Conditions: Chronic Obstructive Pulmonary Disorder
Keywords: COPD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2389
Healthy volunteers: no

Brief summary:
This is a Phase III randomized, double-blind, parallel group, multi-center, 24-week lung function study with BFF MDI (320/9.6 μg and 160/9.6 μg) compared to FF MDI 9.6 μg, BD MDI 320 μg, and open-label Symbicort® TBH (200/6 μg) administered BID.

Detailed description:
This is a Phase III randomized, double-blind, parallel group, multi-center, 24-week lung function study with BFF MDI (320/9.6 μg and 160/9.6 μg) compared to FF MDI 9.6 μg, BD MDI 320 μg, and open-label Symbicort® TBH (200/6 μg) administered BID. Subjects will undergo a 1- to 4-week Screening Period. Subjects who successfully complete the Screening Period will be to one of the following five treatment groups:BFF MDI 320/9.6 μg BID (N=660), BFF MDI 160/9.6 μg BID, FF MDI 9.6 μg BID, BD MDI 320 μg BID, Symbicort®, TBH 400/12 μg BID. Following randomization, subjects will enter the Treatment Period and undergo additional treatment visits over 24 weeks.

Arms:
arm 1: Budesonide and Formoterol Fumarate Inhalation Aerosol 160/4.8 μg per actuation MDI/120 inhalations Taken as 2 inhalations BID arm 2: Budesonide and Formoterol Fumarate Inhalation Aerosol-80/4.8 μg per actuation MDI/120 inhalations Taken as 2 inhalations BID arm 3: Formoterol Fumarate Inhalation Aerosol-4.8 μg per actuation MDI/ 120 inhalations Taken as 2 inhalations BID arm 4: Budesonide inhalation Aerosol 160 μg per actuation MDI/120 inhalations Taken as 2 inhalations BID arm 5: Symbicort Turbuhaler 400/12 μg Taken as 2 inhalations BID

Interventions: intervention 1: BFF MDI 320/9.6 μg intervention 2: BFF MDI 160/9.6 μg intervention 3: FF MDI 9.6 μg intervention 4: BD MDI 320 μg intervention 5: Symbicort® TBH 400/12 μg BID
Intervention descriptions: intervention 1: Blinded Treatment intervention 2: Blinded Treatment intervention 3: Blinded Treatment intervention 4: Blinded Treatment intervention 5: Open Label

Protocol document:
Prot_000.pdf: 
 
 
Revised Clinical Study Protocol 
Study Code 
PT009002 
Date 
24 OCT 2017 
NCT #  
NCT02766608 
EudraCT 
2016-000154-34 
 
 
 
 
 
 
 
 
 
 
A Randomized, Double-Blind, Parallel Group, Multi-Center Study to 
Assess the Efficacy and Safety of PT009 Compared to PT005, PT008, 
and Open-label Symbicort® Turbuhaler®, as an Active Control, on 
Lung Function over a 24-Week Treatment Period in Subjects With 
Moderate to Very Severe COPD 
 
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 
08 March 2016 
Version 2,  Amendment 1 
01 July 2016 
Version 3,  Amendment 2  
24 October 2017 
 
 
 


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Clinical Trial Protocol:  PT009002-02
Study Title:
A Randomized, Double-Blind, Parallel Group, Multi-Center Study to 
Assess the Efficacy and Safety of PT009 Compared to PT005, PT008, 
and Open-label Symbicort® Turbuhaler®, as an Active Control, on 
Lung Function over a 24-Week Treatment Period in Subjects With 
Moderate to Very Severe COPD
Study Number:
PT009002
Study Phase:
III
Product Name:
Budesonide and Formoterol Fumarate Inhalation Aerosol (PT009, BFF 
MDI)
Formoterol Fumarate Inhalation Aerosol (PT005, FF MDI)
Budesonide Inhalation Aerosol (PT008, BD MDI)
Symbicort® Turbuhaler® (TBH) Inhalation Powder
US IND Number:
122166
EudraCT 
Number:
2016-000154-34
Indication:
Chronic Obstructive Pulmonary Disease (COPD)
Investigators:
Multicenter
Sponsor:
Pearl Therapeutics, Inc.
Sponsor Contact:
Version Number
Date
Original Protocol
Version 1.0
Amended Protocol
Version 2.0
Amended Protocol
Version 3.0
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 AMENDED PROTOCOL PT009002-01 
VERSION 2.0, DATED 
 
The current amended study protocol, PT009002-02 (Version 3.0), includes the following 
edits: 
Section(s)/Description of Change
Rationale
Changes to the protocol objectives:
Synopsis/Section 2.2
x
Amendment adds COPD exacerbations to the list 
of secondary objectives.
Changes regarding “time to 1st moderate or severe 
COPD exacerbation” endpoint:
Synopsis/Sections 3.2 and 9.3.2.1
x
New text elevates “time to 1st moderate or severe 
COPD exacerbation” to be a secondary efficacy 
endpoint.
Sections 3.3 and 9.3.3.4
x
Amendment removes time to 1st moderate or 
severe COPD exacerbation as an “other” efficacy 
endpoint.
Changes regarding “time to 1st clinically important 
deterioration” and sustained deterioration 
endpoints:
Sections 3.2 and 9.3.2.2
x
New text elevates “time to 1st clinically important 
deterioration” as a secondary endpoint in the EU 
regulatory approach.
Sections 3.3 and 9.3.3.4
x
New text adds “Time to CID” and “Time to 
sustained CID” to the list of other efficacy 
endpoints.
Changes regarding EXACT and RS-Total Score
endpoints:
Sections 3.2
x
Amendment removes EXACT Total Score as a 
secondary endpoint in the EU regulatory 
x
The evaluation of COPD exacerbations was
elevated to secondary objective status to align 
across the PT009 and PT010 COPD development 
programs.
x
Exacerbations are an important clinical endpoint
and are evaluated as a secondary endpoint to align 
across the PT009 and PT010 COPD development 
programs. There is sufficient sample size to 
observe a possible numerical benefit in the form 
of a trend, even though the study is not optimized 
to demonstrate statistical significance.
x
The composite endpoint of clinically important 
deterioration (CID) is now commonly reported in 
COPD studies and may be a more accurate 
measure of decline in disease status than 
individual CID component measurements.
x
Time to CID is an “other” efficacy endpoint in the 
US regulatory approach.  Time to sustained CID 
is an “other” efficacy endpoint in all regulatory 
approaches. Both composite endpoints may be 
more accurate measures of decline in disease 
status than individual CID component
measurements.
x
The RS-Total Score is a more relevant clinical 
endpoint than the EXACT Total Score in this 


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approach.  
Sections 3.2 and 9.3.2.8
x
New text elevates Evaluating Respiratory 
Symptoms in COPD (E-RS: COPD) total score 
(RS-Total Score) as a secondary endpoint in the 
EU regulatory approach.  
lung function study.
Synopsis/Sections 3, 3.1, 3.2, 9.3.1.1, 9.3.1.2, 9.3.2.3, 
9.3.2.4, 9.3.2.5, 9.3.2.6, 9.3.2.7. 9.3.2.8, 9.3.2.9, 9.3.4, 
and 9.9
x
Amendment removes references to the Japan 
Regulatory Approach.
Japan is not participating in the study. 
Sections 3.1, 3.2, 9.3.1.1, 9.3.1.2, 9.3.2.3, 9.3.2.7, 
9.3.2.8, and 9.3.4.2
x
Amendment clarifies that non-inferiority 
comparisons to Symbicort TBH will only be 
performed for BFF MDI 320/9.6μg.
BFF MDI 320/9.6 μg is the treatment with an ICS 
dose that is nominally comparable to the ICS dose in 
Symbicort TBH.
Synopsis/Section 3.6
x
New text identifies FEV1 AUC0-12 as the primary 
endpoint in the PFT sub-study.
x
All other spirometry parameters are now
identified as “other endpoints”.
FEV1 AUC0-12 is the most important spirometry 
parameter collected in the PFT sub-study.  This 
change differentiates it from the other spirometry 
parameters.
Synopsis/Section 3.6
x
Amendment removes AUC0-6, AUC6-12, and time 
to peak observed value as parameters of interest 
from the PFT sub-study.
Differentiating between treatment groups in these 
parameters is of lesser clinical importance.  The 
planned analyses will retain the analyses of AUC0-12 
and peak value between treatment groups. 
Sections 3.3 and 9.3.3.4
x
New text clarifies that “Time to discontinuation” 
is “Time to treatment discontinuation”.
This change was made to clarify the endpoint in 
question.
Sections 3.3, 7.1.3.5, and 9.3.3.5
x
Amendment renames “EXACT 11-item 
Respiratory Symptoms Total Score” to be 
“Evaluating Respiratory Symptoms in COPD (E-
RS: COPD) Total Score”. 
This change was made to reflect the current name of 
instrument. 
Section 3.5
x
New text clarifies that “the number of days 
missed from work” pertains to the number of days 
The list of HCRU endpoints was updated to align 


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missed due to COPD.
x
New text for some HCRU endpoints indicates that 
a category for “any health-care provider” will be 
created in addition to existing categories.
x
New text indicates that time spent (or not spent) 
in either the ICU or CCU will be summarized for 
some HCRU endpoints.
across the PT009 and PT010 development programs.
Section 7.3.7.3 and 7.3.8
x
Changed the terms “Pneumonia Adjudication 
Committee” and “CCV and Mortality 
Adjudication Committees” to be “Clinical 
Endpoint Committee”.
New text clarifies the current name of the committee.
Sections 9.3.1.1 and 9.3.1.2
x
New text clarifies the following:
x
The efficacy estimand will be the primary 
analysis for superiority
x
The per protocol estimand will be the 
primary analysis for non-inferiority
x
The attributable estimand will be a secondary 
analysis
x
The treatment policy estimand will be a 
supportive analysis
New text clarifies the relationship between the 
estimands and the analysis populations.
Sections 9.3.2.2 and 9.3.3.4
x
New text makes reference to and provides the 
technical definitions of the terms “clinically 
important deterioration” and “sustained clinically 
important deterioration,” respectively.
Both CID and sustained CID are composite endpoints 
that require definition. 
Section 9.3.2.10
x
New text changes the analysis of time to onset of 
action on Day 1 to be a formal comparison to BD 
MDI.
Since BD MDI is not expected to produce 
bonchodilator effects immediately on Day 1, it will be 
used as an active control in this analysis.
Section 9.3.3.4
x
New text clarifies that the analysis of time to 
death is conditional on observing 30 or more 
deaths in the study.
A minimum number of events is needed to fit the 
model and to provide a reasonable estimate of the 
hazard ratio. If “Death” is not analyzed for efficacy, it 
will be evaluated descriptively for safety. 
Section 9.3.3.8
x
New text clarifies the general summarization 
strategy for the EQ-5D-5L data.
New text clarifies the current summarization strategy 
for this instrument.


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Section 9.3.4
x
New text for section 9.3.4 revamps the Type I 
Error control strategy to account for new 
secondary endpoints and the analysis of the 
primary endpoints under the attributable 
estimand. It also removes the non-inferiority 
comparisons of BFF MDI 160/9.6 μg vs 
Symbicort TBH.
New secondary endpoints and the need to include the 
analysis of the primary endpoint as a first secondary 
endpoint for the attributable estimand required a new 
Type I error control strategy.  
Section 9.4.1.4
x
New text defines baseline ECG as the average of 
the pre-dose measurements taken prior to 
treatment at the randomization visit.
Baseline ECG was defined as the most recent pre-
treatment ECG at the randomization visit.  This new 
definition accounts for both pre-treatment ECG 
measurements at the randomization visit. 
Section 9.5
x
New text allows for the possibility of performing 
additional analyses of the HCRU data beyond 
descriptive summaries.
Additional analyses of the HCRU data may be 
performed beyond descriptive summaries.
Section 9.12
x
Section 9.12 was renamed to be “Analysis 
Populations and Estimands”
x
Two subsections were created under Section 9.12.  
Sections 9.12.1 and 9.12.2 were created to define
“analysis populations” and “estimands,” 
respectively. Section 9.12.1 contains the text 
from Section 9.12 under the previous amendment. 
x
Language was added to the beginning of Section 
9.3 to reference Section 9.12.
This section was reconfigured to describe both 
estimands and analysis populations in the same
section.
Section 9.12.1
x
New text clarifies that the mITT population will 
be the primary efficacy analysis population with 
the exception of non-inferiority analyses, where 
the PP population will be the primary population 
for analysis.
x
New text defines a Rescue Ventolin User (RVU) 
population.
x
New text for the per protocol and safety 
populations was inserted. 
x
The primary analysis population for non-
inferiority analyses is typically the per-protocol 
population.
x
Due to the expectation that some subjects will not 
be taking rescue medication at baseline and hence 
not be capable of improving with treatment, the 
RVU population is defined and will be used in the 
evaluation of rescue medication usage.
x
New text for the per protocol and safety 
populations is inserted to make the definition 
consistent across the clinical development 
program, which resulted in no material change in 


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x
The amendment replaces the wording that 
communicates what analyses will be performed in 
what populations.  The new text is more detailed 
and includes the RVU population.
the definition. 
x
New text makes it easier to understand what 
analyses will be performed in what populations.
Section 9.12.2
x
This new section defines the estimands to be used 
in the study.
This new section was inserted to communicate what
estimands will be used in the analysis of the clinical 
trial data.
Section 9.13
This new section describes the subgroup analyses to 
be performed.
This new section clarifies the pre-specified subgroup 
analyses in the study. 
Other administrative changes to correct and/or clarify protocol language were also addressed. These changes 
included edits for consistency, grammar, and typographical errors, which are not summarized in this table.


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SYNOPSIS 
Sponsor
Pearl Therapeutics, Inc. (Pearl)
Name of Finished Product
Budesonide and Formoterol Fumarate Inhalation Aerosol (PT009, BFF MDI)
Formoterol Fumarate Inhalation Aerosol (PT005, FF MDI)
Budesonide Inhalation Aerosol (PT008, BD MDI)
Symbicort® Turbuhaler® (TBH) Inhalation Powder
Name of Active Ingredient(s)
Budesonide and Formoterol Fumarate
Formoterol Fumarate
Budesonide
Study Title
A Randomized, Double-Blind, Parallel Group, Multi-Center Study to Assess the Efficacy 
and Safety of PT009 Compared to PT005, PT008, and Open-label Symbicort® Turbuhaler®,
as an Active Control, on Lung Function over a 24-Week Treatment Period in Subjects with 
Moderate to Very Severe COPD
Study Number: PT009002-02
Study Phase: III
Primary Objectives
•
To assess the effects of BFF MDI relative to FF MDI and BD MDI on lung function
Secondary Objectives
•
To assess the effects of BFF MDI relative to FF MDI and Symbicort TBH on COPD 
exacerbations
•
To assess the effects of BFF MDI relative to FF MDI, BD MDI, and Symbicort® TBH on 
symptoms of COPD
•
To assess the effects of BFF MDI relative to FF MDI, BD MDI, and Symbicort® TBH on 
quality of life
•
To determine the time to onset of action on Day 1
Safety Objective
•
To assess the safety of BFF MDI, FF MDI, BD MDI, and Symbicort® TBH
Pulmonary Function Test (PFT) Sub-Study Objective
•
To characterize FEV1 over 12 hours at Week 12
Study Population
Approximately 2,420 subjects with moderate to very severe COPD will be enrolled to 
provide roughly 1,900 completed subjects.  This study will be conducted in approximately 


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200 sites with each site enrolling 10 to 14 subjects.
To be eligible for the study, subjects must:
•
be receiving one or more inhaled maintenance bronchodilators at Visit 1
•
not be receiving ICS, LABA, and LAMA (as inhaled triple maintenance therapy) within 
30 days of Visit 1
•
be symptomatic (CAT score ≥ 10 ) at Visit 1
•
exhibit post-bronchodilator FEV1/FVC < 0.70 and FEV1 < 80% of the predicted normal 
value calculated using appropriate reference equations at Visit 2
-
if post-bronchodilator percent predicted FEV1 is < 30% then FEV1 must be ≥750 ml
A history of exacerbations in the prior year will be obtained to characterize the population, 
but the entry criteria do not require an exacerbation in the prior year.  FEV1 reversibility to
Ventolin will be used for characterization and stratification purposes only and not for 
determining study eligibility.
Study Design
This is a Phase III randomized, double-blind, parallel group, multi-center, 24-week lung 
function study with BFF MDI (320/9.6 μg and 160/9.6 μg) compared to FF MDI 9.6 μg, BD 
MDI 320 μg, and open-label Symbicort® TBH (400/12 μg) administered BID.
Subjects will undergo a 1- to 4-week Screening Period.
At Visit 1, subjects receiving an ICS/LABA will discontinue the ICS/LABA, but continue 
the ICS component for the remainder of the Screening Period.  Similarly, subjects treated 
with an ICS as part of their inhaled maintenance therapy will continue their ICS for the 
remainder of the Screening Period.  ICS medications will be discontinued at Randomization.
All subjects will be placed on Sponsor-provided Ventolin® HFA (albuterol sulfate 
inhalation aerosol) for rescue use throughout Screening and Randomized Treatment Periods.
In order to allow for adequate washout of previous COPD maintenance medications, subjects 
will undergo a Washout Period of one week or longer, depending on their specific 
medication(s), but no greater than 26 days prior to returning to clinic for Visit 2.
Subjects who successfully complete the Screening Period will be randomized in a 3:3:3:1:1 
scheme to one of the following five treatment groups:
x
BFF MDI 320/9.6 μg BID (N=660)
x
BFF MDI 160/9.6 μg BID (N=660) 
x
FF MDI 9.6 μg BID (N=660)
x
BD MDI 320 μg BID (N=220)
x
Symbicort® TBH 400/12 μg BID (open-label; N=220)
Randomization will be stratified by reversibility to Ventolin (measured at Visit 2), post-
bronchodilator FEV1 (< 50% or 50% to < 80% predicted, measured at Visit 2), blood
eosinophil count (< 150 or ≥ 150 cells per mm3), and country.  Enrollment will be targeted to 
achieve a 2:1 ratio for the blood eosinophil strata with twice as many randomized subjects in 
the ≥ 150 cells per mm3 category.  Following randomization, subjects will enter the 
Treatment Period and undergo 6 additional treatment visits over 24 weeks.
Subjects who discontinue study treatment prior to the end of study (Week 24, Visit 9) will be 




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Duration of Study
The entire study period is expected to range between 27 to 30 weeks for each subject. The 
study is anticipated to last approximately 18 months.
Efficacy Endpoints (US Approach)
Additional efficacy endpoints, including those for the EU approach, are described in Section 
3.
Primary Efficacy Endpoints
•
Change from baseline in morning pre-dose  trough FEV1 at Week 24 (BFF MDI vs FF 
MDI)
•
Change from baseline in FEV1 AUC0-4 at Week 24 (BFF MDI vs BD MDI)
Secondary Efficacy Endpoints
•
Time to first moderate or severe COPD exacerbation (BFF MDI vs FF MDI)
•
Percentage of subjects achieving an MCID of 4 units or more in Saint George’s 
Respiratory Questionnaire (SGRQ) total score at Week 24 (BFF MDI vs FF MDI; BFF 
MDI vs BD MDI)
•
Change from baseline in morning pre-dose trough FEV1 at Week 24 (BFF MDI vs BD 
MDI)
•
Peak change from baseline in FEV1 at Week 24 (BFF MDI vs BD MDI)
•
Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF 
MDI vs BD MDI)
•
Time to onset of action on Day 1 (BFF MDI vs BD MDI)
Safety Endpoints
•
Adverse events (AEs)
•
Vital signs
•
Clinical laboratory testing
•
12-lead electrocardiograms (ECGs)
PFT Sub-study Endpoints (at Week 12 only)
Primary  Endpoint
•
FEV1 AUC0-12
Other Endpoints
•
Peak FEV1
•
FVC, PEFR, and FEF25-75 will be evaluated using AUC0-12 and at peak
Statistical Methods
Primary Efficacy Analysis


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The primary analysis will be conducted on the mITT Population.  The change from baseline 
in morning pre-dose trough FEV1 will be analyzed using linear repeated measures ANCOVA 
model.  The model will include treatment, visit, treatment-by-visit interaction, screening 
eosinophil category, and ICS use at Screening as categorical covariates and baseline FEV1
and percent reversibility to Ventolin as continuous covariates.  All primary analysis 
comparisons will be for superiority.  Analyses of FEV1 AUC0-4 will use a similar model to 
trough FEV1.
Sample Size
For trough FEV1, a standard deviation (SD) of 200 mL for the change from baseline at Week 
24 has been assumed. A SD of 220 mL for FEV1 AUC0-4 at Week 24 is assumed.
US Approach
It is estimated that a sample size of 2,420 subjects (660 per arm in the BFF MDI [320/9.6 μg 
and 160/9.6 μg] and FF MDI groups; and 220 per arm in the BD MDI and Symbicort TBH 
groups) will provide approximately 90% power to detect a difference of 40 mL between BFF 
MDI and FF MDI in change from baseline, and in morning pre-dose trough FEV1 at Week 
24 with Type I error controlled at a two-sided alpha level of 0.05, and approximately 99% 
power to detect a difference between BFF MDI and BD MDI of 100 mL in change from 
baseline in FEV1 AUC0-4 at Week 24 with Type I error controlled at a two-sided alpha level 
of 0.05.  The above calculations assume a 20% dropout rate.
Sample size rationale for the EU approach can be found in Section 9.
Data Monitoring Committee
An external Data Monitoring Committee (DMC) will be set up to provide systematic and 
unbiased assessment of safety data.  Members of the DMC will review data at predetermined 
intervals.  Based on the safety implications of the data, the DMC may recommend 
modification or termination of the study.
Clinical Endpoint Committee
A blinded, independent, external clinical endpoint committee (CEC) will be established for 
this study.  The committee will consist of experts who will provide a centralized review, 
functioning independently of Pearl. Three Clinical Endpoint Adjudication Charters will 
outline the clinical endpoints for adjudication:
•
Cardio and Cerebrovascular (CCV) Clinical Endpoint Adjudication Charter
•
Cause Specific Mortality Clinical Endpoint Adjudication Charter
•
Pneumonia Clinical Endpoint Adjudication Charter 
Date of Original Approved Protocol:
Date of Protocol Amendment 01 (Version 2.0):  
Date of Protocol Amendment 02 (Version 3.0): 


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TABLE OF CONTENTS 
SUMMARY OF CHANGES TO AMENDED PROTOCOL PT009002-01 VERSION 
2.0, DATED 
 ..............................................................................................2 
SYNOPSIS .................................................................................................................................7 
TABLE OF CONTENTS .........................................................................................................12 
LIST OF IN TEXT TABLES ..................................................................................................18 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................20 
1 
INTRODUCTION ...........................................................................................................24 
1.1 
Chronic Obstructive Pulmonary Disease ...............................................................24 
1.2 
Pearl Therapeutics’ BFF MDI ...............................................................................24 
2 
STUDY OBJECTIVES ....................................................................................................25 
2.1 
Primary Objectives.................................................................................................25 
2.2 
Secondary Objectives.............................................................................................25 
2.3 
Safety Objective .....................................................................................................25 
2.4 
Healthcare Resource Utilization (HCRU) Objective .............................................25 
2.5 
Pulmonary Lung Function (PFT) Sub-Study Objectives .......................................25 
3 
STUDY ENDPOINTS .....................................................................................................26 
3.1 
Primary Efficacy Endpoints ...................................................................................26 
3.2 
Secondary Efficacy Endpoints ...............................................................................26 
3.3 
Other Efficacy Endpoints .......................................................................................27 
3.4 
Safety Endpoints ....................................................................................................28 
3.5 
Health Care Resource Utilization Endpoints .........................................................28 
3.6 
Pulmonary Function Test Sub-Study Endpoints ....................................................29 
4 
INVESTIGATIONAL PLAN ..........................................................................................31 
4.1 
Overall Study Design and Plan ..............................................................................31 
4.2 
Rationale of Study and Study Design ....................................................................32 
4.2.1 
Study Rationale ............................................................................................32 
4.2.2 
Population ....................................................................................................32 
4.2.3 
Choice of Study Doses .................................................................................33 
4.2.4 
Choice of Comparators/Control Groups ......................................................33 
4.2.5 
Study Duration .............................................................................................33 
5 
STUDY POPULATION SELECTION AND WITHDRAWAL CRITERIA .................34 
5.1 
Inclusion Criteria ...................................................................................................34 
5.2 
Exclusion Criteria ..................................................................................................35 
5.3 
Subject Identification .............................................................................................38 
5.4 
Prior, Concomitant, and Prohibited Medications ...................................................39 
5.4.1 
Prior Medications .........................................................................................39 
5.4.1.1 
Concomitant Medications and Vaccinations .....................................39 
5.4.1.2 
Allowed Medications to Treat a COPD Exacerbation .......................39 


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5.4.1.3 
Pneumococcal and Annual Influenza Vaccination ............................39 
5.4.2 
Prohibited Medications ................................................................................40 
5.4.3 
Other Prohibited Medications ......................................................................43 
5.5 
Other Restrictions, Illicit Drugs or Drugs of Abuse ..............................................43 
5.5.1 
Illicit Drugs or Drugs of Abuse ...................................................................43 
5.5.2 
Dietary Restrictions .....................................................................................43 
5.6 
Smoking Status ......................................................................................................43 
5.7 
Reasons for Treatment Discontinuation or Study Withdrawal ..............................44 
5.7.1 
Reasons for Treatment Discontinuation.......................................................44 
5.7.2 
Reasons for Study Withdrawal ....................................................................45 
6 
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
CLINICAL SUPPLIES ....................................................................................................46 
6.1 
Subject Information ...............................................................................................46 
6.2 
Product Description ...............................................................................................46 
6.3 
Primary Packaging and Labeling ...........................................................................47 
6.4 
Secondary Packaging and Labeling .......................................................................47 
6.5 
Emergency Unblinding of Treatment Assignment ................................................48 
6.6 
Storage Requirements ............................................................................................48 
6.7 
Instructions for Dispensing and Preparation of Treatments for Administration....49 
6.7.1 
BFF MDI, BD MDI, and FF MDI ...............................................................49 
6.7.2 
Ventolin HFA® (Albuterol Sulfate) .............................................................49 
6.7.3 
Symbicort TBH® (Budesonide and Formoterol Fumarate) ..........................49 
6.8 
Drug Accountability/Return of Clinical Supplies ..................................................49 
7 
STUDY PROCEDURES .................................................................................................51 
7.1 
Efficacy Assessments.............................................................................................51 
7.1.1 
Pulmonary Function Tests (PFTs) ...............................................................51 
7.1.1.2 
Characterization of Reversibility .......................................................52 
7.1.1.3 
FEV1 Baseline Stability Criteria ........................................................52 
7.1.1.4 
Subject’s Electronic Diary Data Collection .......................................53 
7.1.1.5 
Rescue Medication Use......................................................................53 
7.1.1.6 
Medication Compliance .....................................................................53 
7.1.1.7 
Major/minor Symptom Worsening Assessment and Alert System ...53 
7.1.2 
COPD Exacerbation .....................................................................................54 
7.1.2.1 
Severity of COPD Exacerbation ........................................................54 
7.1.2.2 
Duration of COPD Exacerbation .......................................................55 
7.1.2.3 
Approach for Capturing COPD Exacerbations ..................................55 
7.1.2.4 
Investigator-judged COPD Exacerbations .........................................55 
7.1.3 
Subject Questionnaires.................................................................................56 
7.1.3.1 
Chronic Obstructive Pulmonary Disease Assessment Test (CAT)....56 
7.1.3.2 
Baseline Dyspnea Index and Transition Dyspnea Index 
(BDI/TDI) ..........................................................................................56 


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7.1.3.3 
St. George’s Respiratory Questionnaire (SGRQ) ..............................57 
7.1.3.4 
European Quality-of-Life-5 Dimensions Questionnaire (EQ-5D-
5L) ......................................................................................................57 
7.1.3.5 
Exacerbations of Chronic Pulmonary Disease Tool (EXACT) .........58 
7.2 
Safety Assessments ................................................................................................58 
7.2.1 
Medical/Surgical History and Physical Examination ..................................58 
7.2.2 
Vital Sign Measurements .............................................................................59 
7.2.3 
12-Lead Electrocardiogram .........................................................................59 
7.2.4 
Clinical Laboratory Tests .............................................................................60 
7.2.4.1 
Hematology ........................................................................................60 
7.2.4.2 
Clinical Chemistry .............................................................................60 
7.2.4.3 
Urinalysis ...........................................................................................62 
7.2.4.4 
Pregnancy Test ...................................................................................62 
7.3 
Adverse Events ......................................................................................................62 
7.3.1 
Performing Adverse Event (AE) Assessments ............................................62 
7.3.2 
Adverse Event Definitions ...........................................................................62 
7.3.3 
Pre-Randomization AEs...............................................................................63 
7.3.4 
Severity ........................................................................................................63 
7.3.5 
Relationship to Study Drug ..........................................................................63 
7.3.6 
Chronic Obstructive Pulmonary Disease Exacerbations .............................63 
7.3.7 
AEs of Special Interest.................................................................................64 
7.3.7.1 
LABA Effects ....................................................................................64 
7.3.7.2 
Local Steroid Effects..........................................................................64 
7.3.7.3 
Pneumonia..........................................................................................64 
7.3.7.4 
Paradoxical Bronchospasm ................................................................65 
7.3.8 
Major Adverse Cardiovascular Events (MACE) .........................................65 
7.3.9 
Clinical Laboratory Adverse Events ............................................................65 
7.3.10 
Serious Adverse Events (SAEs)...................................................................65 
7.3.10.1 
Reporting of Serious Adverse Events ................................................66 
7.3.10.2 
Supplemental Investigations of SAEs ................................................66 
7.3.10.3 
Post-Study Follow Up of Adverse Events .........................................67 
7.3.10.4 
Notification of Post-Study Serious Adverse Events ..........................67 
7.3.10.5 
Investigational Research Board/Independent Ethics Committee 
Notification of Serious Adverse Events .............................................67 
7.3.10.6 
Health Authority Safety Reports ........................................................67 
7.3.11 
Overdose ......................................................................................................68 
7.3.12 
Pregnancy .....................................................................................................68 
7.3.13 
Hy’s Law ......................................................................................................68 
7.3.14 
Use of Steroids during the Study .................................................................68 
7.3.15 
Clinical Endpoint Committees .....................................................................68 
7.3.15.1 
Cardiovascular and Cerebrovascular (CCV) Clinical Endpoint 
Adjudication Charter ..........................................................................69 


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7.3.15.2 
Cause Specific Mortality Clinical Endpoint Adjudication Charter ...69 
7.3.15.3 
Pneumonia Clinical Endpoint Adjudication Charter .........................69 
7.3.15.4 
Data Monitoring Committee ..............................................................69 
7.4 
Healthcare Resource Utilization ............................................................................69 
7.5 
Termination of the Study .......................................................................................70 
8 
STUDY ACTIVITIES .....................................................................................................71 
8.1 
Visit 1 (Screening) .................................................................................................79 
8.2 
Visit 2 (Screening) .................................................................................................80 
8.3 
Visit 3 (Randomization Day 1) ..............................................................................81 
8.4 
Visits 4, 5, 6, 7, and 8 (Weeks 4, 8, 12, 16 and 20) ...............................................82 
8.5 
Final Visit (Visit 9; Week 24) ................................................................................83 
8.6 
Procedures for Treatment Discontinuation and Study Withdrawal Subjects.........84 
8.7 
Unscheduled Visit and Treatment Discontinuation/Study Withdrawal Visit ........85 
8.8 
Follow-up Telephone Call .....................................................................................85 
8.9 
24-Week Post-Randomization Vital Status Confirmation .....................................86 
8.10 
Completion of the Study ........................................................................................86 
9 
PLANNED STATISTICAL METHODS ........................................................................87 
9.1 
Introduction ............................................................................................................87 
9.2 
Protocol Variables ..................................................................................................87 
9.2.1 
Efficacy Endpoints .......................................................................................87 
9.2.2 
Safety Endpoints ..........................................................................................87 
9.2.3 
Health Care Resource Utilization Endpoints ...............................................87 
9.2.4 
Pulmonary Function Test Sub-study Endpoints ..........................................87 
9.3 
Efficacy Analysis ...................................................................................................87 
9.3.1 
Primary Efficacy Analysis ...........................................................................88 
9.3.1.1 
Morning Pre-dose Trough FEV1 ........................................................88 
9.3.1.2 
FEV1 AUC0-4 ......................................................................................88 
9.3.2 
Secondary Efficacy Analyses ......................................................................89 
9.3.2.1 
Time to First Moderate or Severe COPD Exacerbation ....................89 
9.3.2.2 
Time to Clinically Important Deterioration .......................................89 
9.3.2.3 
Saint George’s Respiratory Questionnaire (SGRQ) ..........................89 
9.3.2.4 
Morning Pre-Dose Trough FEV1 .......................................................90 
9.3.2.5 
Peak Change from Baseline in FEV1 .................................................90 
9.3.2.6 
Rescue Ventolin HFA Usage .............................................................90 
9.3.2.7 
Transition Dyspnea Index ..................................................................91 
9.3.2.8 
Evaluating Respiratory Symptoms in COPD (E-RS: COPD) total 
score (RS-Total Score) .......................................................................92 
9.3.2.9 
FEV1 AUC0-4 ......................................................................................92 
9.3.2.10 
Time to Onset of Action ....................................................................92 
9.3.3 
Other Efficacy Analysis ...............................................................................93 
9.3.3.1 
Additional Spirometry Assessments ..................................................93 
9.3.3.2 
FEV1 Response at Day 1 ....................................................................93 


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9.3.3.3 
Rate of COPD Exacerbations.............................................................93 
9.3.3.4 
Time to Event Analyses .....................................................................93 
9.3.3.5 
Exacerbations of Chronic Pulmonary Disease Tool (EXACT) .........94 
9.3.3.6 
TDI Focal Score .................................................................................94 
9.3.3.7 
St. George’s Respiratory Questionnaire (SGRQ) ..............................95 
9.3.3.8 
EuroQoL (ED-5D) Dimensions Questionnaire (EQ-5D-5L) .............95 
9.3.4 
Type I Error Control ....................................................................................96 
9.3.4.1 
US Approach ......................................................................................96 
9.3.4.2 
EU Approach .....................................................................................98 
9.4 
Safety Analysis ....................................................................................................100 
9.4.1 
Adverse Events ..........................................................................................100 
9.4.1.1 
Adverse Events of Special Interest ..................................................100 
9.4.1.2 
Clinical Laboratory Measurements ..................................................100 
9.4.1.3 
Vital Signs ........................................................................................101 
9.4.1.4 
ECGs ................................................................................................101 
9.5 
HCRU Analyses ...................................................................................................101 
9.6 
PFT Sub-Study Analyses .....................................................................................101 
9.7 
Randomization .....................................................................................................101 
9.8 
Experimental Design ............................................................................................101 
9.9 
Sample Size Consideration ..................................................................................102 
9.10 
Data Validation and Transformation ...................................................................102 
9.11 
Analysis Plan .......................................................................................................103 
9.12 
Analysis Populations and Estimands ...................................................................103 
9.12.1 
Analysis Populations ..................................................................................103 
9.12.2 
Estimands ...................................................................................................104 
9.13 
Subgroup Analyses ..............................................................................................105 
9.14 
Handling of Missing Data ....................................................................................106 
9.15 
Statistical Software ..............................................................................................106 
10 ADMINISTRATIVE CONSIDERATIONS ..................................................................107 
10.1 
Regulatory Authority Approval ...........................................................................107 
10.2 
Ethical Conduct of the Study and IRB or IEC Approval .....................................107 
10.3 
Subject Information and Consent.........................................................................107 
10.4 
Confidentiality .....................................................................................................108 
10.4.1 
Confidentiality of Data ..............................................................................108 
10.4.2 
Confidentiality of Subject/Patient Records ................................................108 
10.5 
Quality Control and Assurance ............................................................................108 
10.6 
Data Management ................................................................................................108 
10.7 
Study Monitoring .................................................................................................108 
10.8 
Retention of Data .................................................................................................109 
10.9 
Financial Disclosure.............................................................................................109 
10.10 Investigator’s Final Report ..................................................................................109 


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10.11 Publication Policy ................................................................................................110 
11 REFERENCE LIST .......................................................................................................112 
12 APPENDICES ...............................................................................................................113 


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LIST OF IN TEXT TABLES
Table 5-1  
Prohibited COPD Medications and Required Washout Periods Prior 
to Visit 2 
40 
Table 5-2  
Prohibited Corticosteroids and Required Washout Periods Prior to 
Visit 1 
41 
Table 5-3  
Other Prohibited Respiratory and/or Nasal Medications and 
Required Washout Periods Prior to Visit 2 ..................................................................41 
Table 5-4  
Non-COPD and Non- Respiratory Medications ...................................42 
Table 5-5  
Non-COPD Medications Allowed Under Certain Conditions ...............43 
Table 6-1  
Product Descriptions .............................................................................46 
Table 6-2  
Description of Boxes ..............................................................................47 
Table 7-1  
Clinical Laboratory Tests .......................................................................61 
Table 8-1  
Overall Schedule of Study Events ..........................................................73 
Table 8-2  
Timed Assessments at Visits 3 through 9 ..............................................75 
Table 8-3  
Timed Assessments for Subjects Participating in the PFT Sub-study 
(Visit 6) 
77 
Table A1-1  
Recommended Minimal Scale Factors for Time, Volume, and Flow 
on Graphical Output ...................................................................................................133 
Table A1-2  
Summary of Equipment Quality Control .............................................134 
Table A1-3  
Range and Accuracy Recommendations Specified for Forced 
Expiratory Maneuvers ................................................................................................136 
LIST OF IN TEXT FIGURES 
Figure 4-1  
Study Design ..........................................................................................32 
Figure 9-1  
Group 1: Type I Error Control for the Analyses of the Primary 
Endpoints (US Approach) ............................................................................................97 
Figure 9-2  
Group 2: The Analysis of the Additional Secondary Endpoints (US 
Approach) 
98 
Figure 9-3  
Group 1: Type I Error Control for the Analyses of the Primary 
Endpoints (EU Approach)............................................................................................99 
Figure 9-4  
Group 2: The Analysis of the Additional Secondary Endpoints (EU 
Approach) 
100 
Figure A2-1  
Example of a Usable Spirogram ..........................................................130 
LIST OF APPENDICES 
Appendix 1 
Instructions for Use of Ventolin HFA Inhaler .....................................114 
Appendix 2 
Subject Instructions for Use of BFF MDI, BD MDI, and FF MDI 
Devices 
118 
Appendix 3 
Instructions for Use of Symbicort® TBH Inhalation Powder Device ..127 
Appendix 4 
Spirometry Assessment Criteria ...........................................................130 


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Appendix 5 
Spirometry Performance Recommendations ........................................132 
Appendix 6 
COPD Assessment Test (CAT) ............................................................138 
Appendix 7 
BDI/TDI Questionnaire ........................................................................139 
Appendix 8 
St. George Respiratory Questionnaire (SGRQ) ...................................145 
Appendix 9 
EUROQOL 5 Dimensions Questionnaire ............................................151 
Appendix 10 
Exacerbations of Chronic Obstructive Pulmonary Disease (EXACT) 154 
Appendix 11 
Rules for Evaluation of Abnormal Liver Laboratory Values ...............159 
Appendix 12 
Dose Indicator Reading ........................................................................162 
Appendix 13 
Sponsor Signatory ................................................................................164 
Appendix 14 
Investigator’s Agreement and Signature Page .....................................165 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
λz
Terminal Elimination Rate Constant
AE
Adverse Event
AR(1)
Autoregressive Order 1
ATS
American Thoracic Society
AUC
Area Under the Curve
AUC0-2
Area Under the Curve From 0 to 2 Hours
AUC0-6
Area Under the Curve From 0 to 6 Hours
AUC0-12
Area Under the Curve From 0 to 12 Hours
AUC6-12
Area Under the Curve From 6 to 12 Hours
AUC0-t
Area Under the Curve from 0 to Time of the Last Measurable 
Concentration
BD
Budesonide
BDI
Baseline Dyspnea Index
BFF
Budesonide and Formoterol Fumarate
BID
Bis In Die, Twice Daily
BP
Blood Pressure
BPM
Beats Per Minute
BTPS
Body Temperature and Pressure Saturated
CBC
Complete Blood Count
CEC
Clinical Endpoint Committee
CFR
Code of Federal Regulations
CI
Confidence Interval
CID
Clinically Important Deterioration
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration Equation (according 
to National Kidney Disease Education Program)
CL/F
Clearance
Cmax
Maximum Plasma Concentration
CMP
Comprehensive Metabolic Panel
CONSORT
CONsolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease


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CRF
Case Report Form
CT
Computerized Tomography
DBP
Diastolic Blood Pressure
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
e.g.
Exempli Gratia, For Example
ERS
European Respiratory Society
EV
Back Extrapolation Volume
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 Second
FF
Formoterol Fumarate
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
hCG
Human Chorionic Gonadotropin
HR
Heart Rate
HFA
Hydrofluoroalkane
IB
Investigators Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICS
Inhaled Corticosteroid
ID
Identification
i.e.
Id Est, That Is
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISMPP
International Society for Medical Publications Professionals
ITT
Intent-to-Treat
IWRS
Interactive Web Response System
L
Liter
LABA
Long-Acting β2-Agonist


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LAMA
Long-Acting Muscarinic Antagonist
MDI
Metered Dose Inhaler
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-Treat
mL
Milliliter
msec (ms)
Millisecond
NHANES III
Third National Health and Nutrition Examination Survey
OTC
Over-the-Counter
PEFR
Peak Expiratory Flow Rate
PIN
Personal Identification Number
PFT
Pulmonary Function Test
QTcF
QT Corrected Using Fridericia’s Formula (QT/[RR 1/3])
RVU
Rescue Ventolin User
SABA
Short-Acting Beta 2 Agonist
SAC
Self-administered Computerized
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard Deviation
t½
Half-Life
TDI
Transition Dyspnea Index
tmax
Time of Maximum Plasma Concentration
US
United States
VC
Vital Capacity
Vd/F
Apparent Volume of Distribution
TRADEMARK INFORMATION 


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Symbicort®
Ventolin®


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1 INTRODUCTION 
Pearl Therapeutics, Inc. (Pearl) is developing a combination product, Budesonide and 
Formoterol Fumarate Inhalation Aerosol (PT009; hereafter referred to as budesonide and 
formoterol fumarate metered dose inhaler [BFF MDI]), as a long-term, twice daily (BID) 
treatment for subjects with chronic obstructive pulmonary disease (COPD).  Pearl is also 
developing Formoterol Fumarate Inhalation Aerosol (PT005; hereafter referred to as 
formoterol fumarate metered dose inhaler [FF MDI]) as a BID maintenance treatment in 
subjects with COPD.  In addition, Pearl is developing Budesonide Inhalation Aerosol 
(PT008; hereafter referred to as budesonide metered dose inhaler [BD MDI]). 
1.1
Chronic Obstructive Pulmonary Disease
COPD is a common, preventable, and treatable disease characterized by persistent airflow 
limitation that is usually progressive and associated with an enhanced chronic inflammatory 
response in the lung and associated airways to noxious particles or gases.  COPD is a leading 
cause of morbidity and mortality worldwide and results in a significant economic and social 
burden that is both substantial and increasing. [Global Initiative for Chronic Obstructive 
Lung Disease [GOLD 2016]. 
Bronchodilator medications are central to the symptomatic management of COPD.  The 
principal bronchodilator treatments are β2-agonists and anticholinergics used as monotherapy 
or in combination.  Treatment with long-acting bronchodilators is more convenient and more 
effective at producing maintained symptom relief than treatment with short-acting 
bronchodilators. 
When combined with a long-acting β2-agonist (LABA), an inhaled corticosteroid (ICS) is 
more effective than the individual components in improving lung function, quality of life, 
and reducing exacerbations in subjects with moderate to very severe COPD.  Regular 
treatment with ICS improves symptoms, lung function, and quality of life and reduces the 
frequency of COPD exacerbations in subjects with a forced expiratory volume in one second 
(FEV1) value of <60% of predicted.  Withdrawal from treatment of ICS may lead to 
exacerbations in some patients [GOLD 2016]. 
1.2
Pearl Therapeutics’ BFF MDI 
Pearl has developed a particle engineering technology that utilizes porous particles for 
pulmonary drug delivery via MDIs.  This technology is based on spray-dried porous particles 
comprised of distearoylphophatidylcholine and calcium chloride that are co-suspended with 
crystalline active drug substances and formulated into suspension-based hydrofluoroalkane 
(HFA) MDIs.  In vitro and in vivo testing suggest that the Pearl formulations will provide 
highly efficient, reproducible administration of therapeutics from MDIs in a wide dosing 
range [Hirst, 2002; Dellamary, 2000].  Pearl is developing a broad range of MDI-based 
inhalation products using its porous particle technology platform. 


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2 STUDY OBJECTIVES 
2.1 
Primary Objectives 
•
To assess the effects of BFF MDI relative to FF MDI and BD MDI on lung function 
2.2 
Secondary Objectives 
•
To assess the effects of BFF MDI relative to FF MDI and Symbicort TBH on COPD 
exacerbations 
•
To assess the effects of BFF MDI relative to FF MDI, BD MDI, and Symbicort® TBH on 
symptoms of COPD 
•
To assess the effects of BFF MDI relative to FF MDI, BD MID, and  Symbicort® TBH 
on quality of life 
•
To determine the time to onset of action on Day 1 
2.3 
Safety Objective 
•
To assess the safety of BFF MDI, FF MDI, BD MDI, and Symbicort® TBH 
2.4 
Healthcare Resource Utilization (HCRU) Objective 
•
To assess overall and COPD-specific HCRU of BFF MDI relative to FF MDI, BD MDI, 
and Symbicort® TBH 
2.5 
Pulmonary Lung Function (PFT) Sub-Study Objectives 
•
To characterize FEV1 over 12 hours at Week 12 


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3 STUDY ENDPOINTS 
The primary endpoints, treatment comparisons of interest, and analysis timeframes may 
differ by country or region due to local regulatory agency requirements. The Sponsor has 
defined 2 registration approaches in this study, the US and EU approaches. The US approach 
is for countries or regions where the primary endpoints are generally evaluated at a point in 
time. The EU approach is for registration purposes in countries or regions where the primary 
endpoints are generally evaluated over a period of time. The multiplicity controls for the 
primary analyses will be delineated by approach. 
3.1 
Primary Efficacy Endpoints 
US APPROACH
•
Change from baseline in morning pre-dose trough FEV1 at Week 24 (BFF MDI vs FF 
MDI) 
•
Change from baseline in FEV1 AUC0-4 at Week 24 (BFF MDI vs BD MDI) 
EU APPROACH
•
Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI vs FF 
MDI; BFF MDI 320/9.6 μg vs Symbicort TBH, non-inferiority)
•
Change from baseline in FEV1 AUC0-4 over 24 weeks (BFF MDI vs BD MDI; BFF MDI 
320/9.6 μg vs Symbicort TBH, non-inferiority) 
3.2 
Secondary Efficacy Endpoints 
US APPROACH
•
Time to first moderate or severe COPD exacerbation (BFF MDI vs FF MDI) 
•
Percentage of subjects achieving an MCID of 4 units or more in Saint George’s 
Respiratory Questionnaire (SGRQ) total score at Week 24 (BFF MDI vs FF MDI; BFF 
MDI vs BD MDI) 
•
Change from baseline in morning pre-dose trough FEV1 at Week 24 (BFF MDI vs BD 
MDI) 
•
Peak change from baseline in FEV1 at Week 24 (BFF MDI vs BD MDI) 
•
Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF 
MDI vs BD MDI) 
•
Time to onset of action on Day 1 (BFF MDI vs BD MDI) 


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EU APPROACH
•
Time to first moderate or severe COPD exacerbation (BFF MDI vs FF MDI) 
•
Time to clinically important deterioration (CID) (BFF MDI vs FF MDI) 
•
Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI vs BD 
MDI) 
•
TDI focal score over 24 weeks (BFF MDI vs FF MDI; BFF MDI vs BD MDI; BFF MDI 
320/9.6 μg vs Symbicort TBH, non-inferiority) 
•
Percentage of subjects achieving an MCID of 4 units or more in Saint George’s 
Respiratory Questionnaire (SGRQ) total score over 24 weeks (BFF MDI vs FF MDI; 
BFF vs BD MDI; BFF MDI 320/9.6 μg vs Symbicort TBH, non-inferiority) 
•
Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF 
MDI vs BD MDI) 
•
Peak change from baseline in FEV1 over 24 weeks (BFF MDI vs BD MDI) 
•
Change from baseline in Evaluating Respiratory Symptoms in COPD (E-RS: COPD) 
total score (RS-Total Score) over 24 weeks (BFF MDI vs FF MDI; BFF MDI vs BD 
MDI; BFF MDI 320/9.6 μg vs Symbicort TBH, non-inferiority)  
•
Time to onset of action on Day 1 (BFF MDI vs BD MDI) 
3.3
Other Efficacy Endpoints
Unless already categorized as a secondary endpoint in one of the regulatory approaches 
above, all of the following endpoints will be categorized as “Other efficacy endpoints”, with 
the treatment comparisons of interest being BFF MDI vs FF MDI, BFF MDI vs BD MDI, 
and BFF MDI vs Symbicort TBH (non-inferiority). 
DAY 1 ENDPOINTS
•
Change from baseline at each post-dose time point and in AUC0-4 for FEV1, forced vital 
capacity (FVC), peak expiratory flow rate (PEFR), and forced expiratory flow from 25% 
to 75% (FEF25-75) 
•
Proportion of subjects achieving an improvement from baseline in FEV1 using different 
thresholds (e.g., ≥ 10%, ≥ 12%, ≥ 15%, ≥100 mL, ≥ 200 mL; and ≥12% and ≥200 mL)
ENDPOINTS OVER 24 WEEKS (UNLESS OTHERWISE STATED) 
•
Rate of moderate or severe COPD exacerbations 
•
Time to CID 
•
Time to sustained CID 
•
Rate of COPD exacerbations of any severity 


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•
Time to treatment discontinuation for any cause 
•
Time to death  
•
Time to treatment failure (treatment discontinuation for any cause, moderate or severe 
exacerbation, or death) 
•
Additional spirometry assessments over Weeks 12 to 24, over 24 weeks, and at each post-
randomization visit: 
-
Change from baseline in morning pre-dose trough for FEV1, FVC, PEFR, and 
FEF25-75  
-
Peak change from baseline within 4 hours in FEV1, FVC, PEFR, and FEF25-75
-
FEV1 AUC0-4, FVC AUC0-4, PEFR AUC0-4, and FEF25-75 AUC0-4
•
Change from baseline in:  the EXACT total score, the Evaluating Respiratory Symptoms 
in COPD (E-RS: COPD) Total Score (RS-Total Score), as well as 3 subscale scores 
(RS-Breathlessness, RS-Cough and Sputum, and RS-Chest Symptoms) over 24 weeks 
and over each 4-week interval of the 24-week Treatment Period 
•
TDI focal score over Weeks 12 to 24, over 24 weeks, and at each post-randomization 
visit 
•
Individual components of the TDI: functional impairment, magnitude of task, and 
magnitude of effort over Weeks 12 to 24, over 24 weeks, and at each post-randomization 
visit 
•
Percentage of subjects achieving a minimal clinically important difference (MCID) 
threshold of 1 unit or more on average in TDI focal score over Weeks 12 to 24 and over 
24 weeks 
•
Changes from baseline over 24 weeks and 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, over 24 weeks, and at each post-randomization visit 
•
Percentage of subjects achieving an MCID of 4 units or more in SGRQ total score at 
Week 24, over Weeks 12 to 24, and over 24 weeks 
•
Quality-of-Life Endpoints: European Quality-of-Life-5 Dimensions (EQ-5D) 
Questionnaire scored at each post-randomization visit 
3.4 
Safety Endpoints 
The safety endpoints for this study include AEs and SAEs, vital signs (BP and HR), clinical 
laboratory values (hematology and clinical chemistry), and ECGs. 
3.5
Health Care Resource Utilization Endpoints
x
The number of days missed from work due to COPD 
x
The number of days that primary caregivers of subjects missed from work as a result of 
the subject’s COPD
x
The percentage of subjects with telephone calls to health-care providers 


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o
Calls to any health-care provider (physician or other) 
o
Calls to physician 
o
Calls to other healthcare provider 
x
The mean number of telephone calls to health-care providers 
o
Calls to any health-care provider (physician or other) 
o
Calls to physician 
o
Calls to other healthcare provider 
x
The percentage of subjects with visits to health-care providers 
o Visits to any health-care provider (general practitioner [GP], specialist, or other) 
o Visits to GP 
o Visits to specialist 
o Visits to other health-care provider 
x
The mean number of visits to health-care providers 
o
Visits to any health-care provider (GP, specialist, or other) 
o
Visits to GP 
o
Visits to specialist 
o
Visits to other health-care provider 
x
The percentage of subjects with Emergency Room (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 mean number of hospitalizations in which subjects spent some time in the Intensive 
Care Unit (ICU) or the Coronary Care Unit (CCU) 
x
The percentage of subjects hospitalized with some time spent in the ICU or CCU 
x
The mean number of days in the hospital with some time spent in the ICU or CCU 
x
The mean number of hospitalizations in which subjects spent no time in the ICU or CCU 
x
The percentage of subjects hospitalized with no time spent in the ICU or CCU 
x
The mean number of days in the hospital with no time spent in the ICU or CCU 
x
The mean number of days in ICU 
x
The percentage of subjects in the ICU 
x
The mean number of days in CCU 
x
The percentage of subjects in the CCU 
x
The percentage of subjects who required ambulance transport 
x
The mean number of times ambulance transport was required 
3.6 
Pulmonary Function Test Sub-Study Endpoints 
The assessments will provide PFT profiles over 12-hours post-dose at Week 12. 


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Primary Endpoint: 
•
FEV1 AUC0-12
Other Endpoints: 
•
Peak FEV1
•
FVC, PEFR, and FEF25-75 will be evaluated using AUC0-12 and at peak


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4 INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a Phase III, randomized, double-blind, parallel group, multi-center, 24-week lung 
function study comparing BFF MDI (320/9.6 μg and 160/9.6 μg) to FF 9.6 μg MDI, BD MDI 
320 μg and Symbicort® TBH, administered BID, in subjects with moderate to very severe 
COPD. 
To be eligible for the study, subjects must: 
•
be receiving one or more inhaled maintenance bronchodilators at Visit 1 
•
not be receiving ICS, LABA, and LAMA (as inhaled triple maintenance therapy) within 
30 days of Visit 1 
•
be symptomatic, as measured by the COPD Assessment Test (CAT score ≥ 10) at Visit 1
•
exhibit post-bronchodilator FEV1/FVC < 0.70 and FEV1 < 80% of the predicted normal 
value calculated using appropriate reference equations at Visit 2 
-
if post-bronchodilator percent predicted FEV1 is < 30% then FEV1 must be ≥750 ml
Subjects will undergo a 1- to 4-week Screening Period. 
Subjects meeting inclusion criteria and no exclusion criteria will be randomized into the
study.  Randomization will be stratified by reversibility to Ventolin, post-bronchodilator 
FEV1, blood eosinophil count, and country.  Enrollment will be targeted to achieve a 2:1 ratio 
for blood eosinophil strata with twice as many randomized subjects in the ≥ 150 cells per 
mm3 category.  Following randomization, subjects will enter the Treatment Period and 
undergo six additional treatment visits over 24 weeks. Note: The End of the Study is defined 
as the date on which data are collected for the last subject’s Follow-up Telephone Call. 
The overall study design is illustrated in Figure 4-1.


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Figure 4-1  Study Design 
This study will be conducted at approximately 200 sites, contributing approximately 10 to 14 
subjects per site.  It is planned that approximately 2,420 subjects will be randomized so that 
approximately 1,900 subjects complete the study. 
4.2
Rationale of Study and Study Design
4.2.1 
Study Rationale 
BFF MDI is being fully developed in order to demonstrate adequate evidence of efficacy and 
safety for marketing approval. 
GOLD guidelines acknowledge combination therapy with an ICS and LABA is more 
effective than the individual components in improving lung function and health status in 
patients with moderate to very severe COPD [GOLD 2016]. BFF MDI is a fixed-dose, dual 
combination MDI product formulated with budesonide and formoterol fumarate for use in 
subjects with moderate to very severe COPD. This Phase III study is intended to demonstrate 
the long-term efficacy and safety of BFF MDI compared with FF MDI and BD MDI on lung 
function, as well as subject-reported symptom outcomes and health status. 
4.2.2 
Population 
This study will evaluate a patient population with moderate to very severe COPD, who has 
airflow limitation and remains symptomatic (demonstrated by a CAT ≥ 10) despite treatment 
with at least one inhaled maintenance bronchodilator.  A beneficial effect of adding ICS to a 
bronchodilator is expected based on lung function measurements in this patient population.  
ICS are recommended for patients with severe and very severe airflow limitation [GOLD 
2016].  Decreasing symptoms is a goal of COPD treatment and adding ICS in a symptomatic 


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population is expected to decrease symptoms [GOLD 2016].  In addition, regular treatment 
with ICS improves symptoms, lung function and quality of life in COPD patients with a 
FEV1 < 60% predicted, which is a population included in this study [GOLD 2016]. 
4.2.3 
Choice of Study Doses 
Data from Phase I and II studies indicate that budesonide at two doses (320 and 160 μg BID) 
and formoterol fumarate at a dose of 9.6 μg BID are the correct doses to investigate in a 
Phase III program in COPD. 
4.2.4 
Choice of Comparators/Control Groups 
Comparing BFF MDI with FF MDI will demonstrate the expected contribution of the 
budesonide component of BFF MDI in stabilizing pre-dose lung function.  The comparison 
of BFF MDI with BD MDI will demonstrate the expected bronchodilatory contribution of the 
formoterol component of BFF MDI.  Inclusion of two doses of BFF MDI may demonstrate a 
dose ordering effect of budesonide on lung function. 
4.2.5 
Study Duration 
The specified study duration of 24 weeks will provide sufficient time to observe lung 
function changes in the chosen patient population. 


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5 STUDY POPULATION SELECTION AND WITHDRAWAL
CRITERIA 
5.1
Inclusion Criteria
Each subject must meet the following criteria, in relationship to Visit 1, unless otherwise 
noted, to be enrolled in this study: 
1. Give their signed written informed consent to participate 
2. Are at least 40 years of age and no older than 80 years  
3. COPD Diagnosis:  subjects with an established clinical history of COPD as defined by 
the American Thoracic Society (ATS)/European Respiratory Society (ERS) [Celli, 2004] 
or by locally applicable guidelines, e.g., JRS Guidelines [JRS, 2013] characterized by:  
-
Progressive airflow limitation associated with an abnormal inflammatory response of 
the lungs to noxious particles or gases, primarily caused by cigarette smoking  
4. COPD Severity: subjects with established COPD clinical history and who are 
symptomatic (CAT ≥ 10) and severity defined and calculated using NHANES III 
reference equations [Or reference norms applicable to other regions, e.g., for Japan, use 
JRS reference equations; (JRS, 2013)] as below: 
-
At Visit 1, FEV1/FVC ratio must be < 0.70 and FEV1 must be < 80% predicted 
normal value 
-
At Visit 2, post-bronchodilator FEV1/FVC ratio of < 0.70 and post-bronchodilator 
FEV1 must be ≥ 30% but < 80% predicted normal value. 
◦
if post-bronchodilator percent predicted FEV1 is < 30% then FEV1 must be 
≥750 ml
-
At Visit 3, the average of the -60 min and -30 min pre-dose FEV1 assessments must 
be < 80% predicted normal value 
5. Required COPD Maintenance Therapy 
-
All subjects must be receiving one or more inhaled bronchodilators as maintenance 
therapy for the management of their COPD for at least six weeks 
Notes:  the following are included 
◦
Scheduled SABA and/or scheduled SAMA 
◦
Nebulized COPD maintenance medications, as long as their use is discontinued at 
Visit 1 and they are not used for the remainder of the study 
6. 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 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)] 
7. Willing and, in the opinion of the investigator, able to adjust current COPD therapy, as 
required by protocol 
8. Demonstrate acceptable MDI administration technique 
9. A female is eligible to participate in the study if: 


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Non-childbearing potential [i.e., physiologically incapable of becoming pregnant, 
including any female who is two years post-menopausal, or surgically sterile (defined 
as having a bi-lateral oophorectomy, hysterectomy or tubal ligation)] 
-
Note:  for purposes of this protocol, menopause is defined as women ≥ 50 years old 
who are amenorrheic for 12 consecutive months or more following cessation of all
exogenous hormonal treatment 
-
Practicing abstinence 
-
If sexually active, a woman of childbearing potential agrees to prevent pregnancy by 
using one of the following methods of birth control from the date the ICF is signed 
until two weeks after the final dose of investigational product is taken: 
◦
Hormonal contraception (e.g., oral contraceptive, contraceptive implant, or 
injectable hormonal contraceptive) 
◦
Double-barrier birth control (e.g., condom plus intrauterine device or diaphragm 
plus spermicide) 
◦
Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy 
-
If a woman is of childbearing potential, she must have a negative serum pregnancy 
test 
10. Screening Period lab tests must be acceptable to the Investigator 
11. Screening Period ECG must be acceptable to the Investigator 
12. Chest x-ray or computed tomography (CT) scan of the chest/lungs must be acceptable to 
the Investigator. A chest x-ray must be conducted if the most recent chest x-ray or CT 
scan is more than 6 months old, except in countries with restrictive radiology assessment 
practice where only subjects who have had a chest x-ray or CT scan 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 chest x-ray as per local practice assessment.  
13. Compliance:  willing to remain at study center as required per protocol to complete all 
study visit assessments. 
5.2 
Exclusion Criteria 
Subjects who meet any of the following criteria, in relationship to Visit 1 unless otherwise 
stated, will be excluded from the study: 
1. Receiving an ICS, LABA, and LAMA (as inhaled triple maintenance therapy) in the past 
30 days 
2. Respiratory 
a.
Current diagnosis of asthma, in the opinion of the Investigator 
b. COPD due to α1-Antitrypsin Deficiency 
c.
Sleep apnea that, in the opinion of the Investigator, is uncontrolled 
d. Other Respiratory Disorders: known active tuberculosis, lung cancer, cystic fibrosis, 
significant bronchiectasis (high resolution CT evidence of bronchiectasis that causes 
repeated acute exacerbations), sarcoidosis, idiopathic interstitial pulmonary fibrosis, 
primary pulmonary hypertension, or pulmonary thromboembolic disease  
Note: allergic rhinitis is not exclusionary 


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e.
Pulmonary resection or Lung Volume Reduction Surgery during the past 6 months 
[i.e., lobectomy, bronchoscopic lung volume reduction (endobronchial blockers, 
airway bypass, endobronchial valves, thermal vapor ablation, biological sealants, and 
airway implants)] 
f.
Hospitalized due to or has poorly controlled COPD within six weeks prior to Visit 1 
g. Lower respiratory tract infections that required antibiotics within six weeks prior to 
Visit 1 
h. Treatment with systemic corticosteroids and/or antibiotics (for criteria 2f or 2g 
above), within four weeks prior to Visit 1 
i.
Pneumonia not clinically resolved within 14 days 
j.
Upper respiratory tract infection not resolved at least 7 days 
k. Clinically significant chest x-ray (frontal and lateral) with suspicion of pneumonia or 
other condition/abnormality that will require additional investigation/treatment, or put 
the subject at risk because of participation in the study 
l.
Immune deficiency and/or severe neurological disorders affecting control of the upper 
airway or other risk factors that place the subject at substantial risk of pneumonia, in 
the opinion of  the Investigator 
m. Long-term-oxygen therapy (≥ 15 hours a day). 
Note: as needed oxygen use is not exclusionary 
n. Any non-invasive positive pressure ventilation device  
Note: Subjects using continuous positive airway pressure or bi-level positive airway 
pressure for Sleep Apnea Syndrome are allowed in the study if not used for 
ventilatory support 
o. Change in smoking status (i.e., start or stop smoking) or initiation of a smoking 
cessation program within 6 weeks and prior to Randomization. 
p. Acute phase of a pulmonary rehabilitation program within 4 weeks or scheduled acute 
phase of a pulmonary rehabilitation program during the study. These subjects will be 
allowed to rescreen after completion of the acute phase of pulmonary rehabilitation. 
Note: subjects who are in the maintenance phase of a pulmonary rehabilitation 
program are not to be excluded 
q. Initiated or altered the dose regimen of intranasal corticosteroids, intranasal 
antihistamines, or a combination thereof, within seven days and prior to 
Randomization 
r.
Unable to withhold short-acting bronchodilators for 6-hours prior to spirometry 
testing at each study visit 
s.
Use of spacer device to compensate for poor hand-to-breath coordination with MDI 
t.
Spirometry Performance:  subjects who 
◦
Acceptability:  cannot perform acceptable spirometry (i.e., meet ATS/ERS 
acceptability criteria) 
◦
Repeatability:  cannot perform technically acceptable spirometry with ≥ 3
acceptable flow-volume curves with ≥ 2 meeting ATS repeatability criteria for 
FEV1 during  ≥ 1 of the pre-bronchodilator assessments at Visit 2 
(-60 minute or -30 minute) and at the post-bronchodilator assessment at Visit 2 


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◦
FEV1 Baseline Stability:  cannot meet protocol-specified baseline stability 
criteria. FEV1 baseline stability is defined as the average of the -60 minute and -30 
minute pre-dose FEV1 assessments at Visit 3 being within ± 20% or 200 mL of 
the mean of the pre-bronchodilator FEV1 assessments obtained at Visit 2  
3. Cardiovascular 
a.
Unstable ischemic heart disease, left ventricular failure, or documented myocardial 
infarction within 6 months  
b. Acute coronary syndrome or undergone percutaneous coronary intervention (PTCA) 
or coronary artery bypass graft (CABG) within 3 months 
c.
Congestive heart failure (CHF) NYHA Class III and IV 
d. Clinically significant abnormal ECG findings as defined below or deemed by the 
Investigator, but not limited to: 
◦
Conduction abnormalities (i.e., left bundle branch block, Wolff-Parkinson-White 
syndrome or evidence of Mobitz Type II second degree or third degree 
atrioventricular block [unless pacemaker or defibrillator has been inserted]) 
◦
Arrhythmias (i.e., atrial fibrillation [AF] atrial flutter, ventricular tachycardia). 
Note:  clinically stable AF appropriately treated with anticoagulation and rate 
controlled therapies (i.e., selective β-blocker, calcium channel blocker, digoxin, 
ablation therapy) for at least six months is allowed.  At pre-randomization visits, 
resting ventricular rate must be < 100 beats per minute [bpm]. During the 
Screening Period, AF must be confirmed by central reading. 
◦
Corrected QT interval for heart rate, using Fridericia’s formula (QTcF), ≥ 
500 milliseconds (msec) with QRS < 120 msec; and  ≥ 530 msec with QRS ≥ 120 
msec 
◦
Ventricular rate < 45 bpm 
◦
Clinical significant ST-T wave abnormalities, as deemed by Investigator.  
Note: non-specific ST-T wave abnormalities not deemed clinically significant are 
allowed 
◦
Uncontrolled hypertension despite pharmacological treatment, as deemed by 
Investigator 
4. Neurological 
a.
Seizure disorder  
Note: subjects with seizures treated with anticonvulsant medication for ≥ 12 months 
with no seizure events are eligible 
b. Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake 
inhibitors (SNRIs) with unstable dosing for ≥ four weeks or altered at any point 
during the Screening Period, or exceeds maximum labeled dose 
c.
Cerebrovascular accident (CVA) within six months 
5. Renal 
a.
Underlying significant renal disease that may place subject at risk, as deemed by 
Investigator 
6. Endocrine 
a.
Uncontrolled hypo- or hyperthyroidism, hypokalemia, or hyperadrenergic state 


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b. Uncontrolled Type I or II diabetes  
7. Liver  
a.
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
Note: Chronic stable Hepatitis B and C is acceptable 
8. Eye 
a.
Narrow angle glaucoma not adequately treated, as deemed by the Investigator.  All 
medications approved for control of intraocular pressures are allowed including 
topical ophthalmic non-selective beta-blockers (such as betaxolol, carteolol, 
levobunolol, metipranolol, and timolol), and prostaglandin analogues 
9. Cancer 
a.
Not in complete remission for at least 5 years 
Note: squamous and basal cell carcinomas 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. Women who are pregnant or lactating, planning to become pregnant during the study, or 
of childbearing potential and not using acceptable contraception method 
11. Hypersensitivity to β2-agonists or corticosteroids or any component of the MDI or DPI 
12. Significantly abuse alcohol or drugs, in the opinion of the investigator 
13. Unable to abstain from protocol-defined prohibited medications during the Screening 
Period and Randomized Treatment period (refer to Section 5.4) 
14. Using any herbal products by inhalation or nebulization within two weeks and does not 
agree to stop for the duration of the study 
15. Received a live attenuated vaccination within seven days  
16. 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 3) 
17. Study Investigators, Sub-investigators, and Coordinators, and their employees or 
immediate family members 
18. Hospitalized for psychiatric disorder or attempted suicide within one year 
19. History of psychiatric disease, intellectual deficiency, poor motivation, or other 
conditions limiting informed consent validity 
20. Treatment with investigational study drug (or device) in another clinical study within the 
last 30 days or five half-lives, whichever is longer   
Note: observational studies (i.e., studies not requiring change to medication or an 
additional intervention) are allowed 
21. Previously randomized in PT009 or PT010 study conducted or sponsored by Pearl 
5.3
Subject Identification
All subjects who undergo screening procedures will be assigned a unique screening 
identification number at Visit 1.  Only subjects continuing to meet inclusion/exclusion 


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criteria at Visit 3 will be assigned a unique subject randomization number. Randomization 
will be centralized with an Interactive Web Response System (IWRS). 
5.4
Prior, Concomitant, and Prohibited Medications
5.4.1 
Prior Medications 
All prescription and over-the-counter (OTC) medications, as well as any herbal or vitamin 
supplements, taken by the subject within 30 days of Visit 1 should be recorded on the 
Prior/Concomitant Medications electronic Case Report Form (eCRF); indication, total daily 
dose, and dates of drug administration should be captured to the best of the subject’s and 
site’s ability. 
5.4.1.1 Concomitant Medications and Vaccinations 
Any current ongoing medications, including OTC drugs and herbal supplements, will be 
allowed provided they are not prohibited by the protocol (see Section 5.4.2).  All 
concomitant medications taken during the study will be recorded on the Concomitant 
Medications eCRF page with indication, total daily dose, and dates of drug administration. 
Any additions, deletions, or changes in the dose of these medications while in the study 
should be entered in the eCRF.  Subjects should also be instructed to contact the Investigator 
if they develop any illnesses, especially those requiring medicinal intervention. 
5.4.1.2 Allowed Medications to Treat a COPD Exacerbation 
Medications to treat a COPD exacerbation should not be used for more than 14 days. Recent 
data have suggested that treatment with systemic steroids for shorter periods of time results 
in similar outcomes with less systemic steroid exposure.  Therefore, it is recommended that 
subjects be treated initially with a 5-day course of steroids [Leuppi, 2013; GOLD 2016] and 
should not exceed 14 days.  During a COPD exacerbation, it is important for subjects to be 
treated as deemed appropriate by the treating health care provider.  However, all 
supplemental medication used to treat the COPD exacerbation should be discontinued as 
soon as it is considered safe by the Investigator and subjects should return to their pre-
exacerbation medication regimen as soon as practical. 
5.4.1.3 Pneumococcal and Annual Influenza Vaccination 
All subjects should be vaccinated with pneumococcal and annual influenza vaccine per local 
guidelines.  For subjects previously vaccinated with pneumococcal vaccine, the Investigator 
should assess whether a booster vaccination is required.  If a subject has egg intolerance or 
refuses to be vaccinated, the vaccination may be omitted.  Pneumococcal and/or annual 
influenza vaccine can be given at Visit 1 or at any other visit throughout the study at the 
discretion of the Investigator; however, administration should occur after obtaining all 
requisite spirometry assessments for that specific test day.  There should be at least 7 days 
between vaccination and subsequent spirometry assessments. 


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5.4.2 
Prohibited Medications 
COPD MEDICATIONS
Subjects meeting entry criteria at Visit 1, who are being treated with any of the medications 
listed in Table 5-1, need to discontinue these medications and observe the minimum washout 
requirement before returning for Visit 2.  These medications are prohibited throughout the 
course of study.  Subjects requiring the use of any listed medications in Table 5-1 should be 
discontinued from randomized treatment but encouraged to continue in the study and 
complete all remaining study visits. 
Table 5-1  
Prohibited COPD Medications and Required Washout Periods 
Prior to Visit 2 
Class of Medication
Minimum Washout Period Prior to Visit 2
SAMA
6 hours
LAMA
7 days: aclidinium, glycopyrronium, umeclidinium
14 days: tiotropium
LABA (inhaled)
7 days: salmeterol, formoterol, vilanterol
14 days: indacaterol, olodaterol
Fixed-dose combinations of LABA/LAMA
7 days: umeclidinium/vilanterol
14 days:  glycopyrronium/indacaterol, 
tiotropium/olodaterol
Fixed-dose combinations of LABA/ICS
7 days
Fixed-dose combinations of SABAs and SAMAs
6 hours
SABAa
6 hours
Oral β-agonists
2 days
Theophylline (total daily dose >400 mg/day)b
7 days
COPD=chronic obstructive pulmonary disease; ICS=inhaled corticosteroid; LABA=long-acting β2-agonist; LAMA=long-acting muscarinic 
antagonist; SABA=short-acting β2-agonist; SAMA=short-acting muscarinic antagonist 
a Discontinue and use only sponsor-provided rescue Ventolin HFA throughout the study 
b Theophylline (≤400 mg/day) is permitted provided the subject has been on a stable dose of therapy for at least four weeks prior to Visit 3 
Subjects will adjust their maintenance therapy for COPD at Visit 1 for the duration of the 
Screening and Treatment Periods as follows: 
•
Subjects who are receiving an ICS/LABA will discontinue the ICS/LABA, but continue 
the ICS component for the remainder of the Screening Period.  The ICS medications will 
be discontinued at Randomization. 
•
Subjects treated with an ICS as part of their inhaled maintenance therapy will continue 
their ICS for the remainder of the Screening Period.  The ICS medications will be 
discontinued at Randomization. 
•
Discontinue all other COPD maintenance “as needed” medications as indicated in 
Table 5-1
•
Initiate Sponsor-provided Ventolin to be administered as needed, up to 8 inhalations per 
day, for control of symptoms 


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•
Subjects receiving phosphodiesterase inhibitors at stable doses for at least 4 weeks prior 
to Visit 1, may continue on these medications throughout the Screening and Treatment 
periods
It is preferred that Ventolin HFA be US-sourced products.  In cases where it is not possible 
for the US-sourced product to be used, a locally available product will be provided by the 
Sponsor.
CORTICOSTEROIDS
Subjects who discontinue use of the medications in Table 5-2 may be considered for study 
enrollment provide they have met the minimum Washout Period prior to Visit 1.  These 
medications, however, are permitted during the Treatment Period (only), if the subject 
requires them for any medical condition. 
Table 5-2  
Prohibited Corticosteroids and Required Washout Periods Prior 
to Visit 1 
Route of Administration
Minimum Washout Period Prior to Visit 1
Depot (intra-articular and intraocular)a
12 weeks
Oral, IV, IMa
4 weeks
IV=intravenous; IM=intramuscular 
a After randomization, subjects may be treated, for any reason, with systemic corticosteroids, when required 
Note:  Subjects who are steroid dependent and maintained on an equivalent of up to 5 mg of 
prednisone per day or up to 10 mg every other day for at least 3 months prior to Visit 1 are 
eligible for enrollment.  The oral steroid dose needs to remain consistent, not exceeding this 
threshold, for the two weeks prior to Visit 3 in order to be randomized.
OTHER RESPIRATORY AND/OR NASAL MEDICATIONS
Subjects meeting entry criteria at Visit 1 who are being treated with any of the medications 
listed in Table 5-3 need to discontinue these medications and observe the minimum wash-out 
requirement before returning for Visit 2. 
Table 5-3  
 
Other Prohibited Respiratory and/or Nasal Medications and 
Required Washout Periods Prior to Visit 2 
Class of Medication
Minimum Washout Period Prior to Visit 2
Leukotriene antagonist (e.g., zafirlukast, montelukast, 
and zilueton)
7 days
Inhaled/oral cromoglycate a
7 days
Inhaled nedocromil
7 days
Ketotifenb
7 days
a Intranasal cromoglycate is allowed 
bKetotifen eye drops allowed 


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NON-COPD AND NON-RESPIRATORY MEDICATIONS
Subjects requiring medications presented in Table 5-4 are prohibited from participating in 
this study.  Subjects who recently discontinued use of these medications may be considered 
for study enrollment provided they have met the minimum Washout Period prior to Visit 1.  
These medications are prohibited throughout the course of the study.  If a subject requires the 
use of any of the listed medications, the subject should be discontinued from randomized 
treatment but encouraged to continue in the study and complete all remaining study visits. 
Table 5-4  
 
Non-COPD and Non- Respiratory Medications 
Prohibited Medications
Minimum Washout Period Prior to Visit 1
Any drug with potential to significantly prolong the QT-
intervala
14 days or 5 half-lives, whichever is longer
Other investigational drugs
30 days or 5 half-lives, whichever is longer
Non-selective β-blocking agents (except carvedilol for 
CHF-NYHA Class I and II)
7 days
Cardiac anti-arrhythmics (Class Ia, III)
7 days, unless amiodarone, then 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 3 months and free of 
seizures for 1 year
Tricyclic antidepressantsa
14 days
Monoamine oxidase inhibitors
14 days
Anti-tumor necrosis factor α antibodies (e.g., 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 drugsb
30 days
Systemic calcineurin inhibitors, systemic antifungal 
agents, protease inhibitors (e.g., ritonavir)o and cimetidine
30 days
Systemic anticholinergicsc
7 days
Chinese complementary and alternative bronchodilatory 
medicines (CAM) (i.e., herbal therapies such as Astragalus 
membranaceus [huáng qí], Panax ginseng [ginseng 
products] and Cordyceps sinensis. A. membranaceus 
[ghost moth caterpillar fungus])d
10 days
Note: Benzodiazepines are not exclusionary 
aSubjects who are on medications that have the potential to prolong the QTc interval may be enrolled provided the dose has remained stable 
for at least 3 months prior to Visit 1, the subject meets all of the ECG inclusion criteria and none of the ECG exclusion criteria and if, in the 
opinion of the Investigator, there are no safety concerns for the subject to participate in the study.  Initiation of medications with the 
potential to significantly prolong the QT interval is prohibited throughout the study. 
bAntipsychotic agents and tricyclic antidepressants used for previously diagnosed underlying medical conditions are allowed if, in the 
opinion of the Investigator, there are no concerns regarding patient safety, and if the patient has been on a stable dose for at least six weeks. 
cAllowed only if used for treatment of overactive bladder which has been constant for at least one month prior to study enrollment. 
dRequires case-by-case review by the Investigator to determine appropriate washout period, if needed. 


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5.4.3 
Other Prohibited Medications 
Table 5-5 lists certain non-COPD medications that may be used under the stated conditions 
during this study.  Each concomitant drug must be individually assessed against all exclusion 
criteria. 
Table 5-5
Non-COPD Medications Allowed Under Certain Conditions
Medications Allowed Under Certain Conditions
Condition
SSRIs or SNRIs
Treatment regimen has been stable for at least four 
weeks prior to Visit 1 and not altered during the 
Screening Period, and does not exceed the 
maximum recommended dose
Intranasal corticosteroids, intranasal antihistamines, 
intranasal cromoglycate or combination thereof
Administered at constant dose and dosing regimen 
for at least seven days prior to Visit 1 and during 
the Screening Period
SNRI=serotonin–norepinephrine reuptake inhibitors; SSRI=selective serotonin reuptake inhibitors
5.5 
Other Restrictions, Illicit Drugs or Drugs of Abuse 
5.5.1 
Illicit Drugs or Drugs of Abuse 
Illicit drugs or drugs of abuse will not be allowed from Visit 1 to the end of the Follow-up 
TC or to whenever the subject withdraws from 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 at the discretion of the Investigator.  
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 must not ingest xanthine and/or xanthine analogue (caffeine)-containing foods and 
beverages and caffeine containing medications for at least 6 hours prior to and for the 
duration of each in-clinic 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 restarting smoking) may have an 
impact on efficacy outcome measures.  Therefore, at Visits 1 through 9, subjects will be 
asked about any recent changes in their smoking status (i.e., subject has gone from a smoker 
to a nonsmoker or vice versa). Any change in smoking status between Visits 1 to 3 will result 
in a screen failure.  Smoking status changes during Visits 3 to 9 will be captured in the eCRF, 
but the subject will be permitted to continue in the study. 
All subjects will be required to refrain from smoking (including medical marijuana, Nicotrol 
inhaler, 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 


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treatments, such as chewing gum and patches as needed, 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 for Treatment Discontinuation or Study Withdrawal 
Subjects who suffer an exacerbation (regardless of severity) 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 randomized treatment and/or withdraw from the study. 
(Please see Section 8.6 and Section 8.7 for additional procedures.) 
Subjects may be withdrawn from the study at their own request, upon the request of the 
Investigator or Pearl at any time and for any reason.  (Please see Section 8.6 and Section 8.7
for additional procedures.) 
5.7.1 
Reasons for Treatment Discontinuation 
If a subject experiences any of the changes of concern listed below, a repeat assessment 
should be obtained, and if confirmed, the subject should be discontinued from randomized 
treatment, but encouraged to continue in the study and complete all remaining study visits: 
x
Calculated QTcF intervals > 500 msec which has increased by ≥ 60 msec from pre-dose 
baseline value at Visit 3 
EU-specific regions only - Calculated QTcF intervals ≥ 500 msec OR ≥ 60 msec from 
pre-dose baseline value at Visit 3 
•
Hepatic impairment, defined as abnormal liver function test of AST, ALT or total 
bilirubin ≥3 times upper limit of normal
If a subject experiences any of the changes of concern listed below, a repeat assessment 
should be obtained, and if confirmed, the Investigator needs to make a determination as to 
the suitability of continuing the subject on randomized treatment: 
•
Following dosing, a heart rate >120bpm and in which there is an increase of >40 bpm
from the pre-dose value for a given study visit 
EU-specific regions only - Following dosing, a heart rate increase of > 25 bpm from the 
pre-dose value for a given study visit 
•
Following dosing, a systolic blood pressure (SBP) > 160mmHg and an increase of > 40 
mmHg from the pre-dose value for a given study visit 
EU-specific regions only - Following dosing, a SBP increase of > 30 mmHg from the 
pre-dose value for a given study visit or a clinically relevant change from baseline as 
determined by the Investigator 
•
A decreased creatinine clearance to a value ≤ 30 mL/minute using the CKD-EPI formula 
or a clinically relevant change from pre-dose baseline as determined by the Investigator 
EU-specific regions only - A decrease of 33% in calculated creatinine clearance from pre-
dose baseline using CKD-EPI 


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5.7.2 
Reasons for Study Withdrawal 
Subjects requiring any prohibited medications listed in Section 5.4.2 (other than study-
provided medication and COPD exacerbation medication), should be withdrawn from study 
participation. 
If a female subject becomes pregnant during the course of the study, study medication will be 
discontinued and the subject will be followed until delivery or final outcome. 




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BFF MDI = Budesonide and Formoterol Fumarate Inhalation Aerosol; BID = Twice Daily; FF MDI = Formoterol Fumarate Inhalation Aerosol; 
HFA = Hydrofluoroalkane; MDI = Metered Dose Inhaler; TBH = Turbuhaler
a Albuterol sulfate is also known as salbutamol sulfate in some countries
b United States (US)-sourced products are the preferred product. In cases where it is not possible for the US-sourced product to be used, a locally 
available product will be provided by Pearl
c Active Control. Symbicort Turbuhaler is also known as Symbicort Turbohaler in some countries. 
6.3 
Primary Packaging and Labeling 
Investigational materials will be packaged by the Sponsor. 
Blinded Supplies: Each BFF MDI, BD MDI, and FF MDI will be contained in a box and 
labeled with a single label.  Inside the box will be a labeled actuator and a labeled foil pouch 
containing the MDI canister of study medication. 
Open-label Supplies: Open-label Ventolin will be provided as individually labeled MDIs 
with a single label on the actuator and a foil pouch containing the Ventolin canister.  Open-
label Symbicort TBH will be provided as individually labeled DPIs with a single label on the 
actuator and a foil pouch containing the Symbicort TBH canister. 
Labels will be printed with black ink and may include the following text: 
Lot # (Packaging Lot Trace ID)
Space for entry of screening #
Component ID #
Space for entry of randomization #
Fill Count & Dosage Form
Visit # (Space for Entry of Interval ID)
Storage Conditions
Protocol #
Country regulatory requirements
Sponsor address Translation Key
ID = identification; # = number
6.4 
Secondary Packaging and Labeling 
Blinded investigational drug and open-label Ventolin and Symbicort TBH supplies will be 
packaged in individual boxes as outlined in Table 6-2. Box configuration is subject to change 
as a result of packaging constraints. 
Table 6-2  
Description of Boxes 
Drug Supplies
Individual Box Contents
Blinded
Ventolin (albuterol sulfate) HFAa
Symbicort (budesonide and formoterol fumarate) TBHb
1 MDI
1 MDI
1 DPI
DPI = dry powder inhaler; HFA = hydrofluoroalkane; MDI = metered dose inhaler; TBH = Turbuhaler
a US-sourced products are the preferred product for use during the study. In regions where it is not possible for US-sourced products to be used, a 
locally available comparable product will be provided by the Sponsor.
b Symbicort Turbuhaler is also known as Symbicort Turbohaler in some countries.
Each box will be labeled with a two-part label printed with black ink and may include the 
following text: 


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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)
6.5 
Emergency Unblinding of Treatment Assignment 
The Investigator or designee 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. 
Emergency unblinding of study drug, for a given subject, must be done utilizing the IWRS as 
a study treatment disclosure envelope will not be provided with the clinical supplies. 
Whenever possible, the Investigator should first discuss options with the Pearl Medical 
Monitor or other appropriate Pearl study personnel before unblinding the subject’s treatment 
assignment.  If this is impractical, the Investigator must notify Pearl as soon as possible, but 
without revealing the treatment assignment of the unblinded subject, unless that information 
is important for the safety of other subjects currently enrolled in the study. 
If the Investigator contacts IWRS to unblind a subject, s/he must provide the requested 
subject identifying information and confirm the necessity to unblind treatment. The date and 
reason for the unblinding must be recorded in the appropriate eCRF. 
6.6
Storage Requirements
Blinded supplies: BFF MDI, BD MDI, and FF MDI should be stored below 25°C (77°F) in 
a dry place. Excursions permitted up to 30°C (86°F). 
Ventolin® HFA supplies: Store between 15°C and 25°C (59°F and 77°F).  Store the inhaler 
with the mouthpiece down.  For best results, the inhaler should be at room temperature 
before use.  Do not use or store near heat or open flame.  Exposure to temperatures above 
120°F (49°C) may cause bursting. Never throw into a fire or incinerator. 
Symbicort® TBH supplies: Should not be stored above 30°C (86° F).  Keep the container 
tightly closed, in order to protect from moisture. 
The temperature of the site’s storage area, for study supplies, must be monitored by site staff 
for temperature ranges consistent with those specified in the protocol.  Documentation of 
temperature monitoring should be maintained at the site and available for review. 


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6.7
Instructions for Dispensing and Preparation of Treatments for 
Administration 
6.7.1 
BFF MDI, BD MDI, and FF MDI
TREATMENT DISPENSING
Individual BFF MDI, BD MDI, and FF MDI inhalers 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 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 2-part label.  Write the subject number and treatment visit number on 
each of the 2-part labels.  The ‘tear-off’ part of the label is to be placed onto the IWRS 
confirmation report. 
TREATMENT PREPARATION FOR ADMINISTRATION
All MDIs must be primed before the first use.  Priming involves releasing 4 sprays 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. 
MDIs must be primed in a separate room from the subject treatment area. Once primed, 
subjects should be instructed on use and dosing (2 puffs in the morning and 2 puffs in the 
evening approximately 12 hours apart).  The MDI should then be given to the subject for 
dose administration. Site personnel should observe the subject take their first dose and should 
record the time of second puff in the eCRF as the time of dose administration. 
Refer to Appendix 2 for additional instructions on the administration and cleaning of the 
BFF MD, FF MDI and BD MDI. 
6.7.2 
Ventolin HFA® (Albuterol Sulfate) 
Refer to Appendix 1 for instructions on the administration and cleaning of Ventolin. Open-
label MDIs will also be packaged in a visit treatment box.  The visit treatment box will have 
a label with a component ID number. 
6.7.3 
Symbicort TBH® (Budesonide and Formoterol Fumarate) 
Refer to Appendix 3 for instructions on preparation and administration of Symbicort® TBH 
(Budesonide and Formoterol Fumarate). 
Open-label DPIs will also be packaged in a visit treatment box.  The visit treatment box will 
have a label with a component ID number. 
6.8 
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 that only the 
Investigator and designated study personnel have access.  Clinical supplies should be 
dispensed only in accordance with the protocol. 


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The Investigator or designee is responsible for keeping accurate records of the clinical 
supplies received from Pearl, the amount dispensed to and returned by the subject, and the 
amount remaining at the conclusion of the study.  Study drug should be handled in 
accordance with Good Pharmacy Practices (e.g., gloves should always be worn by study 
personnel if directly handling study drug that is returned).  The Pearl Medical Monitor or 
designee 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. 
Sites should check with the Pearl representative for appropriate documentation that needs to 
be completed for drug accountability. 
The Investigator or designated study personnel 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 
Pearl Medical Monitor or designee. 
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 or 
designee. 
Used study drug must be stored separately from unused study drug. 
All product complaints (including device malfunctions) must be reported to Pearl or the 
Sponsor’s representative using the Product Complaints Form provided in each site’s 
regulatory binder.  Pearl or their representatives will contact the site to evaluate the nature of 
the complaint and determine if further action is needed. 


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7 STUDY PROCEDURES 
A schedule of events for all study assessments is provided in Table 8-1. Detailed visit 
schedules for all pre-and post-dose timed assessments and for the PFT sub-study are 
described in Table 8-2 and Table 8-3, respectively. 
7.1 
Efficacy Assessments 
7.1.1 
Pulmonary Function Tests (PFTs) 
All PFTs, including FEV1, FVC, and PEFR, as defined in ATS/ERS guidelines, will be 
performed based on ATS criteria (refer to Appendix 4) [Miller, 2005].  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 5).
The volume accuracy of the spirometer is to be checked daily using a 3 L syringe across 
three flow ranges (i.e., low, medium, and high flows), with temperature and barometric 
pressure correction.  The calibration syringe must meet ATS specifications and 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 5).
To standardize spirometry, all sites will be provided with identical spirometry systems 
 with customized, study-specific 
software.  Every effort will be made to provide all sites with standardized spirometry 
equipment.  The volume accuracy of the spirometer is to be checked daily with appropriate 
documentation in a calibration log prior to the conduct of PFT’s on each test day.
In the event that it is not logistically possible to provide such equipment in a specific country, 
use of local PFT equipment will be permitted merely for patient eligibility and 
characterization purposes.  Local equipment needs to be reviewed by the study monitor and 
must meet or exceed ATS minimum performance recommendations (refer to Appendix 5).
All study staff responsible for performing pulmonary function testing will receive 
standardized training at the Investigator Meeting.  All technicians are required to demonstrate 
proficiency in the use of the equipment and the ability to perform technically acceptable 
PFTs (ATS criteria), prior to performing PFTs on study subjects [Miller, 2005].  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 [Miller, 
2005].  All PFT testing 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 or designee for central 
data management. 
For exact spirometry collection and specifications, please refer to Table 8-1 and Table 8-2. 
•
At Visit 1:  a single spirometry assessment will be conducted 
•
At Visit 2:  spirometry will be conducted 60 minutes and 30 minutes prior to 
bronchodilator administration and 30 minutes post-bronchodilator 


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•
Pre-dose assessments: at all remaining visits spirometry will be conducted 60 and 30 
minutes prior to study drug administration 
•
Post-dose assessments: at Visits 3, 4, 6, and 9 spirometry will be done at 5 minutes (Visit 
3 ONLY), 15 minutes, 30 minutes, 1 hour, 2 hours and 4 hours after dosing 
Subjects discontinuing treatment/withdraws consent: pre- and post-dose measurements will 
be obtained at the Premature Discontinuation Visit. 
Subjects will be required to return to the clinic at approximately the same time as Visit 3 for 
all treatment visits (± 2 hours).  All in-clinic dosing must occur prior to 10 AM; timing of 
visits must be planned accordingly.  The subjects will be required to remain at the clinic until 
completion of all protocol-defined assessments. 
Note:  During the Screening Period, spirometry must meet both acceptability and 
repeatability criteria (Visit 2 only). (Refer to Exclusion Criteria, Section 5.2).
PFT SUB-STUDY
For exact PFT Sub-study collection & specifications please see Table 8-3. 
For Subjects participating in the 12-hour PFT sub-study, at Visit 6, additional spirometry 
assessments will be conducted at 6 hours, 8 hours, 10 hours, 11.5 hours and 12 hours after 
dosing. 
7.1.1.2 
Characterization of Reversibility 
Reversibility to Ventolin® HFA (SABA) will be evaluated, for subject characterization 
purposes, at Visit 2 as follows: 
•
Perform pre-bronchodilator PFTs at -60 minutes and -30 minutes prior to administration 
of Ventolin 
•
Administer 4 puffs of Ventolin 
•
Perform post-bronchodilator PFTs at 30 minutes after the administration of Ventolin 
Reversibility will be a comparison of the average best FEV1 effort obtained at -60 minute and 
-30 minute pre-bronchodilator to the best FEV1 effort obtained at 30 minutes post-
bronchodilator following administration of Ventolin.  A subject is considered reversible to 
Ventolin if the improvement in FEV1 at 30 minutes post-Ventolin is ≥ 12% and ≥ 200 mL. 
7.1.1.3 
FEV1 Baseline Stability Criteria 
All comparisons will be made to the baseline (mean of 60 and 30 minutes prior to dosing) 
values obtained at Visit 3 (Randomization).  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 3 must be within ±20% or 200 mL of the mean of 
the pre-dose FEV1 obtained at the preceding visit (average of 2 pre-dose FEV1 values 
obtained at Visit 2).  At Visit 3, 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 2 assessments meet the 
FEV1baseline stability requirements (i.e., within ±20% or 200 mL), the initial 60 minute pre-
dose assessment will not be used and the last 2 assessments will be used to establish the 


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eligibility criteria.  If the test day FEV1 is not within ±20% or 200 mL, the subject will not be 
randomized and will be considered a screen failure. 
7.1.1.4 Subject’s Electronic Diary Data Collection
Prior to issuing the electronic Diary (eDiary) to the subject, site personnel are responsible for 
programming the eDiary and training the subject on its use. Subjects will receive their eDiary 
at Visit 1.  The eDiary is to be completed twice a day throughout the study.  The following 
information will be captured in the eDiary:  time of study medication administration, daily 
symptoms [using the Exacerbations of Chronic pulmonary disease Tool (EXACT) scale], and 
use of any rescue medication (i.e., Ventolin). 
ELECTRONIC DIARY COMPLIANCE REQUIREMENT
Between Visits 1 to 3, subjects will be required to demonstrate acceptable eDiary collections 
and compliance in order to be eligible for randomization. Subject participation may be 
terminated at any time during the study for the following reasons: 
•
Subjects who are unable to meet the compliance requirement (≥ 70% subject completion 
of eDiary assessments) in the 7 days prior to Visit 3 will be considered a screen failure. 
•
Chronic failure, in the judgment of the Investigator, to comply with eDiary compliance, 
despite documentation at the site of repeated efforts to reinforce compliance.  As defined 
for this study, compliance requires ≥ 70% subject completion of eDiary assessments for 
the duration of the study.  Pearl may also instruct a site to discontinue a subject based on 
consistent noncompliance. 
7.1.1.5 Rescue Medication Use 
Use of rescue medication (i.e., Sponsor-provided Ventolin or locally available equivalent 
product) during the conduct of the study is to be recorded, by the subject in the eDiary, on the 
day of use. Each time rescue medication is taken, the number of puffs (i.e., actuations) should 
be captured in the eDiary for the corresponding study day. 
Subjects requiring more than 8 puffs per day on 3 consecutive days with worsening 
symptoms should contact the site. 
7.1.1.6 Medication Compliance 
Subjects will record the times (morning and evening) of study drug dosing in the eDiary, 
except on the mornings of in-clinic dosing.  Study drug compliance will be checked at all 
visits.  Any issues identified (i.e., < 70% compliance) will be documented in the appropriate 
study file and reinstruction will be completed as necessary. 
7.1.1.7 Major/minor Symptom Worsening Assessment and Alert System 
Subjects will capture all major and minor symptoms of a worsening event in the eDiary for 
purposes of a ‘symptom worsening alert’.  In this way both the subject and the site can be 
notified of the potential for worsening symptoms that need further evaluation. 
All questions regarding worsening of symptoms will have a 24-hour recall period.  Questions 
pertaining to the severity of symptoms versus their usual state will have three response 
options (e.g., How breathless have you been in the last 24 hours?  Less breathlessness than 


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usual, Usual level of breathlessness, More breathless than usual) whereas questions related to 
the presence or absence of a symptom will have a dichotomous response (e.g., Have you had 
a sore throat in the last 24 hours?  No or Yes, I had a sore throat). 
An alert will be triggered if two or more major symptoms (e.g., dyspnea, sputum volume, and 
sputum color) worsen for two consecutive days or if one major symptom and one minor 
symptom (e.g., sore throat, cold, fever without other cause, cough, and wheeze) worsen for at 
least two consecutive days.  When either of these criteria is met, the subject will be alerted 
via the eDiary to contact the site as soon as possible for further evaluation.  Likewise, the 
study site will be alerted to contact the subject within the next 24 to 72 hours if he/she has 
not contacted the site for follow-up.
7.1.2 
COPD Exacerbation 
A COPD exacerbation is defined as a change in the subject’s usual COPD symptoms that 
lasts two or more days, is beyond normal day-to-day variation, is acute in onset, and may 
warrant a change in regular medication.  The change in symptoms must include at least one 
major COPD symptom and at least one other major or minor symptom from the list below: 
x
Major COPD symptoms: dyspnea, sputum volume, and sputum color 
x
Minor COPD symptoms: cough, wheeze, sore throat, cold symptoms (rhinorrhea or nasal 
congestion), and fever without other cause  
If symptoms are acute or have progressed rapidly and require treatment less than two days 
from onset of symptoms, the investigator will have to justify the decision for defining the 
event as an exacerbation and record it in the eCRF. 
If a subject’s symptoms and the overall clinical findings support the diagnosis of a COPD 
exacerbation, but the subject has not experienced a worsening of at least one major COPD 
symptom and at least one other major or minor symptom, the investigator will have to justify 
the decision for defining the event as an exacerbation and record it in the eCRF. 
7.1.2.1 Severity of COPD Exacerbation 
COPD exacerbations will be classified as mild, moderate or severe based on the following 
criteria: 
Exacerbations will be considered moderate if they result in: 
x
Use of systemic corticosteroids and/or antibiotics for at least three days; a single depot 
injectable dose of corticosteroids will be considered equivalent to a 3-day course of 
systemic corticosteroids 
Exacerbations will be considered severe if they result in: 
•
An inpatient COPD-related hospitalization (documentation stating that the subject was 
hospitalized for the COPD exacerbation or a record of the subject being admitted for ≥ 24 
hours to  an observation area, the emergency department, or other equivalent healthcare 
facility depending on the country and healthcare system) 
•
COPD-related death 
Exacerbations will be considered mild if they do not meet the requirements to be classified as 
moderate or severe but otherwise fulfill the definition of COPD exacerbation. 


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7.1.2.2 Duration of COPD Exacerbation 
For moderate or severe exacerbations, the duration is defined by the length of prescribed 
treatment, whereas for mild exacerbations, the duration is defined by the length of symptoms.
For moderate or severe COPD exacerbations, the start date will be defined as the start date of 
prescribed treatment with a systemic corticosteroid or systemic antibiotic and the stop date 
will be defined as the last day of either prescribed treatment.  In order to ensure that the same 
event is not counted twice, concurrent moderate or severe COPD exacerbations with start and 
stop dates ≤ 7 days apart will be considered the same event and assigned the maximum 
severity between the two. 
For mild COPD exacerbations, start date will be defined as on the set of worsened symptoms 
as recorded by the subject in the eDiary and stop date will be defined as the last day of 
worsened symptoms.  In order to ensure the same event is not counted twice, mild COPD 
exacerbations with start and stop dates ≤ 7 days apart will be considered the same event.
7.1.2.3 Approach for Capturing COPD Exacerbations 
All moderate or severe COPD exacerbations must be captured using the COPD Exacerbation 
eCRF.  Mild COPD exacerbations will be captured based on symptoms as recorded by the 
subject in the eDiary.  COPD exacerbations of any severity will be considered expected study 
endpoints and will not be reported as adverse events (AEs) unless considered a serious AE 
(SAE). 
SYMPTOM REPORTING
An eDiary will be used to capture daily symptom reporting.  If symptoms meet a specific 
threshold (i.e., one major COPD symptom and at least one other major or minor symptom for 
2 consecutive days), the eDiary generates alerts to the subject and the clinical site.  This alert 
is intended to generate a contact between the subject and the clinical investigator.  The 
clinical investigator makes the decision to escalate or initiate treatment (steroids and/or 
antibiotics and/or hospitalizations). 
Circumstances will occur where symptoms are not captured in the eDiary (e.g. technical 
difficulties, rapid deterioration, or sudden death).  In these cases, the investigator or designee 
will enter the information into the eCRF to capture the symptoms related to a COPD 
exacerbation. 
7.1.2.4 Investigator-judged COPD Exacerbations 
For events which do not meet the outlined symptom criteria for a COPD exacerbation and/or 
when symptoms have a shorter duration, the investigator must justify the decision for 
considering the event an exacerbation and record it on the appropriate eCRF.  An example 
would be when symptoms of COPD warrant urgent treatment due to rapid onset or rapidly 
progressive symptoms.  Such a situation does not allow enough time to fulfill the criteria of 
symptom duration (≥ 2 consecutive days).  In these cases, the Investigator may define such 
an event as a COPD exacerbation.  As clinical presentations may vary among patients with 
COPD, exacerbations defined by an Investigator can be supported by respiratory symptoms 
that do not strictly fulfill all symptom requirements, as defined earlier, but justification and 
clinical relevance must be documented in the eCRF. 


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7.1.3 
Subject Questionnaires 
Subject questionnaires to be completed on site utilizing study-supplied electronic 
questionnaire devices (not the subject’s eDiary) at specified visits throughout the study are 
CAT, BDI/TDI, SGRQ, and EQ-5D-5L, described in detail below.  Various language 
versions for each questionnaire will be utilized, as appropriate, for participating countries.  
Whenever BDI/TDI, SGRQ, and/or EQ-5D-5L are obtained at the same visit, it is 
recommended that the BDI/TDI be collected first followed immediately by the SGRQ and 
the EQ-5D-5L. 
The EXACT questionnaire will be captured via the subject eDiary (refer to Section 7.1.1.4).
7.1.3.1 
Chronic Obstructive Pulmonary Disease Assessment Test (CAT)
The CAT is a self-administered questionnaire designed to assess the condition of subjects 
and overall impact of COPD [Jones, 2009].  Studies have proven that the CAT questionnaire 
has good repeatability and discriminative properties, suggesting 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 Modified Medical Research Council Dyspnea Scale, SGRQ, and the 
6-minute walk test. 
Subjects will complete the CAT (refer to Appendix 6) at Visit 1 and results are used as an 
entry criterion.  The CAT score will describe the burden and symptomatic impact of COPD 
in subjects enrolled in the study. 
7.1.3.2 Baseline Dyspnea Index and Transition Dyspnea Index (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 
indices, which assess breathlessness in components related to functional impairment, 
magnitude of task and magnitude of effort. 
As the name implies, BDI measures a subject’s breathlessness at baseline, prior to initiation 
of study medication. The reliability and validity of the BDI assessment has been reported 
[Mahler,1984] and confirmed against other related measures [Witek, 2003].  The 
Interviewer-administered rating of severity of dyspnea at a single state provides a 
multidimensional measurement of dyspnea based on three components that evoke dyspnea in 
activities of daily living in symptomatic individuals.  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).  The 
appropriate language version of the questionnaires will be used.  The questionnaire can be 
found in Appendix 7.
The TDI measures changes in dyspnea severity, from baseline, as established at baseline by 
the BDI.  The three components of the TDI 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 (-9 to +9) where a lower score reflects a greater 
deterioration in dyspnea severity. 


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The BDI/TDI questionnaire will be captured on the Sponsor-provided tablet and not in the 
eDiary.  Always administer the BDI/TDI questionnaire prior to any other subject 
questionnaires, PFT assessments, and study drug administration to avoid influencing the 
subject’s response.  The BDI/TDI questionnaire is key outcome in many countries for 
marketing approval. 
The BDI will be completed at Visit 3 prior to study drug administration.  The TDI will be 
completed prior to study drug administration at each post-randomization visit and if the 
subject discontinues treatment/withdraws consent. 
7.1.3.3 St. George’s Respiratory Questionnaire (SGRQ)
The SGRQ 4-week recall tool will be used to provide the health status/health-related Quality 
of Life (QoL) measurements (refer to Appendix 8).  The appropriate language version of the 
questionnaires will be available in each participating country.  The subject should complete 
the questionnaire 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 most accurate and best individualized response about how they felt regarding their health 
status/health-related QoL over the last four weeks (i.e., since the study visit).  The 
questionnaire should be checked for completeness and collected prior to study drug 
administration.  At subsequent visits, subjects may not review their previous responses. 
The SGRQ contains 50 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 total score, combining each domain, will be calculated.  In each case, the lowest 
possible value is zero and the highest is 100.  Higher values correspond to greater impairment 
of QoL.  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 also look for any unsolicited comments, written by the 
subject, which may need to be captured elsewhere in the eCRF. Investigators should not 
encourage subjects to change the responses reported in the questionnaire. 
The SGRQ will be captured on the Sponsor-provided tablet and not in the eDiary.  It is to be 
completed prior to study drug administration at Visit 3 and at each post-randomization visit 
and if the subject discontinues treatment/withdraws consent.
7.1.3.4 European Quality-of-Life-5 Dimensions Questionnaire (EQ-5D-5L) 
The EQ-5D-5L is a 5-level standardized instrument measuring health outcomes and is 
applicable to a wide range of health conditions/treatments, thereby providing a simple 
descriptive profile and a single index value for health status [EuroQol, 2014]. 
The EQ-5D-5L consists of two assessments, a descriptive system and a visual analogue scale 
(VAS).  The descriptive system is comprised of the following five dimensions: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression where each dimension has 
five severity levels: no problems, slight problems, moderate problems, severe problems, and 
extreme problems. 
The VAS records the subject’s self-rated health on a 20-cm, 0-100 vertical scale with 
endpoints labeled “the best health you can imagine” and “the worst health you can imagine.” 


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This score is used as a quantitative measure of QoL where a higher score corresponds to a 
better health state and vice versa.  
The EQ-5D-5L (refer to Appendix 9) will be captured on the Sponsor-provided tablet and not 
in the eDiary.  It is to be completed prior to study drug administration at Visit 3 and at each 
post-randomization visit and if the subject discontinues treatment/withdraws consent.
7.1.3.5 Exacerbations of Chronic Pulmonary Disease Tool (EXACT) 
The EXACT is a 14-item instrument developed to assess the frequency, severity and duration 
of COPD exacerbations [Jones, 2011).  This instrument was developed for daily, at home 
administration using a handheld electronic device.  Respondents will be instructed to 
consider their experiences that day (i.e., today) when completing the diary every evening, 
prior to bedtime.  The instrument includes assessments of breathlessness (5 items), cough and 
sputum (2 items), chest symptoms (3 items), and four additional items (difficulty with 
sputum, tired or weak, sleep disturbance, and psychological state). 
The daily EXACT total score will be computed across the 14 items, with a range of 0-100 
and where higher scores are indicative of greater severity.  Total score changes are used to 
identify the onset and recovery from an EXACT-defined exacerbation event. 
The E-RS is an 11-item sub-set of EXACT, which evaluates the severity of the respiratory 
symptoms associated with COPD [Leidy, 2014].  The E-RS was designed to be captured as 
part of the daily EXACT assessment.  On
 the EXACT-Respiratory 
Symptoms Scale was renamed the Evaluating Respiratory Symptoms (E-RS) measure. When 
referring specifically to its use in COPD, the proposed context of use for qualification, the 
full name is now “Evaluating Respiratory Symptoms in COPD (E-RS™: COPD).  
Summation of E-RS item responses produces a total score ranging from 0 to 40, with higher 
scores indicating greater severity.  In addition to the total score, symptom domain scores can 
be calculated for breathlessness (5 items; score range:  0–17), cough and sputum (3 items; 
score range: 0–11) and chest symptoms (3 items; score range: 0–11) by summing the 
responses of items within a respective domain.  As with the total score, higher domain scores 
indicate greater severity. 
The EXACT (refer to Appendix 10) will be completed daily by the subject as part of the 
eDiary assessments. 
7.2 
Safety Assessments 
Safety assessments for this study include physical examination findings, vital signs, ECGs, 
and clinical laboratory tests in addition to recording AEs and SAEs. 
7.2.1 
Medical/Surgical History and Physical Examination 
Medical history, including specific cardiovascular history details, will be collected at Visit 1
and updated throughout the Screening Period. 
The number of COPD exacerbations requiring oral steroids and/or oral antibiotics, or 
hospitalization within 12 months of Visit 1 will be collected. 
A complete physical examination will be performed at Visits 1 and 9 or if the Subject 
discontinues treatment/withdraws consent, and include the following: 


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•
General appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph 
nodes, chest, heart, abdomen, extremities and nervous system  
•
Weight will be measured at Visits 1 and 9, or at the Premature Discontinuation/Early 
Termination Visit; height will be measured at Visit 1 only 
7.2.2 
Vital Sign Measurements 
All vital sign measurements, including heart rate (HR), systolic blood pressure (SBP), 
diastolic blood pressure (DBP), and temperature, will be obtained after the subject has rested 
for 5 minutes in either the supine or seated position.  Vital signs will be measured as follows: 
•
Visit 1:  a single measurement of vital signs will be collected 
•
Visit 2:  a single measurement of vital signs measured 60 minutes pre- and 30 minutes 
post-bronchodilator (completed for Reversibility Testing) 
•
Visit 3:  two vital sign measurements, at least five minutes apart, will be collected 
approximately 60 minutes pre-dose.  A single measurement of post-dose vital signs will 
be obtained at 30 minutes and 4 hours after study drug dosing. 
•
All remaining in-clinic study visits (Visits 4 to 9): 
-
A single vital sign measurement will be collected approximately 60 minutes pre-dose 
-
A single measurement of post-dose vital signs will be obtained at 30 minutes 
-
A single measurement of 4 hour post-dose vital signs will be collected at Visits 4, 6 
and 9 (in addition to Visit 3 noted above). 
Note: A single temperature reading will be collected at Visit 1 and pre-dose at all visits; 
temperature reading will not be repeated post-dose unless clinically indicated. 
Subjects discontinuing treatment/withdrawing consent: a single vital sign measurement will 
be obtained at the Premature Discontinuation Visit. 
PFT SUB-STUDY SUBJECTS ONLY
Subjects participating in the 12-hour PFT sub-study will follow vital sign measurements 
listed above, except vital signs will not be measured 4 hours after study drug dosing.  Instead, 
a single set of vital signs will be measured following the final spirometry assessment (refer to 
Table 8-3).
7.2.3 
12-Lead Electrocardiogram 
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 meeting 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 on study subjects.  After each test has been 
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. 


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The ECG parameters to be assessed include HR, 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 the 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. 
Any sign of arrhythmia should be noted.  During treatment, any indication of Torsade de 
Pointes must be recorded as an AE and reported to the Pearl 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 Medical Monitor must be contacted immediately. 
ECGs will be obtained throughout the conduct of the study. 
A single ECG will be collected at Visit 1 and when the subject discontinues 
treatment/withdraws consent. 
Timed ECGs will be obtained as follows: 
•
At Visit 3 only, pre-dose ECGs will be obtained twice at least 5 minutes apart and within 
60 minutes of dosing 
•
Pre-dose ECGs will be obtained once and within 60 minutes before dosing at Visit 6 and 
Visit 9 
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 procedures for the 
preparation and collection of blood and urine samples along with all containers needed for 
their collection. 
All clinical laboratory tests (hematology, clinical chemistry, and urinalysis) will be collected 
at Visit 1 and within 60 minutes prior to dosing at Visits 3, 6, and 9, and if the subject 
withdraws consent/discontinues treatment. 
7.2.4.1 Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, 
eosinophils and platelet count will be collected at Visit 1 and 60 minutes prior to dosing at 
Visits 3, 6, and 9, and if the subject withdraws consent/discontinues treatment. 
7.2.4.2 Clinical Chemistry 
Albumin, alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), calcium, total 
cholesterol, magnesium, phosphate, sodium, potassium, chloride, creatinine, gamma-
glutamyl transferase, blood glucose, total protein, triglycerides, bicarbonate, aspartate 
aminotransferase (AST), and alanine aminotransferase (ALT) will be collected at Visit 1 and 


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60 minutes prior to dosing at Visits 3, 6, and 9, and if the subject withdraws 
consent/discontinues treatment. 
Refer to Table 7-1 for a list of study-associated laboratory tests. 
Table 7-1
Clinical Laboratory Tests
Hematology
Hemoglobin 
Mean corpuscular hemoglobin 
Hematocrit 
Mean corpuscular hemoglobin 
concentration 
White blood cell count with differential 
Mean corpuscular volume 
Red blood cell count 
Eosinophils
Platelet count 
Clinical Blood Chemistry
Liver Enzyme and Other Liver Function Tests
Other Clinical Blood Chemistry
Alanine aminotransferase 
Albumin
Aspartate aminotransferase 
Blood Urea Nitrogen (BUN)
Alkaline phosphatase 
Calcium
Bilirubin, total 
Chloride
Gamma-glutamyl transferase 
Cholesterol 
Bicarbonate
Creatinine
Glucose
Magnesium 
Potassium
Phosphate
Protein, total 
Sodium
Triglycerides 
Urinalysis
Macroscopic examination including specific gravity, pH, protein, glucose, ketones, blood, and urobilinogen.
Other Tests:
Pregnancy test (women of childbearing potential only): serum hCG at Visit 1 and Visit 9 or Treatment 
Discontinuation
Creatinine clearance will be estimated by the CKD-EPI formula [Levy, 2009]
CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; hCG=human chorionic gonadotropin.


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7.2.4.3 Urinalysis 
Routine macroscopic urinalysis for specific gravity, pH, protein, glucose, ketones, blood, and 
urobilinogen will be measured.  Based on macroscopic results, a microscopic examination 
may be performed, if warranted.  Urinalysis will be collected at Visit 1 and prior to dosing at 
Visits 3, 6, and 9 and if the subject withdraws consent/discontinues treatment. 
7.2.4.4 Pregnancy Test 
A serum pregnancy test will be performed at the central laboratory in pre-menopausal 
women who are not surgically sterile at the Visit 1 and Visit 9 or the Treatment 
Discontinuation/Withdrawal Visit.  A urine pregnancy test will be performed on-site at Visit 
3 and Visit 6 (Table 7-1).
7.3 
Adverse Events 
7.3.1 
Performing Adverse Event (AE) Assessments 
The Investigator is responsible for promptly documenting and reporting all AEs observed 
during the study in the subject’s eCRF and on the AE Reporting Form.  If the AE is 
unexpected, the Investigator should report the AE immediately to Pearl.  In addition, certain 
AEs (as described in Section 7.3.10) 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 (SAE) to Pearl or its designee. 
In the case of SAEs, after discussing the details of the event, the Investigator and the Medical 
Monitor may discontinue the subject from treatment prematurely. 
7.3.2 
Adverse Event Definitions 
The following definitions of terms are guided by the International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH), the US Code of Federal Regulations (21 CFR 312.32) and EU 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 AE (also referred to as an adverse experience) 
can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a drug, without any judgment about 
causality.  An AE can arise from any use of the drug (e.g., 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 
•
A drug interaction 


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•
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 (e.g., surgery, endoscopy, tooth extraction, blood 
transfusion); the condition that leads to the procedure is an AE (e.g., bleeding esophageal 
varices, dental caries) 
•
Overdose of either study drug or concurrent medication without any clinical signs or 
symptoms 
•
Abnormal laboratory values that are not clinically significant; if accompanied by 
signs/symptoms, the signs or symptoms are considered an AE. 
7.3.3 
Pre-Randomization AEs 
AEs occurring from the time the subject signs informed consent until the subject is 
randomized will be summarized as medical history and not as an AE unless the event meets 
the definition of an SAE as defined in Section 7.3.10.
7.3.4 
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 
7.3.5 
Relationship to Study Drug 
The investigator will assess causal relationship between investigational product and each AE, 
and answer yes/no to the question.  ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study 
procedures.  Any SAE that could be associated with a study procedure the causal relationship 
is implied as ‘yes’.
7.3.6 
Chronic Obstructive Pulmonary Disease Exacerbations 
All moderate or severe COPD exacerbations must be captured using the COPD Exacerbation 
eCRF.  Mild COPD exacerbations will be evaluated based on symptoms recorded by the subject 
in the eDiary. Exacerbation(s) of COPD is/are expected to occur as a progression of disease 
despite standardized drug treatment, or treatment(s) with combination therapies.  As a result, 
Pearl has classified a COPD exacerbation as a protocol specified expected event and it is not to 


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be reported as an adverse event (AE) unless considered a serious AE (SAE).  Subsequently, 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 
further medical assessment by Pearl requires it. 
7.3.7 
AEs of Special Interest 
Certain AEs have been identified as adverse events of special interest (AESIs) due to the 
class of drugs being studied.  These AEs will be captured through spontaneous reports and 
the reporting of these AESIs will be described in the SAP.  Some events are described below 
but this is not a comprehensive list of all AESIs. 
7.3.7.1 
LABA Effects 
Known effects of LABAs include cardiovascular and tremor effects. 
7.3.7.2 
Local Steroid Effects 
Local steroid effects include oral candidiasis, hoarseness candidiasis, oropharyngeal 
candidiasis, dysphonia, and throat irritation. 
7.3.7.3 
Pneumonia 
In order to adequately assess and characterize the risk of pneumonia in patients in a non-
biased manner, an external, independent clinical endpoint committee (CEC) will review all 
adverse events reported as pneumonia to ensure appropriate pre-defined and clinically-
consistent pneumonia criteria are met. 
The criteria established to standardize the diagnosis of pneumonia is as follows: 
1. Clinical diagnosis of pneumonia by the investigator 
2. Documentation of chest imaging obtained within 14 days of the diagnosis of 
pneumonia that is compatible with the diagnosis of pneumonia 
3. Treatment with antibiotics (and/or if appropriate antiviral and/or antifungal agents) 
4. At least 2 of the following clinical signs, symptoms, or laboratory findings: 
◦
Increased cough 
◦
Increased sputum purulence or production 
◦
Adventitious breath sounds on auscultation 
◦
Dyspnea or tachypnea 
◦
Fever 
◦
Elevated white blood cell counts 
◦
Hypoxemia 
The CEC will be empowered to request any additional information, including copies of chest 
X-rays or CT scans if needed, to confirm the pneumonia diagnosis. 
Radiographs will be evaluated locally and results (infiltrate compatible with pneumonia) will 
be documented within the eCRF at sites.  If the investigator becomes aware that a diagnosis 
of pneumonia was made without a chest image having been performed, he or she should 
obtain a chest x-ray (frontal and lateral) within 14 days of the date of pneumonia diagnosis. 


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7.3.7.4 
Paradoxical Bronchospasm 
Monitoring for paradoxical bronchospasm will occur at Visits 3, 4, 6 and 9 at 15 and 30 
minutes post-dose.  In this study, paradoxical bronchospasm is defined as a reduction in 
FEV1 of >20% from baseline (i.e., the mean FEV1 values obtained 60 and 30 minutes prior to 
study drug administration) that occurs within 30 minutes post-dosing with associated 
symptoms of wheezing, shortness of breath, or cough.  Spontaneous reporting of paradoxical 
bronchospasm will occur at Visits 5, 7, and 8. 
7.3.8 
Major Adverse Cardiovascular Events (MACE) 
Due to the prevalence of cardiovascular diseases in patients with COPD, MACE will be 
evaluated according to pre-defined criteria as described in the Charters.  The CEC will 
review and adjudicate serious CCV events as MACE using the following definition: 
x
Cardiovascular death 
x
Non-fatal myocardial infarction (MI) 
x
Non-fatal stroke 
Charters will be established to govern these processes prior to First Patient First Visit. 
7.3.9 
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 (e.g., elevated blood urea nitrogen and 
creatinine in the setting of an AE 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 (e.g., an abnormality that 
results in study drug dose reduction, suspension, or treatment 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 (e.g., significant fall in hemoglobin not requiring transfusion) 
For laboratory abnormalities that do not meet the above criteria, but are outside of normal 
range (e.g., < or > normal reference range), the Investigator should indicate whether the 
value is clinically significant or not clinically significant for the subject. 
7.3.10 
Serious Adverse Events (SAEs) 
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 AE 
•
In-patient hospitalization or prolongation of existing hospitalization 


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•
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 
jeopardize the subject or 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 AE or suspected adverse reaction is considered “life-threatening’ if, in the view of the 
Investigator or Sponsor, its occurrence places the 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. 
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. 
7.3.10.1 
Reporting of 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 
Pharmacovigilance or designee no later than 24 hours after the Investigator 
recognizes/classifies the event as an SAE.  All SAEs should be documented and reported 
using the eCRF.  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 (e.g., 
SAE Report Form).  After the initial report, as necessary, the Investigator must provide any 
additional information on an SAE to Pearl Pharmacovigilance or designee within two 
working days after receiving the information.  Follow-up information will be a detailed 
written report that may include copies of hospital records, case reports, autopsy reports, and 
other pertinent documents. 
For subjects discontinuing study treatment (i.e., Treatment Discontinuation) but planning to 
continue study participation (i.e., planning to complete all remaining study visits), all 
AEs/SAEs will be collected through the last study visit or early termination visit. 
Post-study SAEs following the last dose of study drug must be reported to Pearl 
Pharmacovigilance as described in Section 7.3.10.4.
The Investigator is responsible for continuing to report any new or relevant follow-up 
information that s/he learns about the SAE. 
7.3.10.2 
Supplemental Investigations of SAEs 
The Investigator and supporting personnel responsible for subject care should discuss with 
the Pearl Medical Monitor or designee any need for supplemental investigations of SAEs. If 


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additional assessments are conducted, results must be reported to Pearl.  If a subject dies 
during study participation and if a post-mortem examination is performed, a copy of the 
autopsy report should be submitted to Pearl. 
7.3.10.3 
Post-Study Follow Up of Adverse Events 
Any AEs that are unresolved at the subject’s last AE assessment in the study are to be 
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. 
For subjects discontinuing study treatment (i.e., Treatment Discontinuation) but planning to 
continue study participation (i.e., planning to complete all remaining study visits), all 
AEs/SAEs will be collected up will be collected through the last study visit or early 
termination visit. 
7.3.10.4 
Notification of Post-Study Serious Adverse Events 
Investigators are not obligated to actively follow subjects after completion of the study.  
However, if the Investigator becomes aware of a post-study SAE occurring within the 
14 days following the last dose of study drug, the SAE must be reported to Pearl, whether or 
not the event is attributable to study drug.  All SAEs must be reported to Pearl no later than 
24 hours after the Investigator recognizes/classifies the event as an SAE. 
For subjects discontinuing study treatment (i.e., Treatment Discontinuation) but planning to 
continue study participation (i.e., planning to complete all remaining study visits), all 
AEs/SAEs will be collected up will be collected through the last study visit or early 
termination visit.
7.3.10.5 
Investigational Research Board/Independent Ethics Committee Notification of 
Serious Adverse Events 
The Investigator is responsible for promptly notifying her/his Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) of all SAEs, including any follow-up 
information, occurring at their site and any SAE regulatory report, including any follow-up 
reports received from Pearl.  Documentation of IRB/IEC submission must be retained for 
each safety report.  The Investigator is also responsible for notifying Pearl if their IRB/IEC 
requires revisions to the ICF or other measures based on its review of an SAE Report. 
7.3.10.6 
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 timeframe 
specified by each regulatory agency. 
Pearl or its representatives will send copies of each submitted safety report to Investigators 
actively participating in Pearl-sponsored clinical studies.  Safety reports must also be 
submitted to the appropriate IRBs/IECs as soon as possible.  Documentation of submission to 
the IRB/IEC must be retained for each safety report. 


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7.3.11 
Overdose 
An overdose is defined as any dose greater than the highest dose investigated in this study 
that results in clinical signs and symptoms.  In the event of a study drug overdose, the 
Investigator should use their best clinical judgment in treating the overdose; and the Pearl 
Medical Monitor should also be contacted. Investigators should refer to the relevant 
document(s) for detailed information regarding warnings, precautions, contraindications, 
AEs, and other significant data pertaining to the study drug(s) being administered.  Such 
document(s) may include, but not limited to: the Investigator’s Brochure for BFF MDI and 
FF MDI and approved product labeling for open-label products. 
7.3.12 
Pregnancy 
To ensure subject safety, each pregnancy from Visit 1 until study completion must be 
reported to Pearl within 24 hours of learning of its’ occurrence.  The pregnancy should be 
followed in its’ entirety to ascertain 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 Report Form and reported by the Investigator to Pearl Pharmacovigilance 
or designee.  Pregnancy follow-up should be recorded on the same pregnancy paper form and 
should include possible relationship to the study drug in response to the pregnancy outcome.  
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
7.3.13 
Hy’s Law
Cases where a subject shows an AST or ALT ≥ 3x Upper Limit of Normal (ULN) with Total 
Bilirubin (TBL) ≥ 2x ULN may need to be reported as SAEs.  Please refer to Appendix 11
for further instructions in cases of combined increase of aminotransferase and TBL. 
7.3.14 
Use of Steroids during the Study 
At each visit, subjects will be asked whether they have been administered oral, intramuscular, 
or intravenous corticosteroids since their last visit.  Use of oral, IM, or IV corticosteroids for 
the management of COPD exacerbations or other conditions is not a reason for Treatment 
Discontinuation or Study Withdrawal.  Use of corticosteroids, however, should be 
documented in the Concomitant Medications eCRF.  Subjects who are being treated for a 
COPD exacerbation with OCS or have been treated for a COPD exacerbation with OCS 
within 14 days of a scheduled visit will be allowed to perform PFTs under close medical 
supervision.  The Investigator can decide to stop PFTs if subject safety is at risk or symptoms 
make it difficult for the subject to continue. 
Subjects treated with oral, IM, or IV corticosteroids for indications other than COPD, should 
still follow their regular visit schedule.  If a subject requires intraocular corticosteroids, the 
Investigator should make a determination as to the suitability of the subject continuing in the 
study. 
7.3.15 
Clinical Endpoint Committees 
An external Clinical Endpoint committee will be established for this study.  The committee 
will consist of independent experts who will provide a centralized review, functioning 


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independently of Pearl.  Three Clinical Endpoint Adjudication Charters will outline the 
clinical endpoints for adjudication. 
•
Cardio and Cerebrovascular (CCV) Clinical Endpoint Adjudication Charter 
•
Cause Specific Mortality Clinical Endpoint Adjudication Charter 
•
Pneumonia Clinical Endpoint Adjudication Charter 
7.3.15.1 
Cardiovascular and Cerebrovascular (CCV) Clinical Endpoint Adjudication 
Charter 
Cardiovascular and Cerebrovascular (CCV) Clinical Endpoint Adjudication Charter will be 
referenced for the review and assessment of non-fatal serious CCV events and classification 
of major adverse cardiovascular events (MACE). The CEC will review potential clinical 
endpoints to determine if the event meets MACE criteria.
7.3.15.2 
Cause Specific Mortality Clinical Endpoint Adjudication Charter 
Cause Specific Mortality Clinical Endpoint Adjudication Charter will be referenced for the 
review and assessment of the cause of deaths.  The CEC will review fatal reports to
determine if the event meets MACE criteria. Cardiovascular death will be classified as 
MACE.
7.3.15.3 
Pneumonia Clinical Endpoint Adjudication Charter 
Pneumonia Clinical Endpoint Adjudication Charter will be referenced for the review and 
assessment of all reported pneumonia events to ensure appropriate pre-defined and clinically 
consistent pneumonia criteria are met.
7.3.15.4 
Data Monitoring Committee 
An independent, external Data Monitoring Committee (DMC) will provide systematic and 
unbiased assessment of safety data.   Members of the DMC will review data at predetermined 
intervals.  If significant safety issues arise in between scheduled meetings, ad hoc meetings 
will be added to review data.  Based on the safety implications of the data, the DMC may 
recommend study modification(s) or termination of the study. 
7.4 
Healthcare Resource Utilization 
Healthcare resource utilization will be captured at Visits 4 through 9 and whenever treatment 
discontinued/ consent withdrawn.  Data collected will include:  number of missed work days; 
days primary caregiver missed work as a result of the subjects COPD; number and 
percentage of subjects with telephone calls to health care providers; number and percentage 
of subjects with visits to health care providers; number and percentage of subjects with 
Emergency Room (ER) visits; number and percentage of subjects hospitalized along with the 
corresponding number and percentage of days in the hospital, Intensive Care Unit (ICU), or 
Critical Care Unit (CCU); and number and percentage of subjects requiring ambulance 
transport. 


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7.5 
Termination of the Study 
An Investigator may choose to discontinue study participation at any time, for any reason and 
should provide sufficient notice per the terms of the contract with Pearl. 
Pearl 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 instructed to do so 
by Pearl, in a timeframe that is compatible with the subjects’ wellbeing.


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8 STUDY ACTIVITIES 
Please refer to Section 7 for a complete and detailed description of all study procedures and 
their respective timing.  A time and events schedule is provided in Table 8-1. Other detailed 
schedules are provided for timed assessments of all post-randomization visits in Table 8-2
(Post-randomization Visits 3-9) and Table 8-3 (Visit 6, PFT Sub-study Participants) 
GENERAL CONSIDERATIONS
•
Subjects who inadvertently took COPD medication(s) within six hours of the start of 
study procedures must be delayed (but not to exceed dosing by 10am) or rescheduled 
within the specified visit window. 
•
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. 
•
Subjects will be required to refrain from smoking (nicotine gums or patches are allowed) 
for at least four hours prior to each study visit and throughout the duration of each visit. 
•
Subjects will be required to return to clinic at approximately the same time as Visit 3 for 
all treatment visits (± 2 hours) and dosing time should not exceed 10:00AM.  Subjects 
will be required to remain at clinic until completion of all protocol-defined assessments. 
•
In order to minimize diurnal variance, sites should make every effort to assess subjects at 
the same time throughout the study.  Sites should discuss the importance of dosing at a 
consistent time linked to the time of dosing at randomization (e.g., if the initial dose at 
randomization is administered at 8 am, all subsequent doses should be administered at 8 
am and 8 pm.  In this case, all subsequent visits should be scheduled to support in-clinic 
dosing as close to 8 am [the timing of the initial dose at randomization] as possible).
•
To ensure dosing time standardization, 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: 
-
To take their last dose the evening before the scheduled visit 
-
To bring their study medications and eDiary with them to the clinic 
-
To withhold all inhaled medications (oral and intranasal) for at least 6 hours prior to 
PFTs 
-
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 the test day.  Site personnel may request the 
subject to surrender all COPD medications prior to the visit start 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 HFA during study visits. If a subject is 
experiencing severe symptoms and requires Ventolin 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 


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should be stopped.  However, safety assessments should be continued at the 
discretion of the Investigator.




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BDI/TDI=Baseline Dyspnea Index/Transition Dyspnea Index; CAT=COPD Assessment Test; ECG=electrocardiogram; eDiary=electronic diary; EQ-5D=European Quality-of-Life-5 Dimensions; 
HCRU=Healthcare Resource Utilization; MRI=Magnetic resonance imaging; R=randomization; PFT=Pulmonary Function Test; SGRQ=St. George Respiratory Questionnaire 
a
Maximum Screening Period is 28 days after Visit 1. 
Minimum Screening Period is 8 days after Visit 1 (7 days for LABA washout plus 1 day between Visit 2 and Visit 3) or 15 days if tiotropium washout. 
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
Sites should call subjects 1-2 days before each scheduled visit to remind subject of visit and to bring all study assigned medications and eDiary. 
c
Obtain a chest x-ray (frontal and lateral) if a chest x-ray or CT scan not available and not performed within the 6 months of Visit 1.  However, in countries with 
restrictive radiology assessment practice, subjects who have had a chest 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 chest x-ray as per local practice assessment. 
d
Includes evaluation of height at Visit 1 and weight at Visit 1 and Visit 9, or if subject discontinues study early. 
e
After Visit 1, time of last dose of short-acting bronchodilator and other COPD medications needs to be assessed; if < 6 hours, visit should be rescheduled. 
f
Subjects will be tested for reversibility within 30 minutes following 4 puffs of Ventolin HFA at Visit 2. 
g
Serum pregnancy test at Visit 1 and Visit 9; urine pregnancy test at Visit 3 and 6. 
h
Stop prohibited COPD medications.  Subjects receiving an ICS/LABA will discontinue but continue the ICS component for the remainder of Screening Period.  
Subjects treated with an ICS as part of their inhaled maintenance therapy will continue their ICS for remainder of Screening Period.  The ICS medications will be 
discontinued at Randomization.  At the end of Visit 9, return subject to pre-study or other appropriate inhaled maintenance COPD medications. 
i
Sponsor-provided Ventolin HFA is dispensed only after subject determined to be eligible to proceed to Visit 2. 
j
Issue and train subjects on eDiary use, only after subject determined to qualify to proceed to Visit 2. 
k
EXACT included as part of subject diary review. 
l
The BDI/TDI, SGRQ, and EQ-5D-5L should be completed prior to any other visit procedures and in this order:  BDI/TDI followed immediately by the SGRQ, then 
the EQ-5D-5L. 
m
Subjects discontinuing study early should still have vital status check 24 weeks after randomization. 
n
These are minimum procedures that should be completed at Treatment Discontinuation/Withdrawal Visit. 


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Table 8-2  
Timed Assessments at Visits 3 through 9 
Clinical Variable
Pre-Dose
Post-Dose
-60 min
-30 min
5 min
15 min
30 min
1 hr
2 hr
4 hr
Questionnaires
BDI/TDI
SGRQ
EQ-5D-5L
Xa
Review of Electronic Diaryb
Xa
Vital Signsc
Xa,d
X
Xk
12-Lead ECG
Xa,e
Clinical Laboratory Testingf
Xa
Spirometry (FEV1, FVC, PEFR, FEF25-75)g
X
X
Xh
Xh
Xh
Xh
Xh
Xh
Study Drug Collectioni
Xa
Study Drug Dispensingj
Xa
BDI/TDI=Baseline Dyspnea Index/Transition Dyspnea Index; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5 Dimensions Questionnaire; EXACT =Exacerbations of Chronic Pulmonary Disease Tool; FEF25-
75=forced expiratory flow between 25% to 75% of FVC; FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; PEFR=peak expiratory flow rate; SGRQ=St. George’s Respiratory 
Questionnaire 
Note: Time point for dosing is regarded as “0 minutes”.  When data collection time-points are concurrent, variables should be collected in the following order:  BDI/TDI, SGRQ, EQ-5D-5L, vital signs, ECG, 
clinical laboratory assessments, and spirometry.
a
This is not a timed assessment.  Sites should plan to perform these activities to allow for collection of timed spirometry. 
b
EXACT included as part of subject diary review. 
c
Vital signs should be started (approximately 5 to 10 minutes) ahead of the specified time point to ensure spirometry will be conducted as close to the specified time 
points as possible (i.e., spirometry should be conducted within ±15 minutes of specified time prior to study drug administration; ±5 minutes of specified time for 
the first 60 minutes after study drug administration; and  ±15 minutes of specified time point for assessments obtained thereafter). 
d
Pre-dose vital signs (heart rate, blood pressure) will be collected twice, at least 5 minutes apart at Visit 3 only; at all remaining visits pre-dose vital signs will be 
collected once.  Temperature will be obtained pre-dose and will not be repeated post-dose unless clinically indicated. 
e
Pre-dose ECG will be collected at least twice, 5 minutes apart at Visit 3 only; a single pre-dose ECG will be collected at Visits 6 and 9. 
f
All clinical laboratory tests (hematology, chemistry, and urinalysis) will be assessed within 60 minutes prior to dosing at Visits 3, 6, and 9. 
g
Every effort should be made to assess subjects pre-dose and post-dose FEV1 at the same time throughout the study. 
h
5 minutes post-dose spirometry assessment will ONLY be collected at Visit 3; remaining post-dose spirometry measurement to be completed at Visits, 3, 4, 6, and 
9.


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i
At the start of each treatment visit, subjects must withhold all COPD medications, including study medication and rescue Ventolin HFA for at least 6 hours prior to 
start of test day procedures. 
j
Dispense study drug to subject for at-home use following the completion of all post-dose assessments.  Study drug will not be dispensed for at home use at Visit 9. 
k
4 hour post-dose vital signs will be collected at Visit 3, 4, 6 and 9 only. 


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Table 8-3  
Timed Assessments for Subjects Participating in the PFT Sub-study (Visit 6) 
Pre-Dose
Post-Dose
Minutes
Minutes
Hours
Clinical Variable
-60
-30
15
30
1
2
4
6
8
10
11.5
12
Questionnaires
TDI
SGRQ
EQ-5D-5L
Xa
Review of Electronic Diaryb
Xa
Vital Signsc
Xa,d
X
Xe
12-Lead ECG
Xa,f
Clinical Laboratory Testingg
Xa
Spirometry (FEV1, FVC, PEFR, FEF25-75)h
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Collectioni
Xa
Study Drug Dispensingj
Xa
ECG=electrocardiogram; EQ-5D-5L=EuroQol 5 Dimensions Questionnaire; EXACT =Exacerbations of Chronic Pulmonary Disease Tool; FEF25-75=forced expiratory flow between 25% to 75% of FVC; 
FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; PEFR=peak expiratory flow rate; SGRQ=St. George’s Respiratory Questionnaire; TDI= Transition Dyspnea Index 
Note: The time point at which dosing is to occur is regarded as “0 minutes”. When data collection time-points are concurrent, it is recommended that variables be collected in the following order: BDI/TDI, 
SGRQ, EQ-5D-5L, vital signs, ECG, clinical laboratory assessments, and spirometry.
a
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. 
b
EXACT included as part of subject diary review. 
c
Vital signs should be started (approximately 5 to 10 minutes) ahead of the specified time point to ensure spirometry will be conducted as close to the specified time 
points as possible (i.e., spirometry should be conducted within ±15 minutes of specified time prior to study drug administration; ±5 minutes of specified time for 
the first 60 minutes after study drug administration; and  ±15 minutes of specified time point for assessments obtained thereafter). 
d
Pre-dose vital signs (heart rate, blood pressure) will be collected once during the PFT sub-study.  Temperature will be obtained pre-dose and will not be repeated 
post-dose at subsequent time points unless clinically indicate 
e
To be completed after final spirometry assessment. 
f
A single pre-dose ECG will be collected within 60 minutes prior to dosing. 
g
All clinical laboratory tests (hematology, chemistry, and urinalysis) will be assessed within 60 minutes prior to dosing.   
h
Every effort should be made to assess subjects pre-dose and post-dose FEV1 at the same time throughout the study. 


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i
At the start of each treatment visit, subjects must withhold all COPD medications, including study medication and rescue Ventolin HFA for at least 6 hours prior to 
start of test day procedures. 
j
Dispense study drug to subject for at-home use following the completion of all post-dose assessments. 


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8.1
Visit 1 (Screening) 
•
Obtain informed consent 
•
Register the subject in IWRS to obtain subject screening number 
•
Obtain demographic data, including age, race, smoking history/status, 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) 
•
Record COPD exacerbations and AEs (if any). 
Note:  Adverse events that occur during the Screening Period (Visit 1 to Visit 3, before 
study drug dosing) will be summarized as medical history and not as a study AE, unless 
the event meets the definition of an SAE 
•
Obtain height, weight, and vital signs (HR and blood pressure after being supine or seated 
for five minutes, and oral or tympanic temperature) 
•
Obtain a 12-lead ECG 
•
Obtain CAT 
•
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 Period) is not available, 
obtain a new Chest x-ray (frontal and lateral) except in countries with restrictive 
radiology assessment practice where only subjects who have had a chest 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 chest 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) 
-
Dispense Sponsor-provided Ventolin HFA for use as rescue medication during the 
Screening Period 
-
Refer to Appendix 1Appendix 1 for detailed instructions for Ventolin HFA 
preparation, administration and cleaning. 


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-
Distribute and train subject on eDiary use 
-
During the Screening Period, subjects receiving an ICS/LABA will discontinue the 
ICS/LABA, but will continue the ICS component for the remainder of the Screening 
Period.  Similarly, subjects treated with an ICS as part of their inhaled maintenance 
therapy will continue their ICS for the remainder of the Screening Period.  Ventolin®
HFA (albuterol sulfate inhalation aerosol) will be provided by the Sponsor for rescue 
use throughout the study.  The ICS medications will be discontinued at 
Randomization 
-
In order to allow for adequate washout of previous maintenance medications, subjects 
will undergo a Washout Period of at least 1 week (at least 2 weeks if taking Spiriva), 
but not greater than 26 days in duration prior to returning to the clinic for Visit 2. 
•
Schedule Visit 2
•
Subjects will be instructed to bring their eDiary and all study-related drugs to the next 
scheduled clinic visit. 
Note:  It is recommended that sites call subjects the day BEFORE their scheduled Visit 2 
to remind them of these expectations 
8.2
Visit 2 (Screening)
•
Review subject diary entries and retrain subject if subject has not met diary compliance 
requirement of ≥ 70% subject completion of diary assessments.  Review EXACT for 
completion as part of eDiary review 
•
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 
•
Review smoking status 
•
Record COPD exacerbations and AEs (if any) 
Note: Adverse events that occur during the Screening Period (Visit 1 to Visit 3, pre study 
drug dosing) will be summarized as medical history and not as a study AE unless the 
event meets the definition of an SAE. 
•
Review all prior medications and ensure adherence to COPD regimen 
•
Obtain vital signs 
•
Inhalation device and dose indicator training 
•
Obtain spirometry 
•
Perform reversibility test to Ventolin HFA (see Section 7.1.1.2 for instructions) 
•
Schedule Visit 3 
Note:  Visit 3 can be scheduled a minimum of one day after Visit 2 but no later than 
28 days after Visit 1 
•
Ensure subject has adequate supply of Sponsor-provided rescue Ventolin HFA 


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•
Subjects will be instructed to bring their eDiary and all study-related drugs to the next 
scheduled clinic visit. 
Note: It is recommended that sites call subjects the day BEFORE their scheduled Visit 3 
to remind them of these expectations 
8.3
Visit 3 (Randomization Day 1) 
•
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 
seven days preceding Visit 3.  Review EXACT for completion as part of this review. 
•
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if < 6 hours, Visit 3 must be rescheduled) 
•
Complete BDI questionnaire followed by SGRQ questionnaire, and EQ-5D-5L, before 
any other study procedures are performed 
•
Record COPD exacerbations and AEs (if any) 
•
Review smoking status 
•
Perform a urine pregnancy test in all women of childbearing potential
•
Review all concomitant medications and ensure adherence to COPD regimen 
•
Collect Sponsor-provided Ventolin HFA dispensed during the Screening Period 
•
Review inclusion/exclusion criteria and confirm subject eligibility for randomization 
•
Obtain subject randomization number and treatment assignment information from IWRS. 
Note:  The subject is to be considered randomized after receiving a randomization 
number.
•
To allow for proper preparation of study drug, it is recommended that the seal around the 
study day treatment box be opened 15 to 30 minutes prior to dosing 
-
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 Appendix 12 for more details. 
•
Complete all pre-dose assessments (refer to Table 8-2).
-
Train subject on inhalation device use and reading the dose indicator. 
See Section 6.7 and Appendices 2 and 3 (as applicable) for detailed instructions for 
preparation of treatments for administration.  These instructions are to be adhered to 
and are relevant to all study treatment visits. 
•
Once study drug is primed and ready for use, provide assigned study drug to subject 
-
Subject will administer first dose of randomized study drug at the clinic 
•
Perform all post-dosing assessments (refer to Table 8-2) 
•
Return eDiary to subjects and provide retraining if appropriate 


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•
Subjects will be instructed to bring their eDiary and all issued study drug (including used 
study drug and rescue Ventolin HFA) to the next scheduled clinic visit 
Note:  It is recommended that sites call subjects the day BEFORE their scheduled Visit 3 
to remind them of these expectations. 
•
Schedule Visit 4 and ensure subject has adequate supply of study drug including rescue 
Ventolin HFA 
8.4
Visits 4, 5, 6, 7, and 8 (Weeks 4, 8, 12, 16 and 20) 
•
Review subject eDiary for data collection compliance 
•
Determine time of last dose of short-acting bronchodilator and other COPD medications 
(if <6 hours, visit must be rescheduled) 
•
Confirm the subject took their last dose of study medication as scheduled the prior 
evening.  If the time of dosing was not in accordance with the protocol, the visit must be 
rescheduled 
•
Complete TDI questionnaire followed by SGRQ, and EQ-5D-5L before any other study
procedures are performed 
•
Record COPD exacerbations and AEs (if any) 
•
Review smoking status 
•
At Visit 6 only, perform urine pregnancy test in women of childbearing potential
•
Review all concomitant medications and ensure adherence to COPD regimen 
•
Confirm subject eligibility to continue 
•
Collect HCRU information 
•
Complete all pre-dose assessments (refer to Table 8-2) 
•
To allow for proper preparation of study drug, it is recommended the seal around the 
study day treatment box be opened 15 to 30 minutes prior to dosing 
•
Prior to dosing, site personnel will use IWRS to assign subjects adequate supply of study 
drug for in-clinic dosing and to continue dosing at home until the next scheduled visit 
-
See Section 6.7 and Appendices 2 and 3 for detailed instructions for preparation of 
treatments for administration.  These instructions are to be adhered to and are relevant 
to all study treatment visits. 
-
For new MDIs, the recorded count will be the count following the priming of the 
device but before the subject doses 
-
Record/document the dose indicator readings of the used MDI and the replacement 
MDI 
•
Administer in-clinic study drug dose from the new kit assigned at the visit 
•
Perform all post-dosing assessments (refer to Table 8-2) 
•
Return eDiary to subjects and provide retraining if appropriate 


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•
Subjects assigned to blinded study drug 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 Appendices 2 and 12 for dose indicator 
reading instructions) 
-
The dose indicator registers ≤ 10 puffs remaining, 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. 
•
Subjects will be instructed to bring their eDiary and all study drug (including used study 
drug and Sponsor-provided rescue Ventolin HFA) to the next scheduled clinic visit 
Note:  It is recommended that sites call subjects the day BEFORE their scheduled visit to 
remind them of these expectations. 
•
Schedule next visit and ensure subject has adequate supply of study drug including rescue 
Ventolin HFA 
FOR SUBJECTS PARTICIPATING IN THE PFT SUB-STUDY
•
For subjects participating in the PFT sub-study, perform additional post-dose assessments 
at Visit 6 (refer to Table 8-3).
8.5
Final Visit (Visit 9; Week 24) 
•
Collect subject eDiary 
•
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 study medication as scheduled the prior 
evening.  If the time of dosing was not in accordance with the protocol, the visit must be 
rescheduled 
•
Complete TDI questionnaire followed by SGRQ, and EQ-5D-5L before any other study 
procedures are performed 
•
Record COPD exacerbations and AEs (if any) 
•
Review smoking status 
•
Perform serum pregnancy test in 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 
•
Perform all pre-dose assessments (refer to Table 8-2) 
•
Conduct a physical examination, including weight 
•
Collect HCRU information 
•
Review all concomitant medications and ensure adherence to COPD regimen 


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•
Prior to dosing, site personnel will use IWRS to assign subjects a new kit of study drug 
for in-clinic dosing 
-
See Section 6.7 and Appendices 2 and 3 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 
•
Administer in-clinic study drug dose from the new kit assigned at the visit, then collect 
kit for return. 
•
Perform all post-dosing assessments (refer to Table 8-2) 
•
Collect all study drugs including Sponsor-provided Ventolin HFA 
•
At completion of all Visit 9 assessments, return subject to pre-study or appropriate 
maintenance COPD medications 
•
For those subjects who discontinue study treatment but continue to participate in the 
study to complete all remaining study visits, all AEs/SAEs will be collected through the 
last study visit or early termination visit. 
•
Inform subject about reporting all SAEs up to 14 days following the last dose of study 
drug
•
Schedule the follow-up TC at least 14 days from Visit 9 
8.6 
Procedures for Treatment Discontinuation and Study Withdrawal 
Subjects 
Subjects who discontinue study treatment prior to Week 24 will be encouraged to remain in 
the study to complete all remaining study visits during the 24 week treatment period.  
Subjects who agree to continue to be followed post treatment discontinuation will sign an 
ICF addendum.  All subjects who agree to continue study participation beyond treatment 
discontinuation will complete a Treatment Discontinuation/Study Withdrawal Visit (refer to 
Section 8.7) prior to transitioning back to regularly scheduled study visits.  Subjects 
participating in a sub-study who choose to discontinue from treatment will only complete 
regularly scheduled visits and not complete any remaining sub-study assessments.  Treatment 
discontinuation subjects will return to appropriate maintenance COPD medications, per the 
Investigator’s discretion.  For subjects recorded as Treatment Discontinuations that do not 
complete at least one post-treatment data collection, a telephone follow-up call is required at 
least 14 days after last study drug dose. 
If a subject chooses not to continue with study assessments, at a minimum, the subject will 
complete the Treatment Discontinuation/Study Withdrawal Visit (refer to Table 8-1).  These 
subjects will return to appropriate maintenance COPD medications, per the investigators 
discretion.  A follow-up telephone call will be performed at least 14 days after the last study 
drug dose.  In the event the Treatment Discontinuation/Withdrawal Visit is performed >14 


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days post last study drug dosing, a follow-up TC will not be required.  These subjects will be 
followed for vital status at 24 weeks post randomization in accordance with the informed 
consent. 
8.7 
Unscheduled Visit and Treatment Discontinuation/Study 
Withdrawal Visit 
Repeat assessments, if needed, will be captured in unscheduled visits. 
The following minimum procedures will be completed for Treatment Discontinuation/Study 
Withdrawal Visits: 
•
Complete TDI questionnaire first; followed by SGRQ questionnaire and EQ-5D-5L 
before any other study procedures are performed 
•
Collect HCRU information 
•
Record COPD exacerbations and AEs (if any) 
•
Review concomitant medications 
•
Conduct a physical examination, including vital signs 
•
Perform ECG and collect blood samples for hematology, chemistry and urinalysis 
•
Collect a blood sample for pregnancy test for women of child-bearing potential 
•
Collect subject eDiary 
•
Collect all study drugs, including rescue medications 
•
Return subject to pre-study or appropriate maintenance COPD medications 
•
For subjects discontinuing study treatment (i.e., Treatment Discontinuation) but planning 
to continue study participation (i.e., planning to complete all remaining study visits), all 
AEs/SAEs will be collected up will be collected through the last study visit or early 
termination visit. 
•
Inform subject about reporting all SAEs up to 14 days following the last dose of study 
drug
•
Capture the reason for treatment discontinuation 
8.8
Follow-up Telephone Call
Subjects will be followed up through a TC at least 14 days after the last study drug dosing. 
The following information will be requested: 
•
Collect HCRU information 
•
Review previously on-going COPD exacerbations and AEs and record AEs (if any) 
•
Review concomitant medications 
Note:  For subjects who withdraw consent, schedule a follow-up TC at least 14 days after the 
last study drug dosing unless the visit is performed > 14 days post last study drug dosing, a 


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follow-up TC will not be required.  For Treatment Discontinuation Subjects, a telephone 
follow-up call is not required as long as at least one post treatment study visit is completed. 
8.9
24-Week Post-Randomization Vital Status Confirmation 
All subjects who discontinue study treatment prior to 24 weeks post- randomization will have 
their vital status confirmed at 24 weeks post-randomization. 
To confirm the vital status and cause of death, if appropriate, the following attempts will be 
made: 
•
The first and second attempts may be conducted as telephone follow-up call to the subject 
within two weeks after 24 weeks post-randomization 
•
The third attempt will be by certified mail to the subject’s address provided at the time of 
informed consent within three weeks after 24 weeks post-randomization 
•
The fourth attempt will be made as a telephone follow-up call to the next of 
kin/emergency contact provided at the time of informed consent  within four weeks  after 
24 weeks post-randomization 
•
A fifth attempt will be made through a certified letter to the next of kin/emergency 
contact provided at the time of informed consent within five weeks after 24 weeks post-
randomization 
•
After the fifth attempt, the study site will contact the national death registries (if available 
in that country) to confirm date and cause of death 
8.10
Completion of the Study
The Investigator will document the study completion or the reason for early treatment 
discontinuation or study withdrawal by a subject in the eCRF.  Note:  The End of Study is 
defined as the date on which data are collected for the last subject’s Follow-up Telephone 
Call.
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 
•
AE(s) 
•
Administrative reasons (e.g., early termination of the study) 
•
Subject lost to follow up 
•
Lack of efficacy 
•
Major protocol violation 
•
Death 
•
Completion of the study 
•
Protocol-specified criteria (see Section 5) 


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9 PLANNED STATISTICAL METHODS 
9.1
Introduction
This is a Phase III, randomized, double-blind, multicenter, parallel group, chronic dosing, 24-
week lung function study in approximately 2,420 subjects with moderate to very severe COPD 
who remain symptomatic as measured by the COPD Assessment Test (CAT) while receiving one 
or more inhaled bronchodilators administered as maintenance treatments. 
Subjects will be randomized in a 3:3:3:1:1 ratio to one of the following 5 treatment groups:
•
BFF MDI 320/9.6 μg BID (N=660) 
•
BFF MDI 160/9.6 μg BID (N=660) 
•
FF MDI 9.6 μg BID (N=660) 
•
BD MDI 320 μg BID (N=220) 
•
Symbicort TBH 400/12 μg BID (N=220) 
The primary objectives of this study are to assess the effects of BFF MDI relative to BD MDI 
and FF MDI on lung function. In addition, as secondary and other objectives, this study will 
assess the effects of BFF MDI relative to FF MDI, BD MDI, and Symbicort TBH on COPD 
symptoms, quality of life, pulmonary function, safety and tolerability, and HCRU. 
9.2
Protocol Variables
9.2.1 
Efficacy Endpoints 
Refer to Section 3 for complete details on all efficacy endpoints. 
9.2.2 
Safety Endpoints 
Refer to Section 3 for complete details on all safety endpoints. 
9.2.3 
Health Care Resource Utilization Endpoints 
Refer to Section 3 for complete details on all HCRU endpoints. 
9.2.4 
Pulmonary Function Test Sub-study Endpoints 
Refer to Section 3 for complete details on all PFT sub-study endpoints. 
9.3 
Efficacy Analysis 
The primary, secondary, and other efficacy analyses will be performed for different 
estimands.  Estimands and analysis populations are discussed in Section 9.12. 


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9.3.1 
Primary Efficacy Analysis 
9.3.1.1 Morning Pre-dose Trough FEV1
Change from baseline in morning pre-dose trough FEV1 will be analyzed using a linear 
repeated measures ANCOVA model. The model will include treatment, visit, and treatment-
by-visit interaction, and ICS use at Screening as categorical covariates and baseline FEV1,
blood eosinophil count at Screening, and percent reversibility to Ventolin HFA as continuous 
covariates.  Baseline is defined as the average of the non-missing -60 minute and -30 minute 
values obtained prior to dosing at the randomization visit.  An unstructured covariance matrix 
will be used to model within subject variability across time points.  If this model fails to 
converge, a first order autoregressive [AR (1)] structure will be used instead.  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 will be produced for each treatment difference. 
The primary efficacy analysis of the morning pre-dose trough FEV1 will be defined 
differently by regulatory authority. 
•
For the US regulatory approach, the comparisons of BFF MDI vs. FF MDI at Week 24 
will be a primary analysis. 
•
For the EU approach, BFF MDI vs. FF MDI over 24 weeks will be a primary analysis. 
Additionally, BFF MDI 320/9.6 μg vs. Symbicort TBH over 24 weeks will be evaluated 
for non-inferiority as a primary analysis. 
The analysis of this endpoint will be conducted for the efficacy estimand using the mITT 
Population where only data obtained prior to subjects discontinuing from randomized 
treatment will be utilized. This population will provide an estimate of the efficacy of the 
treatments during treatment in the randomized population. Non-inferiority analyses to 
Symbicort TBH will conducted for the per protocol (PP) estimand. Secondary analyses in 
this endpoint will be conducted for the attributable estimand. 
Supportive Analysis:  Analyses will also be conducted for the treatment policy estimand in 
the ITT Population where all observed data will be utilized regardless of whether subjects 
remain on randomized treatment.  The use of this population will provide an estimate of the 
treatment strategy effectiveness. 
9.3.1.2 
FEV1 AUC0-4
Change from baseline in FEV1 AUC0-4 at Week 24 and over 24 weeks will be analyzed in a 
similar manner as for morning pre-dose trough FEV1.  The area under the curve (AUC) will 
be calculated using the trapezoidal rule and will be normalized by dividing by the time (in 
hours) from dosing to the last measurement included (typically 4 hours).  For the mITT 
Population analysis, only one non-missing, post-dose value is required for the calculation of 
AUC.  For the PP Population, the AUC will be calculated provided that there are at least 2 
non-missing values during the first 4 hours post-dose.  Actual time from dosing will be used 
in the calculation if available, otherwise scheduled time will be used. 


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The primary efficacy analysis of FEV1 AUC0-4 will be defined differently by regulatory 
authority: 
•
For the US regulatory approach, the comparisons of BFF MDI vs. BD MDI at Week 24 
will be a primary analysis. 
•
For the EU approach, BFF MDI vs. BD MDI over 24 weeks will be a primary analysis. 
Additionally, BFF MDI 320/9.6 μg vs. Symbicort TBH over 24 weeks will be evaluated 
for non-inferiority as a primary analysis. 
Like morning pre-dose trough FEV1, the analysis of this endpoint will be conducted for the 
efficacy estimand using the mITT Population. Non-inferiority analyses to Symbicort TBH 
will conducted for the PP estimand. Secondary analyses in this endpoint will be conducted 
for the attributable estimand. 
Supportive Analysis:  Analyses will also be conducted for the treatment policy estimand 
using the ITT Population where all observed data will be utilized regardless of whether 
subjects remain on randomized treatment.  The use of this population will provide an 
estimate of the treatment strategy effectiveness. 
9.3.2 
Secondary Efficacy Analyses 
9.3.2.1 
Time to First Moderate or Severe COPD Exacerbation 
The time to first moderate or severe COPD exacerbation will be analyzed to Week 24 using a 
Cox regression model. Treatment comparisons will be performed using the model, adjusting 
for percent predicted post-bronchodilator FEV1, baseline eosinophil count, baseline COPD 
exacerbation history (Yes/No), country, and ICS use at Screening (Yes/No).  Estimated 
adjusted hazard ratios relative to the comparator for each treatment comparison will be 
displayed along with the associated Wald two-sided 95% CIs and p-values. 
9.3.2.2 
Time to Clinically Important Deterioration 
For the EU approach, time to clinically important deterioration will be analyzed to Week 24 
as a secondary efficacy analysis using a Cox regression model. The model will include 
treatment, baseline post-bronchodilator percent predicted FEV1, baseline eosinophil count, 
baseline COPD exacerbation history (Yes/No), country, and ICS use at Screening (yes/no).
Clinically important deterioration is defined as ≥ 100 mL decrease from baseline in trough 
FEV1, or ≥ 4 points increase from baseline in SGRQ total score, or a TDI focal score of -1 
point or less, or treatment-emergent moderate-or-severe COPD exacerbation occurring up to 
Week 24.  
9.3.2.3 
 Saint George’s Respiratory Questionnaire (SGRQ)
Responder analyses will be performed where responders are defined as an improvement of 
≥4.0 points on average at Week 24, over Weeks 12 to 24, and over 24 weeks.  Logistic 


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regression will be used to compare the treatment groups with baseline SGRQ Score, blood 
eosinophil count at Screening, baseline post-bronchodilator percent predicted FEV1, and 
percent reversibility to Ventolin HFA as continuous covariates.  Treatment and ICS use at 
baseline will be categorical covariates. P-values and odds ratios with 95% CIs will be 
produced for each treatment comparison. 
The secondary efficacy analysis of SGRQ will be defined differently by regulatory authority: 
•
For the US regulatory approach, the comparisons of BFF MDI vs FF MDI and BFF MDI 
vs BD MDI at Week 24 will be classified as secondary analyses. 
•
For the EU Approach, BFF MDI vs FF MDI and BFF vs BD MDI over 24 weeks will be 
classified as secondary analyses.  Additionally, BFF MDI 320/9.6 μg vs Symbicort TBH 
over 24 weeks will be evaluated for non-inferiority as a secondary analysis. 
9.3.2.4 
Morning Pre-Dose Trough FEV1
In addition to being a primary efficacy endpoint, morning pre-dose trough FEV1 will also be 
a secondary efficacy endpoint.  The analysis of morning pre-dose trough FEV1 will use the 
same modeling specifications and strategy as with the primary efficacy analysis. 
The secondary efficacy analysis of morning pre-dose trough FEV1 will be defined differently 
by regulatory authority: 
•
For the US regulatory approach, the comparisons of BFF MDI vs BD MDI at Week 24 
will be classified as a secondary analysis. 
•
For the EU Approach, BFF MDI vs BD MDI over 24 weeks will be classified as a 
secondary analysis. 
9.3.2.5 
Peak Change from Baseline in FEV1
Peak change from baseline in FEV1 within four hours post-dosing at Week 24, over Weeks 
12 to 24, and over 24 weeks will be evaluated as a secondary efficacy analysis.  This analysis 
will use the same modeling specifications and strategy as with morning pre-dose trough 
FEV1.
The secondary efficacy analysis of peak change from baseline in FEV1 will be defined 
differently by regulatory authority: 
•
For the US regulatory approach, the comparisons of BFF MDI vs BD MDI at Week 24 
will be classified as a secondary analysis. 
•
For the EU Approach, BFF MDI vs BD MDI over 24 weeks will be classified as a 
secondary analysis. 
9.3.2.6 
Rescue Ventolin HFA Usage 
The number of puffs of rescue medication use taken in the previous 12 hours will be recorded 
in the subject diary in the morning and evening.  Diary data recorded during the last 7 days of 
the Screening Period will be used to calculate the baseline.  The mean daily number of puffs 
of rescue medication use will be calculated overall and for each of the 4-week intervals 


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during the Treatment Period. 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. 
A linear repeated measures ANCOVA model will be used to analyze change from baseline in 
average daily rescue Ventolin HFA use.  The model will include treatment, the number of the 
relevant 4-week interval (1-6), and the treatment by 4-week interval interaction, and ICS use 
at Screening as categorical covariates and blood eosinophil count at Screening, baseline 
rescue Ventolin HFA use, baseline FEV1, and percent reversibility to Ventolin HFA as 
continuous covariates.  An unstructured correlation matrix will be used to model additional 
autocorrelation within subject. If this model fails to converge, an AR(1) structure will be 
used instead; for this model, subject will be considered a random effect. Contrasts will be 
used to obtain estimates of the treatment differences over 24 weeks.  Two-sided p-values and 
point estimates with two-sided 95% CIs will be produced for each treatment difference. 
The secondary efficacy analysis of change from baseline in average daily rescue Ventolin 
HFA use will be defined differently by regulatory authority: 
•
For the US regulatory approach, BFF MDI vs BD MDI over 24 weeks will be classified 
as a secondary analysis. 
•
For the EU Approach, BFF MDI vs BD MDI over 24 weeks will be classified as a 
secondary analysis. 
9.3.2.7 Transition Dyspnea Index 
Assessments of dyspnea will be obtained using the BDI/TDI. 
At Randomization, the severity of dyspnea at baseline will be assessed using the BDI. At 
subsequent visits, change from baseline will be assessed using the TDI.  Scoring and 
handling of missing items will be conducted in accordance with the user’s guide for the TDI 
score.  TDI will be analyzed using a RM linear model. Data from all study treatments will be 
included in the modeling.  
The linear RM ANCOVA model will include treatment, visit, and the treatment by visit 
interaction, and ICS use at Screening as categorical covariates and blood eosinophil count at 
screening, BDI, baseline post-bronchodilator percent predicted FEV1, and percent 
reversibility to Ventolin HFA as continuous covariates.  An unstructured correlation matrix 
will be used to model additional autocorrelation within subject.  If this model fails to 
converge, an AR(1) structure will be used instead; for this model, subject will be considered 
a random effect.  Contrasts will be used to obtain estimates of the treatment differences over 
24 weeks.  Two-sided p-values and point estimates with two-sided 95% CIs will be produced 
for each treatment difference.   
The secondary efficacy analysis of TDI will be defined differently by regulatory authority: 
•
For the US regulatory approach, the analysis of TDI is not considered a secondary 
efficacy analysis.   
•
For the EU Approach, BFF MDI vs FF MDI and BFF MDI vs BD MDI over 24 weeks 
will be classified as secondary analyses.   Additionally, BFF MDI 320/9.6 μg vs


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Symbicort TBH over 24 weeks will be evaluated for non-inferiority as a secondary 
analysis.  
9.3.2.8 
Evaluating Respiratory Symptoms in COPD (E-RS: COPD) total score (RS-
Total Score) 
Mean change from baseline in the daily Evaluating Respiratory Symptoms in COPD (E-RS: 
COPD) total score (RS-Total Score) will be calculated over 24 weeks.  The last 7 days of the 
Screening Period will be used to calculate the baseline. The mean change from baseline in 
RS-Total Score will be analyzed using a similar RM model as for TDI to estimate treatment 
effects over 24 weeks, but using the RS-Total Score baseline mean score instead of the BDI 
as a covariate.  Instead of visit, the number of the relevant 4-week interval (1-6) will be used 
as a categorical covariate in the model. 
The secondary efficacy analysis of RS-Total Score will be defined differently by regulatory 
approach: 
•
For the US regulatory approach, the analysis of RS-Total Score is not considered a 
secondary efficacy analysis. 
•
For the EU Approach, BFF MDI vs FF MDI and BFF MDI vs BD MDI over 24 weeks 
will be classified as secondary analyses.   Additionally, BFF MDI 320/9.6 μg vs 
Symbicort TBH over 24 weeks will be evaluated for non-inferiority as a secondary 
analysis. 
9.3.2.9 
FEV1 AUC0-4
In addition to being a primary efficacy endpoint, FEV1 AUC0-4 will also be a secondary 
efficacy endpoint.  The analysis of FEV1 AUC0-4 will use the same modeling specifications 
and strategy as with the primary efficacy analysis. 
The secondary efficacy analysis of FEV1 AUC0-4 will be defined differently by regulatory 
authority: 
•
For the US regulatory approach, the analysis of FEV1 AUC0-4 is already defined as a 
primary efficacy analysis.   
•
For the EU Approach, the analysis of FEV1 AUC0-4 is already defined as a primary 
efficacy analysis.   
9.3.2.10 
Time to Onset of Action 
The onset of action for BFF MDI will be evaluated on Day 1 by comparing BFF MDI vs BD 
MDI in the mean change from baseline in FEV1 at the 5 minute post-dose timepoint. To 
perform this analysis, a linear model with repeated measures will be fit to the Day 1 post-
baseline data. This model will include baseline FEV1, percent reversibility to Ventolin HFA, 
and baseline eosinophil count as continuous covariates and time point, treatment, the 
treatment by time point interaction, and ICS use at screening as categorical covariates. 


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Responder analyses will be performed where responders are defined as an improvement of a 
100 ml increase from baseline.  The percentage of responders at each time point before Hour 
1 post-dose will be summarized by treatment, and the difference in response rates versus BD 
MDI will be presented along with two-sided p-values and the 95% CI of the difference.  The 
median time to response will also be presented by treatment. 
9.3.3 
Other Efficacy Analysis 
9.3.3.1 
Additional Spirometry Assessments 
FEV1, FVC, PEFR, and FEF25-75 will be collected throughout the study.  For each parameter, 
if not already defined as a primary or secondary analysis, the following analyses will be 
performed over 24 weeks, over Weeks 12 to 24, and at each post-randomization visit: 
•
Change from baseline at each time point 
•
Change from baseline in morning pre-dose trough value 
•
AUC0-4
•
Peak change from baseline within 4 hours of dose 
Similar to the primary and secondary analyses, linear repeated measures ANCOVA models 
will be built to analyze FVC, PEFR, and FEF25-75 over 24 weeks, over Weeks 12 to 24, and at 
Week 24. 
9.3.3.2 
FEV1 Response at Day 1 
The proportion of subjects achieving a peak improvement from baseline on Day 1 in FEV1
will be summarized by treatment.  The thresholds for improvement are as follows: 
•
≥ 10% improvement from baseline
•
≥ 12% improvement from baseline 
•
≥ 15% improvement from baseline
•
≥ 100 mL improvement from baseline
•
≥ 200 mL improvement from baseline
•
≥ 12% and ≥ 200 mL improvement from baseline
Further analyses will be detailed in the SAP. 
9.3.3.3 
Rate of COPD Exacerbations 
The rate of COPD exacerbations of any severity and moderate-to- severe COPD 
exacerbations will be analyzed with a negative binomial regression model.  Details will be 
provided in the SAP. 
9.3.3.4 
Time to Event Analyses 
All of the following variables will be analyzed using a Cox regression model: 


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•
Time to treatment failure 
•
Time to treatment discontinuation for any cause 
•
Time to CID 
•
Time to sustained CID 
•
Time to death  
Treatment failure is defined as a moderate or severe COPD exacerbation or discontinuation 
from treatment for any reason or death. Subjects who do not experience a treatment failure 
will be censored at their Week 24 Visit or Day 168, whichever comes first. 
CID is defined in the secondary analyses section.  Sustained CID is defined as ≥ 100 mL 
decrease from baseline in trough FEV1, or ≥ 4 points increase from baseline in SGRQ total 
score, or a TDI focal score of 1 point or less, any of which is occurring on two consecutive 
analysis visits or for ≥ 50% of all available subsequent analysis visits, or a treatment 
emergent moderate-or-severe COPD exacerbation occurring up to Week 24. 
For time to death (all causes), subjects will be censored at the date of last contact. A Cox 
regression model will be used to compare the treatments, adjusted for baseline percent 
predicted post bronchodilator FEV1 and baseline age as covariates. For this endpoint, the 
primary population will use the ITT Population.  This analysis will only be conducted if there 
are 30 or more deaths in the study. 
9.3.3.5 
Exacerbations of Chronic Pulmonary Disease Tool (EXACT) 
In addition to the Evaluating Respiratory Symptoms in COPD (E-RS: COPD) total score 
(RS-Total Score) secondary analysis, the RM ANCOVA model will be used to evaluate the 
difference between treatments in mean change from baseline in: the daily EXACT Total 
Score, the 11-item RS-Total Score, as well as 3 subscale scores- RS-Breathlessness, RS-
Cough and Sputum, and RS-Chest Symptoms over 24 weeks, and over each 4-week interval 
of the 24-week Treatment Period. 
9.3.3.6 
TDI Focal Score 
In addition to the TDI secondary analyses, the RM ANCOVA model will be used to evaluate 
the difference between treatments over 24 weeks, Weeks 12 to 24, and at each of the 
individual visits.  Similar analyses will be performed for the individual components of the 
TDI: functional impairment, magnitude of task, and magnitude of effort over 24 weeks, 
Weeks 12 to 24, and at each post-randomization visit. 
Responder analyses will be performed for TDI focal score where responders are defined as a 
response of 1.0 points or more on average over 24 weeks and over Weeks 12 to 24.  Logistic 
regression will be used to compare the treatment groups with BDI and blood eosinophil count 
at Screening, percent reversibility to Ventolin HFA as continuous covariates and treatment, 
and ICS use at Screening as a categorical covariate.  P-values and odds ratios with 95% CIs 
will be produced for each treatment comparison. 


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9.3.3.7 
St. George’s Respiratory Questionnaire (SGRQ)
The difference between treatment groups in the change from baseline in SGRQ over 24 
weeks and Weeks 12 to 24 of treatment will be evaluated using a similar RM approach as for 
TDI, but using baseline SGRQ score instead of the BDI.  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 SGRQ total scores will not be imputed.  Two-sided p-values and point 
estimates with 2-sided 95% CIs will be produced for each treatment difference.  
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. 
The percentage of subjects achieving an MCID of 4 units or more on average in SGRQ total 
score at Week 24, over 24 weeks, and over Weeks 12 to 24 will be evaluated with a model 
similar to the one used on the secondary analysis of SGRQ responders. 
9.3.3.8 
EuroQoL (ED-5D) Dimensions Questionnaire (EQ-5D-5L)
Data from the EQ-5D-5L will be analyzed. 
The data will be weighted to calculate an index score based upon subjects’ responses to the 5 
dimensions. The visual analogue scale (VAS) will be scored from 0 (worst imaginable health 
state) through 100 (best imaginable health state) to represent the subject’s self-report 
concerning how bad or how good their health was during that day. 
EQ-5D will be presented in three different ways:  
1. Presenting results from the EQ-5D-5L descriptive system as a health profile at baseline, 
at all visits, and at EoT (%, n) by domain  
2. Presenting results of the VAS as a measure of overall self-rated health status - baseline 
scores, scores at each visit, changes from baseline at each visit, and mean VAS score over 
the treatment period 
3. Presenting results from the EQ-5D-5L index score (using UK value set) at baseline, each 
visit, changes from baseline to each visit, and the mean index score over the treatment 
period.  
Further details may be found in the SAP. 
The compliance of completing the EQ-5D-5L questionnaires will be described by post-
randomization visit, by the number and percentage of subjects who were assessed at that 
visit. 


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9.3.4 
Type I Error Control 
The same general Type I error control strategy will be employed for the US and EU 
regulatory approaches.  In each approach, Type I error will be controlled for the following 
analyses: 
•
The primary analyses for the efficacy estimand 
•
The secondary analysis of the primary endpoints for the attributable estimand 
•
The remaining secondary analyses 
9.3.4.1 
US Approach 
The Type I error rate will be controlled within the primary and secondary efficacy analyses.  
The primary analyses associated with BFF MDI 160/9.6 will proceed only if all of the 
primary analyses associated with BFF MDI 320/9.6 are successful (Figure 9-1).  The 
secondary analysis of the primary endpoints for the attributable estimand and remaining 
secondary analyses for each BFF dose will proceed only if the primary analyses associated 
with that dose of BFF MDI are successful.  
For ease of review, the set of planned analyses has been divided into two groups: 
Group 1: The primary analyses for the efficacy estimand and the secondary analysis of the 
primary endpoints for the attributable estimand.  
Group 2: The remaining secondary analyses for the efficacy estimand.  










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laboratory measurements, baseline will be defined as the last available value prior to 
Randomization.  Potentially clinically significant values will be identified and summarized. 
9.4.1.3 
Vital Signs 
Summary statistics (mean, median, SD, and range) of change from baseline will be tabulated 
by vital sign parameter and treatment for each scheduled assessment time.  For vital signs, 
baseline will be defined as the average of the values prior to dosing on the day of 
Randomization.  In addition, potentially clinically significant values will be identified and 
summarized. 
9.4.1.4 
ECGs 
Summary statistics (mean, median, SD, and range) for absolute values and change from 
baseline will be tabulated by ECG parameter and treatment for each scheduled assessment 
time.  For ECG parameters, baseline values will be defined as the average of the pre-dose 
measurements taken prior to the start of treatment at the randomization visit (Visit 3).  In 
addition, potentially clinically significant values will be identified and summarized.
9.5 
HCRU Analyses 
HCRU endpoints will be descriptively summarized by treatment group.  Additional analyses 
may be performed which will be specified in the SAP. 
9.6
PFT Sub-Study Analyses 
Change from baseline in FEV1 AUC0-12 at Week 12 will be analyzed by treatment.  The SAP 
will contain details of the planned analyses. Data from the PFT sub-study will be 
descriptively summarized by treatment with tables and figures. 
9.7 
Randomization 
Subjects will be randomized in a 3:3:3:1:1 scheme.  Approximately 2,420 subjects will be 
randomized.  Approximately 660 subjects each will be randomized to the BFF MDI 320/9.6 
μg,  BFF MDI 160/9.6 μg, and FF MDI 9.6 μg treatment groups.  Approximately 220 
subjects each will be randomized to the BD MDI 320 μg and Symbicort TBH treatment 
groups.  Randomization will be stratified by reversibility to Ventolin (≥ 12% and 200ml or 
<  12%, measured at Visit 2), post-bronchodilator FEV1 (< 50% or 50% to < 80% predicted, 
measured at Visit 2), blood eosinophil count (< 150 or ≥ 150 cells per mm3), and country.  
Enrollment will be targeted to achieve a 2:1 ratio for the blood eosinophil strata with twice as 
many randomized subjects in the ≥ 150 cells per mm3 category. 
9.8 
Experimental Design 
This study is a multi-center, double-blind, parallel-group, active-controlled design. 


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9.9 
Sample Size Consideration 
Assumptions regarding variability for the primary endpoints are based on Pearl Therapeutics’ 
experience with Phase IIb and III clinical studies. 
For trough FEV1, a standard deviation (SD) of 200 mL for the change from baseline at each 
visit has been assumed. Based on the repeated measures and anticipated dropout of 
approximately 20%, an effective SD for the change over 24 weeks of 157 mL is assumed.  
An effective SD for the change over 12 to 24 weeks of 175 mL is assumed. 
A SD of 220 mL for FEV1 AUC0-4 at Week 24 is assumed.  A SD of 200 mL for 
FEV1 AUC0-4 over 24 weeks is assumed. 
US APPROACH: 
It is estimated that a sample size of 2,420 subjects (660 per arm in each of the BFF MDI and 
FF MDI groups and 220 per arm in the BD MDI and Symbicort TBH groups) will provide 
approximately 90% power to detect a difference of 40 mL between BFF MDI and FF MDI in 
morning pre-dose trough FEV1 at Week 24 with Type I error controlled at a two-sided alpha 
level of 0.05 and approximately 99% power to detect a difference between BFF MDI and BD 
MDI of 100 mL in FEV1 AUC0-4 at Week 24 with Type I error controlled at a two-sided 
alpha level of 0.05.  The above calculations assume a 20% dropout rate.  
EU APPROACH: 
It is estimated that a sample size of 2,420 subjects (660 per arm in the BFF MDI and FF MDI 
groups and 220 per arm in the BD MDI and Symbicort TBH groups) will provide 
approximately 99% power to detect a difference of 40 mL between BFF MDI and FF MDI in 
morning pre-dose trough FEV1 over 24 weeks and approximately 99% power to detect a 
difference between BFF MDI and BD MDI of 100 mL in FEV1 AUC0-4 over 24 weeks.  In 
both cases, Type I error is controlled at a two-sided alpha level of 0.05, and a 20% dropout 
rate is assumed. 
With the same sample size, there is 96% power to declare BFF MDI non-inferior to 
Symbicort TBH in morning pre-dose trough FEV1 over 24 weeks with Type I error 
controlled at a two-sided alpha level of 0.05 and a non-inferiority margin of 50 mL.  There is 
99% power to declare BFF MDI non-inferior to Symbicort TBH in FEV1 AUC0-4 over 24 
weeks with Type I error controlled at a two-sided alpha level of 0.05 and a non-inferiority 
margin of 75 mL. 
9.10 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 of residuals, and influence statistics will be examined to 
identify such cases.  In the event that a single or small number of such outlying values are 
found to exist and found to be highly influential, the effects may be ameliorated either by 


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transformation or by removal of the outlier.  Transformations to be considered may include 
the logarithmic transformation, or normal rank transformations.  Where outliers are removed, 
sensitivity analyses including those values will be reported. 
Changes in spirometry measures from baseline, and from time point to time point will be 
examined graphically before data base lock, and before unblinding, as part of data quality 
management.  This will include production of normal probability plots, kernel density 
estimates, and normal order outlier statistics. 
9.11 Analysis Plan 
All analyses will be specified in a detailed Statistical Analysis Plan (SAP) that will include 
table and data listing shells with mock graphical representations.  The SAP will be signed 
before database lock and unblinding.   
9.12 Analysis Populations and Estimands
9.12.1 
Analysis Populations 
The following analysis populations are defined in this study: 
•
The Intent-To-Treat (ITT) Population is defined as all subjects who are randomized to 
treatment and receive any amount of the study treatment.  Subjects will be analyzed 
according to the treatment they were assigned at randomization.  Data obtained after 
discontinuation of treatment, but prior to withdrawal from the study, will be included.   
•
The Modified Intent-to-Treat (mITT) Population is a subset of the ITT Population, 
defined as all subjects with post-randomization data obtained prior to discontinuation 
from treatment. Any data collected after completion of or discontinuation from 
randomized study medication will be excluded from the mITT analysis but will still be 
included in the ITT analysis. Subjects will be analyzed according to randomized 
treatment group. (Note that a subject who used a study treatment, but took less than one 
full dose of treatment will qualify for this population). Data obtained after treatment 
discontinuation will be excluded. The mITT Population will be the primary population 
for all efficacy analyses except for the non-inferiority analyses. Note: The knowledge that 
a subject did not have a COPD exacerbation constitutes an efficacy assessment. 
•
Differences in rescue Ventolin HFA usage are expected across the study including some 
subjects who used virtually no rescue medication at study entry. In order to represent the 
population of patients who may benefit from study treatment and reduce their use of 
rescue medication, the Rescue Ventolin User (RVU) Population is defined as all 
subjects in the ITT Population with mean baseline rescue Ventolin use of ≥ 1.0 puff/day.
•
The 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 or discontinuation from treatment will be excluded. Since 
receiving the wrong treatment is a major protocol deviation, subjects in the PP population 
will be analyzed as randomized (which for this population is identical to analysis by 
actual treatment received). Any evaluability criteria with a potential impact on efficacy 


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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 time point and/or subsequent time points for an endpoint.  
•
The Safety Population is defined as 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 1 
randomized treatment, they will be analyzed and included in summaries according to the 
treatment they received the most. Subjects receiving no study treatment will be excluded, 
as will subjects who have no post-dose safety assessments. A subject who used a study 
treatment, but took less than 1 full dose of treatment will qualify for this population. 
Note: The statement that a subject had no AEs also constitutes a safety assessment. 
•
Analyses will be performed as follows: 
-
Demographics will be summarized for the mITT, PP, RVU, Safety, and Non-
Randomized Populations, as well as for subjects participating in the 12-hr PFT sub-
study. 
-
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, mITT, and PP Populations. In 
general, the mITT Population will be considered the primary population for the 
efficacy analyses, with the ITT and PP populations being considered supportive. 
9.12.2 
Estimands 
Four estimands of interest are defined for this study: efficacy estimand, attributable estimand, 
treatment policy estimand, and per protocol estimand. 
The efficacy estimand is the primary estimand of interest and is the effect of the randomized 
treatments in all subjects assuming continuation of randomized treatments for the duration of 
the study regardless of actual compliance.  The primary analysis for the efficacy estimand 
will be conducted using the mITT Population where only data obtained prior to subjects 
discontinuing from randomized treatment will be utilized. This assumes that efficacy 
observed on treatment is reflective of what would have occurred after discontinuation of 
randomized treatment had they remained on treatment. 
The attributable estimand is the effect of treatment in subjects attributable to the randomized 
treatment. For this estimand, discontinuation of randomized medication for reasons such as 
tolerability or lack of efficacy is considered a bad outcome.  Analyses of the attributable 
estimand will be conducted using the mITT Population. Data that are missing due to 
treatment discontinuation will be imputed based on the 5th or 95th percentile of the reference 
arms’ distribution if the reason is reasonably attributable to tolerability or lack of efficacy. 
The 5th percentile applies to an endpoint for which a higher value is a better outcome; 
however the 95th percentile applies to an endpoint for which a higher value is a worse 
outcome. For this purpose, FF MDI and BD MDI are considered the reference arms. The 


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estimated average of the two reference means will be used. Other missing data are to be 
imputed using the observed data model, i.e. assumed to be missing at random (MAR). 
The treatment policy estimand is the effect of randomized treatment over the study period 
regardless of whether randomized treatment is continued. Analyses of the treatment policy 
estimand will be conducted using the ITT Population, in which all observed data will be 
utilized regardless of whether subjects remain on randomized treatment. 
The per protocol estimand is the effect of treatment on subjects who are compliant with the 
protocol (i.e., no major protocol deviations), including the use of randomized medication. 
Analysis of this estimand will use the PP Population. 
9.13 Subgroup Analyses 
Subgroup analyses will be performed for change from baseline in morning pre-dose trough 
FEV1, FEV1 AUC0-4, and the rate of moderate or severe COPD exacerbations (efficacy 
estimand only). The following subgroups will be considered: 
•
History of Moderate or Severe COPD Exacerbation in the last 12 Months: 
-
Yes 
-
No
•
Baseline Eosinophil Count: 
-
<150 cells per mm3
-
≥150 cells per mm3
•
Country 
Each subgroup will be analyzed separately using the same model that was used for the 
overall (combined subgroups) analysis. Estimates for the treatment effect and for the 
treatment differences will be displayed in the efficacy endpoint tables for each subgroup.
For each subgroup analysis, a test for the treatment-by-subgroup interaction will be 
performed using the same model that was used for the overall (combined subgroups) analysis 
but with the addition of terms for 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. 
Eosinophil Cut Point Exploration 
Subgroup analyses of trough FEV1 will be conducted in the baseline eosinophil count-high 
(≥150 cells per mm3) and the baseline eosinophil count-low (<150 cells per mm3) subgroups. 
It is acknowledged 150 cells per mm3 may not ultimately be the appropriate threshold for 
evaluation of treatment benefit. Thus, additional analyses will evaluate alternative thresholds, 
and the results from these analyses could then inform thresholds for future clinical studies. 
This exploration will include using additive mixed models that combine nonparametric 


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regression for the relationship of eosinophil levels to trough FEV1 as well as potentially using 
subgroups defined by different cut points. 
9.14
Handling of Missing Data
Pre-dose spirometry values will use the average of the non-missing -60 minutes 
and -30 minutes values.  Weekly averages for eDiary-based parameters will use all 
non-missing values. 
9.15
Statistical Software
Data processing, statistical screening, descriptive reporting and analysis of the efficacy and 
safety data will be performed using 
 
  Graphs may also be 
produced using 
 
 
. 


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1
Regulatory Authority Approval
Pearl will obtain approval to conduct this study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements prior initiating this 
study in a given country. 
10.2
Ethical Conduct of the Study and IRB or IEC Approval 
This study is to be conducted in accordance with Good Clinical Practice (GCP).  These 
standards respect the following guidelines: 
•
Guideline for GCP E6 (R1):  Consolidated Guideline (International Conference on 
Harmonization of Technical Requirements for the Registration of Pharmaceuticals for 
Human Use, May 1996). 
•
US 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, where applicable) is responsible for ensuring that this protocol, 
the site’s ICF, and any other information that will be presented to potential subjects 
(e.g., 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 will provide the Investigator with relevant document(s)/data necessary for IRB/IEC 
review 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, when 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. IRB/IEC approval of an 
amended ICF/other information must be promptly forwarded to Pearl or its’ designee.
10.3
Subject Information and Consent
This 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 and Pearl 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.  A copy of the signed ICF will be provided to 
the subject and the original will be retained by the Investigator. 


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10.4
Confidentiality
10.4.1 
Confidentiality of Data 
By signing this protocol, the Investigator affirms that information furnished to the 
Investigator by Pearl will be maintained in confidence.  Information relating to this study will 
be divulged to an IRB/IEC or similar expert committee, affiliated institution, or employees 
only under an appropriate understanding of confidentiality with said person(s).  Data 
generated by this study will be considered confidential by the Investigator except to the 
extent that it is included in a publication. 
10.4.2 
Confidentiality of Subject/Patient Records 
By signing this protocol, the Investigator agrees that Pearl (or its’ representative), IRB/IEC, 
or Regulatory Agency representatives may consult and/or copy study documents in order to 
verify worksheet/CRF data.  By signing the consent form, the subject agrees to this process.  
If study documents are photocopied during the process of verifying worksheet/CRF 
information, the subject will be identified by a unique code; full names/initials will be 
masked prior to transmission to Pearl.  In addition, the Investigator agrees to treat all subject 
data, used and disclosed in connection with this study, in accordance with all applicable 
privacy laws (i.e., Health Insurance Portability and Accountability Act), rules and 
regulations. 
10.5 Quality Control and Assurance 
Pearl is responsible for implementing and maintaining quality control and quality assurance 
systems with written SOPs to ensure that studies 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 a 
clinical study. 
10.6 Data Management 
Data management procedures and information for this protocol will be provided by Pearl. 
10.7 Study Monitoring 
In accordance with applicable regulations, GCP, and Pearl 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 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 


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•
Conduct source document verification 
•
Identify any issues and address their resolution 
These reviews 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 concerns.  Upon completion of the study, the monitor will conduct the following 
activities in conjunction with the Investigator or site staff, as appropriate: 
•
Return of all study data to Pearl 
•
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 10.8. The Investigator will also permit inspection of the study 
files by Pearls’ Quality Assurance auditors, or designees, including representatives from 
AstraZeneca, and authorized representatives of the and authorized representatives of the FDA 
or other applicable regulatory agencies. 
10.8
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 Pearls’ Quality 
Assurance auditors and by all applicable regulatory authorities.  The period of time these 
documents must be maintained is governed by county-specific regulations.  Pearl or its 
designee will inform the Investigator when these documents may be destroyed.  Pearl or its 
designee must be notified in writing at least 6 months prior to the intended date of disposal of 
any study-related documents to allow Pearl to make alternate storage arrangements. 
10.9 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 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. 
10.10 Investigator’s Final Report
Following completion of the study, the Investigator will submit a final written report to Pearl. 


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10.11 Publication Policy
Pearl 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-sponsored studies should fairly recognize the activities of those that have made a 
significant contribution to the study.  In addition, Pearl recognizes and adheres to the 
precepts of the International Society for Medical Publications Professionals (ISMPP), which 
provides guidance to the preparation of publications, disclosure of conflicts of interest, and 
the protection of intellectual property.  Thus, it is anticipated that authorship will reflect the 
contribution made by Pearl 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 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 (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, in collaboration with the Investigators, 
will establish the appropriate authorship and responsibility for drafting study documents 
in accordance with the principles of the ICMJE and ISMPP.  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 for 
review, approval, and to ensure consistency with the policy in this protocol.  Pearl 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 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 to publish the study in a 
fair and accurate manner, Pearl 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, e.g., protocol and amendments, data tabulations, etc. The journal and 
reviewers will need to make arrangements to maintain the confidentiality of such 


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supplemental information, where relevant, and Pearl 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 CONsolidated Standards of Reporting Trials (CONSORT) Statement 
[Mohler, 2010] and a 25-item checklist which is intended to improve the reporting of a 
randomized controlled trial, facilitate reader understanding of the trial design, 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. 


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11 REFERENCE LIST 
Celli B, MacNee W, ATS/ERS Task Force.  Standards for the diagnosis and treatment of 
patients with COPD:  a summary of the ATS/ERS position paper.  Eur Respir J. 2004; 
23(6):932-46. 
Dellamary LA, Tarara TE, Smith DJ, et al.  Hollow porous particles in metered dose inhalers.  
Pharm Res. 2000;17(2):168-74.
EuroQol Group. EQ-5D. Accessed at http://www.euroqol.org/about-eq-5d/how-to-use-eq-
5d.html (November, 2014). 
Global strategy for the diagnosis, management, and prevention of COPD.  Global Initiative 
for Chronic Obstructive Lung Disease (GOLD) 2016.  http://www.goldcopd.org.  Accessed 
3 March 2016. 
Hirst, PH, Pitcairn GR, Weers JG, et al.  In vivo lung deposition of hollow porous particles 
from a pressurized metered dose inhaler.  Pharm Res. 2002;19(3):258-64. 
Japanese Respiratory Society (JRS).  Guidelines for the Diagnosis and Treatment of COPD, 
4th edition, 2013. 
Jones PW, Harding G, Berry P, et al.  Development and first validation of the COPD 
assessment test.  Eur Respir J.  2009;34(3):648-54. 
Jones PW, Chen W-H, Wilcox TK, et al.  Characterizing and Quantifying the Symptomatic 
Features of COPD Exacerbations.  Chest  2011;139(6)1388-94. 
Leidy NK, Sexton CC, Jones et al.  Measuring respiratory symptoms in clinical trials of 
COPD:  reliability and validity of a daily diary.  Thorax  May 2014;69(5):424-30.
Levey AS, Stevens LA, Schmid CH, et al.  A new equation to estimate glomerular filtration 
rate.  Ann Intern Med. 2009;150(9):604-12. 
Mahler DA, Weinberg DH, Wells CK, Feinstein AR.  The measurement of dyspnea.  
Contents, interobserver agreement, and physiologic correlates of two new clinical indexes.  
Chest. 1984;85(6):751-58.
Miller MR, Hankinson J, Brusasco V, et al.  Standardisation of spirometry.  Eur Respir J. 
2005;26(2):319-338. 
Moher D, Hopewell S, Schulz KF, et al.  CONSORT 2010 Explanation and Elaboration: 
updated guidelines for reporting parallel group randomised trials.  Int J Surg. 2012;10(1):28-
55. doi: 10.1016/j.ijsu.2011.10.001. Epub 2011 Oct 12. Review. 
Witek TJ, Mahler DA.  Minimal important difference of the transition dyspnoea index in a 
multinational clinical trial.  Eur Respir J. 2003;21:267-272.


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12 APPENDICES 
Appendix 1 
Instructions for Use of Ventolin HFA Inhaler .....................................114 
Appendix 2 
Subject Instructions for Use of BFF MDI, BD MDI, and FF MDI 
Devices 
118 
Appendix 3 
Instructions for Use of Symbicort® TBH Inhalation Powder Device ..127 
Appendix 4 
Spirometry Assessment Criteria ...........................................................130 
Appendix 5 
Spirometry Performance Recommendations ........................................132 
Appendix 6 
COPD Assessment Test (CAT) ............................................................138 
Appendix 7 
BDI/TDI Questionnaire ........................................................................139 
Appendix 8 
St. George Respiratory Questionnaire (SGRQ) ...................................145 
Appendix 9 
EUROQOL 5 Dimensions Questionnaire ............................................151 
Appendix 10 
Exacerbations of Chronic Obstructive Pulmonary Disease (EXACT) 154 
Appendix 11 
Rules for Evaluation of Abnormal Liver Laboratory Values ...............159 
Appendix 12 
Dose Indicator Reading ........................................................................162 
Appendix 13 
Sponsor Signatory ................................................................................164 
Appendix 14 
Investigator’s Agreement and Signature Page .....................................165 


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Appendix 1 
Instructions for Use of Ventolin HFA Inhaler
The Parts of Your VENTOLIN HFA Inhaler 
Figure 1 
There are two main parts to your VENTOLIN HFA inhaler: 
1.
The metal canister that holds the medicine and  
2.
The blue plastic actuator that sprays the medicine from the canister (see Figure 1). 
a.
A window in the back of the actuator. 
The counter starts at 204, the number will count down by 1 each time you spray the inhaler.  The counter will 
stop counting at 000. 
Never try to change the numbers or take the counter off the metal canister.  The counter cannot be reset, 
and it is permanently attached to the canister. 
Do not use the actuator with a canister of medicine from any other inhaler.  In addition, do not use a
VENTOLIN HFA canister with an actuator from any other inhaler.
How to Use Your VENTOLIN HFA
Before using your VENTOLIN HFA:
1. Take the inhaler out of the foil pouch.  Safely throw away the pouch and the 
drying packet that comes inside the pouch.  The counter should read 204.  The 
inhaler should be at room temperature before you use it.
2. Check each time to make sure the canister fits firmly in the plastic actuator.  Also, 
look into the mouthpiece to make sure there are no foreign objects there, 
especially if the strap is no longer attached to the actuator or if the cap is not 
being used to cover the mouthpiece. 
Priming your VENTOLIN HFA: 
You must prime the inhaler to get the right amount of medicine.  Prime the inhaler before you use it for the first 
time, if you have not used it for more than 14 days, or if it has been dropped. 
1.
To prime the inhaler, take the cap off the mouthpiece of the actuator. 
2.
Then shake the inhaler well, and spray it into the air away from your face. 
3.
Shake and spray the inhaler like this 3 more times to finish priming it. 
4.
The counter should now read 200, or 60 if you have a sample or institutional canister. 


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Instructions for taking a dose from your VENTOLIN HFA:
Read through the 6 steps below before using VENTOLIN HFA.  If you have any questions, ask your study 
doctor. 
1. Take the cap off the mouthpiece of the actuator.  Shake the inhaler well before each spray. 
2. Hold the inhaler with the mouthpiece down (see Figure 2).  Breathe out through your mouth and push as 
much air from your lungs as you can.  Put the mouthpiece in your mouth and close your lips around it. 
3.
Push the top of the canister all the way down while you breathe in deeply and slowly through your 
mouth (see Figure 3).  Right after the spray comes out, take your finger off the canister.  After you have 
breathed in all the way, take the inhaler out of your mouth and close your mouth. 
 
 
 
 
 
Figure 2  
 
 
 
 
 
 
 
 
 
Figure 3 
4.  Hold your breath as long as you can, up to 10 seconds, then breathe normally. 
5.  If your doctor has prescribed more sprays, wait 1 minute and shake the inhaler again.  Repeat steps 2
through 4.   
6.  Put the cap back on the mouthpiece after every time you use the inhaler, and make sure it snaps firmly into 
place. 
When to Replace Your VENTOLIN HFA  
1.
When the counter reads 020, you should refill your prescription or ask your doctor if you need another 
prescription for VENTOLIN HFA.   
2.
Throw the inhaler away when the counter reads 000 or 6 months after you have taken the inhaler out of 
the foil pouch, whichever happens first.  You should not keep using the inhaler when the counter reads 000 
because you will not receive the right amount of medicine.   
3.
Do not use the inhaler after the expiration date, which is on the packaging it comes in.   
How to Clean Your VENTOLIN HFA  
It is very important to keep the plastic actuator clean so the medicine will not build-up and block the 
spray.  Do not try to clean the metal canister or let it get wet.  The inhaler may stop spraying if it is not 
cleaned correctly. 
Wash the actuator at least once a week. 


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Cleaning instructions:
1.  Take the canister out of the actuator, and take the cap off the mouthpiece.  The strap on the cap will stay 
attached to the actuator. 
2.  Wash the actuator through the top with warm running water for 30 seconds (see Figure 4).  Then wash the 
actuator again through the mouthpiece (see Figure 5). 
 
 
 
 
 
Figure 4  
 
 
 
 
 
 
 
 
 
Figure 5 
3.  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 build-up, repeat step 2.   
4.  Let the actuator air-dry completely, such as overnight (see Figure 6). 
Figure 6 
5.  When the actuator is dry, put the canister in the actuator and make sure it fits firmly.  Shake the inhaler well 
and spray it once into the air away from your face.  (The counter will count down by 1.)  Put the cap back on 
the mouthpiece. 
If your actuator becomes blocked:  
Blockage from medicine build-up is more likely to happen if you do not let the actuator air-dry completely.  If 
the actuator gets blocked so that little or no medicine comes out of the mouthpiece (see Figure 7), wash the 
actuator as described in cleaning steps 1 to 5. 


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Figure 7 
If you need to use your inhaler before the actuator is completely dry, shake as much water off the 
actuator as you can.  Put the canister in the actuator and make sure it fits firmly.  Shake the inhaler well and 
spray it once into the air away from your face.  Then take your dose as prescribed.  Then clean and air-dry it 
completely. 
Storing Your VENTOLIN HFA
Store at room temperature with the mouthpiece down.  Keep out of reach of children. 
Contents Under Pressure:  Do not puncture.  Do not use or store near heat or open flame.  Exposure to 
temperatures above 120°F may cause bursting.  Never throw into fire or incinerator. 




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left (see Figure 2b).  After 10 more puffs are used, the Dose indicator pointer will move 
to the number 100.  This means that there are 100 puffs of medicine left (see Figure 2c). 
x
The Dose indicator number will continue to change after every 20 puffs. 
x
When the number in the Dose indicator window changes to 20 and the color behind the 
number changes to red, this means that there are only 20 puffs left in your inhaler. See 
Figure 2d.
Figure 2d 
Preparing the Inhaler for Use: 
The inhaler comes in a foil pouch that contains a drying packet (desiccant). 
x
Take the inhaler out of the foil pouch. 
x
Throw away the pouch and the drying packet.  Do not eat or inhale the contents of the 
drying packet.  
x
Remove the Cap from the Mouthpiece as shown in Figure 3.  
Figure 2b 
110 puffs 
Figure 2a 
120 puffs 
Figure 2c 
100 puffs 


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Figure 3 
Prime the inhaler before you use it for the first time.
Priming the Inhaler: 
x
Check inside the Mouthpiece for objects before use. 
x
Hold the Actuator with the Mouthpiece pointing away from you and others as shown in 
Figure 4a. 
x
Shake the inhaler well before each puff. 
x
Push down fully on the center (not ‘off center’) of the Dose indicator on top of the 
Canister (see Figure 1) until the Canister stops moving in the Actuator to release a 
puff from the Mouthpiece as shown in Figure 4b.  Note:  It is normal to hear a soft click 
from the dose indicator as it counts down during use. 
x
Repeat this priming step 3 more times for a total of 4 times, shaking the inhaler each time 
before you press it. 
x
After completing the 4 priming puffs, your inhaler is now primed ready to use for the first 
time. 
You must re-prime your inhaler again if you have not used it in more than 7 days.  Take the 
cap off the mouthpiece and shake and spray the inhaler 2 times into the air away from your 
face. 
 
 
Using the Inhaler: 
Your dose of medicine comes from 2 puffs from the inhaler. 
Refer to Figure 5 for Step 1 through Step 8. 
x
Step 1: Remove the Cap from the Mouthpiece. 
x
Step 2: Shake the inhaler well before each puff. 
Figure 4a 
Figure 4b 


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x
Step 3: While holding the inhaler with the Mouthpiece pointing towards you breathe out 
through your mouth to empty as much air from your lungs as possible. 
x
Step 4:  Close your lips around the Mouthpiece and tilt your head back slightly to make 
sure your tongue is away from the Mouthpiece. 
x
Step 5: Take a deep breath in (inhale) slowly through your mouth while pressing down 
firmly on the center (not ‘off center’) of the Dose indicator until the Canister stops 
moving in the Actuator and a puff has been released. Then, stop pressing the Dose 
indicator.
x
Step 6: When you have finished breathing in, remove the Mouthpiece from your mouth 
and hold your breath for 10 seconds or as long as comfortable.    
x
Step 7:  Then, breathe out normally. 
Take your second puff of medicine by repeating Step 2 through Step 7.  
x
Step 8: Replace the Cap back on the Mouthpiece. 


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Figure 5  
How to clean the Inhaler: 


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It is very important to keep your inhaler clean so medicine will not build-up and block the 
spray through the Mouthpiece.  See Figure 6.
Figure 6 
The Canister should be gently pulled from the top of the Actuator once a week and the 
Actuator cleaned.  Do not clean the Canister or let it get wet. 


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•
Step 1: Pull the Canister out of the Actuator as shown in Figure 7.
Figure 7 
•
Step 2:  Set the Canister aside where it will not get wet. 
•
Step 3: Take the Cap off the Mouthpiece.
•
Step 4: Rinse the Actuator through the top with warm running water for 30 seconds.  
Then rinse the actuator again through the Mouthpiece (see Figure 8).  
Figure 8 
•
Step 5: Shake all of the water droplets out of the Actuator. 


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•
Step 6: Look in the Actuator and the Mouthpiece to make sure it is clean and clear.
Repeat Step 4 through Step 6, until the Actuator and the Mouthpiece are clean and clear. 
•
Step 7:  Let the Actuator dry completely, such as overnight as shown in Figure 9.
Do Not put the Canister back into the Actuator if it is still wet. 
Figure 9 
Reassembly of the Inhaler and Instructions for Use after Cleaning: 
•
After the Actuator is completely dry, gently press the Canister down in the Actuator as 
shown in Figure 10.  It is not necessary to press down on the Canister hard enough to 
cause a puff to be released. 
Figure 10 


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•
Re-prime your inhaler 2 times after each cleaning. 
•
Hold the Actuator with the Mouthpiece pointing away from you and others as shown in 
Figure 4. 
•
Shake the inhaler well before each puff. 
•
Push down fully on the center (not ‘off center’) of the Dose indicator on top of the 
Canister until the Canister stops moving in the Actuator to release a puff from the
Mouthpiece. 
•
Repeat this re-priming step 1 more time for a total of 2 times. 
•
After re-priming your inhaler 2 times, your inhaler is now ready to use. 


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Appendix 3 
Instructions for Use of Symbicort® TBH Inhalation 
Powder Device 
Preparing your new Symbicort Turbuhaler 
Before using your new Symbicort Turbuhaler for the first time, you need to prepare it for use 
as follows: 
•
Unscrew the cover and lift it off. You may hear a rattling sound. 
•
Hold your Turbuhaler upright with the red grip at the bottom. 
•
Turn the red grip as far as it will go in one direction.  Then turn it as far as it will go in 
the other direction (it does not matter which way you turn it first).  You should hear a 
click sound. 
•
Do this again, turning the red grip in both directions. 
•
Your Turbuhaler is now ready for use.
How to take an inhalation 
Every time you need to take an inhalation, follow the instructions below. 
1. Unscrew the cover and lift it off.  You may hear a rattling sound. 
2. Hold your Turbuhaler upright with the red grip at the bottom.  
3.  Do not hold the mouthpiece when you load your Turbuhaler.  To load your Turbuhaler 
with a dose, turn the red grip as far as it will go in one direction.  Then turn it as far as it 
will go in the other direction (it does not matter which way you turn it first).  You should 
hear a click sound.  Your Turbuhaler is now loaded and ready to use.  Only load your 
Turbuhaler when you need to use it.  
4.  Hold your Turbuhaler away from your mouth.  Breathe out gently (as far as is
 
comfortable).  Do not breathe out through your Turbuhaler.  


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5.  Place the mouthpiece gently between your teeth.  Close your lips.  Breathe in as deeply 
and as  hard as you can through your mouth.  Do not chew or bite on the mouthpiece. 
6. Remove your Turbuhaler from your mouth. Then breathe out gently. 
The amount of medicine that is inhaled is very small.  This means you may not be able to 
taste it after inhalation.  If you have followed the instructions, you can still be confident that 
you have inhaled the dose and the medicine is now in your lungs.
7. If you are to take a second inhalation, repeat steps 2 to 6. 
8. Replace the cover tightly after use. 
9. Rinse your mouth with water after your daily morning and/or evening doses, and spit it 
out. 
Do not try to remove or twist the mouthpiece.  It is fixed to your Turbuhaler and must not be 
taken off.  Do not use your Turbuhaler if it has been damaged or if the mouthpiece has come 
apart from your Turbuhaler. 
Cleaning your Turbuhaler 
Wipe the outside of the mouthpiece once a week with a dry tissue.  Do not use water or 
liquids. 
How to store Symbicort Turbuhaler 
•  Keep this medicine out of the sight and reach of children. 
• 
Do not use this medicine after the expiry date that is stated on the carton or on the label 
of  your inhaler after EXP. The expiry date refers to the last day of that month. 
•  Do not store above 30°C. 
•  Keep the container/cap tightly closed, in order to protect from moisture. 


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•  Do not throw away any medicines via wastewater or household waste.  Ask your 
pharmacist how to throw away medicines you no longer use.  These measures will help 
protect the environment. 


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Appendix 4 
Spirometry Assessment Criteria 
Acceptable Versus Usable Tests 
Acceptable Tests must meet the following Criteria: 
1. Acceptable start of exhalation with brisk upstroke, no hesitation or false start, and EV <
5% of FVC or 0.150 L, whichever is the greater (see 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, ie., the volume-time curve shows no change in volume (<0.025 L) for 
≥1s, and the subject has tried to exhale for at least 6 seconds 
An acceptable test meets all seven criteria listed.  This is to be considered the “gold 
standard”.
Usable spirometry tracings are those that only meet criteria 1 and 2.  When this occurs, repeat 
testing up to eight attempts for pre-dose and five attempts for post-dose assessments, in an 
effort to obtain three acceptable spirograms.  If only usable tests are obtained, report results 
based on the three best usable trials with observed limitations. 
Figure A2-1  Example of a Usable Spirogram 
EV=back extrapolation volume 
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 PEFR, to determine 


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the new “time zero”.  Forced vital capacity -4.291 L; EV – 0.123 L (2.9% FVC):  back 
extrapolation line through PEF. 
Between-Maneuver Reproducibility Criteria 
Pre-dose Assessments 
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 subject cannot/ 
should not continue (maximum of eight attempts). 
Post-dose Assessments
After two acceptable spirograms have been obtained, apply the following tests: 
•
The two largest values of FVC are within 0.150 L of each other and/or 
•
The two largest values of FEV1 are 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/reproducibility criteria are not met, continue testing until they are met or the 
subject cannot/ should not continue (maximum of five attempts) 


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Appendix 5 
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), 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 (ie., 37°C), ambient 
pressure, saturated with water vapor, body temperature and pressure saturated [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 PEFR, 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 as the zero 


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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 (see Table A1-1).
Table A1-1
Recommended Minimal Scale Factors for Time, Volume, and Flow 
on Graphical Output
Instrument Display
Hardcopy Graphical 
Output
Parameter
Resolution Required
Scale Factor
Resolution Required
Volume a
0.050 L
5 mm-L-1
0.050 L
Flow a
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
a
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 (ie., 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 cmH2O (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 one 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. 
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. 


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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 0.30 mL after 
one 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%. 
VITAL CAPACITY MANEUVERS 
Equipment 
For measurements of vital capacity (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 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.


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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 A1-3, 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
Calibration 
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 timepoint from 
which all FEVt
measurements are taken
Back extrapolation
ATS=American Thoracic Society; BTPS=body temperature and pressure saturated; FEV1=forced expiratory 
volume in 1 second; FEVt=forced expiratory volume in t seconds; FVC=forced vital capacity; VC=vital 
capacity
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 


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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 6 
COPD Assessment Test (CAT) 
(The samples provided here is for illustrative purposes only) 
















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Appendix 9 
EUROQOL 5 Dimensions Questionnaire 


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Appendix 11 
Rules for Evaluation of Abnormal Liver Laboratory 
Values
INTRODUCTION 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a subject meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with Pearl clinical representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met.  
Hy’s Law criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug-Induced Liver Injury (DILI) caused by study drug. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
DEFINITIONS 
Potential Hy’s Law
The levels of AST or ALT ≥3x ULN and TBL ≥2x ULN at any point during the study 
irrespective of an increase in ALP.  The elevations do not have to occur at the same time or 
within a specified time frame. 
Hy’s Law
The levels of AST or ALT ≥3x ULN and TBL ≥2x ULN, where no other reason, other than 
the study drug, can be found to explain the combination of increases, eg., elevated ALP 
indicating cholestasis, viral hepatitis, or another drug.  The elevations do not have to occur at 
the same time or within a specified time frame. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination: 
•
ALT ≥3x ULN
•
AST ≥3x ULN
•
TBL ≥2x ULN
When a subject meets any of the identification criteria in combination, the central laboratory 
will immediately send an alert to the Investigator and Pearl representative. 


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The Investigator will also remain vigilant for any laboratory reports where the identification 
criteria are met, the Investigator will: 
•
Request a repeat of the test (new blood draw) by the central laboratory. 
When the identification criteria are met from central laboratory results the Investigator will 
without delay: 
•
Determine whether the subject meets PHL criteria (see above definition in this Appendix) 
by reviewing all laboratory reports including previous visits. 
•
Notify the Pearl representative. 
•
Promptly enter the laboratory data into the laboratory CRF. 
FOLLOW-UP
Potential Hy’s Law Criteria not met
If the subject does not meet PHL criteria the Investigator will: 
•
Inform the Pearl representative that the subject has not met PHL criteria. 
•
Perform follow up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.
Potential Hy’s Law Criteria met
If the subject does meet PHL criteria the Investigator will: 
•
Notify the Pearl representative who will then inform the central Study Team. 
The Medical Monitor contacts the Investigator, to provide guidance, discuss, and agree on 
method of follow up and the continuous review of data.  Subsequent to this contact, the 
Investigator will: 
•
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 
•
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Pearl Medical Monitor. 
•
If at any time (in consultation with the Pearl Medical Monitor) the PHL case meets 
serious criteria, report the event as an SAE using standard reporting procedures. 


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REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section should be followed for all cases where PHL criteria are met. 
No later than 2 weeks after the biochemistry abnormality was initially detected, the Pearl 
Medical Monitor contacts the Investigator in order to review available data and agree on 
whether there is an alternative explanation for meeting PHL criteria other than DILI caused 
by the study drug.  The Pearl Medical Monitor and other subject matter experts (as 
appropriate) will collaborate in the review and assessment of these cases. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for an SAE: 
•
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF. 
•
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the standard reporting procedures. 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study drug: 
•
Report as an SAE (report term “Hy’s Law case”) according to Pearl standard processes. 
-
The “Medically Important” serious criterion should be used if no other serious criteria 
apply. 
-
As there is no alternative explanation for the HL case, a causality assessment of 
“related” should be assigned.
If, there is an unavoidable delay of over 2 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation. Until an informed decision can be made, the following procedure 
should be followed: 
•
Report as an SAE (report term “Potential Hy’s Law”) applying serious criteria and 
causality assessment as per above. 
Continue follow up and review according to the agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE Report Form according to the outcome of the 
review.


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Appendix 12 
Dose Indicator Reading
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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Appendix 13 
Sponsor Signatory
Study Title:
A Randomized, Double-Blind, Parallel Group, Chronic Dosing 
Study to Assess the Efficacy and Safety of PT009 compared to 
PT005, PT008, and Open-label Symbicort® Turbuhaler®, as an 
active control, on Lung Function over a 24-Week Treatment Period 
in Subjects With Moderate to Very Severe COPD
Protocol Number:
PT009002-02
Final Date:
Signature:
 
 
Date: 
 
 
Name: 
Title: 
 
 Pearl Therapeutics, Inc. 


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Appendix 14 
Investigator’s Agreement and Signature Page
Study Title:
A Randomized, Double-Blind, Parallel Group, Chronic Dosing Study to 
Assess the Efficacy and Safety of PT009 Compared to PT005, PT008, and 
Open-label Symbicort® Turbuhaler®, as an Active Control, on Lung 
Function over a 24-Week Treatment Period in Subjects With Moderate to 
Very Severe COPD
Protocol Number:
PT009002-02
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, Inc. (hereafter referred to as Pearl). 
•
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 fully comply with 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 Pearl 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 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 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. 
•
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 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. 


Budesonide and Formoterol Fumarate Inhalation Aerosol 
Pearl Therapeutics 
Clinical Trial Protocol: PT009002-02 
Version 3.0, 
Confidential and Proprietary 
Page 166 of 166
•
To allow authorized representatives of Pearl 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 
PT009002 
 Date 
11 DEC 2017 
 NCT #  
NCT02766608 
 
 EudraCT 
 
   2016-000154-34 
 
 
 
 
 
 
 
 
 
 
A Randomized, Double-Blind, Parallel Group, Multi-Center Study to 
Assess the Efficacy and Safety of PT009 Compared to PT005, PT008, 
and Open-label Symbicort® Turbuhaler®, as an Active Control, on 
Lung Function over a 24-Week Treatment Period in Subjects With 
Moderate to Very Severe COPD 
 
 
 
 
 


Statistical Analysis Plan 
Study:  PT009002 
11 December 2017 
(Page 1 of 139) 
STATISTICAL ANALYSIS PLAN FOR 
STUDY PT009002 
Protocol Number: 
PT009002-02 (Version 3.0) 
Investigational Drug 
and Drug Number: 
BFF MDI; PT009 
FF MDI; PT005 
BD MDI; PT008 
Symbicort® Turbuhaler® 
Indication: 
COPD 
Dosage Form/Dose: 
•
BFF MDI 320/9.6 μg BID
•
BFF MDI 160/9.6 μg BID
•
FF MDI 9.6 μg BID
•
BD MDI 320 μg BID
•
Symbicort® Turbuhaler® 400/12 μg BID
PT009002 Protocol Title: A Randomized, Double-Blind, Parallel Group, Multi-Center Study to 
Assess the Efficacy and Safety of PT009 Compared to PT005, PT008, and Open-label 
Symbicort® Turbuhaler®, as an Active Control, on Lung Function over a 24-Week Treatment 
Period in Subjects with Moderate to Very Severe COPD  
Date of Issue: 
11 Dec 2017 
Version: 
Version 1.1 




Statistical Analysis Plan 
Study:  PT009002 
11 December 2017 
(Page 3 of 139) 
Change Log 
Version No. 
Effective Date 
Reason for the Change / Revision 
Supersedes 
1.1 
11 Dec 2017 
Figures 7 and 8 (Type I error control charts for EU 
approach) were fixed to reflect that the non-
inferiority testing is performed using the Per 
Protocol Estimand. 
1.0 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
(Page 4 of 139) 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ..................................................................................................................................... 13 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................ 13 
2.1 
STUDY OBJECTIVES ............................................................................................................................ 13 
2.1.1 
Primary Objective ............................................................................................................... 13 
2.1.2 
Secondary Objectives ......................................................................................................... 13 
2.1.3 
Safety Objectives ................................................................................................................ 13 
2.1.4 
Healthcare Resource Utilization (HCRU) Objective .......................................................... 13 
2.1.5 
Pulmonary Lung Function (PFT) Sub-Study Objectives .................................................... 13 
2.2 
STUDY ENDPOINTS ............................................................................................................................. 14 
2.2.1 
Primary Efficacy Endpoints ................................................................................................ 14 
2.2.2 
Secondary Efficacy Endpoints ............................................................................................ 14 
2.2.3 
Other Efficacy Endpoints ................................................................................................... 15 
2.2.4 
Safety Endpoints ................................................................................................................. 16 
2.2.5 
Health Care Resource Utilization Endpoints ...................................................................... 16 
2.2.6 
12-hour Pulmonary Function Test Sub-Study Endpoints ................................................... 17 
3. 
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS ............................................................. 18 
3.1 
STUDY DESIGN ................................................................................................................................... 18 
3.1.1 
Overall Study Design and Plan ........................................................................................... 18 
3.1.2 
Prior, Concomitant, Post-Treatment, Prohibited Medications, and Other Restrictions ...... 20 
3.2 
HYPOTHESIS TESTING ........................................................................................................................ 20 
3.3 
INTERIM ANALYSIS ............................................................................................................................ 21 
3.4 
SAMPLE SIZE ...................................................................................................................................... 21 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE ........................................................................ 22 
5. 
ANALYSIS POPULATIONS ................................................................................................................... 22 
5.1 
POPULATION DEFINITIONS ................................................................................................................. 22 
5.1.1 
Intent-to-Treat (ITT) Population ......................................................................................... 22 
5.1.2 
Modified Intent-to-Treat (mITT) Population ...................................................................... 22 
5.1.3 
Rescue Ventolin User Population ....................................................................................... 23 
5.1.4 
Per-Protocol (PP) Population .............................................................................................. 23 
5.1.4.1 
Record-level Exclusion of PFT Data from the PP Population ........................... 24 
5.1.5 
Safety Population ................................................................................................................ 24 
5.2 
POPULATIONS FOR PRIMARY AND SENSITIVITY ANALYSES ................................................................ 24 
6. 
STATISTICAL ANALYSIS ..................................................................................................................... 25 
6.1 
DATA HANDLING RULES AND DEFINITIONS, INCLUDING HANDLING OF MISSING DATA .................... 25 
6.2 
SUBJECT DISPOSITION AND ANALYSIS POPULATIONS ........................................................................ 26 
6.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS AND EXTENT OF EXPOSURE................................. 27 
6.3.1 
Demography, Physical Characteristics, CAT ..................................................................... 27 
6.3.2 
COPD History, Screening/Baseline Spirometry, and Reversibility .................................... 28 
6.3.3 
Medical and Surgical History at Screening, Reproductive Status and Pregnancy Testing . 29 
6.3.4 
Prior, Concomitant, and Post-Treatment Medications/Treatments ..................................... 29 
6.3.5 
Extent of Exposure to Study Medication and Compliance ................................................. 30 
6.4 
EFFICACY ANALYSES ......................................................................................................................... 31 
6.4.1 
Estimands ........................................................................................................................... 31 
6.4.2 
Baselines and Baseline Covariates for Analysis ................................................................. 32 
6.4.3 
Primary Efficacy Analysis .................................................................................................. 33 
6.4.3.1 
Change from Baseline in Morning Pre-Dose Trough FEV1 .............................. 34 
6.4.3.2 
FEV1 AUC0-4 ..................................................................................................... 35 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
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6.4.3.3 
Assumptions Checks and Removal of Outliers in Sensitivity Analyses ............ 36 
6.4.3.4 
Sensitivity Analyses ........................................................................................... 36 
6.4.4 
Secondary Efficacy Analyses ............................................................................................. 39 
6.4.4.1 
Transition Dyspnea Index .................................................................................. 39 
6.4.4.2 
Peak Change from Baseline in FEV1 ................................................................. 41 
6.4.4.3 
St. George’s Respiratory Questionnaire ............................................................. 41 
6.4.4.4 
Rescue Ventolin HFA Use ................................................................................. 43 
6.4.4.5 
E-RS Total Score ............................................................................................... 45 
6.4.4.6 
Time to Onset of Action Assessed Using FEV1 on Day 1 ................................. 45 
6.4.4.7 
Time to First Moderate or Severe COPD Exacerbation ..................................... 46 
6.4.4.8 
Time to Clinically Important Deterioration ....................................................... 49 
6.4.5 
Other Efficacy Analyses ..................................................................................................... 49 
6.4.5.1 
Other Spirometry Endpoints .............................................................................. 49 
6.4.5.2 
Rate of COPD Exacerbations ............................................................................. 50 
6.4.5.3 
Time to Treatment Failure ................................................................................. 55 
6.4.5.4 
Time to Treatment Discontinuation for Any Cause ........................................... 55 
6.4.5.5 
Time to Death .................................................................................................... 55 
6.4.5.6 
Time to Sustained Clinically Important Deterioration ....................................... 56 
6.4.5.7 
European Quality-of-Life-5 Dimension-5 Level Questionnaire ........................ 56 
6.4.5.8 
12-Hour Pulmonary Function Tests ................................................................... 57 
6.4.6 
Subgroup Analyses ............................................................................................................. 58 
6.4.7 
Control of Type I Error ....................................................................................................... 58 
6.4.7.1 
US Approach ...................................................................................................... 59 
6.4.7.2 
EU Approach ..................................................................................................... 61 
6.4.8 
Correlation Analysis ........................................................................................................... 64 
6.5 
SAFETY ANALYSIS ............................................................................................................................. 64 
6.5.1 
Adverse Events ................................................................................................................... 64 
6.5.1.1 
Adverse Events of Special Interest .................................................................... 67 
6.5.1.2 
Major Adverse Cardiovascular Event (MACE) Determined by Clinical 
Endpoint Committee .......................................................................................... 69 
6.5.1.3 
Pneumonia Events Determined by Clinical Endpoint Committee ..................... 69 
6.5.1.4 
Cause of Death Determined by Clinical Endpoint Committee .......................... 69 
6.5.1.5 
Paradoxical Bronchospasms .............................................................................. 70 
6.5.2 
Clinical Laboratory Measurements ..................................................................................... 71 
6.5.3 
Vital Signs .......................................................................................................................... 74 
6.5.4 
12-Lead Electrocardiogram Measurements ........................................................................ 76 
6.5.5 
Healthcare Resource Utilization ......................................................................................... 77 
6.5.6 
Physical Examination ......................................................................................................... 79 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
(Page 6 of 139) 
 
7. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL .................................................... 79 
8. 
STATISTICAL SOFTWARE ................................................................................................................... 79 
9. 
REFERENCES .......................................................................................................................................... 80 
APPENDIX 1: DATA HANDLING RULES .................................................................................................... 82 
APPENDIX 2: ANALYSIS DATASET SPECIFICATIONS .......................................................................... 90 
APPENDIX 3: SAS CODE FOR STATISTICAL ANALYSES ..................................................................... 90 
APPENDIX 4: CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES AND CENTRAL 
LABORATORY REFERENCE RANGES FOR USE IN FLAGGING ABNORMAL VALUES .... 90 
APPENDIX 5: STANDARD MEDDRA QUERIES (SMQ) ............................................................................ 90 
APPENDIX 6: STATISTICAL DETAILS ....................................................................................................... 90 
APPENDIX 7: TABLE OF CONTENTS END-OF-TEXT TLFS .................................................................. 91 
APPENDIX 8: EQ-5D CROSSWALK SPSS AND SAS CODE FOR STATISTICAL ANALYSES OF 
INDEX SCORE ...................................................................................................................................... 139 
 
List of Tables 
 
Table 1 
Planned Sample Size .............................................................................................. 18 
Table 2      
Power Estimates ..................................................................................................... 21 
Table 3 
Analysis Study Time Window for Spirometry Assessments ................................. 33 
Table 4 
Sensitivity Analyses for Morning Pre-Dose Trough FEV1 and FEV1 AUC0-4 ..... 37 
Table 5 
Sensitivity Analyses for Time to First Moderate or Severe COPD Exacerbations 48 
Table 6 
Adverse Events of Special Interest ........................................................................ 67 
Table 7 
Lab Parameters....................................................................................................... 71 
Table 8 
Potentially Clinically Significant Laboratory Parameter Criteria .......................... 73 
Table 9 
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood 
Pressure Parameters ............................................................................................... 75 
Table 10 
Potentially Clinically Significant Criteria for Heart Rate Parameters ................... 75 
Table 11 
Analysis Study Time Windows for Vital Signs Assessments ................................ 76 
Table 12 
Criteria for PCS ECG Values................................................................................. 77 
 
List of Figures 
  
Figure 1 
Study Design .......................................................................................................... 20 
Figure 2  
Overarching Intervals of Moderate-or-Severe (QMS) and Severe (QS) COPD 
Exacerbations ......................................................................................................... 53 
Figure 3  
Overarching Intervals (I) of Mild-Moderate-or-Severe COPD Exacerbation Events 
Based on eDiary Symptom Data ............................................................................ 54 
Figure 4  
Overarching Intervals (QQ) of Mild-Moderate-or-Severe COPD Exacerbation 
Events Incorporating Both CRF Data and eDiary Symptom Data......................... 54 
Figure 5  
Group 1: Type I Error Control for the Analyses of the Primary Endpoints (US 
Approach) .............................................................................................................. 60 
Figure 6  
Group 2: The Analysis of the Secondary Endpoints (US Approach) .................... 61 
Figure 7  
Group 1: Type I Error Control for the Analyses of the Primary Endpoints (EU 
Approach) .............................................................................................................. 62 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
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Figure 8  
Group 2: The Analysis of the Secondary Endpoints (EU Approach) .................... 63 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
(Page 8 of 139) 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AR(1) 
Autoregressive order 1 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
Area under the curve 
AUC0-4  
Area Under the Curve From 0 to 4 Hours 
AUC0-12  
Area Under the Curve From 0 to 12 Hours 
BD 
Budesonide 
BDI 
Baseline Dyspnea Index 
BFF MDI 
Budesonide and Formoterol Fumarate Metered Dose Inhaler 
BID 
Bis in die, twice daily 
BPM 
Beats Per Minute 
BMI 
Body mass index 
CAT 
Chronic Obstructive Pulmonary Disease Assessment Test 
CCU 
Coronary care unit 
CCV 
Cardio- and cerebrovascular 
CD 
Compact disc 
CI 
Confidence Interval 
CID 
Clinically important deterioration 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration Equation (according 
to National Kidney Disease Education Program) 
cm 
Centimeter 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case Report Form 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
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CTCAE 
Common Terminology Criteria for Adverse Events 
δ 
Non-inferiority margin 
DMC 
Data monitoring committee 
E-RS 
Evaluating Respiratory Symptoms 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDiary 
Electronic Diary 
e.g. 
Exempli Gratia, For Example 
eGFR 
Estimated glomerular filtration rate 
EQ-5D 
EuroQol 5 Dimensions Questionnaire 
EQ-5D-5L 
EuroQol 5 Dimensions Questionnaire 5-level  
ER 
Emergency room 
EU 
European Union 
ex-actuator 
Dose delivered from the actuator (i.e., mouthpiece) of the MDI  
EXACT 
Exacerbations of Chronic Pulmonary Disease Tool – Patient Reported 
Outcomes 
FEV1 
Forced expiratory volume in 1 second 
FEF25-75 
Forced expiratory flow between 25% and 75% of FVC 
FF 
Formoterol Fumarate 
FVC 
Forced vital capacity 
H0 
Null Hypothesis 
H1 
Alternative hypothesis 
hCG 
Human chorionic gonadotropin 
HCRU 
Health Care Resource Utilization 
HFA 
Hydrofluoroalkane 
HLGT 
High Level Group Term 
HLT 
High Level Term 
ICF 
Informed consent form 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
(Page 10 of 139) 
 
ICS 
Inhaled corticosteroid 
ICU 
Intensive care unit 
ID 
Identification 
i.e. 
Id est; that is 
ITT 
Intent-to-treat 
IWRS 
Interactive web response system 
L 
Liter 
LABA 
Long-acting β2 agonist 
LAMA 
Long-acting muscarinic antagonist 
MACE 
Major adverse cardiovascular event 
MAR 
Missing at random 
MCAR 
Missing completely at random 
MCMC 
Markov chain Monte Carlo 
MCID 
Minimal clinically important difference 
MDI 
Metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MNAR 
Missing not at random 
µg 
Microgram 
mITT 
Modified intent-to-treat  
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeter of mercury 
msec (ms) 
Millisecond 
NHANES 
National Health and Nutrition Examination Survey 
OTC 
Over-the-counter 
PCS 
Potentially clinically significant 
PEFR 
Peak expiratory flow rate 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
(Page 11 of 139) 
 
PFT 
Pulmonary function test 
PMM 
Pattern mixture model  
PP 
Per-protocol 
PT 
Preferred Term 
PT005 
Formoterol Fumarate Inhalation Aerosol 
PT008 
Budesonide Inhalation Aerosol 
PT009 
Budesonide and Formoterol Fumarate Inhalation Aerosol 
QoL 
Quality of life 
QTcF 
QT corrected using Fridericia’s formula 
RM 
Repeated measures 
ROM 
Read-only memory 
SABA 
Short-acting β2-agonist 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SGRQ 
St. George’s Respiratory Questionnaire 
SMQ 
Standard MedDRA Query 
TBH 
Turbuhaler 
TC 
Telephone call 
TDI 
Transition Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual analog scale 
 
 
 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
(Page 12 of 139) 
 
Trademark Information 
Trademarks Not Owned By Pearl 
KoKo Spirometer® 
SAS® Software 
Symbicort® 
Ventolin® 
 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
(Page 13 of 139) 
 
1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary and 
analysis of data to be performed at the end of Pearl Therapeutics, Inc. (Pearl) Study PT009002. 
The SAP should be read in conjunction with the study protocol. This version of the SAP has 
been developed using the PT009002-02 Amended Protocol (Version 3.0 dated 24 October 2017) 
and the PT009002 case report form (CRF) (Version 01 dated 27 May 2016). 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
The overall objective is to assess the efficacy and safety of treatment with BFF MDI 320/9.6 μg 
(budesonide and formoterol fumarate metered dose inhaler), BFF MDI 160/9.6 μg, FF MDI 
9.6 μg (formoterol fumarate metered dose inhaler), BD MDI 320 μg (budesonide metered dose 
inhaler), and Symbicort® Turbuhaler® (TBH) 400/12 μg over 24 weeks in subjects with moderate 
to very severe chronic obstructive pulmonary disease (COPD).  
 
Primary Objective 
2.1.1
• To assess the effects of BFF MDI relative to FF MDI and BD MDI on lung function 
 
Secondary Objectives 
2.1.2
• To assess the effects of BFF MDI relative to FF MDI and Symbicort TBH on COPD 
exacerbations 
• To assess the effects of BFF MDI relative to FF MDI, BD MDI, and Symbicort® TBH on 
symptoms of COPD 
• To assess the effects of BFF MDI relative to FF MDI, BD MID, and Symbicort® TBH on 
quality of life (QoL) 
• To determine the time to onset of action on Day 1 
 
Safety Objectives 
2.1.3
• To assess the safety of BFF MDI, FF MDI, BD MDI, and Symbicort® TBH 
 
Healthcare Resource Utilization (HCRU) Objective 
2.1.4
• To assess overall and COPD-specific HCRU of BFF MDI relative to FF MDI, BD MDI, and 
Symbicort® TBH 
 
Pulmonary Lung Function (PFT) Sub-Study Objectives 
2.1.5
• To characterize forced expiratory volume in 1 second (FEV1) over 12 hours at Week 12 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
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2.2 
Study Endpoints 
The primary endpoints, treatment comparisons of interest, and analysis timeframes may differ by 
country or region due to local regulatory agency requirements. The Sponsor has defined two different 
registration approaches in this study. The registration approaches will be called: (1) United States 
(US) and (2) European Union (EU). The US approach is for countries or regions where the primary 
endpoints are generally evaluated at a point in time. The EU approach is for registration purposes in 
countries or regions where the primary endpoints are generally evaluated over a period of time. The 
multiplicity controls for the primary analyses are delineated by approach in section 6.4.7. 
 
Primary Efficacy Endpoints  
2.2.1
US APPROACH 
• Change from baseline in morning pre-dose trough FEV1 at Week 24 (BFF MDI versus FF 
MDI) 
• Change from baseline in FEV1 area under the curve from 0 to 4 hours (AUC0-4) at Week 24 
(BFF MDI vs BD MDI) 
 
EU APPROACH 
• Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI vs FF 
MDI; BFF MDI 320/9.6 μg vs Symbicort® TBH, non-inferiority) 
• Change from baseline in FEV1 AUC0-4 over 24 weeks (BFF MDI vs BD MDI; BFF MDI 
320/9.6 μg vs Symbicort® TBH, non-inferiority) 
 
Secondary Efficacy Endpoints 
2.2.2
US APPROACH 
• 
Percentage of subjects achieving an MCID of 4 units or more in Saint George’s Respiratory 
Questionnaire (SGRQ) total score at Week 24 (BFF MDI vs FF MDI; BFF MDI vs BD MDI) 
• Change from baseline in morning pre-dose trough FEV1 at Week 24 (BFF MDI vs BD MDI) 
• 
Peak change from baseline in FEV1 at Week 24 (BFF MDI vs BD MDI) 
• 
Change from baseline in average daily rescue Ventolin Hydrofluoroalkane (HFA) use over 24 
weeks (BFF MDI vs BD MDI) 
• 
Time to onset of action on Day 1 (BFF MDI vs BD MDI) 
• 
Time to first moderate or severe COPD exacerbation (BFF MDI vs FF MDI) 
 
EU APPROACH  
• Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI versus 
BD MDI) 
• 
Transition Dyspnea Index (TDI) focal score over 24 weeks (BFF MDI vs FF MDI; BFF MDI 
vs BD MDI; BFF MDI 320/9.6 μg vs Symbicort® TBH, non-inferiority) 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
(Page 15 of 139) 
 
• Percentage of subjects achieving an MCID of 4 units or more in SGRQ total score over 24 
weeks (BFF MDI vs FF MDI; BFF vs BD MDI; BFF MDI 320/9.6 μg vs Symbicort® TBH, 
non-inferiority) 
• Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF MDI 
vs BD MDI) 
• Peak change from baseline in FEV1 over 24 weeks (BFF MDI vs BD MDI) 
• Change from baseline in the Evaluating Respiratory Symptoms in COPD (E-RS: COPD) 
total score (RS-Total Score) over 24 weeks (BFF MDI vs FF MDI; BFF MDI vs BD MDI; 
BFF MDI 320/9.6 μg  vs Symbicort® TBH, non-inferiority) 
• Time to onset of action on Day 1 (BFF MDI vs BD MDI) 
• Time to first moderate or severe COPD exacerbation (BFF MDI vs FF MDI) 
• Time to clinically important deterioration (CID) (BFF MDI vs FF MDI) 
 
 
Other Efficacy Endpoints 
2.2.3
Unless already categorized as a secondary endpoint in one of the regulatory approaches above, 
all of the following endpoints will be categorized as “Other efficacy endpoints”, with the 
treatment comparisons of interest being BFF MDI vs FF MDI, BFF MDI vs BD MDI, and BFF 
320/9.6 μg MDI vs Symbicort® TBH (non-inferiority). 
DAY 1 ENDPOINTS 
• Change from baseline at each post-dose time point and in AUC0-4 for FEV1, forced vital 
capacity (FVC), peak expiratory flow rate (PEFR), and forced expiratory flow from 25% to 
75% (FEF25-75) 
• Proportion of subjects achieving an improvement from baseline in FEV1 using different 
thresholds (e.g., ≥10%, ≥12%, ≥15%, ≥100 mL, ≥200 mL; and ≥12% and ≥200 mL) 
ENDPOINTS OVER 24 WEEKS (Unless Otherwise Stated): 
• Rate of moderate or severe COPD exacerbations 
• Rate of COPD exacerbations of any severity 
• Time to treatment discontinuation for any cause 
• Time to treatment failure (treatment discontinuation for any cause, moderate or severe 
exacerbation, or death) 
• Time to CID 
• Time to sustained CID 
• Time to Death 
• Additional spirometry assessments over Weeks 12 to 24, over 24 weeks, and at each post-
randomization visit: 
o Change from baseline in morning pre-dose trough for FEV1, FVC, PEFR, and FEF25-75 
o Peak change from baseline within 4 hours in FEV1, FVC, PEFR, and FEF25-75 
o FEV1 AUC0-4, FVC AUC0-4, PEFR AUC0-4, and FEF25-75 AUC0-4 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
(Page 16 of 139) 
 
• Change from baseline in: the EXACT total score, the Evaluating Respiratory Symptoms 
in COPD (E-RS: COPD) Total Score (RS-Total Score), as well as 3 subscale scores 
(RS-Breathlessness, RS-Cough and Sputum, and RS-Chest Symptoms) over 24 weeks 
and over each 4-week interval of the 24-week Treatment Period  
• TDI focal score over Weeks 12 to 24, over 24 weeks, and at each post-randomization visit 
• Individual components of the TDI: functional impairment, magnitude of task, and magnitude 
of effort over Weeks 12 to 24, over 24 weeks, and at each post-randomization visit 
• Percentage of subjects achieving a minimal clinically important difference (MCID) threshold 
of 1 unit or more on average in TDI focal score over Weeks 12 to 24 and over 24 weeks 
• Changes from baseline over 24 weeks and 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, over 24 weeks, and at each post-randomization visit 
• Percentage of subjects achieving an MCID of 4 units or more in SGRQ total score at Week 
24, over Weeks 12 to 24, and over 24 weeks 
• Quality-of-Life Endpoints: European Quality-of-Life-5 Dimensions (EQ-5D-5L) 
Questionnaire scored at each post-randomization visit 
 
Safety Endpoints 
2.2.4
The safety endpoints for this study include: 
• Adverse events (AEs), Treatment-emergent AEs, Serious AEs (SAEs), AEs of special 
interest (AESIs) 
• 12-lead electrocardiograms (ECGs) 
• Clinical laboratory values (hematology and clinical chemistry) 
• Vital signs measurements (blood pressure and heart rate) 
 
Health Care Resource Utilization Endpoints 
2.2.5
• The number of days missed from work due to COPD 
• The number of days that primary caregivers of subjects missed from work as a result of the 
subject’s COPD 
• The percentage of subjects with telephone calls to health-care providers 
o Calls to any health-care provider (physician or other) 
o Calls to physician 
o Calls to other healthcare provider 
• The mean number of telephone calls to health-care providers 
o Calls to any health-care provider (physician or other) 
o Calls to physician 
o Calls to other healthcare provider 


 
Statistical Analysis Plan 
Study:  PT009002  
11 December 2017 
(Page 17 of 139) 
 
• The percentage of subjects with visits to health-care providers 
o Visits to any health-care provider (general practitioner [GP], specialist, or other) 
o Visits to GP 
o Visits to specialist 
o Visits to other health-care provider 
• The mean number of visits to health-care providers 
o Visits to any health-care provider (GP, specialist, or other) 
o Visits to GP 
o Visits to specialist 
o Visits to other health-care provider 
• The percentage of subjects with Emergency Room (ER) visits 
• The mean number of visits to ERs 
• The percentage of subjects hospitalized 
• The mean number of subject hospitalizations 
• The mean number of days in the hospital 
• The mean number of hospitalizations in which subjects spent some time in the Intensive Care 
Unit (ICU) or the Coronary Care Unit (CCU) 
• The percentage of subjects hospitalized with some time spent in the ICU or CCU 
• The mean number of days in the hospital with some time spent in the ICU or CCU 
• The mean number of hospitalizations in which subjects spent no time in the ICU or CCU 
• The percentage of subjects hospitalized with no time spent in the ICU or CCU 
• The mean number of days in the hospital with no time spent in the ICU or CCU 
• The mean number of days in ICU 
• The percentage of subjects in the ICU 
• The mean number of days in CCU 
• The percentage of subjects in the CCU 
• The percentage of subjects who required ambulance transport 
• The mean number of times ambulance transport was required 
 
12-hour Pulmonary Function Test Sub-Study Endpoints 
2.2.6
The assessments will provide PFT profiles over 12-hours post-dose at Week 12. 
Primary Endpoint: 
• FEV1 AUC0-12 
 


 
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Other Endpoints 
• Peak FEV1 
• FVC,  PEFR, and FEF25-75 will be evaluated using AUC0-12 and at peak 
 
3. 
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS 
3.1 
Study Design 
 
Overall Study Design and Plan 
3.1.1
This is a Phase III, multi-center, randomized, double-blind, parallel-group, chronic-dosing (24 
weeks), lung function study to assess the efficacy and safety of BFF MDI (320/9.6 µg and 
160/9.6 µg) compared to FF MDI 9.6 µg, BD MDI 320 µg and Symbicort® TBH as an open-
label active control, administered twice daily (BID), in subjects with moderate to very severe 
COPD. 
This study will be conducted at approximately 200 sites, contributing approximately 10 to 14 
subjects per site. Subjects meeting all inclusion criteria and no exclusion criteria will be 
randomized into this study. A total of 2420 subjects with moderate to very severe COPD will be 
randomized in a 3:3:3:1:1 scheme to one of the five treatment groups: 
• BFF MDI 320/9.6 µg BID (660 subjects) 
• BFF MDI 160/9.6 µg BID (660 subjects) 
• FF MDI 9.6 µg BID (660 subjects) 
• BD MDI 320 µg BID (220 subjects) 
• Symbicort® TBH 400/12 µg BID (open-label, 220 subjects) 
Approximately 1900 subjects are expected to complete the study. Randomization will be 
stratified by reversibility to Ventolin [(≥ 12% and 200 mL) or (< 12% or < 200 mL improvement 
over pre-bronchodilator FEV1), measured at Visit 2], post-bronchodilator FEV1 (< 50% or 50% 
to < 80% predicted, measured at Visit 2), blood eosinophil count (< 150 or ≥ 150 cells per mm3), 
and country. Enrollment will be targeted to achieve a 2:1 ratio for blood eosinophil strata with 
twice as many randomized subjects in the ≥ 150 cells per mm3 category. 
Table 1 
Planned Sample Size 
 
BFF MDI 
320/9.6 µg 
BFF MDI 
160/9.6 µg 
FF MDI 
9.6 µg 
BD MDI 
320 µg 
Symbicort® 
TBH 
400/12 µg 
Overall 
Allocation Ratio 
3 
3 
3 
1 
1 
 
Subjects Enrolled 
660 
660 
660 
220 
220 
2420 


 
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Subjects 
Completing the 
Study 
518 
518 
518 
173 
173 
1900 
 
Subjects who discontinue randomized treatment prior to Week 24 (Visit 9) will be encouraged to 
remain in the study to complete all remaining study visits during the 24 week treatment period. 
Subjects who agree to continue to be followed post treatment discontinuation will sign an 
informed consent form (ICF) addendum. All subjects who agree to continue study participation 
beyond treatment discontinuation will complete a Treatment Discontinuation/Withdrawal Visit 
prior to transitioning back to regularly scheduled study visits. Subjects participating in the sub-
study who discontinue randomized treatment will only complete regularly scheduled visits and 
not complete any remaining sub-study assessments. Subjects who discontinue randomized 
treatment will be returned to appropriate maintenance COPD medications, per the investigator’s 
discretion. 
If a subject chooses not to continue with study assessments, at a minimum the subject will complete 
the Treatment Discontinuation/Withdrawal Visit (refer to the Schedule of Events in the Study 
Protocol). These subjects will return to appropriate maintenance COPD medications, per the 
investigator’s discretion. A follow-up telephone call will be performed at least 14 days after the last 
study drug dose. In the event the Treatment Discontinuation/Withdrawal Visit is performed >14 days 
post last study drug dosing, a follow-up telephone call (TC) will not be required. These subjects will 
be followed for vital status at 24 weeks post randomization in accordance with the informed consent. 
Sub-Study 
12-Hour Pulmonary Function Test Sub-study: Serial PFTs will be conducted over 12 hours in 
a subset of approximately 510 randomized subjects (153 subjects from each of BFF MDI arms 
and the FF MDI arm, and 51 subjects from the BD MDI arm) at Week 12 (Visit 6) only. On the 
test day, additional serial spirometry will be obtained at 6, 8, 10, 11.5 and 12 hours post-dose. 
The Schedules of Events and Timed Assessments are in the study protocol. 
The overall study design is summarized and illustrated in Figure 1. 
 


 
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Figure 1 
Study Design 
 
 
Prior, Concomitant, Post-Treatment, Prohibited Medications, and Other 
3.1.2
Restrictions 
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 electronic CRF 
(eCRF). All concomitant medications taken during the study will be recorded on the 
Concomitant Medications eCRF page with indication, total daily dose, dose regimen, and dates 
of drug administration. Refer to the Protocol for information about prohibited medications. 
3.2 
Hypothesis Testing 
For the primary comparisons, the general null hypothesis for each pair-wise comparison to a BFF 
MDI mono-component will be that the mean treatment difference is zero (mean treatment effects 
are equal). The alternative two-sided hypothesis is that the mean treatment difference is greater 
or less than zero (mean treatment effects are not equal). The primary comparisons of BFF MDI 
320/9.6 µg to Symbicort® TBH will be for non-inferiority and will use a margin (δ) of 50 mL for 
morning pre-dose trough FEV1 and a margin of 75 ml for FEV1 AUC0-4. P-values will be 
reported as 2-sided.  
The primary null (H0) and alternative (H1) hypotheses, with µ representing the mean, are 
presented below. The superiority hypotheses will take the following forms depending on the 
control group: 
• H0: µBFF xxx/9.6  = µFF 9.6 
H1: µBFF xxx/9.6  ≠ µFF 9.6 


 
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• H0: µBFF xxx/9.6   = µBD 320 
H1: µBFF xxx/9.6   ≠ µBD 320 
The non-inferiority hypotheses will take the following forms: 
• H0: µSymbicort - µBFF 320/9.6 ≥ δ 
H1: µSymbicort - µBFF 320/9.6 < δ 
Where δ will be 50 or 75 mL. Two-sided 95% confidence interval (CI) for µSymbicort - µBFF will 
be computed. If the upper bound is observed to be less than δ, non-inferiority of BFF MDI 
320/9.6 μg relative to Symbicort® TBH will be declared. 
Secondary and other efficacy analyses will involve the above hypotheses applied to secondary 
efficacy endpoints. The directionality of the non-inferiority hypotheses will be reversed for E-RS 
total score. The non-inferiority margins will be set to 0.75 for TDI, 10% for achievement of 
MCID in SGRQ, 75 mL for peak change from baseline in FEV1, and -1.5 for E-RS total score. 
3.3 
Interim Analysis 
No interim efficacy analyses are planned for this study. 
The Data Monitoring Committee (DMC) will review safety data approximately every 6 months. 
Further detail is given in the DMC Charter.  
3.4 
Sample Size 
It is estimated that a sample size of 2420 subjects (660 per arm in the BFF MDI and FF MDI 
groups and 220 per arm in the BD MDI and Symbicort® TBH groups) will provide power 
estimates as summarized in Table 2. All calculations assume Type I error control at a 2-sided 
alpha level of 0.05 and 20% dropout rate. 
Table 2      
Power Estimates 
Endpoint 
Assumed Difference 
At Week 24 
(US) 
Over 24 Weeks 
(EU) 
Trough FEV1 BFF - FF = 40 mL 
90% 
99% 
Symbicort® - BFF = 0 mL * 
 
96% 
AUC0-4 
FEV1 
BFF - BD = 100 mL 
99% 
99% 
Symbicort® - BFF = 0 mL * 
 
99% 
* Non-inferiority comparisons using the margins of δ = 50 mL for the pre-dose trough FEV1 and δ = 75 mL 
for AUC0-4 FEV1. 


 
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Assumptions regarding variability for the primary endpoints are based on Pearl’s experience with 
Phase IIb and III clinical studies. A standard deviation (SD) of 200 mL for the change from 
baseline at each visit has been assumed for trough FEV1 and 220 mL for FEV1 AUC0-4. Based 
on the repeated measures analysis and anticipated dropout of approximately 20%, an effective 
SD for the change over 24 weeks of 157 mL and 200 mL for trough FEV1 and FEV1 AUC0-4, 
respectively, is assumed. For Weeks 12 to 24, an effective SD for the change in trough FEV1 of 
175 mL is assumed. 
The non-inferiority margin of 50 mL for the evaluation of pre-dose trough FEV1 represents the 
approximate anticipated treatment effect in this endpoint. The non-inferiority margin of 75 mL 
for the evaluation of FEV1 AUC0-4 represents a value less than the anticipated treatment effect in 
this endpoint. 
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. 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) to Everest Clinical 
Research will be defined in the iCardiac DMP (Data Management Plan), and data handling rules 
related to this data are included in Appendix 1 of this SAP. The quality of all PFT’s obtained at 
each time point will be graded independently at iCardiac by qualified personnel. Quality grading 
assessments will be based on American Thoracic Society (ATS)/ERS criteria and will be 
included in data transfers. 
5. 
ANALYSIS POPULATIONS 
5.1 
Population Definitions 
 
Intent-to-Treat (ITT) Population 
5.1.1
The Intent-To-Treat Population is defined as all subjects who are randomized to treatment and 
receive any amount of the study treatment. Subjects will be analyzed according to the treatment 
they were assigned at randomization. Data obtained after discontinuation of treatment, but prior 
to withdrawal from the study, will be included. The ITT population will be used for sensitivity 
analyses. 
 
Modified Intent-to-Treat (mITT) Population  
5.1.2
The Modified Intent-to-Treat Population is a subset of the ITT Population, defined as all 
subjects with post-randomization data obtained prior to discontinuation from treatment. Any data 
collected after completion of or discontinuation from randomized study medication will be 
excluded from the mITT analysis but will still be included in the ITT analysis. Subjects will be 


 
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analyzed according to randomized treatment group. (Note that a subject who used a study 
treatment, but took less than one full daily dose of treatment will qualify for this population). The 
mITT Population will be the primary population for all efficacy analyses except for the non-
inferiority analyses. Note: The knowledge that a subject did not have a COPD exacerbation 
constitutes an efficacy assessment. 
 
 
Rescue Ventolin User Population 
5.1.3
Differences in rescue Ventolin HFA usage are expected across the study with some subjects 
using virtually no rescue medication at study entry. In order to represent the population of 
patients who may benefit from study treatment and reduce their use of rescue medication, the 
Rescue Ventolin User (RVU) Population is defined as all subjects in the ITT Population with 
average baseline Rescue Ventolin use of ≥ 1 puff/day. 
 
Per-Protocol (PP) Population 
5.1.4
The Per-Protocol 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 or discontinuation from treatment will be excluded. Since receiving the 
wrong treatment is a major protocol deviation, subjects in the PP population will be analyzed as 
randomized (which for this population is identical to analysis by actual treatment received). Any 
evaluability criteria with a potential impact on the primary 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 time point and/or subsequent time 
points for an endpoint. The PP Population will be the main population for all non-inferiority 
analyses. 
 
Protocol deviations and criteria for exclusion from the PP Population will be established at the 
blinded data review meeting (BDRM) prior to database lock. Reasons for exclusion from the PP 
Population will include, but are not limited to, the following: 
• An incorrect diagnosis of COPD. 
• Subjects who do not have an established clinical history of COPD and severity, where an 
established clinical history of COPD and severity is to be identified at the BDRM. 
• CAT < 10 at Screening (Visit 1). 
• Subjects who do not meet protocol-specified FEV1 baseline stability criteria. FEV1 baseline 
stability is defined as the average of the -60 minute and -30 minute pre-dose FEV1 
assessments at Visit 3 being within ±20% or 200 mL of the pre-bronchodilator FEV1 
assessments obtained at Visit 2. 


 
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5.1.4.1 
Record-level Exclusion of PFT Data from the PP Population 
PFT records are excluded from the PP population under the following conditions: 
• For subjects who take any protocol-prohibited medication that would affect PFT assessments 
on the date of an assessment, PFT measurements taken at that assessment will be excluded 
from the PP population. 
• For those subjects who require rescue Ventolin HFA less than 6 hours before study visit, or 
who take any dose of rescue Ventolin HFA during the visit, all spirometry data post-Ventolin 
HFA administration will be considered missing for that day for the PP population. 
• Subjects have to meet three restriction criteria prior to spirometry: (1) subject was not to 
smoke for at least 4 hours prior to study visit and throughout the duration of each study visit, 
(2) subject was not to use xanthine-containing products (i.e., coffee, tea, cola and chocolate) 
for at least 6 hours prior to and for the duration of each in-clinic study visit, and (3) subject 
was not to have COPD bronchodilator medications for at least 6 hours prior to study visit. 
For subjects who fail to meet any of the restriction criteria, PFT data at the affected visits will 
be removed from the PP population. Such restrictions will be applied only if data pertaining 
to these criteria (including the timing) were collected. 
• Subjects who did not take the evening dose of study medication on the day prior to a visit 
will have their PFT data excluded from the PP population for that visit. 
 
Safety Population 
5.1.5
The Safety Population is defined as all subjects who are randomized to treatment and receive 
any amount of the study treatment. 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. Subjects 
receiving no study treatment will be excluded, as will subjects who have no post-dose safety 
assessments. A subject who used a study treatment, but took less than 1 full daily dose of 
treatment will qualify for this population. Note: the statement that a subject had no AEs also 
constitutes a safety assessment. 
 
5.2 
Populations for Primary and Sensitivity Analyses 
Demographics will be summarized for the mITT, PP, RVU, Safety, and Non-Randomized 
Populations, as well as for subjects participating in the 12-hr PFT sub-study. 
Extent of exposure will be summarized for the Safety Population. The Safety Population will be 
used to summarize safety and healthcare resource utilization. 
Efficacy analyses will be performed for the ITT, mITT, and PP Populations. The mITT 
Population will be considered the primary population for the efficacy analyses, with the ITT and 
PP populations being considered supportive with several exceptions. The ITT Population will be 
used as primary for some efficacy analyses (e.g., time to death), and the PP Population will be 


 
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considered primary for the non-inferiority comparisons of BFF MDI 320/9.6 μg vs. Symbicort® 
TBH. Rescue medication endpoints will be analyzed with mITT, ITT, PP, and RVU populations. 
6. 
STATISTICAL ANALYSIS 
Analyses will be performed when the final database is available. All data collected contributing 
to the analysis will be provided in listings. 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. 
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 
normality or non-normality distribution of underlying data. 
Categorical variables will be summarized with frequency counts and percentages (where 
appropriate). 
6.1 
Data Handling Rules and Definitions, Including Handling of Missing Data 
Missing data will be maintained as missing in the analysis datasets, unless specified otherwise. 
For variables where missing data are imputed, the analysis dataset will contain a new variable 
with the imputed value and the original variable value will be maintained as missing. 
Data Imputation for Adverse Events Summaries by Severity and Relationship to Study Drug 
For the AE summaries by severity (mild, moderate, or severe), 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 related. Imputed values will not be listed in data 
listings. 
Data Imputation for Laboratory, Vital Sign, and ECG Summaries (Continuous Parameters) 
Data from unscheduled visits will not be used for by-visit summaries. Data from both scheduled 
and unscheduled visits will be used for shift tables and for determining incidence of clinically 
significant values. 
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. 


 
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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. 
Pre-dose spirometry values will use the average of the non-missing -60 minutes and -30 minutes 
values. Weekly averages for eDiary-based parameters (where eDiary means electronic diary) will 
use all non-missing values. 
On-treatment COPD exacerbations 
An exacerbation will be considered “on-treatment” if its start date is before or on the last 
treatment date. For treatment discontinuations, this definition is extended to include 
exacerbations starting one day after the last treatment date. (If it is decided during a clinic visit to 
discontinue study drug and to switch to a treatment for the ongoing exacerbation symptoms, the 
subject typically would not take the morning dose of study drug at that visit, and their 
exacerbation start date will be one day after the last treatment date. Such exacerbations will still 
be considered “on-treatment”). 
6.2 
Subject Disposition and Analysis Populations 
Disposition for all randomized subjects will be tabulated (Table 1.1.1) and listed (Listing 1.2). 
The tabulation will include the number of subjects in each randomized treatment who were not 
treated, who received the study treatment, who discontinued treatment prematurely, who 
withdrew from the study prematurely, and who completed the study. The number and percentage 
of randomized subjects included in the mITT, PP, RVU, Safety, and 12-hr PFT Sub-study 
Populations will also be tabulated (Table 1.1.1). Informed consent is listed in Listing 9.6. 
The numbers of subjects randomized and in the analysis populations will be provided by country, 
center, and treatment in Table 1.1.2. The number of subjects randomized by stratification factor 
and cross-classification of reversibility to Ventolin HFA and disease severity will be tabulated in 
Table 1.1.4. 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 also 
be listed (Listing 1.3). A list of subjects with discrepant IWRS-based and actual stratification 
factors will also be provided (Listing 1.7).  
A summary of reasons subjects were not randomized will be provided for all subjects not 
randomized (Table 1.1.3). A listing of reasons subjects were not randomized will also be 
provided (Listing 1.4). Subjects excluded from the ITT, mITT, PP, RVU, and Safety analysis 
populations will be listed (Listing 1.6) for all subjects randomized. Reasons for premature 
discontinuation from study treatment will be summarized for the Safety Population (Table 1.2.1). 
Similarly, reasons for subjects’ withdrawal from the study will be summarized for the ITT 
Population (Table 1.2.2). 


 
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Time to discontinuation of treatment and withdrawal from the study will be presented 
graphically by means of the Kaplan-Meier plots (Tables and Figures 1.2.3 and 1.2.4). 
The reason for exclusion from the PP Population will be tabulated by study treatment for all 
mITT subjects (Table 1.3.1). A listing of subjects who did not comply with restrictions on 
smoking, use of rescue medication, and xanthine-containing products (protocol deviations 
requiring removal of data from the PP Population analysis) prior to spirometry (Section 5.1.4.1) 
will be provided in Listing 6.1.1. Use of rescue medication at pre-dose or during the post-dose 
assessments on each specific test day (yes/no), will be tabulated 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, by visit and overall during the study in 
Table 1.13 (Safety Population) and listed (Listing 1.5). 
6.3 
Demographic and Baseline Characteristics and Extent of Exposure 
The definitions for the derived demographic or baseline characteristic variables can be found in 
Appendix 1. 
 
Demography, Physical Characteristics, CAT 
6.3.1
Subject demographics, total CAT score, use of inhaled corticosteroids (ICSs) at screening, and 
smoking status/history will be summarized for the mITT, RVU, PP, and Safety Populations and 
for Non-Randomized subjects (Tables 1.4.1 through 1.4.5, respectively, and Listing 1.2). The 
ITT population does not need to be tabulated because it is the same as the mITT population for 
demographics and baseline characteristics. If the Safety Population has the same treatment 
assignment as the mITT, then these summaries will be identical as well and hence not produced. 
Inhaled corticosteroid use (yes/no) will be summarized for all populations except for the Non-
Randomized subjects. Demographics will also be summarized for the subjects in the 12-hr PFT 
sub-study (the 12-hr PFT mITT Population) (Table 1.4.6). 
Demographic and baseline characteristic variables summarized will include the following: 
• Age 
• Age Group 
• Age of onset of COPD 
• Gender 
• Race 
• Ethnicity (Hispanic or Non-Hispanic) 
• COPD Assessment Test (CAT) total score and total score category (<10, ≥10, <15, ≥15, <20, 
≥20, Missing) 
• Used inhaled corticosteroids at Screening (all populations except for Non-Randomized 
subjects) 


 
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• Baseline eosinophil count (<150 cells per mm3 vs.  ≥150 cells per mm3) 
• Baseline exacerbation history (Group as 0, 1, and ≥2) 
• Smoking status (current vs. former smoker) 
• Number of years smoked 
• Average number of cigarettes smoked per day 
• Number of pack years smoked, calculated as (number of cigarettes per day/20) x number of 
years smoked 
• Weight 
• Height 
• Body mass index (BMI) 
Screening and pre-treatment CAT data will be listed (Listing 4.2).  
 
COPD History, Screening/Baseline Spirometry, and Reversibility 
6.3.2
Duration of COPD, 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 by treatment and all subjects for the mITT and 
Safety Populations and listed (Tables 1.5.1, 1.5.2 and Listing 4.1). A summary for the Safety 
Population will only be performed if the Safety Population is different from the mITT/ITT 
Population. Severity of COPD at Screening Visit 2 post-Ventolin HFA will also be included in 
these summaries. History of moderate or severe COPD exacerbations within the past 12 months 
will be summarized and listed for subjects in the Safety and mITT Populations (Tables 1.9.1, 
1.9.2, and Listing 4.3). 
Descriptive statistics will be provided for screening period pre-bronchodilator and 
post-bronchodilator and baseline spirometry parameters (Tables 1.6.1 to 1.6.4 for the mITT, PP, 
RVU, and 12-hr PFT Sub-study Populations, respectively, and Listing 2.2). 
Characterization of Reversibility: 
Reversibility to Ventolin HFA will be evaluated at Visit 2 and used as a stratification variable at 
randomization to ensure an even distribution of reversibility across the treatment arms. A subject 
is considered reversible if the improvement in FEV1 at 30 minutes post-Ventolin is ≥ 12% and ≥ 
200 mL. 
Reversibility to Ventolin HFA at Screening Visit 2 will be summarized for the mITT and 12-hr 
PFT Sub-study Populations and listed (Tables 1.7.1, 1.7.2, Listing 2.2 and Listing 5.2 for 
Ventolin HFA dispensing). The number and percentage of subjects reversible will be included in 
these summaries. Also included will be a summary of the change in FEV1 from pre-dose FEV1 
to post-bronchodilator assessment. If multiple time points are available post-bronchodilator, then 
the one with the highest FEV1 will be used. 


 
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Additionally, the number and percentage of subjects meeting each of the following response 
criteria will be summarized for Ventolin HFA bronchodilator: 
• ≥12% improvement post-bronchodilator in FEV1 from pre-bronchodilator 
• ≥150 mL improvement post-bronchodilator in FEV1 from pre-bronchodilator 
• ≥200 mL improvement post-bronchodilator in FEV1 from pre-bronchodilator 
 
Medical and Surgical History at Screening, Reproductive Status and Pregnancy 
6.3.3
Testing 
Medical and Surgical History at Screening will be summarized for the Safety Population and 
listed for all randomized subjects (Table 1.8.1.1 and Listing 4.4). Cardiovascular medical history 
of interest at Screening will be summarized for the Safety Population and listed for all 
randomized subjects (Table 1.8.1.2 and Listing 4.5). 
Screening Reproductive Status and Pregnancy Testing Results will be listed (Listing 4.6). 
 
Prior, Concomitant, and Post-Treatment Medications/Treatments 
6.3.4
All prescription and OTC medications taken by the subject during 30 days before Screening and 
all concomitant therapy taken by the subject while on study will be recorded on the Prior and 
Concomitant Medications case report form (CRF) page. 
Coding: Verbatim medication/treatment terms will be coded by Everest Clinical Research and 
will be assigned a preferred term and an ATC (anatomic therapeutic class) term using the latest 
version of the World Health Organization Drug Dictionary (WHO-DD) available (version: 
3Q2016 or later). 
Multiple ATC assignments: If there are multiple ATC codes assigned to the same 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 after 
the start of the randomized study treatment in the study to the date prior to the last dose of study 
treatment for the subject. A medication with an onset date on or after the date of discontinuation 
from or completion of randomized study treatment for the subject will not be considered 
concomitant, but will be considered a Post-Treatment medication/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, COPD-Exacerbation, and Non-COPD related medications/treatments will 
be summarized by preferred term and actual treatment received for the Safety Population (Tables 
1.11.1 to 1.11.3). COPD-related summaries will not include the COPD-exacerbation 
medications. Prior, concomitant/post-treatment COPD, COPD-Exacerbation, and Non-COPD 
medications will be displayed in separate listings (Listings 4.7 to 4.9, respectively). 
Reported prior medications for COPD, COPD-Exacerbation, and non-COPD-related medications 
will be tabulated for the Safety Population (Tables 1.10.1 to 1.10.4) and listed separately 
(Listings 4.7 to 4.9, respectively). 
Prior COPD Medications will be tabulated (for the Safety population) for subjects having 
received any one, two, all three, or none of the following treatments (whether in fixed 
combination products or separately): (1) a muscarinic antagonist, (2) a β2 agonist, and (3) an 
inhaled corticosteroid (Table 1.10.2). For this purpose, scheduled SAMA (Short-acting 
muscarinic antagonist) or SABA treatments are included. In addition, tabulations for long-acting 
muscarinic antagonists (LAMA) and long-acting β2 agonists (LABA) will also be included. 
Post-treatment medications will be tabulated for subjects having received any one, two, all three, 
or none of the following treatments: (1) a muscarinic antagonist, (2) a β2 agonist, and (3) an ICS 
(Table 1.11.2). 
 
Extent of Exposure to Study Medication and Compliance 
6.3.5
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 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 is the last date of treatment will be 2, and 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 but will be 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 will be summarized for each treatment for the 
Safety Population. 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). In addition, treatment compliance will be provided in this summary. 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%. 
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 5.3. A listing of treatment dosing and dispensing information will be 
provided in Listing 5.1. Any comments related to study medication or any other additional study 
comments will be listed (Listing 9.6). 


 
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6.4 
Efficacy Analyses 
 
Estimands 
6.4.1
Four estimands of interest are defined for this study: efficacy estimand, attributable estimand, 
treatment policy estimand, and per protocol estimand. 
The primary estimand of interest is the efficacy estimand and is the effect of the randomized 
treatment in all subjects assuming continuation of randomized treatments for the duration of the 
study regardless of actual compliance. The primary analysis for the efficacy estimand will be 
conducted using the mITT Population where only data obtained prior to subjects discontinuing 
from randomized treatment will be utilized. This assumes that efficacy observed on treatment is 
reflective of what would have occurred after discontinuation of randomized treatment had they 
remained on treatment. 
The attributable estimand is the effect of treatment in subjects attributable to the randomized 
treatment. For this estimand, discontinuation of randomized medication for reasons such as 
tolerability or lack of efficacy is considered a bad outcome. Analyses of the attributable estimand 
will be conducted using the mITT Population. Data that are missing due to treatment 
discontinuation will be imputed based on the 5th or 95th percentile of the reference arms’ 
distribution if the reason is reasonably attributable to tolerability or lack of efficacy. The 5th 
percentile applies to an endpoint for which a higher value is a better outcome; however the 95th 
percentile applies to an endpoint for which a higher value is a worse outcome. For this purpose, 
FF MDI and BD MDI are considered the reference arms. The estimated average of the two 
reference means will be used. Other missing data are to be imputed using the observed data 
model, i.e. assumed to be missing at random (MAR). The number of imputations used for the 
derivation of the attributable estimand will be between 100 and 1000. More detail about the 
computation of the attributable estimand will be provided in subsequent sections (especially 
6.4.3.1) and in the Details Appendix of this SAP. 
Treatment discontinuations reasonably attributable to tolerability or lack of efficacy will be 
identified during the BDRM and documented in the BDRM minutes prior to unblinding. 
Discontinuations will be attributed to tolerability if the subject had an adverse event determined 
by the investigator to be related to study drug, and for which study drug was permanently 
discontinued. Discontinuations will be attributed to lack of efficacy if ‘lack of efficacy’ is 
indicated to be the primary reason for discontinuation from study drug. For the remaining 
discontinuation categories, where specific reasons or criteria frequently need to be considered, 
decisions will be made and documented at the BDRM. 
The treatment policy estimand is the effect of randomized treatment over the study period 
regardless of whether randomized treatment is continued. Analyses of the treatment policy 
estimand will be conducted using the ITT Population, in which all observed data will be utilized 
regardless of whether subjects remain on randomized treatment. 
The per protocol estimand is the effect of treatment on subjects who are compliant with the 
protocol (i.e., no major protocol deviations), including the use of randomized medication.  


 
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Analysis of this estimand will use the PP Population.  Exclusions from the PP Population will be 
finalized at the BDRM prior to database lock and recorded in the meeting minutes.   
There are five pairwise comparisons of treatments of interest, namely, BFF MDI (2 doses: 
320/9.6 µg and 160/9.6 µg) vs. FF MDI, BFF MDI (2 doses: 320/9.6 µg and 160/9.6 µg) vs. BD 
MDI, and BFF MDI 320/9.6 µg vs. Symbicort® TBH. Estimation results will be provided by 
randomized treatment and for each treatment difference for all comparisons, in each estimand. 
All comparisons will be performed for testing superiority except that the comparison of BFF 
MDI 320/9.6 μg to Symbicort® TBH will be for non-inferiority. Non-inferiority analyses will use 
the per protocol estimand, unless specifically stated otherwise. 
 
Baselines and Baseline Covariates for Analysis 
6.4.2
The mean of all evaluable 60- and 30-minute pre-dose spirometry assessments conducted at 
Day 1 (Visit 3) will be used to establish baseline for all FEV1, FVC, FEF25-75, and PEFR 
parameters. 
For the diary symptom score parameters and rescue medication usage, baseline will be the 
average of the non-missing values from the 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 randomized study treatment. 
For COPD exacerbation history, baseline is whether the subject had a moderate-or-severe COPD 
exacerbation (Yes/No) in the last 12 months prior to Visit 1 (from the Visit 1 CRF page). 
ICS use at screening (Yes or No) is to be defined as follows - a subject will be considered to 
have had “ICS Use at Screening” if: 
• the subject was taking a medication that contained a glucocorticoid component (active 
ingredient) that is listed in the WHODRUG SDG (standardized drug grouping) of 
“CORTICOSTEROIDS”, and 
• the route of administration was “INHALED”, and 
• the medication was used at any time during the screening period (or in the 30 days prior to 
the screening period). 
Baseline blood eosinophil count is the average of non-missing blood eosinophil count values 
prior to the first dose of study medication. 
Baseline age is the age in years at the time of Informed Consent. 
Baseline post-bronchodilator FEV1 is the highest available value of FEV1 obtained after dosing 
with Ventolin at Visit 2. 


 
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Baseline percent reversibility to Ventolin is 100 x (POST-PRE)/PRE, where PRE is the mean of 
the available 30 minute and 60 minute values of FEV1 prior to dosing with Ventolin at Visit 2, 
and POST is the post-bronchodilator FEV1 value defined above. 
Visits and Time Windows for Visit-Based Efficacy Assessments: 
Efficacy data obtained during unscheduled visits will not be used for any of the pre-defined 
efficacy analyses. Efficacy from scheduled and unscheduled visits will be listed. 
For efficacy analysis based on time points, the change from baseline in PFT assessments will be 
allocated to derived nominal collection time windows using the time intervals specified below. 
Table 3 
Analysis Study Time Window for Spirometry Assessments 
Calculated 
Study Time Window 
Time Interval for the Study 
Time Window 
Pre-dose 60 min. 
≥45 minutes prior to dose 
Pre-dose 30 min. 
≥0 to <45 minutes prior to dose 
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 to 179 min. post-dose 
Post-dose 4 hrs. 
3 to <5 hrs. post-dose 
Post-dose 6 hrs. 
5 to <7.5 hrs. post-dose 
Post-dose 8 hrs. 
7.5 to <9 hrs. post-dose 
Post-dose 10 hrs. 
9 to <10.75 hrs. post-dose 
Post-dose 11.5 hrs. 
10.75 to <11.75 hrs. post-dose 
Post-dose 12 hrs. 
11.75 to < 14 hrs. post-dose, but 
must be prior to any subsequent 
dose of study medication or 
maintenance medication. 
Note: The minutes are rounded to the nearest whole number 
before applying time windows. 
If there are multiple spirometry values for the same parameter within the same post-baseline 
study time window on the same day, the last value will be chosen for analysis. 
 
Primary Efficacy Analysis 
6.4.3
Analyses will be conducted on the efficacy estimand, on the attributable estimand, on the 
treatment policy estimand, and on the per protocol estimand. The primary analyses of the 
efficacy, treatment policy, and per protocol estimands use only observed data. The attributable 


 
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estimand will use the mITT Population but then impute missing data as described in section 
6.4.1. 
6.4.3.1 
Change from Baseline in Morning Pre-Dose Trough FEV1 
Change from baseline in morning pre-dose trough FEV1 is the primary endpoint in the US 
approach (BFF vs. FF at Week 24) and the EU approach (BFF vs. FF and non-inferiority of BFF 
320/9.6 μg vs. Symbicort® over 24 weeks). It is also a secondary endpoint in the US approach 
(BFF vs. BD at Week 24) and the EU approach (BFF vs. BD over 24 weeks). 
Change from baseline in morning pre-dose trough FEV1 at each visit is defined as the average of 
the 60 and 30 minute pre-dose values minus baseline. In subjects missing either of these pre-dose 
assessments, the value will be calculated from the single measurement. In subjects missing both 
pre-dose values, morning pre-dose trough FEV1 at that visit will not be calculated. Spirometry 
data from unscheduled visits will not be used for this analysis. Assessments obtained during 
early termination visits will be used if their timing is consistent with the next scheduled 
collection of spirometry data. 
The change from baseline in morning pre-dose trough FEV1 will be analyzed using a repeated 
measures (RM) linear mixed model. The model will include treatment, visit, and treatment by 
visit interaction, and ICS use at Screening as categorical covariates and baseline FEV1, baseline 
blood eosinophil count, and percent reversibility to Ventolin HFA as continuous covariates. An 
unstructured covariance (UN) matrix will be used to model correlation within a subject. If the 
UN model fails to converge, then a first-order autoregressive (AR(1)) structure will be used 
instead. In the AR(1) model, subject will be included as a random effect. 
Contrasts will be used to obtain estimates of the treatment differences at Week 24, over weeks 12 
to 24, over 24 weeks, and at each post-randomization visit. Two-sided p-values and point 
estimates with two-sided 95% CIs will be produced for each treatment difference. 
The primary analysis will be conducted for the efficacy estimand. The analysis of the primary 
endpoints with the attributable estimand is considered secondary. Analyses will be also 
conducted for the treatment policy and per protocol estimands as supportive except for the non-
inferiority comparisons of BFF MDI 320/9.6 µg vs. Symbicort® TBH, for which the per protocol 
estimand will be primary (Table 2.1.1 and Figure 2.1.1 for the efficacy estimand, Table 2.1.2 and 
Figure 2.1.2 for the attributable estimand, Table 2.1.3 and Figure 2.1.3 for the treatment policy 
estimand, Table 2.1.4 and Figure 2.1.4 for the per protocol estimand). All comparisons will be 
for superiority except that the comparison of BFF MDI 320/9.6 µg to Symbicort® TBH will be 
for non-inferiority and will use a margin of 50 mL. 
For the attributable estimand (for the analysis at Week 24 and the analysis over 24 weeks), 
multiple imputation for missing values for morning pre-dose trough FEV1 will use mean changes 
from baseline based on the 5th percentile of the reference arms’ distribution when missingness is 
reasonably attributable to tolerability or lack of efficacy (see Section 6.4.1). Other missing data 
are to be imputed using the observed data model. The variance used for the multiple imputation 


 
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are described in the Details Appendix to this SAP. The number of imputations used for the 
derivation of the attributable estimand will be between 100 and 1000. Work by Seaman, White 
and Leacy (2014) and Cro (2017) show that Rubin’s rules can be validly used in conjunction 
with so called control-based multiple imputation methods, of which our attributable analysis is 
one type. Given these results we believe the attributable analysis to be conservative from a Type 
I error control perspective. 
Exploration of the robustness of findings to missing data is discussed in Section 6.4.3.4. 
6.4.3.2 
FEV1 AUC0-4  
FEV1 AUC0-4 is the primary endpoint in the US approach (BFF vs. BD at Week 24), and the EU 
approach (BFF vs. BD and non-inferiority of BFF 320/9.6 μg vs. Symbicort® over 24 weeks). 
FEV1 AUC0-4 is the area under the curve for FEV1 calculated using the trapezoidal rule, after the 
subtraction of the baseline FEV1 value, and the AUC will be transformed into a weighted 
average by dividing by the time (in hours) from dosing to the last measurement included 
(typically 4 hours). For all estimands, only one non-missing post-dose value is required for the 
calculation of AUC. Actual time from dosing will be used if available; otherwise scheduled time 
will be used. 
The differences between treatment groups in FEV1 AUC0-4 at Week 24, over 24 weeks, over 
weeks 12 to 24, and at Day 1 and each post-randomization visit, will be evaluated using an RM 
linear mixed model with baseline FEV1, percent reversibility to Ventolin HFA, and baseline 
eosinophil count as continuous covariates and treatment, visit, treatment by visit interaction, and 
ICS use at Screening as categorical covariates. Covariance structure will be chosen by the same 
approach as for the morning pre-dose trough FEV1 model. Two-sided p-values and point 
estimates with two-sided 95% CIs will be produced for each treatment difference of interest 
(Tables 2.1.5 to 2.1.8 for the efficacy estimand, attributable estimand, treatment policy estimand, 
and per protocol estimand, respectively). 
All comparisons will be for superiority except that the comparison of BFF MDI 320/9.6 µg to 
Symbicort® TBH will be for non-inferiority and will use a margin of 75 mL. The primary 
analysis will be conducted using the efficacy estimand except for the non-inferiority comparison 
of BFF MDI 320/9.6 µg vs. Symbicort® TBH, for which the per protocol estimand will be 
primary.  
For the attributable estimand of FEV1 AUC0-4 (for the analysis at Week 24 and over 24 weeks), 
data that are missing due to treatment discontinuation will be imputed in a similar manner to that 
of missing data for the attributable estimand for morning pre-dose trough FEV1 in Section 
6.4.3.1 above. The analysis of this endpoint with the attributable estimand is considered 
secondary. 


 
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6.4.3.3 
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, atypical values can arise. Such values may disproportionately affect 
model-based estimates of the fixed effect and variance parameters. Prior to database lock and 
unblinding, the change from baseline values for efficacy endpoints will be examined as part of 
data quality management. This may include production of normal probability plots, kernel 
density estimates, and normal order outlier statistics. Based on this blinded evaluation, if atypical 
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. 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 for the change from baseline in the morning trough FEV1 and 
AUC0-4 FEV1 data will be checked by visually inspecting the distribution of the residuals. Also, 
model fit and the assumption of homogeneity of variance will be verified by inspection of scatter 
plots of predicted vs. residuals, residuals vs. treatment, residuals vs. ICS use (yes/no), and by box 
plots of residuals for model variables with a potential effect on variance (treatment, visit, and 
ICS use). 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, visits (if unstructured covariance model fail to 
converge), and/or ICS use categories (yes/no). Note that the unstructured covariance structure 
allows for heterogeneity among the visits. 
Some further assumptions checks are mentioned in the Details Appendix to this SAP. 
6.4.3.4 
Sensitivity Analyses   
Sensitivity analyses will be conducted for the change from baseline in morning pre-dose trough 
FEV1 and FEV1 AUC0-4 to evaluate the robustness of the primary analysis findings to missing 
data. 
Robustness of results to missing data will be explored using tipping point analyses (Ratitch 
2013) for the efficacy, attributable and treatment policy estimands. The following table 
summarizes the multiple imputation-based sensitivity analyses under the PMM (pattern mixture 
model) framework that will be undertaken. 


 
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Table 4 
Sensitivity Analyses for Morning Pre-Dose Trough FEV1 and FEV1 AUC0-4 
Efficacy Estimand 
Attributable Estimand 
Treatment Policy Estimand 
mITT Population 
mITT Population 
ITT Population 
Tipping point analysis 
#1: 
 
All missing data are 
imputed using the 
observed data model 
except that for 
subjects in the 
treatment arm (not the 
comparator arm) 
values that are 
considered MNAR 
are imputed with the 
change from baseline 
in the treatment arm 
decremented by up to 
500 mL until the p-
value ≥ 0.05.  
 
Tipping point 
analysis #2: 
  
All missing data are 
imputed using the 
observed data model 
except that for 
subjects in the 
treatment arm (not 
the comparator arm) 
values are imputed 
with the change from 
baseline in the 
treatment arm 
decremented by up 
to 500 mL until the 
p-value ≥ 0.05. 
 
 
Tipping point  
analysis: 
 
MI based on the 5th 
percentile of the reference 
arms’ distribution if 
treatment discontinuation 
is due to tolerability or 
lack of efficacy of study 
drug (as in the primary 
analysis of this estimand). 
Otherwise, all missing data 
are imputed using the 
observed data model 
except that for subjects in 
the treatment arm (not the 
comparator arm), values 
are imputed with the 
change from baseline in 
the treatment arm 
decremented by up to 500 
mL until the p-value ≥ 
0.05. 
 
Tipping point analysis: 
 
All missing data are 
imputed using the observed 
data model except that for 
subjects in the treatment 
arm (not the comparator 
arm) values are imputed 
with the change from 
baseline in the treatment 
arm decremented by up to 
500 mL until the p-value ≥ 
0.05. 
 
MNAR = Missing not at random. MNAR will be defined and documented in the BDRM minutes prior to 
unblinding. The tipping point will be shown to at least a precision of 10 mL. Imputed values may not be impossible 
values – i.e. changes from baseline that would imply a negative FEV1 value. Thus the values will be imputed from a 
truncated distribution. 
The primary analysis is for the efficacy estimand that includes data collected up until the time of 
discontinuation of treatment. The efficacy estimand quantifies the difference in outcomes for all 
patients as if they continued on their initially randomized treatment. The primary analysis uses a 
linear mixed model and assumes that all missing data are MAR or MCAR. 
Although the analysis for the attributable estimand starts with the same amount of missingness, 
less remains after imputation for missingness deemed attributable to the treatments is performed.  
These remaining missing data are imputed using the observed data model in the main analysis 
under the assumption of MAR. More detail about the computation of the attributable estimand 
will be provided in subsequent sections and in the Details Appendix to this SAP. 
Tipping-point analyses will be conducted to examine the impact of varying the treatment mean 
for missing data in subjects who discontinue BFF MDI. Multiple imputation (MI) techniques will 
be used to impute the missing data for these patients by varying the mean in the treatment arm. 


 
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The change from baseline in the treatment arm will be decremented by up to 500 mL until the p-
value for the comparison of treatment to comparator becomes ≥ 0.05. A total of 10 imputations 
will be used for each set of tipping point analyses. This imputation technique will be applied in 
sensitivity analyses as described below. 
Tipping Point Analysis of the Primary Estimand: 
• Tipping Point #1: this first set of analyses will impute diminished effects only for subjects on 
BFF MDI whose missing data are determined to be MNAR. 
• Tipping Point #2: this analysis will impute diminished effects for all missing data in the BFF 
MDI arm. 
Note that for both tipping point analyses, all other missing data will be imputed using the 
observed data model. 
Tipping Point Analysis of the Attributable Estimand: 
For the attributable estimand, by definition, missing data in all arms due to tolerability and lack 
of efficacy are already imputed based on the 5th percentile of the reference arms’ distribution, 
therefore the remaining missing data imputed using the observed data model in the main analysis 
are likely MAR or MCAR. Hence, there is no need to conduct a tipping analysis like #1 planned 
for the efficacy estimand. A tipping point analysis like #2 will be conducted where the non-
attributable missing data will be imputed using progressively diminished effects. 
Tipping Point Analysis of the Treatment Policy Estimand: 
For the treatment policy estimand, a tipping point analysis like #2 will be conducted where 
missing data in the treatment arm will be imputed using progressively diminished effects. 
In all of these analyses, the imputed values that would have been seen are then combined with 
the observed values to provide a complete dataset. These data are then analyzed using the same 
linear mixed model used for the primary analysis. This analysis is repeated multiple times and 
the results are combined using Rubin’s formulae [Rubin, 1987]. 
For the tipping point analyses, tables giving results for each progressively diminished effect will 
be produced (Tables 2.1.10.1 to 2.1.10.8 for the change from baseline in morning pre-dose 
trough FEV1, Tables 2.1.11.1 to 2.1.11.8 for FEV1 AUC0-4). Figures of delta (decrement in 
treatment effect) versus p-values will also be produced (Figures 2.1.10.1a to 2.1.10.8h for the 
change from baseline in morning pre-dose trough FEV1, 2.1.11.1a to 2.1.11.8h for FEV1 AUC0-
4). Details of the sensitivity analyses will be discussed in the Statistical Methods Appendix to the 
CSR. 
Cumulative Responder Analysis 


 
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Additional sensitivity analyses will be implemented based on a cumulative responder approach 
(Farrar et al., 2006) for the change from baseline in morning pre-dose trough FEV1 at Week 24 
and over 24 weeks for the efficacy estimand estimand (Tables 2.1.12.1 to 2.1.12.3) and treatment 
policy estimand (Tables 2.1.12.2 to 2.1.12.4), and change from baseline in FEV1 AUC0-4 at 
Week 24 and over 24 weeks (Tables 2.1.13.1 and 2.1.13.3 for the efficacy estimand, Tables 
2.1.13.2 and 2.1.13.4 for treatment policy estimand). 
Cumulative distribution plots by treatment arm will also be produced. The observed change from 
baseline in morning pre-dose trough FEV1 at Week 24 and 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 (Figures 2.1.12.1 and 2.1.12.3 for the efficacy estimand, Figures 
2.1.12.2 and 2.1.12.4 for treatment policy estimand). Similarly, the cumulative proportion of 
responders plots for FEV1 AUC0-4 will be generated (Figures 2.1.13.1 and 2.1.13.3 for the 
efficacy estimand, Figures 2.1.13.2 and 2.1.13.4 for treatment policy estimand). Subjects without 
post-baseline data will be considered non-responders in the analysis. For display purposes only, 
the range of the x-axis will be from -1 to +1 liters [L] by increments of 0.01 liters in order to 
avoid the undue influence of outlying values. The cumulative responder curves for each 
treatment will then be compared pairwise using Kolmogorov-Smirnov tests. Cumulative 
responder analyses for the attributable estimand will not be performed because they are not well 
defined: methodology to apply Rubin’s rules for combining multiply imputed data for such an 
analysis is not readily available. 
 
Secondary Efficacy Analyses 
6.4.4
Secondary efficacy analyses will be conducted for the efficacy estimand, the attributable 
estimand, the treatment policy estimand, and the per protocol estimand. The efficacy estimand 
will be considered primary for superiority comparisons, and the per protocol estimand will be 
considered primary for the non-inferiority comparisons of BFF 320/9.6 μg vs. Symbicort®. The 
analysis of the primary endpoints with the attributable estimand is considered to be a secondary 
efficacy analysis; otherwise, the attributable estimand will be supportive. The other estimands 
will be supportive. 
6.4.4.1 
Transition Dyspnea Index 
Assessments of dyspnea will be obtained using the BDI/TDI (where BDI is the Baseline Dyspnea 
Index). The BDI/TDI questionnaire can be found in Protocol Appendix 7. 
TDI focal score is a secondary efficacy endpoint in the EU approach (BFF vs. FF, BFF vs. BD, 
and non-inferiority of BFF 320/9.6 μg vs. Symbicort® over 24 weeks). 
 
At Randomization (Visit 3), 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 
6.1.6). 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). 


 
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At subsequent visits (as per Schedule of Events: see of the Schedule of Events in the protocol), 
change from baseline will be assessed using the TDI. TDI components include: Change in 
Functional Impairment, Change in Magnitude of Task, and Change in Magnitude of Effort 
(Listing 6.1.6). 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). 
The difference between treatment groups in TDI focal score over weeks 12-24 and over 24 
weeks and at each post-randomization visit will be analyzed using a similar RM approach as for 
the primary endpoint, but using BDI instead of baseline FEV1 in the model, and adding baseline 
post-bronchodilator percent predicted FEV1 as a continuous covariate. Thus, the model will 
include treatment, visit, treatment by visit interaction, and ICS use at Screening as categorical 
covariates and BDI, baseline eosinophil count, percent reversibility to Ventolin HFA and 
baseline post-bronchodilator percent predicted FEV1 as continuous covariates. 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 2-sided 95% CIs will be produced for 
each treatment difference (Tables and Figures 2.2.1 for the efficacy estimand). The efficacy 
estimand using on-treatment data will be considered the main analysis. Analyses for the 
attributable estimand, treatment policy estimand, and the analysis of on-treatment data for the per 
protocol estimand will be conducted as supportive (Tables and Figures 2.2.2 to 2.2.4, 
respectively). 
The attributable estimand will be computed in a similar manner as the attributable estimand is 
computed for change from baseline in morning pre-dose trough FEV1 at Week 24 as described in 
Section 6.4.1. 
All comparisons will be for superiority except that the comparison of BFF MDI 320/9.6 µg to 
Symbicort® TBH will be for non-inferiority rather than superiority, and will use a margin of 0.75. 
The main analysis will be conducted using the efficacy estimand (with analyses on the 
attributable, treatment policy, and per protocol estimands as supportive) except for the non-
inferiority comparisons of BFF MDI 320/9.6 µg vs. Symbicort® TBH, for which the per protocol 
estimand analysis will be the main analysis. 
In addition, the difference between treatments for the individual components of the TDI: 
functional impairment, magnitude of task, and magnitude of effort will each be analyzed over 24 
weeks, over weeks 12-24, and at each post-baseline visit using the same modeling approach as 
for the TDI focal score (Tables 2.2.5 and Figures 2.2.5.1-2.2.5.3 for the functional impairment, 
magnitude of task, and magnitude of effort for the efficacy estimand). 
Furthermore, responder analyses will be performed for the TDI focal score where responders are 
defined as subjects with a response of 1.0 points or more (corresponding to at least a minor 
improvement) on average over 24 weeks and on average over weeks 12-24. Logistic regression 
will be used to compare the treatment groups with BDI, baseline eosinophil count, and percent 
reversibility to Ventolin HFA as continuous covariates and treatment, and ICS use at Screening 


 
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as categorical covariates. P-values and odds ratios with 95% CIs will be produced for each 
treatment comparison (Table 2.2.6 for the efficacy estimand). 
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 in the analysis. 
TDI and BDI data will be listed in Listing 6.1.6. 
6.4.4.2 
Peak Change from Baseline in FEV1 
Peak FEV1 will be included in the analyses of the efficacy, attributable, treatment policy, and per 
protocol estimands as long as there is at least one non-missing post-dose value. 
The peak change from baseline in FEV1 within 4 hours post-dosing is a secondary endpoint in 
the US approach (BFF vs. BD at Week 24) and the EU approach (BFF vs. BD over 24 weeks). 
The peak change from baseline in FEV1 within 4 hours post-dosing at Week 24, over weeks 12-
24 and over 24 weeks will be evaluated as a secondary efficacy analysis. This analysis will use 
the same modeling as with morning pre-dose trough FEV1. The peak change from baseline on 
Day 1 and at each post randomization visit will also be analyzed (Tables and Figures 2.3.1 to 
2.3.4 for the efficacy estimand, attributable estimand, treatment policy estimand, and per 
protocol estimand, respectively). 
The attributable estimand will be computed in a similar manner as the attributable estimand is 
computed for change from baseline in morning pre-dose trough FEV1 at Week 24 as described in 
Section 6.4.1. 
Tipping Point Analyses for Peak Change from Baseline in FEV1 at Week 24 
Robustness of results to missing data will be explored using tipping point analyses (Ratitch 
2013). Details of the methods are similar to sensitivity analyses of FEV1 and AUC0-4 (found in 
Section 6.4.3.4 and in the Details Appendix to this SAP, and using the maximum value of δ = 
500 mL), but with the model for peak change from baseline in FEV1 described above. Multiple-
imputation results will be combined using Rubin’s formulae [Rubin, 1987]. 
Additional sensitivity analyses will be implemented based on a cumulative responder approach 
as described in section 6.4.3.4 for the peak change from baseline in FEV1 within 4 hours post-
dose at Week 24 (Tables 2.3.5.1 and 2.3.5.2 for the efficacy and treatment policy estimand, 
respectively). A cumulative distribution plot by treatment arm will also be produced (Figure 
2.3.5.1 and 2.3.5.2 for the efficacy and treatment policy estimand, respectively). 
6.4.4.3 
St. George’s Respiratory Questionnaire 
Percentage of subjects achieving an MCID of ≥4 in SGRQ total score is a secondary endpoint in 
the US approach (BFF vs. FF and BFF vs. BD at Week 24) and in the EU approach (BFF vs. FF, 
BFF vs. BD and non-inferiority of BFF 320/9.6 μg vs. Symbicort® over 24 weeks). Change in 


 
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SGRQ total score and change in individual domain score from baseline over 24 weeks, over 
weeks 12 to 24, and at each post-baseline visit are ‘other’ endpoints. 
The SGRQ will be used to provide the health status/health-related QoL measurements in this 
study (see Protocol Appendix 8). 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. Individual items of SGRQ data will be listed (Listings 6.1.7 for All Subjects 
Randomized). 
A score will be calculated for each component and a "Total" score will also be calculated 
(Listings 6.1.9 for All Subjects Randomized). In each case, the lowest possible value is zero and 
the highest is 100. Higher values correspond to greater impairment of QoL. 
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. 
Responder analyses of SGRQ as a secondary efficacy endpoint will be performed, where 
responders are defined as subjects with an improvement of ≥4.0 points at Week 24, on average 
over 24 weeks, and over weeks 12-24. For the SGRQ responder analyses, subjects who 
discontinue treatment for any reason or are missing all post-baseline data will be considered to 
be non-responders for the analysis using the efficacy estimand or per protocol estimand. For the 
treatment policy estimand, subjects who withdraw from the study will be considered non-
responders. Logistic regression will be used to compare the treatment groups with baseline 
SGRQ score, baseline eosinophil count, baseline post-bronchodilator percent predicted FEV1, 
and percent reversibility to Ventolin HFA as continuous covariates, and treatment and ICS use at 
Screening as categorical covariates. P-values and odds ratios with 95% CIs will be produced for 
each treatment comparison (Tables 2.4.3 to 2.4.6 for the efficacy, attributable, treatment policy 
and per protocol estimands). 
All comparisons will be for superiority except that the comparison of BFF MDI 320/9.6 µg to 
Symbicort® TBH will be for non-inferiority rather than superiority, and will use a margin of 10%. 
The main analysis will be conducted using the efficacy estimand (with analyses on the 
attributable, treatment policy, and per protocol estimands as supportive) except for the non-
inferiority comparisons of BFF MDI 320/9.6 µg vs. Symbicort® TBH, for which the per protocol 
estimand will be the main analysis. 
The attributable estimand (for responder analysis of SGRQ) will be computed as follows. First, 
multiple imputations will be performed on the continuous total SGRQ scores in a similar manner 
as for the attributable estimand that is computed for change from baseline in morning pre-dose 
trough FEV1 (Section 6.4.1), except that the 95th percentile will be used instead of the 5th 


 
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percentile. After that, it will be determined whether the subject has attained the MCID. The 
analysis will proceed using logistic regression as described above, followed by combining of 
results across the multiple imputations using the formulae of Rubin [Rubin, 1987]. 
The difference between treatment groups in the change from baseline in SGRQ total score over 
24 weeks, over Weeks 12 to 24, and each post-baseline visit will be evaluated using a similar 
RM approach as for TDI focal score, but using baseline SGRQ score replacing BDI in the model. 
Thus the model will include treatment, visit, and treatment by visit interaction, ICS use at 
Screening as categorical covariates and baseline SGRQ score, baseline eosinophil count, percent 
reversibility to Ventolin HFA, and baseline post-bronchodilator percent predicted FEV1 as 
continuous covariates. Missing SGRQ total scores will not be imputed. Two-sided p-values and 
point estimates with 2-sided 95% CIs will be produced for each treatment difference (Table and 
Figure 2.4.1 for the efficacy estimand). 
Individual domains of the SGRQ will also be analyzed in a similar fashion as the total score 
(Table 2.4.2 for the efficacy estimand). 
Tipping Point Analyses for Percentage of Subjects achieving an MCID of 4 Units or More in 
SGRQ Total Score at Week 24 
Robustness of results to missing data will be explored using tipping point analyses (Ratitch 
2013). Details of the methods are similar to sensitivity analyses of FEV1 and AUC0-4 (found in 
Section 6.4.3.1 and in the Details Appendix to this SAP, and using the maximum value of δ = 16 
units), but with the model for SGRQ total score described above. 
6.4.4.4 
Rescue Ventolin HFA Use 
Change from baseline in average daily rescue Ventolin HFA use is a secondary endpoint in the US 
approach (BFF vs. BD over 24 weeks) and the EU approach (BFF vs. BD over 24 weeks). 
The number of puffs of rescue Ventolin HFA taken in the previous 12 hours since the previous 
(AM or PM) dose will be recorded in the subject diary in the morning and evening. The mean 
daily number of puffs of rescue Ventolin HFA used by subjects during the study will be 
calculated overall and for each of the 4-week intervals during the treatment period and provided 
in a diary data listing (Listing 6.1.3 for All Subjects Randomized). Diary data recorded during 
the last 7 days of the Screening Period will be used to calculate the baseline. 
For every interval of time over which the mean number of puffs of rescue will be calculated, 
records with 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. That is, the mean daily number of puffs of daytime rescue use (M_DT) will 
be set to the total number of daytime puffs divided by the number of half-days when daytime 
rescue use was recorded. The mean daily number of puffs of nighttime rescue use (M_DN) will 
be set to the total number of nighttime puffs divided by the number of half-days when the 
nighttime rescue use was recorded. The mean daily rescue use (puffs) is then two multiplied by 
the mean of M_DT and M_DN. 


 
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The difference between treatment groups in the change from baseline in rescue Ventolin HFA 
usage over 24 weeks will be evaluated using a linear RM analysis of covariance (ANCOVA) 
model which will include treatment, 4-week time interval (Interval 1 – Interval 6), treatment by 
time-interval interaction, and ICS use at Screening as categorical covariates, and baseline rescue 
Ventolin HFA use, baseline eosinophil count, baseline FEV1, and percent reversibility to 
Ventolin HFA as continuous covariates. A UN matrix will be used to model additional 
autocorrelation within subject. If this model fails to converge, an AR(1) structure will be used 
instead. In the AR(1) model, subject will be included as a random effect. 
Contrasts will be used to obtain estimates of the treatment differences over the entire 24 weeks. 
Two-sided p-values and point estimates with two-sided 95% CIs will be produced for each 
treatment difference. The main analysis will be conducted using the efficacy estimand (Table and 
Figure 2.5.1). Supportive analyses will use the attributable estimand, treatment policy estimand, 
the per protocol estimand, and the RVU Population (Tables and Figures 2.5.1 to 2.5.4, 2.5.7). 
The attributable estimand (for the analysis of average daily rescue Ventolin HFA use) will be 
computed in a similar manner as the attributable estimand is computed for change from baseline 
in morning pre-dose trough FEV1 at Week 24 as described in Section 6.4.3.1 except that the 95th 
percentile will be used instead of the 5th percentile. 
As supportive analyses, the treatment difference for each 4-week interval and over weeks 12 to 
24 will be evaluated and summarized. Additionally, as supportive analyses, daytime rescue 
Ventolin® HFA use and night-time rescue Ventolin HFA use will be evaluated and summarized 
in a similar fashion. Two-sided p-values and point estimates with 2-sided 95% CIs will be 
produced for each treatment difference (Tables and Figures 2.5.5, 2.5.6, 2.5.8 and 2.5.9 for the 
efficacy estimand and the RVU Population). 
Tipping Point Analyses for Rescue Ventolin HFA Use Over 24 Weeks 
Robustness of results to missing data will be explored using tipping point analyses (Ratitch 
2013). Details of the methods are similar to sensitivity analyses of FEV1 and AUC0-4 (found in 
Sections 6.4.3.4 and in the Details Appendix to this SAP, and using the maximum value of δ = 4 
puffs), but with the model for rescue Ventolin HFA use described above. Multiple-imputation 
results will be combined using Rubin’s formulae [Rubin, 1987]. 
Additional sensitivity analyses will be implemented based on a cumulative responder approach 
as described in section 6.4.3.4 for the average daily rescue Ventolin HFA use over 24 weeks 
(Tables 2.5.10 and 2.5.11 for the efficacy estimand and treatment policy estimand). A 
cumulative distribution plot by treatment arm will also be produced (Figures 2.5.10 and 2.5.11 
for the efficacy estimand and treatment policy estimand). Cumulative responder analysis for the 
attributable estimand will not be performed as methodology to apply Rubin’s rules for 
combining multiply imputed data for such an analysis is not readily available. 


 
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6.4.4.5 
E-RS Total Score 
Change from baseline in E-RS Total score is a secondary efficacy endpoint in the EU approach 
(BFF vs. FF, BFF vs. BD and non-inferiority of BFF 320/9.6 μg vs. Symbicort® over 24 Weeks). 
The EXACT is a 14-item patient reported outcome (PRO) instrument from the daily diary which 
will be used to measure the effect of treatment on exacerbations, and on the severity of 
respiratory symptoms. Mean change from baseline in the daily EXACT Total Score, the 11-item 
E-RS Total Score, as well as 3 subscale scores, RS-Breathlessness, RS-Cough and Sputum, and 
RS-Chest Symptoms, will be calculated over each post-randomization 4-week interval of the 24-
week Treatment Period. The last 7 days of the Screening Period will be used to calculate the 
baseline.  
The mean change from baseline in E-RS Total Score, RS-Breathlessness, RS-Cough and 
Sputum, RS-Chest Symptoms and the EXACT Total Score over each 4-week interval will be 
analyzed using a similar RM model as for TDI to estimate treatment effects over 24 weeks, but 
using the corresponding baseline mean score instead of the BDI as a covariate.  Instead of visit, 
the number of the relevant respective 4-week interval (Interval 1 to Interval 6) will be used as a 
categorical covariate in the model. Thus the model will include treatment, time interval, and 
treatment by time-interval interaction, and ICS use at Screening as categorical covariates and 
baseline score, baseline eosinophil count, percent reversibility to Ventolin HFA, and baseline 
post-bronchodilator percent predicted FEV1 as continuous covariates. A UN correlation matrix 
will be used to model additional autocorrelation within subject. If this model fails to converge, 
an AR(1) structure will be used instead. In the AR(1) model, subject will be included as a 
random effect. 
The E-RS Total score over 24 weeks is a secondary efficacy endpoint. The RS subscale scores 
and the EXACT Total score are “other” endpoints. EXACT data will be listed in Listing 6.1.5. 
The analysis of E-RS Total score will be secondary for the EU only. Two-sided p-values and 
point estimates with 2-sided 95% CIs will be produced for each treatment difference (Tables and 
Figures 2.6.1 to 2.6.4 for the efficacy estimand, attributable estimand, treatment policy estimand, 
and per protocol estimand, respectively; Tables 2.6.5 and 2.6.6 for EXACT total and domain 
scores). Analyses on the attributable estimand, treatment policy estimand, and per protocol 
estimand will pertain to the E-RS Total score only. 
The attributable estimand (for the analysis of E-RS Total score) will be computed in a similar 
manner as the attributable estimand is computed for change from baseline in morning pre-dose 
trough FEV1 at Week 24 as described in Section 6.4.3.1 except that the 95th percentile will be 
used instead of the 5th percentile. 
6.4.4.6 
Time to Onset of Action Assessed Using FEV1 on Day 1 
Time to onset of action on Day 1 is a secondary efficacy endpoint in the US and the EU 
approaches (BFF vs. BD). 
The onset of action for BFF MDI will be evaluated on Day 1 by comparing BFF MDI vs BD 


 
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MDI in the mean change from baseline in FEV1 at the 5 minute post-dose timepoint.  
Comparisons will also be made at additional timepoints but will not be controlled for 
multiplicity. Baseline is defined as the average of the non-missing -60 minute and -30 minute 
values obtained prior to dosing at Day 1 (Visit 3). 
To perform this analysis, a linear model with repeated measures will be fit to the Day 1 post-
baseline data. This model will include baseline FEV1, percent reversibility to Ventolin HFA, and 
baseline eosinophil count as continuous covariates and time point, treatment, the treatment by 
time point interaction, and ICS use at screening as categorical covariates. An unstructured 
correlation matrix will be used to model additional autocorrelation within subject. If this model 
fails to converge, an AR(1) structure will be used instead. In the AR(1) model, subject will be 
included as a random effect. The resulting tables and figures are Tables and Figures 2.7.1 to 
2.7.2 for the efficacy and per protocol estimands, respectively. 
On Day 1 during the first four hours post-dosing and by time point, the proportion of subjects 
achieving an improvement from baseline in FEV1 using different thresholds (i.e., ≥10%, ≥12%, 
≥15%, ≥100 mL, ≥200 mL, and ≥12% and 200 mL) will be estimated for each treatment. 
Subjects without post-baseline data will be considered to be non-responders in the analysis. 
The percentage of responders at each post-dose time point will be summarized by treatment. 
Logistic regression will be used to compare the treatments, adjusting for baseline FEV1, 
reversibility to Ventolin HFA, and baseline eosinophil count as continuous covariates, and ICS 
use at Screening as a categorical covariate. The odds ratio for treatment will be determined, 
along with the Wald two-sided 95% CI. The Wald chi-square test will be used to calculate p-
values for comparisons between treatments. Rate differences will also be estimated, using non-
linear modeling to construct the CI (Tables 2.7.3 to 2.7.8 for the efficacy estimand). 
The median time to response will also be presented by treatment. The median will be defined as 
the first time point on Day 1 such that at least 50% of the subjects of the given treatment group 
have achieved the response at or before that time. If the 4 Hour time point does not meet this 
condition, the median is not defined. Since the number of time points of FEV1 collection is 
limited, constructing a CI or performing treatment comparison is not feasible for the median time 
to response. These estimates will be incorporated in Table 2.7.3. 
6.4.4.7 
Time to First Moderate or Severe COPD Exacerbation 
Time to first moderate or severe COPD exacerbation is a secondary endpoint in the US and the 
EU approaches (BFF vs. FF). The non-inferiority comparison of BFF 320/9.6 μg to 
Symbicort® is not part of the type I error control strategy. 
Time to first moderate or severe COPD exacerbation is the time from first dose of study 
medication to the time of onset of the first moderate or severe COPD exacerbation. 
Only on-treatment exacerbations will be included for calculating the time to first moderate or 
severe COPD exacerbation for the efficacy estimand and per-protocol estimand (see section 6.1). 


 
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Exacerbations occurring after the premature discontinuation of treatment will be considered for 
the treatment policy estimand.  
For the attributable estimand, missing data that have been reasonably attributed to tolerability or 
lack of efficacy will be imputed based on the 95th percentile of the reference arms’ distribution. 
The imputed value will be drawn from a negative binomial distribution with mean exacerbation 
rate (and variance) based on the 95th percentile of the reference arms’ distribution, with estimates 
set to the average of estimates for the two reference treatments from the analysis of the 
exacerbation rates. Other missing data are to be imputed using the observed data model, i.e. 
assumed to be missing at random (MAR) or missing completely at random (MCAR). Further 
information about the computation of the attributable estimand is described in the Details 
Appendix to this SAP (Appendix 6); however, the timing of imputed events is also needed. 
These will be obtained for each imputed event by randomly drawing a value from the uniform 
distribution over the interval that starts with time of treatment discontinuation (in study days) and 
ends at 24 weeks. 
The time to first moderate or severe COPD exacerbation will be analyzed up through the Week 
24 Visit using a Cox regression model. Treatment comparisons will be performed using the 
model, adjusting for percent predicted post-bronchodilator FEV1, baseline eosinophil count, 
baseline COPD exacerbation history (Yes/No), country, and ICS use at Screening (Yes/No). 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% CIs and 
p-values (Tables 2.12.1 to 2.12.4 for the efficacy estimand, attributable estimand, treatment 
policy estimand, and per-protocol estimand).  
Time to first moderate or severe COPD exacerbation will be analyzed and displayed graphically 
for each treatment using a Kaplan-Meier curve (Tables and Figures 2.12.1 to 2.12.4 for the 
efficacy estimand, attributable estimand, treatment policy estimand, per protocol estimand, and 
Listing 6.1.2.3). Subjects who complete the study (and the study treatment) and do not 
experience a COPD exacerbation over treatment period will be censored at the Week 24 visit. 
For the efficacy and per-protocol estimands, subjects who do not experience a COPD 
exacerbation and discontinue treatment early will be censored at the date of treatment 
discontinuation. For the treatment policy estimand, subjects who do not experience a COPD and 
withdraw from the study will be censored at the last date of last assessment or contact (including 
telephone contact), and subject who do not experience a COPD exacerbation and complete the 
trial will be censored at the date of the Week 24 Visit. For the non-inferiority comparison of BFF 
MDI 320/9.6 µg MDI to Symbicort®, a non-inferiority margin for the hazard ratio of 1.1 will be 
employed. 
Kaplan-Meier curves for time to moderate or severe COPD exacerbations will be constructed for 
completers vs. discontinuations (Figure 2.12.1.1), and, in separate plots, for MAR/MCAR vs. 
MNAR, and attributable vs. non-attributable discontinuation types (Figures 2.12.1.2 and 
2.12.1.3). 
Tipping Point Analyses for Time to First Moderate or Severe COPD Exacerbation 


 
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Robustness of results to missing data will be explored using tipping point analyses (Ratitch 
2013). A brief overview of the approach is summarized in the table below.  
Table 5 
Sensitivity Analyses for Time to First Moderate or Severe COPD Exacerbations 
 
Efficacy Estimand 
Attributable Estimand 
Treatment Policy 
Estimand 
mITT Population 
mITT Population 
ITT Population 
Tipping point analysis 
#1: 
 
All missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm 
(not the comparator 
arm) values that are 
considered MNAR are 
imputed with the rate in 
the treatment arm 
increased by up to 1.5 
exacerbations/year until 
the p-value ≥ 0.05.  
 
Tipping point analysis 
#2: 
  
All missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm 
(not the comparator 
arm) values are 
imputed with the rate 
in the treatment arm 
increased by up to 1.5 
exacerbations/year 
until the p-value ≥ 
0.05. 
 
 
Tipping point  
analysis: 
 
MI using the 95th 
percentile of the 
reference arms’ 
distribution (for the 
rate of moderate or 
severe COPD 
exacerbation) if 
treatment 
discontinuation is due 
to tolerability or lack 
of efficacy of study 
drug (as in the primary 
analysis of this 
estimand). Otherwise 
all missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm 
(not the comparator 
arm) values are 
imputed with the rate 
in the treatment arm 
increased by up to 1.5 
exacerbations/year 
until the p-value ≥ 
0.05. 
Tipping point analysis: 
 
All missing data are 
imputed using the 
observed data model 
except that for subjects 
in the treatment arm (not 
the comparator arm) 
values are imputed with 
the rate in the treatment 
arm increased by up to 
1.5 exacerbations/year 
until the p-value ≥ 0.05.  
 MNAR = Missing not at random.  
The multiple imputation will be applied to the moderate or severe COPD exacerbation events 
within the negative-binomial analysis framework for the rate of moderate or severe COPD 
exacerbations, using values of δ that increase the rate in the treatment arm by up to 1.5 
exacerbations/year. For this method, an underlying negative binomial stochastic process for the 
rate of exacerbations is assumed and post-treatment-discontinuation counts will be imputed 
conditional upon the reason for treatment discontinuation (see Appendix 6 for details). 


 
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A dataset with event counts through Week 24 will be created; however, the timing of imputed 
events is also needed. These will be obtained for each imputed event by randomly drawing a 
value from the uniform distribution over the interval that starts with time of treatment 
discontinuation (in study days) and ends at Week 24. Missing values will first be imputed for the 
missing COPD exacerbation events prior to the computation of the time to the first moderate or 
severe COPD exacerbation (for the sensitivity analysis). After imputation, the analysis will 
proceed to use Cox regression (as described above) and subsequently the multiple-imputation 
results will be combined using Rubin’s formulae [Rubin, 1987]. 
6.4.4.8 
Time to Clinically Important Deterioration 
Clinically important deterioration (CID) is defined as ≥ 100 mL decrease from baseline in trough 
FEV1, or ≥ 4 points increase from baseline in SGRQ total score, or a TDI focal score of -1 point 
or less, or treatment-emergent moderate-or-severe COPD exacerbation occurring up to Week 24. 
Time to CID is a secondary efficacy endpoint in the EU approach (BFF vs. FF). The non-
inferiority comparison of BFF 320/9.6 μg to Symbicort® is not part of the type I error control 
strategy. 
Time to CID analysis will be performed using the Cox regression model. The model will include 
treatment, baseline post-bronchodilator percent predicted FEV1, baseline eosinophil count, 
baseline COPD exacerbation history (Yes/No), country, and ICS use at Screening (yes/no). Time 
to a CID event will be based on the component event which occurs first. Subjects who do not 
have a CID event will be censored at the earliest day among the component censoring times. 
COPD exacerbations happening after Week 24 will not be counted as CID events. Estimated 
adjusted hazard ratios will be displayed along with associated 95% CI and p-values (Tables 
2.15.1 to 2.15.4 for the efficacy estimand, attributable estimand, treatment policy estimand, and 
per-protocol estimand). Time to CID will be displayed for each treatment group using a Kaplan-
Meier curve (Figures 2.15.1 to 2.15.4 for the efficacy estimand, attributable estimand, treatment 
policy estimand, and per protocol estimand). 
For the attributable estimand, missing data that have been reasonably attributed to tolerability or 
lack of efficacy will be imputed based on either the 5th or the 95th percentile of the reference 
arms’ distribution. The attributable estimand for time to CID will be computed by applying the 
percentile penalty to each of four component variables simultaneously; it uses multiple by-visit 
imputation of pre-dose trough FEV1 (at visits for which they are missing) (as described in 
Section 6.4.3.1), of the SGRQ total score (as described in Section 6.4.4.3), of the TDI focal score 
in a manner similar to that for SGRQ, and of time to first moderate-or-severe COPD 
exacerbation (as described in Section 6.4.4.7). 
 
Other Efficacy Analyses 
6.4.5
6.4.5.1 
Other Spirometry Endpoints 
The analysis for between-treatment comparisons of changes from baseline in morning pre-dose 
trough FEV1 over 24 weeks, over weeks 12-24 and at each post-randomization visit through 
Week 24 has already been described in Section 6.4.3.1 (Tables and Figures 2.1.1 to 2.1.6). 


 
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Analyses for FEV1 AUC0-4 over 24 weeks, over weeks 12-24, and at each post-randomization 
visit have been described in a similar manner in Section 6.4.4.2 (Table and Figure 2.1.9 for the 
efficacy estimand). Peak change from baseline within 4 hours in FEV1 over 24 weeks, over 
weeks 12 to 24, and at Day 1 and at each post-randomization visit where measured through 
Week 24 will be estimated and compared between treatment groups using a linear mixed RM 
model with the same model as pre-dose trough FEV1 (Table and Figure 2.3.1 for the efficacy 
estimand). 
Similar analyses will be conducted for FVC, PEFR, and FEF25-75 over 24 weeks, over weeks 12 
to 24, and at each post-randomization visit where measured for the efficacy estimand and 
treatment policy estimand, respectively. The baseline covariate for each model will be endpoint-
specific (Tables and Figures 2.8.1 to 2.8.3 for change from baseline in morning pre-dose trough 
FVC, PEFR, and FEF25-75; Tables and Figures 2.9.1 to 2.9.3 for peak change from baseline 
within 4 hours for FVC, PEFR, and FEF25-75; Tables and Figures 2.10.1 to 2.10.3 for FVC 
AUC0-4, PEFR AUC0-4, and FEF25-75 AUC0-4). The analyses for change from baseline at each 
post-dose time point in FEV1, FVC, PEFR, and FEF25-75 on Day 1 will be provided (Tables and 
Figures 2.7.1 for FEV1 and 2.11.1 to 2.11.3 for FVC, PEFR, and FEF25-75, respectively, for the 
efficacy estimand; Listings 6.3.1 to 6.3.7). 
6.4.5.2 
Rate of COPD Exacerbations 
COPD Exacerbations 
A COPD exacerbation will be defined as a change in the subject’s usual COPD symptoms that 
lasts 2 or more days, is beyond normal day-to-day variation, is acute in onset, and may warrant a 
change in regular medication. The change in symptoms must include at least one major COPD 
symptom and at least one other major (dyspnea, sputum volume, and sputum color) or minor 
symptom (cough, wheeze, sore throat, cold symptoms, and fever without other cause). 
Exacerbations will be considered moderate if they result in:  
 
• Use of systemic corticosteroids and/or antibiotics for at least 3 days; a single depot injectable 
dose of corticosteroids will be considered equivalent to a 3-day course of systemic 
corticosteroids. 
Exacerbations will be considered severe if they result in:  
• An inpatient COPD-related hospitalization (documentation stating that the subject was 
hospitalized for the COPD exacerbation or a record of the subject being admitted for ≥24 
hours to an observation area, the emergency department, or other equivalent healthcare 
facility depending on the country and healthcare system). 
• COPD-related death. 
Moderate and severe COPD exacerbations will be entered in the eCRF.  


 
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Additionally, the investigator may identify certain events (recorded on the same CRF page) 
which don’t entirely meet the criteria above as exacerbations; the justifications supporting the 
investigator’s judgment will be recorded on a separate page on the eCRF. 
COPD exacerbations not meeting the criteria for moderate or severe COPD exacerbations will be 
considered to be mild COPD exacerbations. For more detail about moderate-or-severe, severe, 
and any-severity COPD exacerbation events (and their start and end dates) and how they are 
operationally defined, see the subsections titled “Duration of COPD Exacerbation,” “Moderate-
or-Severe Exacerbation and Severe Exacerbation: Operational Definitions”, and “Exacerbation 
of any Severity: Operational Definition”. 
The rate of moderate or severe COPD exacerbations will be analyzed using negative binomial 
regression as implemented in SAS PROC GENMOD. Treatments will be compared adjusting for 
baseline post-bronchodilator percent predicted FEV1 and baseline eosinophil count as continuous 
covariates and baseline COPD exacerbation history (Yes, No), country, and ICS use at Screening 
(yes/no) as categorical covariates. COPD exacerbations will be considered separate events 
provided that there are more than 7 days between the recorded stop date of the earlier event and 
the start date of the later event. Time at risk of experiencing an exacerbation will be used as an 
offset variable in the model. 
For the efficacy estimand, the time at risk is defined as time of exposure to randomized treatment 
– not during or within 7 days after an exacerbation of equal or greater severity – until the last 
dosing date. More precisely, this is the amount of time between the date of first dose of study 
medication and the date of discontinuation from or completion of study medication minus the 
number of days while the subject was experiencing any exacerbation and minus the seven days 
subsequent to any exacerbation. Any days subsequent to the date of discontinuation from or 
completion of study medication are not subtracted. 
For moderate-or-severe COPD exacerbations that were identified apart from an eDiary alert, the 
symptom information is listed in Listing 6.1.2.2. 
The number of exacerbations and the percentage of subjects who experience exacerbations, 
exacerbation rates, and rate ratios comparing treatments will be summarized for the efficacy 
estimand for moderate-or-severe exacerbations (Table 2.12.7), for any severity of exacerbations 
(Table 2.12.8). 
Follow-up time at risk will be summarized and displayed graphically for the efficacy estimand 
for moderate or severe COPD exacerbations (Table and Figure 2.12.7a) and for any severity of 
exacerbations (Table and Figure 2.12.8a). 
Duration of COPD Exacerbation  
For moderate or severe exacerbations, the duration is defined by the length of prescribed 
treatment (using the eCRF COPD exacerbation page), whereas for mild exacerbations, the 
duration is defined by the length of symptoms. 


 
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For moderate or severe COPD exacerbations, the start date will be defined as the start date of 
prescribed treatment with a systemic corticosteroid or systemic antibiotic and the stop date will 
be defined as the latter of the last day of prescribed treatment with a systemic corticosteroid or 
systemic antibiotic (if applicable). If the subject dies before being treated or hospitalized, then 
the start and stop date will be the date of death. In order to ensure that the same event is not 
counted twice, consecutive or concurrent moderate or severe COPD exacerbations with equal to 
or fewer than 7 days between the recorded stop date of the earlier event and start date of the later 
event will be considered the same event and assigned the maximum severity between the two. 
For mild COPD exacerbations, start date will be defined as the onset of worsened symptoms as 
recorded by the subject in the eDiary, and the stop date will be defined as the last day of 
worsened symptoms. In order to ensure that the same event is not counted twice, consecutive or 
concurrent mild COPD exacerbations with equal to or fewer than 7 days between the recorded 
stop date of the earlier event and start date of the later event will be considered the same event. 
In addition, in order to not double-count exacerbations that are moderate or severe, eDiary data 
from dates within 7 days of a moderate or severe exacerbation will not be included as additional 
mild COPD exacerbations. This implies that continuing worsened symptoms that meet the 
definition of a mild exacerbation would need to be present at least 2 days prior to the 7-day 
period immediately preceding the start date of a moderate or severe COPD exacerbation in order 
to be considered a separate event. Similarly, worsened symptoms would need to be present for at 
least 2 days after the 7-day period immediately following a moderate or severe COPD 
exacerbation to be considered a separate event. 
Analyses of each severity of exacerbation will account for the time that subjects are at risk of 
having an exacerbation of that severity or greater. Time during or immediately following – i.e. 
within 7 days of – an exacerbation will not be considered as part of the time that the subject was 
at risk. However, time during or immediately following an exacerbation of lower severity will be 
included since, for example, a subject experiencing a mild exacerbation is still at risk of the event 
increasing in severity and becoming a moderate exacerbation. Thus, for example, in the analysis 
of severe COPD exacerbations, subjects will still be considered to be at risk of an exacerbation 
even during or within 7 days after a mild or moderate exacerbation. Likewise, in the analysis of 
moderate-or-severe COPD exacerbations, subjects will still be considered to be at risk of an 
exacerbation even during or within 7 days after a mild exacerbation. 
Moderate-or-Severe Exacerbation and Severe Exacerbation: Operational Definitions 
Moderate exacerbations and severe exacerbations will be defined based on information from the 
COPD Exacerbation eCRF page. A time interval from a single COPD exacerbation eCRF page 
will be designated as being during an event of a moderate-or-severe COPD exacerbation if either 
antibiotics or oral corticosteroids were administered for the exacerbation. 
Call this time interval a “P-Interval”. The start date of the P-Interval is the earliest start date of 
the above, and the stop date will be defined as the last stop day of the above. If the subject was 
hospitalized due to the exacerbation or if the exacerbation led to a COPD-related death, then the 


 
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severity of “severe” will be assigned to this P-interval; otherwise the severity of “moderate” will 
be assigned. The later among the stop date of the treatment with a systemic corticosteroid and the 
stop date of the treatment with an antibiotic will be the end date of the COPD exacerbation (i.e. 
the end of the P-Interval). 
An overarching interval of (any number of) such P-Intervals – including any P-Intervals with an 
end date not more than 7 days prior to the start date of some other P-Interval or with a start date 
not more than 7 days after the end date of some other P-Interval – and including the days in any 
gaps between them – will be called an “QMS-Interval”. This QMS-interval will represent the 
consolidated duration of several exacerbations recorded on different CRF pages. This QMS-
Interval will be considered to be a single event of a moderate-or-severe COPD exacerbation. See 
Figure 2. 
A P-interval of severe COPD exacerbation is called a “severe” P-Interval. Any QMS interval that 
contains at least one “severe” P-Interval will also be called a “QS-Interval”. This QS-Interval 
will be considered to be a single event of a severe COPD exacerbation. See Figure 2. 
Figure 2  
Overarching Intervals of Moderate-or-Severe (QMS) and Severe (QS) COPD 
Exacerbations 
P 
(Severe) 
3 days 
P 
(Severe) 
 8  days   
P 
5 days 
P 
(Severe) 
QMS 
 
QMS 
QS 
 
QS 
A P-interval is a moderate-or-severe COPD exacerbation instance from a single CRF page. 
In a “Severe” P-Interval, the maximum severity of the COPD exacerbation is “severe”. 
A QMS interval is an overarching moderate-or-severe COPD exacerbation event encompassing multiple 
CRF pages. 
A QS interval is an overarching severe COPD exacerbation event encompassing multiple CRF pages. 
Exacerbation of any Severity: Operational Definition 
Using eDiary data, a day will be designated as being during an event of a COPD exacerbation of 
some severity if (1) there was at least one major symptom and there was at least one other major 
or minor symptom and if (2) on an adjacent day there was at least one major symptom and there 
was at least one other major or minor symptom. Denote such a day as a “Category-D” day. 
An interval of (any number of) such Category-D days – including any Category-D days not more 
than 7 days apart from some other Category-D day – and including the days in any gaps between 
them – will be called an “I-Interval”. See Figure 3. 
An overarching interval coalescing (any number of) P-Intervals and I-Intervals – including any 
such P-or-I-intervals with an end date not more than 7 days prior to the start date of some other 
P-or-I-Interval or with a start date not more than 7 days after the end date of some other P-or-I-
interval – and including the days in any gaps between them – will be called a “QQ-Interval”. 


 
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This QQ-interval will represent the consolidated duration of several exacerbations recorded on 
different CRF pages or identified from subject diary data. This QQ-Interval will be considered to 
be a single event of an any-severity COPD exacerbation. See Figure 4. 
Figure 3  
Overarching Intervals (I) of Mild-Moderate-or-Severe COPD Exacerbation Events 
Based on eDiary Symptom Data 
D D D D D D D D  5 days  D D D D D D  9 days   D D D      10 days     D D 
I 
 
I 
 
I 
A Category-D day is a day with mild-moderate-or-severe COPD exacerbation based on e-diary symptom 
data. 
An I-Interval is an overarching mild-moderate-or-severe COPD exacerbation event encompassing 
multiple clusters of e-diary symptom days. 
Figure 4  
Overarching Intervals (QQ) of Mild-Moderate-or-Severe COPD Exacerbation 
Events Incorporating Both CRF Data and eDiary Symptom Data  
P 
2 days 
I 
3 days 
I 
 10 days  
P 
QQ 
 
QQ 
A P-Interval is a moderate-or-severe COPD exacerbation instance from a single CRF page. 
An I-Interval is an overarching mild-moderate-or-severe COPD exacerbation event based on e-diary 
symptom data. 
A QQ-Interval is an overarching mild-moderate-or-severe COPD exacerbation event – encompassing 
multiple P-Intervals and I-Intervals – incorporating both CRF data and e-diary symptom data. 
 
In summary, we combine CRF based moderate-or-severe COPD exacerbation events (or severe 
COPD exacerbation events) if they are close enough together in time (Figure 2). We also 
combine mild-moderate-or-severe COPD exacerbations if they are close enough together in time; 
this coalescing is done first within-data-source (CRF [Figure 2] or diary [Figure 3]) and then 
between the two sources (Figure 4). 
Time-at-Risk for COPD Exacerbations of Various Severities: Operational Definition 
During a time when a subject is not experiencing a severe COPD exacerbation (i.e. QS interval) 
– and is not in the seven days following a severe COPD exacerbation – a subject is considered to 
be at risk of having a severe exacerbation. During a time when a subject is not experiencing a 
moderate-or-severe COPD exacerbation (i.e. QMS interval) – and is not in the seven days 
following a moderate-or-severe COPD exacerbation – a subject is considered to be at risk of 
having a moderate-or-severe exacerbation. During a time when a subject is not experiencing an 
any-severity COPD exacerbation (i.e. QQ interval) – and is not in the seven days following an 
any-severity COPD exacerbation – a subject is considered to be at risk of having an any-severity 
exacerbation. 
Overarching coalesced intervals (i.e. events) of COPD exacerbation will be listed for severe 
exacerbations, moderate -to-severe exacerbations, and any-severity exacerbations (Listing 
6.1.2.3). A severe COPD exacerbation event must be classified also as a moderate-or-severe 


 
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event and also as an any-severity event. A moderate-or-severe COPD exacerbation event must be 
classified also as an any-severity event. 
Rate of COPD exacerbations of any severity will be analyzed in a manner similar to the rate of 
moderate or severe COPD exacerbations (Table 2.12.8 for the efficacy estimand). 
The count of COPD exacerbations of any severity is the number of QQ-Intervals (for a subject) 
as defined previously. Time at risk of experiencing an exacerbation will be used as an offset 
variable in the model. Time during an exacerbation (of any severity) or in the 7 days following 
an exacerbation (of any severity) will not be included in the calculation of exposure (i.e. time at 
risk). Data related to COPD exacerbations of any severity are listed in Listings 6.1.2.1, 6.1.2.2, 
6.1.2.3, and 6.1.4. For moderate-or-severe COPD exacerbations that were identified apart from 
an eDiary alert, the symptom information is listed in Listing 6.1.2.2. 
6.4.5.3 
Time to Treatment Failure 
Treatment failure is defined as a moderate or severe COPD exacerbation or premature 
discontinuation from treatment for any reason or death. Time to treatment failure will be 
displayed graphically for each treatment group using a Kaplan-Meier curve and analyzed using a 
log-rank test to compare the curves between the treatments (Figure 2.13.1). Subjects who do not 
experience a treatment failure will be censored at their Week 24 Visit or Day 168, whichever 
comes first. The time to treatment failure will be analyzed using the Cox model for the efficacy 
estimand. The model will include treatment, baseline post-bronchodilator percent predicted 
FEV1, baseline eosinophil count, baseline COPD exacerbation history (Yes/No), country, and 
ICS use at Screening (yes/no). Estimated adjusted hazard ratios will be displayed along with 
associated 95% CI and p-values (Table 2.14.1). 
6.4.5.4 
Time to Treatment Discontinuation for Any Cause 
Time to discontinuation from treatment for any cause will be summarized and graphically 
displayed using a Kaplan-Meier plot (Table and Figure1.2.3). Statistical comparisons will not be 
performed. Time to study discontinuation will be summarized similarly, but using the treatment 
policy estimand (Table and Figure 1.2.4). 
6.4.5.5 
Time to Death 
For time to death (all causes), subjects will be censored at the date of last contact. The primary 
analysis will use the treatment policy estimand. The Cox regression model will include 
treatment, baseline post-bronchodilator percent predicted FEV1, and baseline age. Estimated 
adjusted hazard ratios will be displayed along with associated 95% CI and p-values (Table and 
Figure 2.14.1 for the treatment policy estimand). The analysis of time to death will be conducted 
contingent upon having at least 30 deaths in the study. Otherwise, the analysis will be limited to 
counts and listings. 


 
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6.4.5.6 
Time to Sustained Clinically Important Deterioration 
Sustained CID is defined as ≥ 100 mL decrease from baseline in trough FEV1, or ≥ 4 points 
increase from baseline in SGRQ total score, or a TDI focal score of -1 point or less, any of which 
is occurring on two consecutive analysis visits or for ≥ 50% of all available subsequent analysis 
visits, or a treatment emergent moderate-or-severe COPD exacerbation occurring up to Week 24. 
Time to sustained CID analysis will be performed using the Cox regression model. The model 
will include baseline post-bronchodilator percent predicted FEV1, baseline eosinophil count, 
baseline COPD exacerbation history (Yes/No), country, and ICS use at Screening (yes/no). Time 
to a sustained CID event will be based on the component event which occurs first. Subjects who 
do not have a sustained CID event will be censored at the earliest day among the component 
censoring times. COPD exacerbations happening after Week 24 will not be counted as sustained 
CID events. Estimated adjusted hazard ratios will be displayed along with associated 95% CI and 
p-values (Table 2.15.5). Time to sustained CID will be displayed for each treatment group using 
a Kaplan-Meier curve (Figure 2.15.5). 
6.4.5.7 
European Quality-of-Life-5 Dimension-5 Level Questionnaire 
The European Quality-of-Life-5 Dimension-5 Level Questionnaire (EQ-5D-5L) data will be 
weighted to calculate an index score based upon subjects’ responses to the 5 dimensions. The 
visual analogue scale (VAS) will be scored from 0 (worst imaginable health state) through 100 
(best imaginable health state) to represent the subject’s self-report concerning how bad or how 
good their health was during that day.  
EQ-5D-5L will be presented in three different ways:  
1. Presenting results from the EQ-5D-5L descriptive system as a health profile at baseline, at all 
visits, and at EoT (%, n) by domain. 
2. Presenting results of the VAS as a measure of overall self-rated health status - baseline scores, 
scores at each visit, changes from baseline at each visit, and mean VAS score over the 
treatment period. 
3. Presenting results from the EQ-5D-5L index score (using UK value set) baseline, each visit, 
changes from baseline to each visit, and the mean index score over the treatment period.  
The percentage of subjects’ categorical responses to each of the 5-dimensions will be 
summarized (Tables 2.16.1 for the efficacy estimand). Descriptive statistics for the index score 
(Table 2.16.2 for the efficacy estimand) and VAS (Table 2.16.3 for the efficacy estimand) will 
be presented by treatment group. VAS scores over 24 weeks will be analyzed using a similar RM 
ANCOVA model which is used for primary efficacy analysis. The model will include treatment, 
visit, treatment-by-visit interaction, country, and gender as categorical covariates and baseline 
score and age as continuous covariates (Tables and Figures 2.16.2 for the index score and Table 
2.16.3 for VAS for the efficacy estimand). EQ-5D data are listed in Listing 6.1.11. 


 
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For calculations of index score, the method recommended by the national institute for health and 
care excellence (NICE) August 2017 will be applied. Cross-walk between EQ-5D-3L value set 
and EQ-5D-5L descriptive system have been developed by Van Hout et al 2012 (Van Hout et al. 
2012) and this cross-walk value set for EQ-5D-5L will be used to calculate the index score (Van 
Reenan 2015). Appendix 8 contains the SAS/SPSS codes for crosswalk between 5L and 3L for 
calculation of index score. 
No imputation will be made for missing data in either the EQ-5D-5L or VAS responses. 
The compliance of completing the EQ-5D-5L questionnaires is a critical issue in the QoL and 
health-state evaluation, and will be described by post-randomization visit, by displaying the 
number and percentage of subjects who were assessed (per subject, at least 1 question answered) 
at that visit (Table 2.16.4 for the efficacy estimand). 
6.4.5.8 
12-Hour Pulmonary Function Tests 
12-hour lung function data will be collected in a subset of approximately 510 randomized 
subjects at Week 12 (Visit 6). Spirometry data are listed in Listings 6.2, 6.3.9 for FEV1, 6.3.12 
for FVC, 6.3.15 for PEFR, and 6.3.18 for FEF25-75 for the efficacy estimand). Participation in the 
12-hr PFT Sub-study is listed in Listing 9.7. 
Descriptive summaries for change from baseline in FEV1, FVC, PEFR, and FEF25-75 will be 
presented at each post-dose time point over 12 hours and at 12-hour post-dose trough at Week 12 
(Visit 6) (Tables and Figures 2.17.2, Listing 6.3.9 for FEV1; Tables and Figures 2.17.5, and 
Listing 6.3.12 for FVC; Tables and Figures 2.17.8, and Listing 6.3.15 for PEFR; Tables and 
Figures 2.17.11, and Listing 6.3.18 for FEF25-75 for the efficacy estimand). The 12-hour post-
dose trough is defined as the average of the 11.5 and 12 hour post-dose values. In subjects 
missing either of these assessments, the value will be calculated from the single measurement. In 
subjects missing both values, this value will be missing. 
Area under the curve AUC0-12 will be calculated using the trapezoidal rule, after first having 
subtracted the baseline FEV1 value, and transformed into a weighted average by dividing by the 
time in hours between the first and the last measurement included. For both the efficacy and per 
protocol estimand analysis, 1 non-missing post-dose value is required for the calculation of 
AUC. Actual time from dosing will be used if available; otherwise scheduled time will be used. 
The differences between treatments in FEV1 AUC0-12 at Week 12 will be evaluated using an 
ANCOVA with baseline FEV1, baseline eosinophil count, and percent reversibility to Ventolin 
HFA as continuous covariates and treatment and ICS use at Screening as categorical covariates. 
Two-sided p-values and point estimates with two-sided 95% CIs will be produced for each 
treatment difference for the efficacy estimand (Tables and Figures 2.17.1 for AUC0-12). In 
addition, the peak change from baseline in FEV1 over 12 hours at Week 12 will be estimated and 
compared between treatments using an ANCOVA with the same model as described for AUC 
FEV1 (Table 2.17.3 for the efficacy estimand). 


 
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Similar analyses will be performed for AUC0-12 of FVC, PEFR, and FEF25-75 (Tables 2.17.4 for 
FVC AUC0-12, 2.17.7 for PEFR AUC0-12, 2.17.10 for FEF25-75 AUC0-12 for the efficacy 
estimand). The baseline covariate will be endpoint-specific. 
 
Subgroup Analyses 
6.4.6
Subgroup analyses will be performed for change from baseline in morning pre-dose trough 
FEV1, AUC0-4 FEV1, and rate of moderate or severe COPD exacerbations (efficacy estimand 
only). The following subgroups will be considered: 
• History of Moderate or Severe COPD Exacerbation in the last 12 Months: 
o Yes 
o No 
• Baseline Eosinophil Count: 
o <150 cells per mm3 
o ≥150 cells per mm3 
• Country 
Each subgroup will be analyzed separately using the same model that was used for the overall 
(combined subgroups) analysis. Estimates for the treatment effect and for the treatment 
differences will be displayed in the efficacy endpoint tables for each subgroup (Tables 4.1.1 to 
4.3.3). 
For each subgroup analysis, a test for the treatment-by-subgroup interaction will be performed 
using the same model that was used for the overall (combined subgroups) analysis but with the 
addition of terms for 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 (Table 4.4 for the 
efficacy estimand). 
Eosinophil Cut Point Exploration 
Subgroup analyses of trough FEV1 will be conducted in the baseline eosinophil count-high 
(≥150 cells per mm3) and the baseline eosinophil count-low (<150 cells per mm3) subgroups. It is 
acknowledged 150 cells per mm3 may not ultimately be the appropriate threshold for evaluation 
of treatment benefit. Thus, additional analyses will evaluate alternative thresholds, and the 
results from these analyses could then inform thresholds for future clinical studies. This 
exploration will include using additive mixed models that combine nonparametric regression for 
the relationship of eosinophil levels to trough FEV1 (Figures 4.5.1, 4.5.1.1 and 4.5.1.2) as well 
as potentially using subgroups defined by different cut points. 
 
Control of Type I Error 
6.4.7
The same general Type I error control strategy will be employed for the US and EU regulatory 
approaches. In each approach, Type I error will be controlled for the following analyses: 


 
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• The primary analyses under the efficacy estimand 
• The secondary analysis of the primary endpoints under the attributable estimand 
• The secondary analyses  
6.4.7.1 
US Approach 
The Type I error rate will be controlled within the primary and secondary efficacy analyses.  The 
primary analyses associated with BFF MDI 160/9.6 will proceed only if all of the primary 
analyses associated with BFF MDI 320/9.6 are successful. The secondary analysis of the primary 
endpoints under the attributable estimand and remaining secondary analyses for each BFF dose 
will proceed only if the primary analyses associated with that dose of BFF MDI are successful.  
For ease of review, the set of planned analyses has been divided into two groups: 
Group 1: The primary analyses under the efficacy estimand and the secondary analysis of the 
primary endpoints under the attributable estimand.  
Group 2: The remaining secondary analyses under the efficacy estimand. 
 
 


 
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Figure 5  
Group 1: Type I Error Control for the Analyses of the Primary Endpoints (US 
Approach) 
 
 
 
In Group 1, a sequential multiplicity approach will be used in the analysis of the primary 
endpoints. In this approach, the analyses of the primary endpoints are listed in a pre-specified 
order in which they will be tested. Each hypothesis will be tested at the 2-sided 0.05 level. If a p-
value is less than 0.05, then that hypothesis is rejected and the next hypothesis is tested. If a 
primary hypothesis is not rejected, then testing will stop. However, it is noted that p-values will 
still be calculated for all subsequent analyses for descriptive purposes. 
Group 2 analyses are presented in Figure 6. 
 
 


 
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Figure 6  
Group 2: The Analysis of the Secondary Endpoints (US Approach) 
 
 
In Group 2, the secondary comparisons to the mono-component control arms will be treated as 
separate families of hypotheses. The Type I error in each family of secondary analyses will be 
controlled to alpha with either a sequential testing method or the Hochberg procedure. 
 
6.4.7.2 
EU Approach  
The EU Approach will follow a similar general strategy as the US Approach. The control of 
Type I error in the EU Approach differs from the US Approach in the need to compare BFF MDI 
320/9.6 μg to Symbicort® for non-inferiority and the number of secondary endpoints being 
evaluated. Otherwise, the Type I error control strategy is similar. The graphical representations 
of the primary, secondary, and subgroup analyses are presented below. 
 
 


 
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Figure 7  
Group 1: Type I Error Control for the Analyses of the Primary Endpoints (EU 
Approach) 
 
 
 
 
If the Group 1 analyses are successful within a BFF MDI dose, the analysis of the remaining 
secondary endpoints for that BFF MDI dose (Group 2) will proceed under the efficacy estimand. 
Group 2 analyses are presented in Figure 8. 
 
 


 
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Figure 8  
Group 2: The Analysis of the Secondary Endpoints (EU Approach)  
 
 
 


 
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Correlation Analysis 
6.4.8
Pearson correlation coefficients will be generated between the primary and secondary continuous 
endpoints (from both US and EU approaches). SGRQ total score will be used in place of the 
SQRQ responder. The mITT population will be used.  
Note that for morning trough FEV1, AUC0-4 FEV1, TDI, and change from baseline in SGRQ, the 
estimates over 24 weeks were obtained as LS means from MMRM analyses, and were not 
derived at the subject level. For the purpose of the correlation analysis, the endpoints over 24 
weeks will be represented by simple averages of available data over 24 weeks. 
The correlations will be organized in a matrix, with its upper triangle filled with pairwise 
Pearson correlation coefficients. All treatment groups will be pooled (Table 2.18.1), and also 
analyzed individually (Tables 2.18.2 to 2.18.6). 
6.5 
Safety Analysis 
All safety analyses are based on the Safety Population. Hypothesis testing will not be performed 
for any safety analyses. 
All AE data, clinically significant laboratory values, vital signs, and ECG values will be 
categorized according to their onset date into the following study periods: 
• Events occurring during the treatment period (“On-Treatment”) are events with an onset date 
on or after the first date of dose and up to and including the last day of randomized treatment 
(for study drug completers) or the last day of randomized treatment + 1 day (for premature 
treatment discontinuation). Events known to have occurred before the time of the first dose 
of study treatment are not included. 
• Events occurring during the post-treatment-discontinuation follow-up are events with an 
onset date after the last day of randomized treatment (for study drug completers) or on or 
after the last day of randomized treatment + 2 days (for premature treatment discontinuation). 
The exception is that deaths are still considered to be during the Treatment Period if any 
adverse event that led to that death occurred during the Treatment Period. 
 
 
Any AEs, clinically significant laboratory values, vital signs, and ECG values during the 
randomized-treatment period will be tabulated and listed. Beginning on the day after the date of 
discontinuation from or completion of study medication has passed, any new clinically 
significant ECGs, laboratory values, and vital signs will not be included in the tabulation or the 
computation of incidence rates, but will still be listed. Any new AEs, SAEs, and deaths during 
the post-randomized-treatment maintenance period will be tabulated and listed. 
 
 
Adverse Events 
6.5.1
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. 


 
Statistical Analysis Plan 
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A glossary of MedDRA preferred terms used for AEs reported in the study along with the 
associated Investigator’s verbatim will be provided in Listing 7.2. 
An AE is considered treatment-emergent if an event occurs after the first dose of randomized 
study medication in the study, or if the AE worsened during the study after the first dose of study 
medication in the study (intensity and/or severity changed to a worsened grade), and the event 
onset is on or before the last day of randomized treatment (for study drug completers) or the last 
day of randomized treatment + 1 day (for premature treatment discontinuation). AEs with onset 
date after the last day of randomized treatment (for study drug completers) or the last day of 
randomized treatment + 1 day (for premature treatment discontinuation) will not be considered 
treatment-emergent, but will be listed in adverse event data listings, and will be tabulated 
separately. For the purposes of this SAP, the terms “treatment-emergent AE” and “On-Treatment 
AE” are synonymous. A more detailed definition may be found in Appendix 1 (Data Handling 
Rules, Category 16). AEs that occur between the time the subject signs the informed consent 
form for the study and the time when that subject is randomized are to be recorded as medical 
history unless the event met the definition of an SAE. 
The incidence of an AE will be defined as the number and percentage of subjects experiencing 
an event. Adverse events will be tabulated at the level of the Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and the MedDRA system organ class. No hypothesis tests 
will be performed. 
An overview table will be prepared for the Safety Population with the incidences of subjects with 
at least one treatment-emergent adverse event (TEAE), at least one serious TEAE, at least one 
TEAE related to study treatment, at least one serious TEAE related to study treatment, at least 
one TEAE leading to premature treatment discontinuation, and a report of death (Tables 3.1.1, 
3.1.13, and 3.1.14). 
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. SAE-specific report information will be 
listed in Table 3.8.2.1 and Table 3.8.2.2. 
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 for all 
subjects screened (Tables 3.8.2.1). Adverse events leading to permanent discontinuation of study 
treatment will be listed for the Safety Population (Table 3.6.1). A listing of any reported deaths 


 
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during the study (prior to randomization, during the randomized-treatment period, or during the 
post-randomized-treatment maintenance period) will be provided (Table 3.15.2.1); 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.  
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: 
• The incidence of all treatment-emergent adverse events (Tables 3.2.1.1, 3.2.1.2, Table 
3.2.1.3) 
• The incidence of subjects with adverse events by SOC during the post-randomized-treatment 
maintenance period (Tables 3.2.1.18, 3.2.1.19) 
• The incidence of treatment-emergent adverse events occurring in SMQs (Standard MedDRA 
Queries)/groupings of interest (Tables 3.2.3.1, 3.2.3.2) 
• The incidence of non-serious treatment-emergent adverse events occurring in ≥5% of 
subjects in a treatment (Tables 3.2.4.1, 3.2.4.2) 
• The incidence of all treatment-related treatment-emergent adverse events (Tables 3.4.1, 
3.4.2) 
• The incidence of discontinuation from study treatment due to a treatment-emergent adverse 
events (Tables 3.5.1, 3.5.2) 
• The incidence of treatment-emergent serious adverse events (Tables 3.7.1.1.1, 3.7.1.1.2, 
3.7.1.1.3) 
• The incidence of subjects with serious adverse events by SOC during the post-randomized 
treatment maintenance period ((Tables 3.7.2.3, 3.7.2.4) 
• The incidence of all treatment-related treatment-emergent serious adverse events (Tables 
3.9.1, 3.9.2) 
• The incidence of all treatment-emergent adverse events by highest severity to treatment 
(Tables 3.11.1.1 through 3.11.4.2 for the four treatments) 
• The incidence of treatment-emergent adverse events occurring in at least 2% of subjects in 
any treatment (Tables 3.2.2.1, 3.2.2.2 sorted by descending frequency of events in a preferred 
term). 
• 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 


 
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occurrence (total number of events per 1000 person-years of exposure) by treatment, primary 
system organ class, and preferred term: 
o Frequency and rate of AEs (Tables 3.3.1, 3.3.2) 
o Frequency and rate of SAEs (Tables 3.8.3.1, 3.8.3.2) 
o Frequency and rate of neoplasms (Tables 3.10.3.1 and 3.10.3.2 – All Cancer, 3.10.4.1 and 
3.10.4.2 - Excluding Non-Melanoma Skin Cancer). 
 
6.5.1.1 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) have been defined based on known effects of  LABAs 
and ICS. These include but are not limited to cardiovascular, tremor effects, hyperglycemia, and 
hypokalemia for LABAs; and local (eg, candidiasis and voice effects) and systemic (eg, bone 
and skin effects, diabetes control, ocular and taste effects, adrenal suppression) steroid class 
effects and lung infection for ICS. 
Standard MedDRA queries (SMQs) will be utilized when possible, and a selection of high-level 
group terms (HLGTs), high-level terms (HLTs), and preferred terms (PTs) will be utilized to 
represent other situations. The terms proposed for use in the assessment of AESIs associated 
with ICS and LABAs are listed in Table 6. SMQs will be utilized when possible and a selection 
of preferred terms in other situations (Appendix 5). 
Table 6 
Adverse Events of Special Interest 
Medical Concept 
Selection of MedDRA Terms 
Adrenal suppression 
Adrenal cortical hypofunctions HLT 
Agitation or anxiety 
Collection of PTs 
Bone fracture 
Collection of HLGTs, HLTs, and PTs. 
Candidiasis  
Collection of PTs 
Cardiovascular 
Cardiac arrhythmias SMQ 
Cardiac failure SMQ 
Ischemic heart disease SMQ 
Torsades de Pointe/QT prolongation SMQ 
Cardiovascular death 
Collection of PTs 
Cerebrovascular condition 
CNS haemorrhages and cerebrovascular conditions 
SMQ 
Diabetes mellitus 
Hyperglycaemia/new onset diabetes mellitus SMQ 
Dysgeusia or ageusia 
Collection of PTs 
Dysphonia or aphonia 
Collection of PTs 
Headache  
Headache (PT) 
Hypercortisolism 
Collection of PTs 
Hypertension 
Blood pressure ambulatory increased (PT) 
Blood pressure increased (PT) 
Blood systolic increased (PT) 


 
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Medical Concept 
Selection of MedDRA Terms 
Hypokalemia 
Collection of PTs 
Lower respiratory tract infections other than 
pneumonia 
Bronchitis (PT) 
Bronchitis viral (PT) 
Bronchitis bacterial (PT) 
Lower respiratory tract infection (PT) 
Lower respiratory tract infection viral (PT) 
Lower respiratory tract infection bacterial (PT) 
Infective exacerbation of chronic obstructive airway 
disease (PT) 
Ocular effects 
Visual disorders HLT 
Glaucoma SMQ 
increased intraocular pressure collection of PTs 
Cataract collection of PTs 
Osteoporosis and osteopenia 
Osteoporosis/osteopenia (SMQ) 
Palpitation 
Palpitations PT 
Paradoxical bronchospasm 
Collection of PTs 
Pneumonia  
Collection of PTs 
Psychiatric effect 
Collection of PTs 
Skin effects 
Skin atrophy (PT) 
Skin striae (PT)  
Acne (PT)  
Contusion (PT)  
Ecchymosis (PT)  
Increased tendency to bruise (PT)  
Petechiae (PT)  
Purpura (PT)  
Malassezia folliculitis (collection of PTs)  
Hypertrichosisa (collection of PTs)  
Alopecia (collection of PTs) 
Sleep effects 
Initial insomnia (PT) 
Insomnia (PT) 
Sleep disorder (PT) 
Sudden death 
Collection of PTs 
Throat irritation 
Collection of PTs 
Tremor 
Tremor HLT 
Weight gain 
Collection of PTs 
Abbreviations: CNS=central nervous system; PT=preferred term. 
 
Appendix 5 (which will be based on the latest version of MedDRA available at the time of 
database lock) provides detail on selection of terms (narrow/wide designations for preferred 
terms are provided). 
Adverse Events in MedDRA SMQs/Groupings of Interest by Term will be tabulated (Tables 
3.12.1, 3.12.2). 


 
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6.5.1.2 
Major Adverse Cardiovascular Event (MACE) Determined by Clinical 
Endpoint Committee 
The clinical endpoint committee (CEC) will review and adjudicate serious cardio- and 
cerebrovascular (CCV) events as MACE. MACE events are defined as the following: 
• Cardiovascular death 
• Non-fatal myocardial infarction (MI) 
• Non-fatal stroke 
The CEC will review and assess these non-fatal serious CCV events and all deaths as to whether 
or not they fulfill criteria (based on CEC working practices) for MACE. 
MACE events will be summarized by adjudicated CRF category and treatment group (Tables 
3.13.1.1, 3.13.1.2). The assessment of MACE events will include the rate of confirmed MACE 
events (Tables 3.13.2.1, 3.13.2.2). Adjudicated MACE events will be listed in Listing 7.4. 
The incidence of subjects with adjudicated MACE AEs by category will be summarized in Table 
3.13.3.1 and Table 3.13.3.2. 
6.5.1.3 
Pneumonia Events Determined by Clinical Endpoint Committee 
All AEs/SAEs with preferred terms that could relate to pneumonia will be adjudicated to provide 
a more complete assessment of all physician-reported pneumonias. The incidence of confirmed 
pneumonia events will be tabulated (Tables 3.14.1.1, 3.14.1.2). The assessment of pneumonia 
events will include the rate of confirmed pneumonia events (Tables 3.14.2.1, 3.14.2.2). 
Adjudicated pneumonia events will be listed in Listing 7.4. 
 
In order to account for specific patient risk factors, data permitting, time to first pneumonia will 
be compared between treatments using Cox proportional hazards (Tables 3.14.3.1, 3.14.3.2). 
Specific patient risk factors (baseline FEV1, age, and medical history of pneumonia in the last 5 
years [Yes or No]) will be evaluated for inclusion. 
The incidence of subjects with adjudicated pneumonia AEs by category will be summarized in 
Table 3.13.3.1 and Table 3.13.3.2. 
6.5.1.4 
Cause of Death Determined by Clinical Endpoint Committee 
Causes of death will be listed by subject and summarized by treatment for (1) all-cause mortality, 
(2) mortality of probable cardiovascular cause, (3) mortality of probable respiratory cause, (4) 
mortality of cancer and (5) 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 one day (Tables 3.15.2.1 and 3.15.2.2). The incidence of subjects with a 
death event will be tabulated by adjudicated CRF category and treatment during the randomized-
treatment period (Tables 3.15.1.1, 3.15.1.2) and during the post-randomized-treatment 


 
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maintenance period (Tables 3.15.1.3 and 3.15.1.4). To control for possible differences in 
exposure between treatments, the death will be summarized with frequency and rate of 
occurrence (total number of events per 1000 person-years of exposure) by treatment, primary 
system organ class, and preferred term (Tables 3.15.3.1, 3.15.3.2). Adjudicated death events will 
be listed in Listing 7.4. 
6.5.1.5 
Paradoxical Bronchospasms 
During Visits 3, 4, 6 and 9, the paradoxical bronchospasm event is defined as a reduction in 
FEV1 of >20% from the morning trough, that occurs within 30 minutes post-dosing with 
associated symptoms of wheezing, shortness of breath, or cough. Spontaneous reporting of 
paradoxical bronchospasm will occur at Visits 5, 7, and 8. 
All paradoxical bronchospasm events will be captured on the AE CRF page. For those events 
that occurred during Visits 3, 4, 6 and 9, a programmatic check will be done to verify whether they 
satisfy the condition on the change in FEV1, and will be queried as necessary. Paradoxical 
bronchospasms will be summarized by treatment during the randomized-treatment period (Table 
3.2.3). 


 
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Clinical Laboratory Measurements 
6.5.2
Lab parameters collected include the following: 
Table 7 
Lab Parameters 
Hematology 
Hemoglobin  
Mean corpuscular 
hemoglobin  
Hematocrit  
Mean corpuscular 
hemoglobin concentration 
White blood cell count with differential  
Mean corpuscular 
volume  
Red blood cell count  
Eosinophils 
Platelet count  
 
Clinical Blood Chemistry 
 
Liver Enzyme and Other Liver Function Tests 
Other Clinical Blood 
Chemistry 
Alanine aminotransferase  
Albumin 
Aspartate aminotransferase  
Blood Urea Nitrogen 
(BUN) 
Alkaline phosphatase  
Calcium 
Bilirubin, total  
Chloride 
Gamma-glutamyl transferase  
Cholesterol  
 
Bicarbonate 
 
Creatinine 
 
Glucose 
 
Magnesium  
 
Potassium 
 
Phosphate 
 
Protein, total  
 
Sodium 
 
Triglycerides  
Urinalysis 
Macroscopic examination including specific gravity, pH, protein, glucose, ketones, blood, and  
urobilinogen. 
Other Tests: 
Pregnancy test (women of childbearing potential only): serum hCG at Visit 1 (Screening) and 
Final Visit (Visit 9) or Treatment Discontinuation Visit 
Creatinine clearance will be estimated by the CKD-EPI formula [Levy, 2009] 
Abbreviations: CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; hCG=human chorionic  
gonadotropin 
 


 
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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: 
• A laboratory abnormality that leads to a dose-limiting toxicity (e.g., 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 (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 blood chemistry and kidney function, Listing 8.3 for urinalysis, and Listing 4.6 for 
pregnancy test results at screening and after the start of treatment). Data will be listed in SI units 
where available. Comments for laboratory testing will be listed (Listing 8.4). For listings, 
laboratory values will be flagged as Low or High based on the reference ranges provided by the 
central laboratory, Covance (Appendix 4). 
The baseline measurement for a laboratory parameter will be the last available measurement 
prior to the start of dosing. 
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 the by-visit summaries but both scheduled and unscheduled-visit are candidates for 
the end-of-treatment summary. Data from both scheduled and unscheduled visits will be listed. 
The summaries will be provided by treatment (Tables 3.15.1 through 3.15.4, for hematology, 
blood chemistry, kidney function, and urinalysis, respectively). 
Data from unscheduled visits will not be used for the by-visit summaries but both scheduled-visit 
data and unscheduled-visit data are candidates for clinically significant values, for the end-of-


 
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treatment summary, and for shift tables. Shift tables will be produced using the categories 
defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 grades 
for the Safety Population (Tables 3.15.5 to 3.15.8 for hematology, chemistry, kidney function 
and urinalysis, 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 Covance (found in Appendix 4) as per 
Pearl, Inc. These flags along with the reference ranges will be provided in the laboratory data 
listings. 
Potentially Clinically Significant (PCS) 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 8 
Potentially Clinically Significant 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 
(upper limit of normal) 
White Blood Cell Count 
<2000/µL  
>35,000/µL 
Platelet Count 
<50,000/µL 
>999,000/µL  
Chemistry 
eGFR-EPI (where eGFR denotes 
estimated glomerular filtration rate) 
<30 mL/min/1.73 m2 
AST (aspartate aminotransferase) >3 x ULN 
ALT (alanine aminotransferase) 
>3 x ULN 
Alkaline Phosphatase 
>5 x ULN 
Total Bilirubin 
>2 x ULN 
Blood Glucose* (random values) <2.2 mmol/L (<39.6 mg/dL) 
>13.9 mmol/L (>250 mg/dL) if baseline is 
below 10.0 mmol/L (180 mg/dL), >16.7 
mmol/L (>300 mg/dL) if baseline is greater 
than 10.0 mmol/L (180 mg/dL). 
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. 


 
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Clinically significant laboratory values will be tabulated for the Safety Population (Table 3.15.9). 
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 3.15.10 and 3.15.11). For all laboratory parameters 
other than glucose and potassium noted in Table 7, all laboratory data for the parameter 
identified as potentially clinically significant for a subject will be listed (Table 3.15.12 - Safety 
Population). 
 
Vital Signs 
6.5.3
Changes from Baseline in on-treatment supine or seated systolic blood pressure, supine or 
seated diastolic blood pressure, and heart rate will be evaluated, where baseline is defined as the 
average of all available pre-dose measurements taken prior to the start of dosing at the 
Randomization Visit (Visit 3). If there are no Visit 3 pre-dose values, the baseline will be defined 
as the average of pre-bronchodilator values at Visit 2. No Hypothesis testing will be performed. 
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, Inc.: 
 


 
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Table 9 
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood Pressure 
Parameters 
Parameter (mmHg) 
Post-Baseline Criteria 
Systolic Blood Pressure, increase 
≥180 and increase from baseline ≥20  
Systolic Blood Pressure, decrease 
≤90 and decrease from baseline ≥20 
Diastolic Blood Pressure, increase 
≥105 and increase from baseline ≥15 
Diastolic Blood Pressure, decrease 
≤50 and decrease from baseline ≥15 
 
Potentially clinically significant changes in heart rate will be assessed as follows: 
Table 10 
Potentially Clinically Significant Criteria for Heart Rate Parameters 
Parameter 
Post-Baseline Criteria 
Tachycardia Event 
≥110 bpm and increase ≥15% from baseline 
Bradycardia Event 
≤50 bpm and decrease ≥15% from baseline 
bpm = beats per minute. 
Vital sign measurements (Heart rate, systolic blood pressure, diastolic blood pressure and body 
temperature, weight, 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, 
1.4.2.1, 1.4.3.1, 1.4.4.1 and 1.4.5.1 for the mITT, ITT, PP, and Safety Populations, and all 
subjects not randomized respectively). 
Summary statistics (n, mean, median, standard deviation and range) of the absolute value and 
change from baseline for systolic blood pressure, diastolic blood pressure, heart rate, and 
temperature will be tabulated by treatment, visit, and time point. These summaries 
(Table 3.17.1.1, Table 3.17.1.2) will be prepared for baseline and each scheduled post-baseline 
nominal time point at each scheduled post-baseline visit and end of treatment. End of Treatment 
will be summarized for each scheduled post-baseline time point (pre-dose 1 hr, and post-dose 30 
minutes and 4 hours). “End of Treatment” for each of these assessment points is defined as the 
last non-missing on-treatment assessment available for the time point. Data from unscheduled 
visits will not be used for the by-visit summaries but both scheduled and unscheduled-visit data 
are candidates for clinically significant values and for the end-of-treatment summary. Data from 
both scheduled and unscheduled visits will be listed. Time windows will be derived for each 
post-baseline visit using the time intervals for the study time windows detailed in Table 11. No 
hypothesis tests will be performed. 


 
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Table 11 
Analysis Study Time Windows for Vital Signs Assessments 
Calculated Study Time Window 
Time Interval for the Study Time Window 
Pre-dose 
≥0 min. prior to dose 
Post-dose 30 min. 
>0 to <75 min. post-dose 
Post-dose 2 hrs 
≥ 75 min. 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 3 
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 9 and Table 10 
(Table 3.17.2.1- Safety Population). 
All vital sign assessments for subjects with potentially clinically significant values will be listed 
(Tables 3.17.3.1, 3.17.3.2, 3.17.4.1, Table 3.17.4.2). 
 
12-Lead Electrocardiogram Measurements 
6.5.4
Changes from baseline in Heart Rate, PR Interval, QRS Axis, QRS Interval, QT Interval and 
QTcF (Fridericia Corrected QT) 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 3). If there are no Visit 3 pre-dose values, the baseline will be defined as the value 
obtained at Visit 1. The QTcF is defined as [QT/(RR1/3)]. Heart rate (bpm) is estimated as 
60,000/RR, where RR is in units of ms. These assessments will be tabulated for each treatment 
and assessment time.  
 
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. These assessments will be tabulated for each treatment and each scheduled 
nominal time point at each visit and at end of treatment (Table 3.18.1, Table 3.18.2). End of 
Treatment is defined as the last non-missing on-treatment assessment available. Data from 
unscheduled visits will not be used for the by-visit summaries but both scheduled and 
unscheduled-visit data are candidates for clinically significant values and for the end-of-
treatment summary. Data from both scheduled and unscheduled visits will be listed. Mean pre-
dose change from baseline for heart rate and QTcF will be plotted across post-baseline visits by 


 
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treatment (Figure 3.18.1a and Figure 3.18.1f). ECG data from subjects with pacemakers will not 
be included in analyses, but will be listed. 
If there are multiple ECG values for the same parameter at pre-dose of a visit date (other than for 
Visit 3), 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. 
Table 12 
Criteria for PCS ECG Values 
Parameter 
Post-Baseline Criteria 
QTcF Prolongation 
(1) ≥ 500 msec if < 500 msec at study baseline and ≥ 15 msec 
change from study baseline 
(2) ≥ 530 msec if ≥ 500 msec at study baseline and ≥ 15 msec 
change from study baseline  
(3) ≥ 500 msec and ≥ 15 msec change from study baseline  
(4) Change of ≥60 msec from study baseline regardless of initial 
value  
 
Potentially clinically significant ECG parameter values will be identified based on criteria listed 
in Table 12. The number and percentage of subjects who had such values observed any time 
post-dose will be tabulated for each treatment (Table 3.18.3, 3.18.4) and listed (Tables 3.18.5, 
3.18.6 for QTcF prolongation), (Tables 3.18.7, 3.18.8 for PR interval increase), and (Tables 
3.18.9, 3.18.10 for QRS prolongation). No hypothesis tests will be performed. 
 
Healthcare Resource Utilization 
6.5.5
Data on healthcare resource utilization (HCRU) will be collected at all visits post-baseline and 
summarized by treatment group. 
The following variables will be calculated unadjusted (per subject) over the entire Treatment 
Period and tabulated by actual treatment received for those subjects for whom they or one or 
more of their family members missed work: 
• The number of days missed work due to COPD. 
• The number of days that caregivers of subjects missed from work as a result of the subject’s 
COPD. 
The following variables will be tabulated by actual treatment received and relationship to COPD 
(COPD-related, not COPD-related, and combined). The mean and the mean per person-year will 
be calculated across all subjects in a treatment. 
• The percentage of subjects with telephone calls to health-care providers: 
o Calls to any health-care provider (physician or other) 


 
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o Calls to physician 
o Calls to other healthcare provider 
• The mean number of telephone calls to health-care providers: 
o Calls to any health-care provider (physician or other) 
o Calls to physician 
o Calls to other healthcare provider 
• The percentage of subjects with visits to health-care providers: 
o Visits to any health-care provider (GP, specialist, or other) 
o Visits to GP 
o Visits to specialist 
o Visits to other health-care provider 
• The mean number of visits to health-care providers: 
o Visits to any health-care provider (GP, specialist, or other) 
o Visits to GP 
o Visits to specialist 
o Visits to other health-care provider 
• Ambulance Transport 
o The percentage of subjects who required ambulance transport 
o The mean number of times ambulance transport was required 
• ER Visits 
o The percentage of subjects with ER visits 
o The mean number of visits to ERs 
• Hospitalizations 
o The percentage of subjects hospitalized 
o The mean number of subject hospitalizations  
o The mean number of days in the hospital 
• Hospitalizations with some time spent in the ICU or CCU 
o The percentage of subjects hospitalized with some time spent in the ICU or CCU 
o The mean number of subject hospitalizations with some time spent in the ICU or CCU 
o The mean number of days in the hospital with some time spent in the ICU or CCU 
• Hospitalizations with No time spent in the ICU or CCU 
o The percentage of subjects hospitalized with No time spent in the ICU or CCU 


 
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o The mean number of subject hospitalizations with No time spent in the ICU or CCU 
o The mean number of days in the hospital with No time spent in the ICU or CCU 
• ICU 
o The percentage of subjects in the ICU 
o The mean number of days in ICUs 
• CCU 
o The percentage of subjects in the CCU 
o The mean number of days in CCUs 
Analyses will be performed using the mITT 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 3.20.1 and Listing 9.4). 
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 number of times ambulance 
transport was required, the number of subject hospitalizations, the number of days in the 
hospital, the number of days in the ICU, and the number of days in the CCU (Table 3.20.2 and 
Listings 9.4 and 9.5).  
 
Physical Examination 
6.5.6
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. 
7. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL  
Figures 7 and 8 (Type I error control charts for EU approach) were fixed to reflect that the non-
inferiority testing is performed using the Per Protocol Estimand. 
8. 
STATISTICAL SOFTWARE 
Data processing, statistical screening, descriptive reporting and analysis of the efficacy and 
safety data will be performed using SAS (Version 9.3 or higher). Graphs may also be produced 
using R (R Development Core Team, 2003). 


 
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9. 
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R Development Core Team. R: A language and environment for statistical computing, 2003. R 
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