 16 
Analysis Set: ITT Population 
Table 1.4.1 
Demographics and Baseline Characteristics Overall and by CAT Score 
Subpopulation ................................................................................................................... 16 
Analysis Set: ITT Population 
Table 1.5.1 
Severity and Duration of COPD Overall and by CAT Score Subpopulation.................... 16 
Analysis Set: ITT Population 
Table 1.6.1 
Screening Pre- and Post-Bronchodilator and Baseline Spirometry Parameters 
Overall and by CAT Score Subpopulation ....................................................................... 16 
Analysis Set: ITT Population 
Table 1.7.1 
Reversibility to Ventolin HFA Overall and by CAT Score Subpopulation ...................... 16 
Analysis Set: ITT Population 
Table 1.8.1 
Reversibility to Atrovent HFA Overall and by CAT Score Subpopulation ...................... 16 
Analysis Set: ITT Population 
Table 1.9.1 
Medical/Surgical History .................................................................................................. 17 
Analysis Set: Safety Population 
Table 1.9.2 
Cardiovascular Risk Factors of Interest ............................................................................ 17 
Analysis Set: Safety Population 
Table 1.9.3 
History of Moderate or Severe COPD Exacerbations Within Past 12 Months ................. 17 
Analysis Set: ITT Population 
Table 1.10.1 
Prior Medications - COPD-Related .................................................................................. 17 
Analysis Set: Safety Population 
Table 1.10.2 
Prior Medications - Non-COPD-Related .......................................................................... 17 
Analysis Set: Safety Population 
Table 1.11.1 
Concomitant Medications - COPD Related ...................................................................... 17 
Analysis Set: Safety Population 
Table 1.11.2 
Concomitant Medications - Non-COPD Related .............................................................. 17 
Analysis Set: Safety Population 


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Table 1.12 
Study Treatment Exposure and Compliance ..................................................................... 17 
Analysis Set: Safety Population 
Table 1.13 
Changes in Smoking Status After Start of Treatment ....................................................... 17 
Analysis Set: Safety Population 
2. 
EFFICACY DATA SUMMARY TABLES AND FIGURES, INCLUDING HCRU 
TABLES ........................................................................................................................................... 18 
CHANGE FROM BASELINE IN MORNING PRE-DOSE TROUGH FEV1 ........................................... 18 
Table 2.1.1 
Morning Pre-Dose Trough FEV1 (L) at Week 24 ............................................................. 18 
Analysis Set: ITT Population 
Figure 2.1.1.1 
Adjusted Mean Change From Baseline in Morning Pre-Dose Trough FEV1 (L) ± 
SE Over Time ................................................................................................................... 18 
Analysis Set: ITT Population 
Figure 2.1.1.2 
Treatment Differences From Placebo MDI*: Adjusted Mean Change From 
Baseline (95% CI) in Morning Pre-Dose Trough FEV1 (L) Over Time ........................... 18 
Analysis Set: ITT Population 
Table 2.1.2 
Morning Pre-Dose Trough FEV1 (L) at Week 24 ............................................................. 18 
Analysis Set: PP Population 
Figure 2.1.2 
Adjusted Mean Change From Baseline in Morning Pre-Dose Trough FEV1 (L) ± 
SE Over Time ................................................................................................................... 18 
Analysis Set: PP Population 
Table 2.1.3.1 
Missing Data for Change From Baseline in Morning Pre-Dose Trough FEV1 by 
Visit and Reason ............................................................................................................... 18 
Analysis Set: ITT Population 
Table 2.1.4.1 
Sensitivity Analysis: Treatment Comparisons for Change From Baseline in 
Morning Pre-Dose Trough FEV1 (L) at Week 24 ............................................................. 18 
Analysis Set: ITT Population 
Table 2.1.4.4 
 Cumulative Proportion of Responders Based on Change From Baseline in 
Morning Pre-dose Trough FEV1 at Week 24.................................................................... 18 
Analysis Set: ITT Population 
Figure 2.1.4.31 
Cumulative Proportion of Responders Based on Change From Baseline in 
Morning Pre-dose Trough FEV1 at Week 24.................................................................... 18 
Analysis Set: ITT Population 
TRANSITION DYSPNEA INDEX (TDI) ................................................................................................. 19 
Table 2.2.1 
TDI Focal Score Overall and by CAT Score Subpopulation ............................................ 19 
Analysis Set: ITT Population 
Figure 2.2.1.1.1 
Adjusted Mean TDI Focal Score ± SE Over Time ........................................................... 19 
Analysis Set: ITT Population 
Figure 2.2.1.1.2 
Treatment Differences From Placebo MDI*: Adjusted Mean TDI Focal Score 
(95% CI) Over Time ......................................................................................................... 19 
Analysis Set: ITT Population 
Figure 2.2.1.2.1 
Adjusted Mean TDI Focal Score ± SE Over Time: CAT Score Subpopulation of 
>= 10 ................................................................................................................................ 19 
Analysis Set: ITT Population 


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Figure 2.2.1.2.2 
Adjusted Mean TDI Focal Score ± SE Over Time: CAT Score Subpopulation of 
>= 15 ................................................................................................................................ 19 
Analysis Set: ITT Population 
Figure 2.2.1.2.3 
Adjusted Mean TDI Focal Score ± SE Over Time: CAT Score Subpopulation of 
>= 20 ................................................................................................................................ 19 
Analysis Set: ITT Population 
Table 2.2.2.1 
TDI Component Scores for Functional Impairment, Magnitude of Task, and 
Magnitude of Effort Overall and by CAT Score Subpopulation ...................................... 19 
Analysis Set: ITT Population 
Table 2.2.3 
Response in TDI Focal Score (Achievment of a Minimum Clinically Important 
Difference Threshold of ≥1 Unit on Average) Over 24 Weeks Overall and by CAT 
Score Subpopulation ......................................................................................................... 19 
Analysis Set: ITT Population 
PEAK CHANGE FROM BASELINE IN FEV1 ......................................................................................... 20 
Table 2.3.1 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-Dose ............................. 20 
Analysis Set: ITT Population 
Figure 2.3.1 
Adjusted Mean Peak Change From Baseline in FEV1 (L) ± SE Within 2 Hours 
Post-Dose ......................................................................................................................... 20 
Analysis Set: ITT Population 
ST. GEORGE RESPIRATORY QUESTIONNAIRE (SGRQ) .................................................................. 21 
Table 2.4.1 
SGRQ Total Score Overall and by CAT Score Subpopulation ........................................ 21 
Analysis Set: ITT Population 
Figure 2.4.1.1 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over 
Time ................................................................................................................................. 21 
Analysis Set: ITT Population 
Figure 2.4.1.2 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over 
Time: CAT Score Subpopulation of >= 10 ...................................................................... 21 
Analysis Set: ITT Population 
Figure 2.4.1.3 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over 
Time: CAT Score Subpopulation of >= 15 ...................................................................... 21 
Analysis Set: ITT Population 
Figure 2.4.1.4 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over 
Time: CAT Score Subpopulation of >= 20 ...................................................................... 21 
Analysis Set: ITT Population 
Table 2.4.2 
Total Score of Each SGRQ Domain Overall and by CAT Score Subpopulation ............. 21 
Analysis Set: ITT Population 
Table 2.4.3 
Response in SGRQ Total Score (Achievment of a Minimum Clinically Important 
Difference Threshold of ≥4 Units on Average) Overall and by CAT Score 
Subpopulation ................................................................................................................... 21 
Analysis Set: ITT Population 
NUMBER OF PUFFS OF RESCUE VENTOLIN HFA ............................................................................ 22 
Table 2.5.1 
Mean Daily, Daytime, and Nighttime Number of Puffs of Rescue Ventolin HFA ........... 22 
Analysis Set: Rescue Ventolin User Population 


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Figure 2.5.1.1 
Adjusted Mean Change From Baseline in Mean Daily Number of Puffs of Rescue 
Ventolin HFA ± SE Over Time ........................................................................................ 22 
Analysis Set: Rescue Ventolin User Population 
Figure 2.5.1.2 
Adjusted Mean Change From Baseline in Mean Daytime Number of Puffs of 
Rescue Ventolin HFA ± SE Over Time ........................................................................... 22 
Analysis Set: Rescue Ventolin User Population 
Figure 2.5.1.3 
Adjusted Mean Change From Baseline in Mean Nighttime Number of Puffs of 
Rescue Ventolin HFA± SE Over Time ............................................................................ 22 
Analysis Set: Rescue Ventolin User Population 
Table 2.5.2 
Percentage of Days With No Rescue Ventolin HFA Use Over 24 Weeks ....................... 22 
Analysis Set: Rescue Ventolin User Population 
TIME TO ONSET OF ACTION ASSESSED USING FEV1 ON DAY 1 .................................................. 23 
Table 2.6.1 
FEV1 (L) by Post-Dose Timepoint on Day 1 .................................................................... 23 
Analysis Set: ITT Population 
Figure 2.6.1 
Adjusted Mean Change From Baseline in FEV1 (L) ± SE Over the 2 Hour Post-
Dose Interval on Day 1 ..................................................................................................... 23 
Analysis Set: ITT Population 
OTHER SPIROMETRY MEASURES INCLUDING PERCENT RESPONDERS ANALYSES 
FOR DAY 1 ...................................................................................................................................... 24 
Table 2.7 
FEV1 AUC0-2 (L) .............................................................................................................. 24 
Analysis Set: ITT Population 
Figure 2.7 
Adjusted Mean FEV1 AUC0-2 (L) ± SE Over Time .......................................................... 24 
Analysis Set: ITT Population 
Table 2.8 
FVC AUC0-2 (L)................................................................................................................ 24 
Analysis Set: ITT Population 
Figure 2.8 
Adjusted Mean FVC AUC0-2 (L) ± SE Over Time ........................................................... 24 
Analysis Set: ITT Population 
Table 2.9 
Peak Change From Baseline in FVC (L) Within 2 Hours Post-Dose ............................... 24 
Analysis Set: ITT Population 
Figure 2.9 
Adjusted Mean Peak Change From Baseline in FVC (L) ± SE Within 2 Hours 
Post-Dose ......................................................................................................................... 24 
Analysis Set: ITT Population 
Table 2.10 
Morning Pre-Dose Trough FVC (L) ................................................................................. 24 
Analysis Set: ITT Population 
Figure 2.10 
Adjusted Mean Change From Baseline in Morning Pre-Dose Trough FVC (L) ± 
SE ..................................................................................................................................... 24 
Analysis Set: ITT Population 
Table 2.11.1 
Percentage of Subjects With ≥10% Improvement From Baseline in FEV1 During 2 
Hour Post-Dose Interval and by Post-Dose Timepoint on Day 1 ..................................... 24 
Analysis Set: ITT Population 
Table 2.11.2 
Percentage of Subjects With ≥12% Improvement From Baseline in FEV1 During 2 
Hour Post-Dose Interval and by Post-Dose Timepoint on Day 1 ..................................... 24 
Analysis Set: ITT Population 


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Table 2.11.3 
Percentage of Subjects With ≥100 mL Improvement From Baseline in FEV1 
During 2 Hour Post-Dose Interval and by Post-Dose Timepoint on Day 1 ...................... 25 
Analysis Set: ITT Population 
Table 2.11.4 
Percentage of Subjects With ≥200 mL Improvement From Baseline in FEV1 
During 2 Hour Post-Dose Interval and by Post-Dose Timepoint on Day 1 ...................... 25 
Analysis Set: ITT Population 
Table 2.11.5 
Percentage of Subjects With Improvement From Baseline in FEV1 of Both ≥12% 
and ≥200 mL During 2 Hour Post-Dose Interval and by Post-Dose Timepoint on 
Day 1 ................................................................................................................................ 25 
Analysis Set: ITT Population 
Table 2.12 
FVC (L) Over the 2 Hour Post-Dose Interval on Day 1 ................................................... 25 
Analysis Set: ITT Population 
Figure 2.12 
Adjusted Mean Change From Baseline in FVC (L) ± SE Over the 2 Hour Post-
Dose Interval on Day 1 ..................................................................................................... 25 
Analysis Set: ITT Population 
EXACERBATIONS ................................................................................................................................... 25 
Table 2.13.1 
Rate of COPD Exacerbations Overall and by CAT Score Subpopulation ........................ 25 
Analysis Set: ITT Population 
Table 2.13.2 
Rate of COPD Exacerbations With Imputation Overall and by CAT Score 
Subpopulation ................................................................................................................... 25 
Analysis Set: ITT Population 
Table 2.14 
Time to First COPD Exacerbation of Any Severity and Time to First Moderate or 
Severe COPD Exacerbation.............................................................................................. 25 
Analysis Set: ITT Population 
Figure 2.14.1.x 
Kaplan-Meier Curves for Time to First COPD Exacerbation of Any Severity 
Overall and by CAT Score Subpopulation ....................................................................... 25 
Analysis Set: ITT Population 
Figure 2.14.2.x 
Kaplan-Meier Curves for Time to First Moderate or Severe COPD Exacerbation 
Overall and by CAT Score Subpopulation ....................................................................... 26 
Analysis Set: ITT Population 
Table 2.15 
Time to Treatment Failure Overall and by CAT Score Subpopulation ............................ 26 
Analysis Set: ITT Population 
Figure 2.15 
Kaplan-Meier Curves for Time to Treatment Failure Overall and by CAT Score 
Subpopulation ................................................................................................................... 26 
Analysis Set: ITT Population 
Table 2.16.1 
Time to First Clinically Important Deterioration (CID) Overall and by CAT Score 
Subpopulation ................................................................................................................... 26 
Analysis Set: ITT Population 
Figure 2.16.1.x 
Kaplan-Meier Curves for Time to First CID Overall and by CAT Score 
Subpopulation ................................................................................................................... 26 
Analysis Set: ITT Population 
Table 2.16.2 
Time to First Clinically Important Deterioration (CID) With Death Overal Overall 
and by CAT Score Subpopulation .................................................................................... 26 
Analysis Set: ITT Population 


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Figure 2.16.2.x 
Kaplan-Meier Curves for Time to First CID With Death and Time to First 
Occurrence of Each Component of CID With Death Overall and by CAT Score 
Subpopulation ................................................................................................................... 26 
Analysis Set: ITT Population 
Table 2.17 
Time to First Sustained Clinically Important Deterioration (CID) and Time to First 
Occurrence of Each Component of Sustained CID Overall and by CAT Score 
Subpopulation ................................................................................................................... 26 
Analysis Set: ITT Population 
Figure 2.17.x 
Kaplan-Meier Curves for Time to First Sustained CID and Time to First 
Occurrence of Each Component of Sustained CID Overall and by CAT Score 
Subpopulation ................................................................................................................... 26 
Analysis Set: ITT Population 
SYMPTOMS............................................................................................................................................... 27 
Table 2.18.1 
Mean Daily, Daytime, and Nighttime Total Symptom Scores ......................................... 27 
Analysis Set: ITT Population 
Table 2.18.2 
Mean Daily, Daytime, and Nighttime Cough Symptom Scores ....................................... 27 
Analysis Set: ITT Population 
Table 2.18.3 
Mean Daily, Daytime, and Nighttime Shortness of Breath Symptom Scores .................. 27 
Analysis Set: ITT Population 
Table 2.18.4 
Mean Daily, Daytime, and Nighttime Sputum Volume Symptom Scores ........................ 27 
Analysis Set: ITT Population 
Table 2.18.5 
Mean Number of Nighttime Awakenings ......................................................................... 27 
Analysis Set: ITT Population 
CORRELATIONS ...................................................................................................................................... 28 
Table 2.19.1 
Pearson Correlation Matrix of Key Efficacy Endpoints (Excluding Correlations 
with Efficacy Endpoints Over Weeks 12-24) ................................................................... 28 
Analysis Set: All Available Data 
Table 2.19.2 
Pearson Correlation Matrix of Key Efficacy Endpoints Over Weeks 12-24 With 
Other Key Efficacy Endpoints and With Each Other ....................................................... 28 
Analysis Set: All Available Data 
SUBGROUP ANALYSES ......................................................................................................................... 29 
Table 2.22.2 
Demographics and Baseline Characteristics by GOLD Category..................................... 29 
Analysis Set: ITT Population 
Table 2.22.3 
Demographics and Baseline Characteristics by GOLD Severity ...................................... 29 
Analysis Set: ITT Population 
Table 2.24.2 
Severity and Duration of COPD by GOLD Category ....................................................... 29 
Analysis Set: ITT Population 
Table 2.24.3 
Severity and Duration of COPD by GOLD Severity ........................................................ 29 
Analysis Set: ITT Population 
Table 2.25.2 
Reversibility to Ventolin HFA by GOLD Category ......................................................... 29 
Analysis Set: ITT Population 
Table 2.25.3 
Reversibility to Ventolin HFA by GOLD Severity........................................................... 29 
Analysis Set: ITT Population 


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Table 2.26.2 
Reversibility to Atrovent HFA by GOLD Category ......................................................... 29 
Analysis Set: ITT Population 
Table 2.26.3 
Reversibility to Atrovent HFA by GOLD Severity .......................................................... 29 
Analysis Set: ITT Population 
Table 2.27.2 
Study Treatment Exposure and Compliance by GOLD Category .................................... 29 
Analysis Set: Safety Population 
Table 2.27.3 
Study Treatment Exposure and Compliance by GOLD Severity ..................................... 29 
Analysis Set: Safety Population 
Table 2.28.2 
Morning Pre-Dose Trough FEV1 (L) by GOLD Category ............................................... 30 
Analysis Set: ITT Population 
Figure 2.28.2.1 
Forest Plot for Morning Pre-Dose Trough FEV1 (L) ± SE at Week 24 by GOLD 
Category ........................................................................................................................... 30 
Analysis Set: ITT Population 
Table 2.28.3 
Morning Pre-Dose Trough FEV1 (L) by GOLD Severity ................................................. 30 
Analysis Set: ITT Population 
Figure 2.28.3.1 
Forest Plot for Morning Pre-Dose Trough FEV1 (L) ± SE at Week 24 by GOLD 
Severity ............................................................................................................................. 30 
Analysis Set: ITT Population 
Table 2.30.2 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-Dose by GOLD 
Category ........................................................................................................................... 30 
Analysis Set: ITT Population 
Figure 2.30.2.1 
Forest Plot for Peak FEV1 (L) ± SE Within 2 Hours Post-Dose at Week 24 by 
GOLD Category ............................................................................................................... 30 
Analysis Set: ITT Population 
Table 2.30.3 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-Dose by GOLD 
Severity ............................................................................................................................. 30 
Analysis Set: ITT Population 
Figure 2.30.3.1 
Forest Plot for Peak FEV1 (L) ± SE Within 2 Hours Post-Dose at Week 24 by 
GOLD Severity ................................................................................................................. 30 
Analysis Set: ITT Population 
HEALTHCARE RESOURCE UTILIZATION .......................................................................................... 31 
Table 2.37.1 
Healthcare Resource Utilization: Number of Days Missed From Work........................... 31 
Analysis Set: Safety Population 
Table 2.37.2 
Healthcare Resource Utilization by Relationship to COPD and Treatment ..................... 31 
Analysis Set: Safety Population 
3. 
SAFETY ............................................................................................................................................ 32 
ADVERSE EVENTS .................................................................................................................................. 32 
Table 3.1.1 
Overall Summary of Adverse Events ............................................................................... 32 
Analysis Set: Safety Population 
Table 3.2.1.1.x 
Adverse Events by MedDRA Primary System Organ Class and Preferred Term ............ 32 
Analysis Set: Safety Population 
Table 3.2.1.2.x 
Adverse Events With Onset After the Last Date of Treatment by MedDRA 
Primary System Organ Class and Preferred Term ............................................................ 32 
Analysis Set: Safety Population 


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Table 3.2.2.x 
Adverse Events Occurring in >=2% of Subjects in a Treatment by Descending 
Frequency ......................................................................................................................... 32 
Analysis Set: Safety Population 
Table 3.2.3 
Adverse Events in MedDRA SMQs/Groupings of Interest by Term ................................ 32 
Analysis Set: Safety Population 
Table 3.2.4.x 
Non-serious Adverse Events Occurring in ≥5% of Subjects in a Treatment by 
MedDRA Primary System Organ Class and Preferred Term ........................................... 32 
Analysis Set: Safety Population 
Table 3.3.x 
Rate of Adverse Events Adjusted for Exposure by MedDRA Primary System 
Organ Class and Preferred Term ...................................................................................... 32 
Analysis Set: Safety Population 
Table 3.4.x 
Adverse Events Suspected to be Drug-Related by MedDRA Primary System 
Organ Class and Preferred Term ...................................................................................... 32 
Analysis Set: Safety Population 
Table 3.5.x 
Adverse Events Causing Study Drug Discontinuation by MedDRA Primary 
System Organ Class and Preferred Term .......................................................................... 32 
Analysis Set: Safety Population 
Table 3.6.x 
Listing of Adverse Events Leading to Permanent Discontinuation of Study 
Treatment.......................................................................................................................... 32 
Analysis Set: All Subjects Randomized 
Table 3.7.1.x 
Serious Adverse Events by MedDRA Primary System Organ Class and Preferred 
Term ................................................................................................................................. 33 
Analysis Set: Safety Population 
Table 3.7.2.x 
Serious Adverse Events With Onset After the Last Date of Treatment by MedDRA 
Primary System Organ Class and Preferred Term ............................................................ 33 
Analysis Set: Safety Population 
Table 3.8.1 
Listing of Serious Adverse Events (SAEs) ....................................................................... 33 
Analysis Set: All Subjects Screened 
Table 3.8.2 
Listing of SAE-Specific Report Information .................................................................... 33 
Analysis Set: All Subjects Screened 
Table 3.9.x 
Rate of Serious Adverse Events Adjusted for Exposure, by MedDRA Primary 
System Organ Class and Preferred Term .......................................................................... 33 
Analysis Set: Safety Population 
Table 3.10.x 
Serious Adverse Events Suspected to be Drug-Related by MedDRA Primary 
System Organ Class and Preferred Term .......................................................................... 33 
Analysis Set: Safety Population 
Table 3.11.1.x 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – 
GFF MDI 14.4/9.6 μg ....................................................................................................... 33 
Analysis Set: Safety Population 
Table 3.11.2.x 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – 
FF MDI 9.6 μg .................................................................................................................. 33 
Analysis Set: Safety Population 
Table 3.11.3.x 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – 
GP MDI 14.4 μg ............................................................................................................... 33 
Analysis Set: Safety Population 


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Table 3.11.4.x 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – 
Placebo MDI..................................................................................................................... 33 
Analysis Set: Safety Population 
Table 3.12.x 
Death Events, by MedDRA Primary System Organ Class and Preferred Term ............... 33 
Analysis Set: Safety Population 
Table 3.13 
Listing of Deaths............................................................................................................... 34 
Analysis Set: All Subjects Screened 
LABORATORY PARAMETERS .............................................................................................................. 35 
Table 3.14.1 
Laboratory Parameters by Visit and Time of Assessment – Hematology Panel ............... 35 
Analysis Set: Safety Population 
Table 3.14.2 
Laboratory Parameters by Visit and Time of Assessment – Blood Chemistry Panel ....... 35 
Analysis Set: Safety Population 
Table 3.14.3 
Laboratory Parameters by Visit and Time of Assessment – Kidney Function ................. 35 
Analysis Set: Safety Population 
Table 3.14.4 
Laboratory Parameters by Visit and Time of Assessment – Urinalysis pH and 
Specific Gravity ................................................................................................................ 35 
Analysis Set: Safety Population 
Table 3.14.5 
Shift Table for Laboratory Hematology Data: NCI-CTC Grading ................................... 35 
Analysis Set: Safety Population 
Table 3.14.6 
Shift Table for Laboratory Chemistry Data: NCI-CTC Grading ...................................... 35 
Analysis Set: Safety Population 
Table 3.14.7 
Shift Table for Kidney Function: NCI-CTC Grading ....................................................... 35 
Analysis Set: Safety Population 
Table 3.14.8 
Post-Baseline Newly Occurring or Worsening Potentially Clinically Significant 
Laboratory Values Based on CTCAE 4.03 and Other Criteria ......................................... 35 
Analysis Set: Safety Population 
Table 3.14.9 
All Potassium Records for Subjects With Newly Occurring or Worsening 
Potentially Clinically Significant Potassium Values Post-Baseline ................................. 35 
Analysis Set: Safety Population 
Table 3.14.10 
All Glucose Records for Subjects With Newly Occurring or Worsening Potentially 
Clinically Significant Glucose Values Post-Baseline ....................................................... 35 
Analysis Set: Safety Population 
Table 3.14.11 
All Records for Subjects With Newly Occurring or Worsening Potentially 
Clinically Significant Values Post-Baseline Other Than Those for Glucose and 
Potassium ......................................................................................................................... 36 
Analysis Set: Safety Population 
VITAL SIGNS ............................................................................................................................................ 37 
Table 3.15.1 
Vital Sign Measurements by Visit and Time of Assessment ............................................ 37 
Analysis Set: Safety Population 
Table 3.15.2 
Post-Baseline Potentially Clinically Significant Vital Sign Values .................................. 37 
Analysis Set: Safety Population 
Table 3.15.3 
Listing of Potentially Clinically Significant Systolic and Diastolic Blood Pressure 
Increases and Decreases ................................................................................................... 37 
Analysis Set: Safety Population 


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Table 3.15.4 
Listing of Potentially Clinically Significant Tachycardia and Bradycardia Events .......... 37 
Analysis Set: All Subjects Randomized 
12-LEAD ELECTROCARDIOGRAM (ECG) ........................................................................................... 38 
Table 3.16.1 
ECG Parameters by Visit and Time of Assessment .......................................................... 38 
Analysis Set: Safety Population 
Figure 3.16.1a 
Mean Change From Baseline for QTcF (ms) ± SE Over Time During Treatment ........... 38 
Analysis Set: Safety Population 
Figure 3.16.1b 
Mean Change From Baseline for QTcF (ms) ± SE Over 2 Hours Post-Dose on Day 
1 ........................................................................................................................................ 38 
Analysis Set: Safety Population 
Figure 3.16.1c 
Mean Change From Baseline for Heart Rate (bpm) ± SE Over Time During 
Treatment.......................................................................................................................... 38 
Analysis Set: Safety Population 
Figure 3.16.1d 
Mean Change From Baseline for Heart Rate (bpm) ± SE Over 2 Hours Post-Dose 
on Day 1 ........................................................................................................................... 38 
Analysis Set: Safety Population 
Table 3.16.2 
Post-Baseline Potentially Clinically Significant (PCS) ECG Values ............................... 38 
Analysis Set: Safety Population 
Table 3.16.3 
Listing of ECG's Meeting QTcF Interval Prolongation Criteria ....................................... 38 
Analysis Set: All Subjects Randomized 
Table 3.16.4 
Listing of PR Interval Increases: Post-Baseline Increases of >50 ms From Baseline....... 38 
Analysis Set: All Subjects Randomized 
Table 3.16.5 
Listing of QRS Prolongations: Post-Baseline Prolongations of >40 ms From 
Baseline ............................................................................................................................ 38 
Analysis Set: All Subjects Randomized 
4. 
SUBJECT DATA LISTINGS ........................................................................................................... 39 
4.1 
SUBJECT DISCONTINUATIONS/COMPLETIONS ..................................................................... 39 
Listing 1.1 
Study Centers .................................................................................................................... 39 
Analysis Set: All Subjects Screened 
Listing 1.2 
Subject Disposition and Demographic Data ..................................................................... 39 
Analysis Set: All Subjects Screened 
Listing 1.3 
Randomized Treatment, Actual Treatment, and Duration of Treatment .......................... 39 
Analysis Set: All Subjects Randomized 
Listing 1.4 
Reasons Subjects Were Not Randomized ......................................................................... 39 
Analysis Set: Non-Randomized Analysis Set 
Listing 1.5 
Changes in Smoking Status During Study ........................................................................ 39 
Analysis Set: All Subjects Randomized 
4.2 
PROTOCOL DEVIATIONS ............................................................................................................ 40 
Listing 2.1 
Violation of Inclusion/Exclusion Criteria and Waivers .................................................... 40 
Analysis Set: All Subjects Randomized 
Listing 2.2 
Screening Lung Function and Ventolin HFA and Atrovent HFA Reversibility ............... 40 
Analysis Set: All Subjects Randomized 


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4.3 
SUBJECTS EXCLUDED FROM THE ITT, PP, RESCUE VENTOLIN USER, AND 
SAFETY POPULATIONS ............................................................................................................... 41 
4.4 
BASELINE CHARACTERISTICS .................................................................................................. 42 
Listing 4.1 
COPD Diagnosis ............................................................................................................... 42 
Analysis Set: All Subjects Randomized 
Listing 4.2 
Screening CAT Assessment .............................................................................................. 42 
Analysis Set: All Subjects Randomized 
Listing 4.3 
Screening MMRC Scale ................................................................................................... 42 
Analysis Set: All Subjects Randomized 
Listing 4.4 
History of Moderate or Severe COPD Exacerbations ....................................................... 42 
Analysis Set: All Subjects Randomized 
Listing 4.5.1 
Relevant Medical and Surgical History ............................................................................ 42 
Analysis Set: All Subjects Randomized 
Listing 4.5.2 
Cardiovascular Risk Factors of Interest ............................................................................ 42 
Analysis Set: All Subjects Randomized 
Listing 4.6 
Screening Reproductive Status and Pregnancy Test Results ............................................ 42 
Analysis Set: All Subjects Randomized 
Listing 4.7 
Prior, Concomitant, and Post-Treatment COPD Medications .......................................... 42 
Analysis Set: All Subjects Randomized 
Listing 4.8 
Prior, Concomitant, and Post-Treatment Non-COPD-Related Medications ..................... 42 
Analysis Set: All Subjects Randomized 
Listing 4.9 
Suspect Drug Assessment for SAEs ................................................................................. 42 
Analysis Set: All Subjects Randomized 
4.5 
DOSING AND COMPLIANCE ....................................................................................................... 43 
Listing 5.1.1 
Study Drug Dosing, Dispensing, and Return .................................................................... 43 
Analysis Set: All Subjects Randomized 
Listing 5.1.2 
Atrovent HFA and Ventolin HFA Dispensing .................................................................. 43 
Analysis Set: All Subjects Randomized 
Listing 5.2 
Compliance and Exposure to Study Treatment ................................................................. 43 
Analysis Set: All Subjects Randomized 
4.6 
INDIVIDUAL EFFICACY DATA AND HCRU DATA ................................................................. 44 
4.6.1 EFFICACY ....................................................................................................................................... 44 
Listing 6.1.1 
Subjects Who Failed Restrictions Prior to Spirometry Assessment ................................. 44 
Analysis Set: All Subjects Randomized 
Listing 6.1.2 
Reason for Missingness Overall and by Visit ................................................................... 44 
Analysis Set: All Subjects Randomized 
Listing 6.1.3 
Spirometry Measurements ................................................................................................ 44 
Analysis Set: All Subjects Randomized 
Listing 6.1.4 
FEV1 (L) at Each Post-Dose Timepoint Through 2 Hours on a Test Day ........................ 44 
Analysis Set: ITT Population 
Listing 6.1.5 
FVC (L) at Each Post-Dose Timepoint Through 2 Hours on a Test Day ......................... 44 
Analysis Set: ITT Population 


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Listing 6.1.6 
Subject Dosing and Symptoms Diary, Including Rescue Medication Use ....................... 44 
Analysis Set: All Subjects Randomized 
Listing 6.1.7 
COPD Exacerbations ........................................................................................................ 44 
Analysis Set: All Subjects Randomized 
Listing 6.1.8 
Baseline Dyspnea Index (BDI) /Transition Dyspnea Index (TDI) ................................... 44 
Analysis Set: All Subjects Randomized 
Listing 6.1.9 
St. George Respiratory Questionnaire (SGRQ) ................................................................ 44 
Analysis Set: All Subjects Randomized 
Listing 6.1.10 
Individual Items of the St. George Respiratory Questionnaire (SGRQ) ........................... 44 
Analysis Set: All Subjects Randomized 
4.6.2 HEALTHCARE RESOURCE UTILIZATION ................................................................................ 45 
Listing 6.2 
Healthcare Resource Utilization ....................................................................................... 45 
Analysis Set: Safety Population 
4.7 
ADVERSE EVENT LISTINGS........................................................................................................ 46 
Listing 7.1 
Adverse Events by Primary System Organ Class, Preferred Term, Treatment, 
Country, Center, Subject ID, and Onset Day .................................................................... 46 
Analysis Set: All Subjects Randomized 
Listing 7.2 
Glossary of Adverse Event Preferred Terms vs. Investigator’s Verbatim ........................ 46 
Listing 7.3 
Adverse Events by Treatment, Country, Center, Subject ID, and Onset Day ................... 46 
Analysis Set: All Subjects Randomized 
4.8 
LABORATORY VALUES ............................................................................................................... 47 
Listing 8.1 
Laboratory Test Results (Hematology Panel) ................................................................... 47 
Analysis Set: All Subjects Randomized 
Listing 8.2 
Laboratory Test Results (Morphology) ............................................................................ 47 
Analysis Set: All Subjects Randomized 
Listing 8.3 
Laboratory Test Results (Chemistry Panel and Kidney Function) ................................... 47 
Analysis Set: All Subjects Randomized 
Listing 8.4 
Laboratory Test Results (Urinalysis Panel) ...................................................................... 47 
Analysis Set: All Subjects Randomized 
Analysis Set: All Subjects Randomized 
4.9 
OTHER CLINICAL OBSERVATIONS AND MEASUREMENTS ............................................... 48 
Listing 9.1 
Vital Signs, Weight, and Height ....................................................................................... 48 
Analysis Set: All Subjects Randomized 
Listing 9.2 
12-Lead Electrocardiogram (ECG) ................................................................................... 48 
Analysis Set: All Subjects Randomized 
Listing 9.3 
Pregnancy Testing After Start of Treatment in the Study ................................................. 48 
Analysis Set: All Subjects Randomized 


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SHELLS FOR END-OF-TEXT TLFS 
 


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1. Subject Disposition, Demographic, Baseline, and Other Summary Tables 
 
Table 1.1.1 
Subject Disposition 
Analysis Set: All Subjects Randomized 
 
Table 1.1.3 
Distribution of Subjects in Analysis Populations, by Center and Treatment 
Analysis Set: All Subjects Randomized 
 
Table 1.1.4 
Reasons for Subjects Not Randomized 
Analysis Set: Non-Randomized Analysis Set 
 
Table 1.1.5 
Subjects Excluded From ITT, PP, Rescue Ventolin User, and Safety Populations 
Analysis Set: All Subjects Randomized 
 
Table 1.2.2 
Reason for Early Discontinuation 
Analysis Set: ITT Population 
 
Table 1.3 
Reason for Exclusion From the PP Population 
Analysis Set: ITT Population 
 
Table 1.4.1 
Demographics and Baseline Characteristics Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 1.5.1 
Severity and Duration of COPD Overall and by CAT Score Subpopulation  
Analysis Set: ITT Population 
 
Table 1.6.1 
Screening Pre- and Post-Bronchodilator and Baseline Spirometry Parameters Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 Table 1.7.1 
Reversibility to Ventolin HFA Overall and by CAT Score Subpopulation  
Analysis Set: ITT Population 
 
Table 1.8.1 
Reversibility to Atrovent HFA Overall and by CAT Score Subpopulation  
Analysis Set: ITT Population 


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Table 1.9.1 
Medical/Surgical History 
Analysis Set: Safety Population 
 
Table 1.9.2 
Cardiovascular Risk Factors of Interest 
Analysis Set: Safety Population 
 
Table 1.9.3 
History of Moderate or Severe COPD Exacerbations Within Past 12 Months 
Analysis Set: ITT Population 
 
Table 1.10.1 
Prior Medications - COPD-Related 
Analysis Set: Safety Population 
 
Table 1.10.2 
Prior Medications - Non-COPD-Related 
Analysis Set: Safety Population 
 
Table 1.11.1 
Concomitant Medications - COPD Related 
Analysis Set: Safety Population 
 
Table 1.11.2 
Concomitant Medications - Non-COPD Related 
Analysis Set: Safety Population 
 
Table 1.12 
Study Treatment Exposure and Compliance 
Analysis Set: Safety Population 
 
Table 1.13 
Changes in Smoking Status After Start of Treatment 
Analysis Set: Safety Population 
 


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2. Efficacy Data Summary Tables and Figures, Including HCRU Tables 
 
Change From Baseline in Morning Pre-Dose Trough FEV1 
 
Table 2.1.1 
Morning Pre-Dose Trough FEV1 (L) at Week 24 
Analysis Set: ITT Population 
 
Figure 2.1.1.1 
Adjusted Mean Change From Baseline in Morning Pre-Dose Trough FEV1 (L) ± SE Over Time 
Analysis Set: ITT Population 
 
Figure 2.1.1.2 
Treatment Differences From Placebo MDI*: Adjusted Mean Change From Baseline (95% CI) in Morning Pre-Dose Trough FEV1 (L) Over 
Time 
Analysis Set: ITT Population 
 
Table 2.1.2 
Morning Pre-Dose Trough FEV1 (L) at Week 24 
Analysis Set: PP Population 
 
Figure 2.1.2 
Adjusted Mean Change From Baseline in Morning Pre-Dose Trough FEV1 (L) ± SE Over Time 
Analysis Set: PP Population 
 
Table 2.1.3.1 
Missing Data for Change From Baseline in Morning Pre-Dose Trough FEV1 by Visit and Reason 
Analysis Set: ITT Population 
 
Table 2.1.4.1 
Sensitivity Analysis: Treatment Comparisons for Change From Baseline in Morning Pre-Dose Trough FEV1 (L) at Week 24 
Analysis Set: ITT Population 
 
Table 2.1.4.4 
 Cumulative Proportion of Responders Based on Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 
Analysis Set: ITT Population 
 
Figure 2.1.4.31 
Cumulative Proportion of Responders Based on Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 
Analysis Set: ITT Population 
 
 


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Transition Dyspnea Index (TDI) 
 
Table 2.2.1 
TDI Focal Score Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Figure 2.2.1.1.1 Adjusted Mean TDI Focal Score ± SE Over Time  
Analysis Set: ITT Population 
 
Figure 2.2.1.1.2 Treatment Differences From Placebo MDI*: Adjusted Mean TDI Focal Score (95% CI) Over Time 
Analysis Set: ITT Population 
 
Figure 2.2.1.2.1 Adjusted Mean TDI Focal Score ± SE Over Time: CAT Score Subpopulation of >= 10 
Analysis Set: ITT Population 
 
Figure 2.2.1.2.2 Adjusted Mean TDI Focal Score ± SE Over Time: CAT Score Subpopulation of >= 15 
Analysis Set: ITT Population 
 
Figure 2.2.1.2.3 Adjusted Mean TDI Focal Score ± SE Over Time: CAT Score Subpopulation of >= 20 
Analysis Set: ITT Population 
 
Table 2.2.2.1 
TDI Component Scores for Functional Impairment, Magnitude of Task, and Magnitude of Effort Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 2.2.3 
Response in TDI Focal Score (Achievment of a Minimum Clinically Important Difference Threshold of ≥1 Unit on Average) Over 24 Weeks 
Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 


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Peak Change From Baseline in FEV1 
 
Table 2.3.1 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-Dose 
Analysis Set: ITT Population 
 
Figure 2.3.1 
Adjusted Mean Peak Change From Baseline in FEV1 (L) ± SE Within 2 Hours Post-Dose 
Analysis Set: ITT Population 
 


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St. George Respiratory Questionnaire (SGRQ) 
 
Table 2.4.1 
SGRQ Total Score Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Figure 2.4.1.1 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over Time 
Analysis Set: ITT Population  
 
Figure 2.4.1.2 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over Time: CAT Score Subpopulation of >= 10 
Analysis Set: ITT Population 
 
Figure 2.4.1.3 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over Time: CAT Score Subpopulation of >= 15 
Analysis Set: ITT Population 
 
Figure 2.4.1.4 
Adjusted Mean Change From Baseline in SGRQ Total Score (units) ± SE Over Time: CAT Score Subpopulation of >= 20 
Analysis Set: ITT Population 
 
Table 2.4.2 
Total Score of Each SGRQ Domain Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 2.4.3 
Response in SGRQ Total Score (Achievment of a Minimum Clinically Important Difference Threshold of ≥4 Units on Average) Overall and by 
CAT Score Subpopulation  
Analysis Set: ITT Population 
 
 
 


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Number of Puffs of Rescue Ventolin HFA 
 
Table 2.5.1 
Mean Daily, Daytime, and Nighttime Number of Puffs of Rescue Ventolin HFA  
Analysis Set: Rescue Ventolin User Population 
 
Figure 2.5.1.1 
Adjusted Mean Change From Baseline in Mean Daily Number of Puffs of Rescue Ventolin HFA ± SE Over Time  
Analysis Set: Rescue Ventolin User Population 
 
Figure 2.5.1.2 
Adjusted Mean Change From Baseline in Mean Daytime Number of Puffs of Rescue Ventolin HFA ± SE Over Time  
Analysis Set: Rescue Ventolin User Population 
 
Figure 2.5.1.3 
Adjusted Mean Change From Baseline in Mean Nighttime Number of Puffs of Rescue Ventolin HFA± SE Over Time  
Analysis Set: Rescue Ventolin User Population 
 
Table 2.5.2 
Percentage of Days With No Rescue Ventolin HFA Use Over 24 Weeks 
Analysis Set: Rescue Ventolin User Population 
 
 
 


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Time to Onset of Action Assessed Using FEV1 on Day 1 
 
Table 2.6.1 
FEV1 (L) by Post-Dose Timepoint on Day 1 
Analysis Set: ITT Population 
 
Figure 2.6.1 
Adjusted Mean Change From Baseline in FEV1 (L) ± SE Over the 2 Hour Post-Dose Interval on Day 1  
Analysis Set: ITT Population 
 
 
 


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Other Spirometry Measures Including Percent Responders Analyses for Day 1 
 
Table 2.7 
FEV1 AUC0-2 (L)  
Analysis Set: ITT Population 
 
Figure 2.7 
Adjusted Mean FEV1 AUC0-2 (L) ± SE Over Time 
Analysis Set: ITT Population 
 
Table 2.8 
FVC AUC0-2 (L) 
Analysis Set: ITT Population 
 
Figure 2.8 
Adjusted Mean FVC AUC0-2 (L) ± SE Over Time 
Analysis Set: ITT Population 
 
Table 2.9 
Peak Change From Baseline in FVC (L) Within 2 Hours Post-Dose  
Analysis Set: ITT Population 
 
Figure 2.9 
Adjusted Mean Peak Change From Baseline in FVC (L) ± SE Within 2 Hours Post-Dose 
Analysis Set: ITT Population 
 
Table 2.10 
Morning Pre-Dose Trough FVC (L)  
Analysis Set: ITT Population 
 
Figure 2.10 
Adjusted Mean Change From Baseline in Morning Pre-Dose Trough FVC (L) ± SE 
Analysis Set: ITT Population 
 
Table 2.11.1 
Percentage of Subjects With ≥10% Improvement From Baseline in FEV1 During 2 Hour Post-Dose Interval and by Post-Dose Timepoint on 
Day 1 
Analysis Set: ITT Population 
 
Table 2.11.2 
Percentage of Subjects With ≥12% Improvement From Baseline in FEV1 During 2 Hour Post-Dose Interval and by Post-Dose Timepoint on 
Day 1 
Analysis Set: ITT Population 
 


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Table 2.11.3 
Percentage of Subjects With ≥100 mL Improvement From Baseline in FEV1 During 2 Hour Post-Dose Interval and by Post-Dose Timepoint on 
Day 1 
Analysis Set: ITT Population 
 
Table 2.11.4 
Percentage of Subjects With ≥200 mL Improvement From Baseline in FEV1 During 2 Hour Post-Dose Interval and by Post-Dose Timepoint on 
Day 1 
Analysis Set: ITT Population 
 
Table 2.11.5 
Percentage of Subjects With Improvement From Baseline in FEV1 of Both ≥12% and ≥200 mL During 2 Hour Post-Dose Interval and by Post-
Dose Timepoint on Day 1 
Analysis Set: ITT Population 
 
Table 2.12 
FVC (L) Over the 2 Hour Post-Dose Interval on Day 1  
Analysis Set: ITT Population 
 
Figure 2.12 
Adjusted Mean Change From Baseline in FVC (L) ± SE Over the 2 Hour Post-Dose Interval on Day 1   
Analysis Set: ITT Population 
 
 
Exacerbations 
 
Table 2.13.1 
Rate of COPD Exacerbations Overall and by CAT Score Subpopulation  
Analysis Set: ITT Population 
 
Table 2.13.2 
Rate of COPD Exacerbations With Imputation Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 2.14 
Time to First COPD Exacerbation of Any Severity and Time to First Moderate or Severe COPD Exacerbation 
Analysis Set: ITT Population 
 
Figure 2.14.1.x 
Kaplan-Meier Curves for Time to First COPD Exacerbation of Any Severity Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 


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Figure 2.14.2.x 
Kaplan-Meier Curves for Time to First Moderate or Severe COPD Exacerbation Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 2.15 
Time to Treatment Failure Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Figure 2.15 
Kaplan-Meier Curves for Time to Treatment Failure Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 2.16.1 
Time to First Clinically Important Deterioration (CID) Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Figure 2.16.1.x 
Kaplan-Meier Curves for Time to First CID Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 2.16.2 
Time to First Clinically Important Deterioration (CID) With Death Overal Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Figure 2.16.2.x 
Kaplan-Meier Curves for Time to First CID With Death and Time to First Occurrence of Each Component of CID With Death Overall and by 
CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 2.17 
Time to First Sustained Clinically Important Deterioration (CID) and Time to First Occurrence of Each Component of Sustained CID Overall 
and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Figure 2.17.x 
Kaplan-Meier Curves for Time to First Sustained CID and Time to First Occurrence of Each Component of Sustained CID Overall and by CAT 
Score Subpopulation 
Analysis Set: ITT Population 
 
 


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Symptoms 
 
Table 2.18.1 
Mean Daily, Daytime, and Nighttime Total Symptom Scores 
Analysis Set: ITT Population 
 
Table 2.18.2 
Mean Daily, Daytime, and Nighttime Cough Symptom Scores 
Analysis Set: ITT Population 
 
Table 2.18.3 
Mean Daily, Daytime, and Nighttime Shortness of Breath Symptom Scores 
Analysis Set: ITT Population 
 
Table 2.18.4 
Mean Daily, Daytime, and Nighttime Sputum Volume Symptom Scores 
Analysis Set: ITT Population 
 
Table 2.18.5 
Mean Number of Nighttime Awakenings 
Analysis Set: ITT Population 
 
 
 


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Correlations 
 
Table 2.19.1 
Pearson Correlation Matrix of Key Efficacy Endpoints (Excluding Correlations with Efficacy Endpoints Over Weeks 12-24) 
Analysis Set: All Available Data 
 
Table 2.19.2 
Pearson Correlation Matrix of Key Efficacy Endpoints Over Weeks 12-24 With Other Key Efficacy Endpoints and With Each Other 
Analysis Set: All Available Data 
 
 


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Subgroup Analyses  
 
 
Table 2.22.2 
Demographics and Baseline Characteristics by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.22.3 
Demographics and Baseline Characteristics by GOLD Severity 
Analysis Set: ITT Population 
 
Table 2.24.2 
Severity and Duration of COPD by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.24.3 
Severity and Duration of COPD by GOLD Severity 
Analysis Set: ITT Population 
 
Table 2.25.2 
Reversibility to Ventolin HFA by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.25.3 
Reversibility to Ventolin HFA by GOLD Severity 
Analysis Set: ITT Population 
 
Table 2.26.2 
Reversibility to Atrovent HFA by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.26.3 
Reversibility to Atrovent HFA by GOLD Severity 
Analysis Set: ITT Population 
 
Table 2.27.2 
Study Treatment Exposure and Compliance by GOLD Category 
Analysis Set: Safety Population 
 
Table 2.27.3 
Study Treatment Exposure and Compliance by GOLD Severity 
Analysis Set: Safety Population 
 


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Table 2.28.2 
Morning Pre-Dose Trough FEV1 (L) by GOLD Category 
Analysis Set: ITT Population 
 
Figure 2.28.2.1 
Forest Plot for Morning Pre-Dose Trough FEV1 (L) ± SE at Week 24 by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.28.3 
Morning Pre-Dose Trough FEV1 (L) by GOLD Severity 
Analysis Set: ITT Population 
 
Figure 2.28.3.1 
Forest Plot for Morning Pre-Dose Trough FEV1 (L) ± SE at Week 24 by GOLD Severity 
Analysis Set: ITT Population 
 
Table 2.30.2 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-Dose by GOLD Category 
Analysis Set: ITT Population 
 
Figure 2.30.2.1 
Forest Plot for Peak FEV1 (L) ± SE Within 2 Hours Post-Dose at Week 24 by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.30.3 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-Dose by GOLD Severity 
Analysis Set: ITT Population 
 
Figure 2.30.3.1 
Forest Plot for Peak FEV1 (L) ± SE Within 2 Hours Post-Dose at Week 24 by GOLD Severity 
Analysis Set: ITT Population 
 
 
 
 


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Healthcare Resource Utilization 
 
Table 2.37.1 
Healthcare Resource Utilization: Number of Days Missed From Work 
Analysis Set: Safety Population 
 
Table 2.37.2 
Healthcare Resource Utilization by Relationship to COPD and Treatment 
Analysis Set: Safety Population 
 


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3. Safety 
 
Adverse Events 
 
Table 3.1.1 
Overall Summary of Adverse Events 
Analysis Set: Safety Population 
 
Table 3.2.1.1.x 
Adverse Events by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.2.1.2.x 
Adverse Events With Onset After the Last Date of Treatment by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.2.2.x 
Adverse Events Occurring in >=2% of Subjects in a Treatment by Descending Frequency 
Analysis Set: Safety Population 
 
Table 3.2.3 
Adverse Events in MedDRA SMQs/Groupings of Interest by Term 
Analysis Set: Safety Population 
 
Table 3.2.4.x 
Non-serious Adverse Events Occurring in ≥5% of Subjects in a Treatment by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.3.x 
Rate of Adverse Events Adjusted for Exposure by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.4.x 
Adverse Events Suspected to be Drug-Related by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.5.x 
Adverse Events Causing Study Drug Discontinuation by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.6.x 
Listing of Adverse Events Leading to Permanent Discontinuation of Study Treatment 
Analysis Set: All Subjects Randomized 


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Table 3.7.1.x 
Serious Adverse Events by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.7.2.x 
Serious Adverse Events With Onset After the Last Date of Treatment by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.8.1 
Listing of Serious Adverse Events (SAEs) 
Analysis Set: All Subjects Screened 
 
Table 3.8.2 
Listing of SAE-Specific Report Information 
Analysis Set: All Subjects Screened 
 
Table 3.9.x 
Rate of Serious Adverse Events Adjusted for Exposure, by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.10.x 
Serious Adverse Events Suspected to be Drug-Related by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.11.1.x 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – GFF MDI 14.4/9.6 μg 
Analysis Set: Safety Population 
 
Table 3.11.2.x 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – FF MDI 9.6 μg 
Analysis Set: Safety Population 
 
Table 3.11.3.x 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – GP MDI 14.4 μg  
Analysis Set: Safety Population 
 
Table 3.11.4.x 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – Placebo MDI 
Analysis Set: Safety Population 
 
Table 3.12.x 
Death Events, by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 


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Table 3.13 
Listing of Deaths 
Analysis Set: All Subjects Screened 
 
 


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Laboratory Parameters 
 
Table 3.14.1 
Laboratory Parameters by Visit and Time of Assessment – Hematology Panel 
Analysis Set: Safety Population 
 
Table 3.14.2 
Laboratory Parameters by Visit and Time of Assessment – Blood Chemistry Panel 
Analysis Set: Safety Population 
 
Table 3.14.3 
Laboratory Parameters by Visit and Time of Assessment – Kidney Function 
Analysis Set: Safety Population 
 
Table 3.14.4 
Laboratory Parameters by Visit and Time of Assessment – Urinalysis pH and Specific Gravity 
Analysis Set: Safety Population 
 
Table 3.14.5 
Shift Table for Laboratory Hematology Data: NCI-CTC Grading 
Analysis Set: Safety Population 
 
Table 3.14.6 
Shift Table for Laboratory Chemistry Data: NCI-CTC Grading 
Analysis Set: Safety Population 
 
Table 3.14.7 
Shift Table for Kidney Function: NCI-CTC Grading 
Analysis Set: Safety Population 
 
Table 3.14.8 
Post-Baseline Newly Occurring or Worsening Potentially Clinically Significant Laboratory Values Based on CTCAE 4.03 and Other Criteria 
Analysis Set: Safety Population 
 
Table 3.14.9 
All Potassium Records for Subjects With Newly Occurring or Worsening Potentially Clinically Significant Potassium Values Post-Baseline  
Analysis Set: Safety Population  
 
Table 3.14.10 
All Glucose Records for Subjects With Newly Occurring or Worsening Potentially Clinically Significant Glucose Values Post-Baseline  
Analysis Set: Safety Population  
 


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Table 3.14.11 
All Records for Subjects With Newly Occurring or Worsening Potentially Clinically Significant Values Post-Baseline Other Than Those for 
Glucose and Potassium 
Analysis Set: Safety Population 
 
 
 


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Vital Signs 
 
Table 3.15.1 
Vital Sign Measurements by Visit and Time of Assessment 
Analysis Set: Safety Population 
 
Table 3.15.2 
Post-Baseline Potentially Clinically Significant Vital Sign Values 
Analysis Set: Safety Population 
 
Table 3.15.3 
Listing of Potentially Clinically Significant Systolic and Diastolic Blood Pressure Increases and Decreases 
Analysis Set: Safety Population 
 
Table 3.15.4 
Listing of Potentially Clinically Significant Tachycardia and Bradycardia Events 
Analysis Set: All Subjects Randomized 
 
 


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12-Lead Electrocardiogram (ECG) 
 
Table 3.16.1 
ECG Parameters by Visit and Time of Assessment 
Analysis Set: Safety Population 
 
Figure 3.16.1a 
Mean Change From Baseline for QTcF (ms) ± SE Over Time During Treatment 
Analysis Set: Safety Population 
 
Figure 3.16.1b 
Mean Change From Baseline for QTcF (ms) ± SE Over 2 Hours Post-Dose on Day 1  
Analysis Set: Safety Population 
 
Figure 3.16.1c 
Mean Change From Baseline for Heart Rate (bpm) ± SE Over Time During Treatment 
Analysis Set: Safety Population 
 
Figure 3.16.1d 
Mean Change From Baseline for Heart Rate (bpm) ± SE Over 2 Hours Post-Dose on Day 1  
Analysis Set: Safety Population 
 
Table 3.16.2 
Post-Baseline Potentially Clinically Significant (PCS) ECG Values 
Analysis Set: Safety Population 
 
Table 3.16.3 
Listing of ECG's Meeting QTcF Interval Prolongation Criteria 
Analysis Set: All Subjects Randomized 
 
Table 3.16.4 
Listing of PR Interval Increases: Post-Baseline Increases of >50 ms From Baseline 
Analysis Set: All Subjects Randomized 
 
Table 3.16.5 
Listing of QRS Prolongations: Post-Baseline Prolongations of >40 ms From Baseline 
Analysis Set: All Subjects Randomized 
 


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4. Subject Data Listings 
 
4.1 Subject Discontinuations/Completions 
 
Listing 1.1 
Study Centers 
Analysis Set: All Subjects Screened 
 
Listing 1.2 
Subject Disposition and Demographic Data 
Analysis Set: All Subjects Screened 
 
Listing 1.3 
Randomized Treatment, Actual Treatment, and Duration of Treatment 
Analysis Set: All Subjects Randomized  
 
Listing 1.4 
Reasons Subjects Were Not Randomized 
Analysis Set: Non-Randomized Analysis Set 
 
Listing 1.5 
Changes in Smoking Status During Study 
Analysis Set: All Subjects Randomized 
 


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4.2 Protocol Deviations 
 
Listing 2.1 
Violation of Inclusion/Exclusion Criteria and Waivers 
Analysis Set: All Subjects Randomized 
 
Listing 2.2 
Screening Lung Function and Ventolin HFA and Atrovent HFA Reversibility 
Analysis Set: All Subjects Randomized 
 
 
 


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4.3 Subjects Excluded From the ITT, PP, Rescue Ventolin User, and Safety Populations 
 
See Table 1.1.4 in Section 1. 
 
 


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4.4 Baseline Characteristics 
 
Listing 4.1 
COPD Diagnosis  
Analysis Set: All Subjects Randomized 
 
Listing 4.2 
Screening CAT Assessment 
Analysis Set: All Subjects Randomized 
 
Listing 4.3 
Screening MMRC Scale 
Analysis Set: All Subjects Randomized 
 
Listing 4.4 
History of Moderate or Severe COPD Exacerbations 
Analysis Set: All Subjects Randomized 
 
Listing 4.5.1 
Relevant Medical and Surgical History 
Analysis Set: All Subjects Randomized 
 
Listing 4.5.2 
Cardiovascular Risk Factors of Interest 
Analysis Set: All Subjects Randomized 
 
Listing 4.6 
Screening Reproductive Status and Pregnancy Test Results 
Analysis Set: All Subjects Randomized 
 
Listing 4.7 
Prior, Concomitant, and Post-Treatment COPD Medications 
Analysis Set: All Subjects Randomized 
 
Listing 4.8 
Prior, Concomitant, and Post-Treatment Non-COPD-Related Medications 
Analysis Set: All Subjects Randomized 
 
Listing 4.9 
Suspect Drug Assessment for SAEs 
Analysis Set: All Subjects Randomized 
 
 


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4.5 Dosing and Compliance 
 
Listing 5.1.1 
Study Drug Dosing, Dispensing, and Return 
Analysis Set: All Subjects Randomized 
 
Listing 5.1.2 
Atrovent HFA and Ventolin HFA Dispensing 
Analysis Set: All Subjects Randomized 
 
Listing 5.2 
Compliance and Exposure to Study Treatment 
Analysis Set: All Subjects Randomized 
 


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4.6 Individual Efficacy Data and HCRU Data 
 
4.6.1 Efficacy 
 
Listing 6.1.1 
Subjects Who Failed Restrictions Prior to Spirometry Assessment 
Analysis Set: All Subjects Randomized 
 
Listing 6.1.2 
Reason for Missingness Overall and by Visit 
Analysis Set: All Subjects Randomized 
 
Listing 6.1.3 
Spirometry Measurements 
Analysis Set: All Subjects Randomized 
 
Listing 6.1.4 
FEV1 (L) at Each Post-Dose Timepoint Through 2 Hours on a Test Day 
Analysis Set: ITT Population 
 
Listing 6.1.5 
FVC (L) at Each Post-Dose Timepoint Through 2 Hours on a Test Day 
Analysis Set: ITT Population 
 
Listing 6.1.6 
Subject Dosing and Symptoms Diary, Including Rescue Medication Use 
Analysis Set: All Subjects Randomized 
 
Listing 6.1.7 
COPD Exacerbations 
Analysis Set: All Subjects Randomized 
 
Listing 6.1.8 
Baseline Dyspnea Index (BDI) /Transition Dyspnea Index (TDI) 
Analysis Set: All Subjects Randomized 
 
Listing 6.1.9 
St. George Respiratory Questionnaire (SGRQ) 
Analysis Set: All Subjects Randomized 
 
Listing 6.1.10 
Individual Items of the St. George Respiratory Questionnaire (SGRQ) 
Analysis Set: All Subjects Randomized 


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4.6.2 Healthcare Resource Utilization 
 
Listing 6.2 
Healthcare Resource Utilization 
Analysis Set: Safety Population 
 


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4.7 Adverse Event Listings 
 
Listing 7.1 
Adverse Events by Primary System Organ Class, Preferred Term, Treatment, Country, Center, Subject ID, and Onset Day 
Analysis Set: All Subjects Randomized 
 
Listing 7.2 
Glossary of Adverse Event Preferred Terms vs. Investigator’s Verbatim 
 
Listing 7.3 
Adverse Events by Treatment, Country, Center, Subject ID, and Onset Day 
Analysis Set: All Subjects Randomized 
 
 


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4.8 Laboratory Values 
 
Listing 8.1 
Laboratory Test Results (Hematology Panel) 
Analysis Set: All Subjects Randomized 
 
Listing 8.2 
Laboratory Test Results (Morphology) 
Analysis Set: All Subjects Randomized 
 
Listing 8.3 
Laboratory Test Results (Chemistry Panel and Kidney Function) 
Analysis Set: All Subjects Randomized 
 
Listing 8.4 
Laboratory Test Results (Urinalysis Panel) 
Analysis Set: All Subjects Randomized 
 
Listing 8.5 
Laboratory Test Comments 
Analysis Set: All Subjects Randomized 
 
 


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4.9 Other Clinical Observations and Measurements 
 
Listing 9.1 
Vital Signs, Weight, and Height 
Analysis Set: All Subjects Randomized 
 
Listing 9.2 
12-Lead Electrocardiogram (ECG) 
Analysis Set: All Subjects Randomized 
 
Listing 9.3 
Pregnancy Testing After Start of Treatment in the Study 
Analysis Set: All Subjects Randomized 
 


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APPENDIX 8 
TABLE OF CONTENTS FOR POST-TEXT TLFs IN THE 
ASIA POPULATION 
__________________________________________________________________ 
 
 
Study Number: 
PT003014 
Investigational Drug and Drug 
Number: 
Glycopyrronium and Formoterol Fumarate Inhalation 
Aerosol (GFF MDI); PT003 
Glycopyrronium Inhalation Aerosol (GP MDI); PT005 
Formoterol Fumarate Inhalation Aerosol (FF MDI); 
PT001 
Indication: 
COPD 
Dosage Form/Strength: 
GFF MDI 14.4/9.6 μg ex-actuator BID 
GP MDI 14.4 μg ex-actuator BID 
FF MDI 9.6 μg ex-actuator BID 
 
PT003014 Protocol 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 
 
 


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General Instructions for End-of-Text TFLs 
 
The main study mock-ups document for PT003014 provides details regarding the presentation of TLFs 
(including titling, formatting, page layouts, content, etc.). 
 
TLFs that are identical in presentation to those outlined in the main PT003014 SAP are listed but not 
presented. 
 


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TABLE OF CONTENTS FOR END-OF-TEXT TLFs 
 
1. 
SUBJECT DISPOSITION, DEMOGRAPHIC, BASELINE, AND OTHER SUMMARY 
TABLES ............................................................................................................................................. 9 
Table 1.1.1 
Subject Disposition ............................................................................................................. 9 
Analysis Set: All Subjects Randomized 
Table 1.1.3 
Distribution of Subjects in Analysis Populations, by Country, Center, and 
Treatment............................................................................................................................ 9 
Analysis Set: All Subjects Randomized 
Table 1.1.4 
Reasons for Subjects Not Randomized ............................................................................... 9 
Analysis Set: Non-Randomized Analysis Set 
Table 1.1.5 
Subjects Excluded From ITT, PP, Rescue Ventolin User, and Safety Populations ............ 9 
Analysis Set: All Subjects Randomized 
Table 1.2.2 
Reason for Early Discontinuation Overall and by CAT Score Subpopulation ................... 9 
Analysis Set: ITT Population 
Table 1.3 
Reason for Exclusion From the PP Population ................................................................... 9 
Analysis Set: ITT Population 
Table 1.4.1 
Demographics and Baseline Characteristics Overall and by CAT Score 
Subpopulation ..................................................................................................................... 9 
Analysis Set: ITT Population 
Table 1.5.1 
Severity and Duration of COPD Overall and by CAT Score Subpopulation...................... 9 
Analysis Set: ITT Population 
Table 1.6.1 
Screening Pre- and Post-Bronchodilator and Baseline Spirometry Parameters 
Overall and by CAT Score Subpopulation ......................................................................... 9 
Analysis Set: ITT Population 
Table 1.7.1 
Reversibility to Ventolin HFA Overall and by CAT Score Subpopulation ........................ 9 
Analysis Set: ITT Population 
Table 1.8.1 
Reversibility to Atrovent HFA Overall and by CAT Score Subpopulation ...................... 10 
Analysis Set: ITT Population 
Table 1.12 
Study Treatment Exposure and Compliance ..................................................................... 10 
Analysis Set: Safety Population 
Table 1.13 
Changes in Smoking Status After Start of Treatment ....................................................... 10 
Analysis Set: Safety Population 
2. 
EFFICACY DATA SUMMARY TABLES ...................................................................................... 11 
CHANGE FROM BASELINE IN MORNING PRE-DOSE TROUGH FEV1 ........................................... 11 
Table 2.1.1 
Morning Pre-Dose Trough FEV1 (L) at Week 24 ............................................................. 11 
Analysis Set: ITT Population 
Figure 2.1.1.1 
Adjusted Mean Change From Baseline in Morning Pre-Dose Trough FEV1 (L) ± 
SE Over Time ................................................................................................................... 11 
Analysis Set: ITT Population 


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Figure 2.1.1.2 
Treatment Differences From Placebo MDI*: Adjusted Mean Change From 
Baseline (95% CI) in Morning Pre-Dose Trough FEV1 (L) Over Time ........................... 11 
Analysis Set: ITT Population 
Table 2.1.2 
Morning Pre-Dose Trough FEV1 (L) at Week 24 ............................................................. 11 
Analysis Set: PP Population 
Figure 2.1.2 
Adjusted Mean Change From Baseline in Morning Pre-Dose Trough FEV1 (L) ± 
SE Over Time ................................................................................................................... 11 
Analysis Set: PP Population 
Table 2.1.4.4 
 Cumulative Proportion of Responders Based on Change From Baseline in 
Morning Pre-dose Trough FEV1 at Week 24.................................................................... 11 
Analysis Set: ITT Population 
Figure 2.1.4.31 
Cumulative Proportion of Responders Based on Change From Baseline in 
Morning Pre-dose Trough FEV1 at Week 24.................................................................... 11 
Analysis Set: ITT Population 
TRANSITION DYSPNEA INDEX (TDI) ................................................................................................. 11 
Table 2.2.1 
TDI Focal Score Overall and by CAT Score Subpopulation ............................................ 11 
Analysis Set: ITT Population 
ST. GEORGE RESPIRATORY QUESTIONNAIRE (SGRQ) .................................................................. 12 
Table 2.4.1 
SGRQ Total Score Overall and by CAT Score Subpopulation ........................................ 12 
Analysis Set: ITT Population 
Table 2.4.2 
Total Score of Each SGRQ Domain Overall and by CAT Score Subpopulation ............. 12 
Analysis Set: ITT Population 
Table 2.4.3 
Response in SGRQ Total Score (Achievment of a Minimum Clinically Important 
Difference Threshold of ≥4 Units on Average) Overall and by CAT Score 
Subpopulation ................................................................................................................... 12 
Analysis Set: ITT Population 
NUMBER OF PUFFS OF RESCUE VENTOLIN HFA ............................................................................ 12 
Table 2.5.1 
Mean Daily, Daytime, and Nighttime Number of Puffs of Rescue Ventolin HFA ........... 12 
Analysis Set: Rescue Ventolin User Population 
Table 2.5.2 
Percentage of Days With No Rescue Ventolin HFA Use Over 24 Weeks ....................... 12 
Analysis Set: Rescue Ventolin User Population 
TIME TO ONSET OF ACTION ASSESSED USING FEV1 ON DAY 1 .................................................. 12 
Table 2.6.1 
FEV1 (L) by Post-Dose Timepoint on Day 1 .................................................................... 12 
Analysis Set: ITT Population 
EXACERBATIONS ................................................................................................................................... 12 
Table 2.13.1 
Rate of COPD Exacerbations Overall and by CAT Score Subpopulation ........................ 12 
Analysis Set: ITT Population 
Table 2.13.2 
Rate of COPD Exacerbations With Imputation Overall and by CAT Score 
Subpopulation ................................................................................................................... 12 
Analysis Set: ITT Population 


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Table 2.14 
Time to First COPD Exacerbation of Any Severity and Time to First Moderate or 
Severe COPD Exacerbation.............................................................................................. 13 
Analysis Set: ITT Population 
Figure 2.14.1.x 
Kaplan-Meier Curves for Time to First COPD Exacerbation of Any Severity 
Overall and by CAT Score Subpopulation ....................................................................... 13 
Analysis Set: ITT Population 
Figure 2.14.2.x 
Kaplan-Meier Curves for Time to First Moderate or Severe COPD Exacerbation 
Overall and by CAT Score Subpopulation ....................................................................... 13 
Analysis Set: ITT Population 
Table 2.15 
Time to Treatment Failure Overall and by CAT Score Subpopulation ............................ 13 
Analysis Set: ITT Population 
Figure 2.15 
Kaplan-Meier Curves for Time to Treatment Failure Overall and by CAT Score 
Subpopulation ................................................................................................................... 13 
Analysis Set: ITT Population 
3. 
SAFETY ............................................................................................................................................ 14 
ADVERSE EVENTS .................................................................................................................................. 14 
Table 3.1.1 
Overall Summary of Adverse Events ............................................................................... 14 
Analysis Set: Safety Population 
Table 3.2.1.1 
Adverse Events by MedDRA Primary System Organ Class and Preferred Term ............ 14 
Analysis Set: Safety Population 
Table 3.2.1.2 
Adverse Events With Onset After the Last Date of Treatment by MedDRA 
Primary System Organ Class and Preferred Term ............................................................ 14 
Analysis Set: Safety Population 
Table 3.2.2 
Adverse Events Occurring in >=2% of Subjects in a Treatment by Descending 
Frequency ......................................................................................................................... 14 
Analysis Set: Safety Population 
Table 3.2.3 
Adverse Events in MedDRA SMQs/Groupings of Interest by Term ................................ 14 
Analysis Set: Safety Population 
Table 3.2.4 
Non-serious Adverse Events Occurring in ≥5% of Subjects in a Treatment by 
MedDRA Primary System Organ Class and Preferred Term ........................................... 14 
Analysis Set: Safety Population 
Table 3.3 
Rate of Adverse Events Adjusted for Exposure by MedDRA Primary System 
Organ Class and Preferred Term ...................................................................................... 14 
Analysis Set: Safety Population 
Table 3.4 
Adverse Events Suspected to be Drug-Related by MedDRA Primary System 
Organ Class and Preferred Term ...................................................................................... 14 
Analysis Set: Safety Population 
Table 3.5 
Adverse Events Causing Study Drug Discontinuation by MedDRA Primary 
System Organ Class and Preferred Term .......................................................................... 14 
Analysis Set: Safety Population 
Table 3.6 
Listing of Adverse Events Leading to Permanent Discontinuation of Study 
Treatment.......................................................................................................................... 14 
Analysis Set: All Subjects Randomized 


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Table 3.7.1 
Serious Adverse Events by MedDRA Primary System Organ Class and Preferred 
Term ................................................................................................................................. 15 
Analysis Set: Safety Population 
Table 3.7.2 
Serious Adverse Events With Onset After the Last Date of Treatment by MedDRA 
Primary System Organ Class and Preferred Term ............................................................ 15 
Analysis Set: Safety Population 
Table 3.8.1 
Listing of Serious Adverse Events (SAEs) ....................................................................... 15 
Analysis Set: All Subjects Screened 
Table 3.8.2 
Listing of SAE-Specific Report Information .................................................................... 15 
Analysis Set: All Subjects Screened 
Table 3.9 
Rate of Serious Adverse Events Adjusted for Exposure, by MedDRA Primary 
System Organ Class and Preferred Term .......................................................................... 15 
Analysis Set: Safety Population 
Table 3.10 
Serious Adverse Events Suspected to be Drug-Related by MedDRA Primary 
System Organ Class and Preferred Term .......................................................................... 15 
Analysis Set: Safety Population 
Table 3.11.1 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – 
GFF MDI 14.4/9.6 μg ....................................................................................................... 15 
Analysis Set: Safety Population 
Table 3.11.2 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – 
FF MDI 9.6 μg .................................................................................................................. 15 
Analysis Set: Safety Population 
Table 3.11.3 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – 
GP MDI 14.4 μg ............................................................................................................... 15 
Analysis Set: Safety Population 
Table 3.11.4 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – 
Placebo MDI..................................................................................................................... 15 
Analysis Set: Safety Population 
Table 3.12 
Death Events, by MedDRA Primary System Organ Class and Preferred Term ............... 15 
Analysis Set: Safety Population 
Table 3.13 
Listing of Deaths............................................................................................................... 16 
Analysis Set: All Subjects Screened 
4. 
SUBGROUP ANALYSES ................................................................................................................ 17 
Table 2.22.2 
Demographics and Baseline Characteristics by GOLD Category..................................... 17 
Analysis Set: ITT Population 
Table 2.22.3 
Demographics and Baseline Characteristics by GOLD Severity ...................................... 17 
Analysis Set: ITT Population 
Table 2.24.2 
Severity and Duration of COPD by GOLD Category ....................................................... 17 
Analysis Set: ITT Population 
Table 2.24.3 
Severity and Duration of COPD by GOLD Severity ........................................................ 17 
Analysis Set: ITT Population 
Table 2.25.2 
Reversibility to Ventolin HFA by GOLD Category ......................................................... 17 
Analysis Set: ITT Population 
Table 2.25.3 
Reversibility to Ventolin HFA by GOLD Severity........................................................... 17 
Analysis Set: ITT Population 


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Table 2.26.2 
Reversibility to Atrovent HFA by GOLD Category ......................................................... 17 
Analysis Set: ITT Population 
Table 2.26.3 
Reversibility to Atrovent HFA by GOLD Severity .......................................................... 17 
Analysis Set: ITT Population 
Table 2.27.2 
Study Treatment Exposure and Compliance by GOLD Category .................................... 17 
Analysis Set: Safety Population 
Table 2.27.3 
Study Treatment Exposure and Compliance by GOLD Severity ..................................... 17 
Analysis Set: Safety Population 
Table 2.28.2 
Morning Pre-Dose Trough FEV1 (L) by GOLD Category ............................................... 17 
Analysis Set: ITT Population 
Figure 2.28.2.1 
Forest Plot for Morning Pre-Dose Trough FEV1 (L) ± SE at Week 24 by GOLD 
Category ........................................................................................................................... 18 
Analysis Set: ITT Population 
Table 2.28.3 
Morning Pre-Dose Trough FEV1 (L) by GOLD Severity ................................................. 18 
Analysis Set: ITT Population 
Figure 2.28.3.1 
Forest Plot for Morning Pre-Dose Trough FEV1 (L) ± SE at Week 24 by GOLD 
Severity ............................................................................................................................. 18 
Analysis Set: ITT Population 
Table 2.30.2 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-Dose by GOLD 
Category ........................................................................................................................... 18 
Analysis Set: ITT Population 
Figure 2.30.2.1 
Forest Plot for Peak FEV1 (L) ± SE Within 2 Hours Post-Dose at Week 24 by 
GOLD Category ............................................................................................................... 18 
Analysis Set: ITT Population 
Table 2.30.3 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-Dose by GOLD 
Severity ............................................................................................................................. 18 
Analysis Set: ITT Population 
Figure 2.30.3.1 
Forest Plot for Peak FEV1 (L) ± SE Within 2 Hours Post-Dose at Week 24 by 
GOLD Severity ................................................................................................................. 18 
Analysis Set: ITT Population 


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SHELLS FOR END-OF-TEXT TLFS 
 


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1. Subject Disposition, Demographic, Baseline, and Other Summary Tables 
 
Table 1.1.1 
Subject Disposition 
Analysis Set: All Subjects Randomized 
 
Table 1.1.3 
Distribution of Subjects in Analysis Populations, by Country, Center, and Treatment 
Analysis Set: All Subjects Randomized 
 
Table 1.1.4 
Reasons for Subjects Not Randomized 
Analysis Set: Non-Randomized Analysis Set 
 
Table 1.1.5 
Subjects Excluded From ITT, PP, Rescue Ventolin User, and Safety Populations 
Analysis Set: All Subjects Randomized 
 
Table 1.2.2 
Reason for Early Discontinuation Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 1.3 
Reason for Exclusion From the PP Population 
Analysis Set: ITT Population 
 
Table 1.4.1 
Demographics and Baseline Characteristics Overall and by CAT Score Subpopulation  
Analysis Set: ITT Population 
 
 
Table 1.5.1 
Severity and Duration of COPD Overall and by CAT Score Subpopulation  
Analysis Set: ITT Population 
 
 
Table 1.6.1 
Screening Pre- and Post-Bronchodilator and Baseline Spirometry Parameters Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 1.7.1 
Reversibility to Ventolin HFA Overall and by CAT Score Subpopulation  
Analysis Set: ITT Population 
 


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Table 1.8.1 
Reversibility to Atrovent HFA Overall and by CAT Score Subpopulation  
Analysis Set: ITT Population 
 
 
 
Table 1.12 
Study Treatment Exposure and Compliance 
Analysis Set: Safety Population 
 
Table 1.13 
Changes in Smoking Status After Start of Treatment 
Analysis Set: Safety Population 
 


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2. Efficacy Data Summary Tables 
 
Change From Baseline in Morning Pre-Dose Trough FEV1 
 
Table 2.1.1 
Morning Pre-Dose Trough FEV1 (L) at Week 24 
Analysis Set: ITT Population 
 
Figure 2.1.1.1 
Adjusted Mean Change From Baseline in Morning Pre-Dose Trough FEV1 (L) ± SE Over Time 
Analysis Set: ITT Population 
 
Figure 2.1.1.2 
Treatment Differences From Placebo MDI*: Adjusted Mean Change From Baseline (95% CI) in Morning Pre-Dose Trough FEV1 (L) Over 
Time 
Analysis Set: ITT Population 
 
Table 2.1.2 
Morning Pre-Dose Trough FEV1 (L) at Week 24 
Analysis Set: PP Population 
 
Figure 2.1.2 
Adjusted Mean Change From Baseline in Morning Pre-Dose Trough FEV1 (L) ± SE Over Time 
Analysis Set: PP Population 
 
Table 2.1.4.4 
 Cumulative Proportion of Responders Based on Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 
Analysis Set: ITT Population 
 
Figure 2.1.4.31 
Cumulative Proportion of Responders Based on Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 
Analysis Set: ITT Population 
 
Transition Dyspnea Index (TDI) 
 
Table 2.2.1 
TDI Focal Score Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 
 


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St. George Respiratory Questionnaire (SGRQ) 
 
Table 2.4.1 
SGRQ Total Score Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 2.4.2 
Total Score of Each SGRQ Domain Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 2.4.3 
Response in SGRQ Total Score (Achievment of a Minimum Clinically Important Difference Threshold of ≥4 Units on Average) Overall and by 
CAT Score Subpopulation  
Analysis Set: ITT Population 
 
Number of Puffs of Rescue Ventolin HFA 
 
Table 2.5.1 
Mean Daily, Daytime, and Nighttime Number of Puffs of Rescue Ventolin HFA  
Analysis Set: Rescue Ventolin User Population 
 
Table 2.5.2 
Percentage of Days With No Rescue Ventolin HFA Use Over 24 Weeks 
Analysis Set: Rescue Ventolin User Population 
 
Time to Onset of Action Assessed Using FEV1 on Day 1 
 
Table 2.6.1 
FEV1 (L) by Post-Dose Timepoint on Day 1 
Analysis Set: ITT Population 
 
Exacerbations  
 
Table 2.13.1 
Rate of COPD Exacerbations Overall and by CAT Score Subpopulation  
Analysis Set: ITT Population 
 
Table 2.13.2 
Rate of COPD Exacerbations With Imputation Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 


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Table 2.14 
Time to First COPD Exacerbation of Any Severity and Time to First Moderate or Severe COPD Exacerbation 
Analysis Set: ITT Population 
 
Figure 2.14.1.x 
Kaplan-Meier Curves for Time to First COPD Exacerbation of Any Severity Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Figure 2.14.2.x 
Kaplan-Meier Curves for Time to First Moderate or Severe COPD Exacerbation Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Table 2.15 
Time to Treatment Failure Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
Figure 2.15 
Kaplan-Meier Curves for Time to Treatment Failure Overall and by CAT Score Subpopulation 
Analysis Set: ITT Population 
 
 


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3. Safety 
 
Adverse Events 
 
Table 3.1.1 
Overall Summary of Adverse Events 
Analysis Set: Safety Population 
 
Table 3.2.1.1 
Adverse Events by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.2.1.2 
Adverse Events With Onset After the Last Date of Treatment by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.2.2 
Adverse Events Occurring in >=2% of Subjects in a Treatment by Descending Frequency 
Analysis Set: Safety Population 
 
Table 3.2.3 
Adverse Events in MedDRA SMQs/Groupings of Interest by Term 
Analysis Set: Safety Population 
 
Table 3.2.4 
Non-serious Adverse Events Occurring in ≥5% of Subjects in a Treatment by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.3 
Rate of Adverse Events Adjusted for Exposure by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.4 
Adverse Events Suspected to be Drug-Related by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.5 
Adverse Events Causing Study Drug Discontinuation by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.6 
Listing of Adverse Events Leading to Permanent Discontinuation of Study Treatment 
Analysis Set: All Subjects Randomized 


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Table 3.7.1 
Serious Adverse Events by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.7.2 
Serious Adverse Events With Onset After the Last Date of Treatment by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.8.1 
Listing of Serious Adverse Events (SAEs) 
Analysis Set: All Subjects Screened 
 
Table 3.8.2 
Listing of SAE-Specific Report Information 
Analysis Set: All Subjects Screened 
 
Table 3.9 
Rate of Serious Adverse Events Adjusted for Exposure, by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.10 
Serious Adverse Events Suspected to be Drug-Related by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 
Table 3.11.1 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – GFF MDI 14.4/9.6 μg 
Analysis Set: Safety Population 
 
Table 3.11.2 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – FF MDI 9.6 μg 
Analysis Set: Safety Population 
 
Table 3.11.3 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – GP MDI 14.4 μg  
Analysis Set: Safety Population 
 
Table 3.11.4 
TEAEs by Primary System Organ Class, Preferred Term, and Highest Severity – Placebo MDI 
Analysis Set: Safety Population 
 
Table 3.12 
Death Events, by MedDRA Primary System Organ Class and Preferred Term 
Analysis Set: Safety Population 
 


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Table 3.13 
Listing of Deaths 
Analysis Set: All Subjects Screened 
 


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4. Subgroup Analyses 
 
Table 2.22.2 
Demographics and Baseline Characteristics by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.22.3 
Demographics and Baseline Characteristics by GOLD Severity 
Analysis Set: ITT Population 
 
Table 2.24.2 
Severity and Duration of COPD by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.24.3 
Severity and Duration of COPD by GOLD Severity 
Analysis Set: ITT Population 
 
Table 2.25.2 
Reversibility to Ventolin HFA by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.25.3 
Reversibility to Ventolin HFA by GOLD Severity 
Analysis Set: ITT Population 
 
Table 2.26.2 
Reversibility to Atrovent HFA by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.26.3 
Reversibility to Atrovent HFA by GOLD Severity 
Analysis Set: ITT Population 
 
Table 2.27.2 
Study Treatment Exposure and Compliance by GOLD Category 
Analysis Set: Safety Population 
 
Table 2.27.3 
Study Treatment Exposure and Compliance by GOLD Severity 
Analysis Set: Safety Population 
 
Table 2.28.2 
Morning Pre-Dose Trough FEV1 (L) by GOLD Category 
Analysis Set: ITT Population 


GFF MDI/GP MDI/FF MDI 
Protocol PT003014 
Final Version 
07 Mar 2017 
Page 18 of 18 
 
 
 
 
 
Figure 2.28.2.1 
Forest Plot for Morning Pre-Dose Trough FEV1 (L) ± SE at Week 24 by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.28.3 
Morning Pre-Dose Trough FEV1 (L) by GOLD Severity 
Analysis Set: ITT Population 
 
Figure 2.28.3.1 
Forest Plot for Morning Pre-Dose Trough FEV1 (L) ± SE at Week 24 by GOLD Severity 
Analysis Set: ITT Population 
 
Table 2.30.2 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-Dose by GOLD Category 
Analysis Set: ITT Population 
 
Figure 2.30.2.1 
Forest Plot for Peak FEV1 (L) ± SE Within 2 Hours Post-Dose at Week 24 by GOLD Category 
Analysis Set: ITT Population 
 
Table 2.30.3 
Peak Change From Baseline in FEV1 (L) Within 2 Hours Post-Dose by GOLD Severity 
Analysis Set: ITT Population 
 
Figure 2.30.3.1 
Forest Plot for Peak FEV1 (L) ± SE Within 2 Hours Post-Dose at Week 24 by GOLD Severity 
Analysis Set: ITT Population