Clinical trial NCT03358147
Conditions: Asthma
Sponsor: Pearl Therapeutics, Inc.
Start date: 2017-12-13; Completion date: 2019-09-12
Enrollment: 1077 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study Comparing the Efficacy and Safety of PT001 to Placebo and Open-label Spiriva® Respimat® in Subjects With Persistent Asthma

Detailed description:
A Randomized, Double-Blind, Parallel Group, Multi-Center 24-Week Study Comparing the Efficacy and Safety of Three Doses of PT001 to Placebo and Open-label Spiriva® Respimat® in Subjects With Persistent Asthma

Arms: arm 1: GP MDI 14.4 μg per actuation taken as 2 inhalations BID arm 2: GP MDI 7.2 μg per actuation taken as 2 inhalations BID arm 3: GP MDI 3.6 μg per actuation taken as 2 inhalations BID arm 4: Taken as 2 inhalations BID arm 5: Open Label Spiriva Respimat 2.5 μg
Interventions: intervention 1: GP MDI 28.8 μg intervention 2: GP MDI 14.4 μg intervention 3: GP MDI 7.2 μg intervention 4: Placebo MDI intervention 5: Spiriva Respimat 2.5 μg
Intervention descriptions: intervention 1: GP MDI (PT001)14.4 μg per actuation taken as 2 inhalations BID intervention 2: GP MDI (PT001) 7.2 μg per actuation taken as 2 inhalations BID intervention 3: GP MDI (PT001) 3.6 μg per actuation taken as 2 inhalations BID intervention 4: Placebo taken as 2 inhalations BID intervention 5: Spiriva Respimat 2.5 μg QD (open-label)

Protocol documents:
Prot_000.pdf: 
 
 
Revised Clinical Study Protocol 
Study Code 
PT001102 
NCT #  
NCT03358147 
Date: 
   
  08 MARCH 2019 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Double-Blind, Parallel Group, Multi-Center 24 Week Study 
Comparing the Efficacy and Safety of Three Doses of PT001 to Placebo and 
Open-label Spiriva® Respimat® in Subjects With Persistent Asthma 
 
 
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 
13 OCTOBER 2017 
Version 2, Amendment 1 
13 APRIL 2018 
Version 3, Amendment 2 
07 JUNE2018 
Version 4, Amendment 3  
22 AUGUST 2018 
Version 5, Amendment 4 
08 MARCH 2019 
 
 


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Pearl Therapeutics, Inc.
Clinical Study Protocol: PT001102-04
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Clinical Study Protocol: PT001102-04
Study Title
A Randomized, Double-Blind, Parallel Group, Multi-Center 24-Week 
Study Comparing the Efficacy and Safety of Three Doses of PT001 to 
Placebo and Open-label Spiriva® Respimat® in Subjects With 
Persistent Asthma
Study Number
PT001102
Study Phase
Phase II/III
Product Name
Glycopyrronium Inhalation Aerosol (PT001, GP MDI) 
Indication
Asthma
Investigators
Multicenter
Sponsor
Pearl Therapeutics, Inc.
Sponsor Contact:
Version Number
Date
Original Protocol
Version 1.0
13 October 2017
Amended Protocol #1
Version 2.0
13 April 2018
Amended Protocol #2
Version 3.0
07 June 2018
Amended Protocol #3
Version 4.0
22 August 2018
Amended Protocol #4
Version 5.0
08 March 2019
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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Clinical Study Protocol: PT001102-04
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SUMMARY OF CHANGES TO AMENDED PROTOCOL PT001102-04 
(VERSION 5.0), DATED 08 MARCH 2019
The amended study protocol, PT001102-04 (Version 5.0), includes the following edits:
No.
Description of Change
Rationale
1
Removed Visit 5 (Week 4) post-dose 
vital sign measurements
Sections affected:
7.2.2 Vital Sign Measurements
8.1 General Study Considerations 
(Table 8-2 Sequence and Timing for 
Selected Assessments at Treatment 
Visits 4 through 10)
Post-dose spirometry assessment was 
removed from Visit 5 in Amendment 
03, but post-dose vital signs at Visit 5 
were left in error.  This assessment has 
now been removed as there should be 
no post-dose assessments performed at 
Visit 5.
2
Reduced the time gaps around Visits 1, 
2, and 3 by 2 days 
Sections affected:
4.1 Study Design (Figure 4-1 Study 
Design Overview)
8.1 General Study Considerations 
(Table 8-1 Schedule of Events)
8.4 Visit 3 (Day -20 to Day -1)
Holter monitoring sub-study is 
complete and the extended time gaps 
around Visits 1, 2, and 3 are no longer 
needed.
3
Added height requirement at Visits 4, 5, 
and 7 for subjects 12 to 18 years of 
age
Sections affected:
7.2.1 Medical/Surgical/Asthma 
Exacerbation History and Physical 
Examination
8.1 General Study Considerations 
(Table 8-1 Schedule of Events)
8.5 Visit 4 (Randomization, Day 1)
8.6 Visits 5, 6, 8, and 9 (Weeks 4, 8, 16, 
and 20)
8.7 Visit 7 (Week 12)
8.8 Final Visit (Visit 10, Week 24)
Height is needed for subjects 12 to 18 
years of age in order to calculate 
creatinine clearance using the Schwartz 
formula.


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No.
Description of Change
Rationale
4
Age range for creatinine clearance 
equations corrected.
Sections affected:
5.2, Exclusion Criterion #13
5.9.1, Reasons for Study Drug 
Discontinuation
7.2.5, Clinical Laboratory Tests (Table 
7-2 List of Clinical Safety Laboratory 
Tests)
Clarification that subjects 18 years of 
age should have the Schwartz equation 
used for creatinine clearance only if the 
day of the visit is on their 18th birthday.
5
Moved rate of moderate/severe asthma 
exacerbation from an “other” 
endpoint to a secondary endpoint and 
time to first moderate/severe asthma 
exacerbation from a secondary 
endpoint to an “other endpoint”
Sections affected:
Synopsis
3.2 Secondary Efficacy Endpoints
3.3 Other Endpoints
9.5.2.2 Rate of Moderate/Severe 
Asthma Exacerbations
9.5.3.3 Time to First Asthma 
Exacerbation
9.5.3.4 Rate of Severe Asthma 
Exacerbation or Exacerbations of 
Any Severity
In situations where multiple subjects 
experiencing an event tend to 
experience more than one event, an 
analysis of the event rate is more 
powerful than an analysis of time to 
first event.  A blinded review of data 
from this study indicates that there are 
more events than subjects with at least 
one event.  Hence, the hierarchy order 
will be switched for the rate and time to 
first analyses of moderate/severe 
exacerbations.
6
Changed PEFR analysis at each clinic 
visit to over 4-week intervals 
Sections affected:
9.5.3.8 Change from Baseline in 
Morning PEFR and Evening PEFR
Clarification that PEFR will be 
analyzed over 4-week intervals 
7
Amended censoring wording for 
CompEx endpoint for remove Day 
168
Sections affected:
9.5.3.10 CompEx
Clarification that CompEx will be 
censored at the Week 24 visit only


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Clinical Study Protocol: PT001102-04
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No.
Description of Change
Rationale
8
Added wording that any clarification to 
the definition and analysis of 
consecutive asthma exacerbations 
will be detailed in the statistical 
analysis plan
Clarification for definition and analysis 
of consecutive asthma exacerbations.
9
Made the following modifications to 
Holter Monitoring Sub-study 
endpoints:
Removed analysis of subjects meeting 
withdrawal criteria
Added endpoint of "Change from 
baseline in the frequency of 
supraventricular couplets"
Changed "Supraventricular ectopic 
events" to "Supraventricular ectopic 
beats"
Sections affected:
3.5.2 Secondary Holter Monitoring 
Sub-Study Endpoints
Clarification of Holter monitoring sub-
study endpoints
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 Study Drug
Glycopyrronium Inhalation Aerosol (PT001, GP metered dose inhaler [GP MDI])
Name of Active Ingredient: Glycopyrronium
Study Title: A Randomized, Double-Blind, Parallel Group, Multi-Center 24-Week Study 
Comparing the Efficacy and Safety of Three Doses of PT001 to Placebo and Open-label 
Spiriva® Respimat® in Subjects With Persistent Asthma
Study Protocol Number: PT001102-04
Study Phase: II/III 
Primary Objective: To assess the effect of 3 doses of GP MDI compared to Placebo 
MDI and Spiriva® Respimat® on lung function over 24 weeks in subjects with persistent 
asthma.
Secondary Objective: To assess the effect of 3 doses of GP MDI compared to Placebo 
MDI and Spiriva Respimat on exacerbations, quality of life, and symptoms over 24 weeks 
in subjects with persistent asthma.
Safety Objective: To assess the safety of 3 doses of GP MDI compared to Placebo MDI 
and Spiriva Respimat over 24 weeks in subjects with persistent asthma.
24-Hour Holter Monitoring Sub-Study Objective: To assess the cardiovascular safety 
of 3 doses of GP MDI compared to Placebo MDI and Spiriva Respimat as evaluated by 
24-hour Holter monitoring.
Study Design
This Phase II/III randomized, double-blind, parallel group, multi-center, dose 
confirmation study will compare 3 doses of GP MDI (28.8, 14.4, and 7.2 μg) to Placebo 
MDI and open-label Spiriva Respimat (2.5 μg). The 3 doses of GP MDI and the Placebo 
MDI will be administered twice daily (BID) and Spiriva Respimat will be administered 
once daily (QD), both for 24 weeks.
At Visit 1, subjects will sign an informed consent form (ICF) and assent form (as 
applicable) and inclusion/exclusion criteria will be assessed. All eligible subjects must 
have been taking a stable regimen of an inhaled corticosteroid (ICS)/long-acting β2-
agonist (LABA) for at least 4 weeks, and be willing to continue this medication regimen 
throughout the trial. Subjects also taking tiotropium 2.5 μg QD for at least 4 weeks prior 
to Visit 1 may be enrolled if they are willing to discontinue tiotropium at Visit 1. 
Tiotropium will be replaced with Sponsor-provided ipratropium bromide 
hydrofluoroalkane (hereafter referred to as ipratropium) taken as 2 inhalations 4 times 
daily until randomization, when ipratropium will be discontinued. Sponsor-provided 


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albuterol for rescue use will be dispensed and subjects will begin recording their asthma 
medications, peak expiratory flow rates, asthma symptom scores, and rescue albuterol use 
in an electronic diary. 
Subjects must demonstrate a forced expiratory volume in 1 second (FEV1) of >40% and 
<85% of predicted (>40% and <90% of predicted for subjects 12 to <18 years of age) at 
Visit 1 (and Visit 2 if spirometry is required), and must demonstrate reversibility to 
albuterol at Visit 1 or Visit 2. 
Subjects will return for Visit 2 after adequate washout of prohibited asthma medications.
There will be a minimum of 7 days between Visit 1 and Visit 2. Spirometry will only be 
performed at Visit 2 if reversibility criteria to albuterol were not met at Visit 1. The 
Asthma Control Questionnaire (ACQ) will be administered, and multiple other 
assessments will be made including fractional nitric oxide in inhaled breath (FENO).
At Visit 3, reversibility of FEV1 to ipratropium will be assessed for characterization and 
randomization stratification. For subjects participating in the Holter monitoring sub-
study, a 24-hour Holter monitor will also be placed.
At Visit 4, subjects meeting randomization criteria (including demonstrating an FEV1 of 
>40% and <85% of predicted [>40% and <90% of predicted for subjects 12 to <18 years 
of age]) will be randomized in a 2:2:2:2:1 scheme to 1 of the following 5 treatment 
groups:
•
GP MDI 28.8 μg BID (double-blind)
•
GP MDI 14.4 μg BID (double-blind)
•
GP MDI 7.2 μg BID (double-blind)
•
Placebo MDI BID (double-blind)
•
Spiriva Respimat 2.5 μg QD (open-label)
Randomization will be stratified by baseline percent predicted FEV1 (≤60% or >60%), 
reversibility to ipratropium (<12% or <200 mL vs ≥12% and ≥200 mL improvement in 
FEV1), and by the ICS included in their fixed-dose ICS/LABA combination product 
(budesonide [eg, Symbicort®, with formoterol fumarate dihydrate], mometasone furoate 
[eg, Dulera®, with formoterol fumarate dihydrate], fluticasone furoate [eg, Breo® Ellipta®, 
with vilanterol trifenatate], or fluticasone propionate [eg, Advair® or AirDuo™ 
RespiClick®, with salmeterol]).
Following randomization, subjects will enter the Treatment Period and undergo 6 
additional treatment visits over 24 weeks. For subjects participating in the Holter 
monitoring sub-study, a Holter monitor will be placed at Visit 7 and removed the 
following day.
Subjects who discontinue randomized study drug prior to the end of the study will be 
encouraged to remain in the study to complete all remaining study visits and procedures.


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24-Hour Holter Monitoring Sub-Study: Holter monitoring will be conducted over 24 
hours in a subset of approximately 562 randomized subjects (125 subjects in each GP 
MDI group and the Placebo MDI group and 62 subjects in the Spiriva Respimat group) at 
Visit 3 (Holter monitoring baseline) and Visit 7 (Week 12).
Study Population: Approximately 2250 subjects with persistent asthma who are 
symptomatic despite treatment with a fixed-dose ICS/LABA (± tiotropium) will be 
recruited in order to enroll approximately 1125 subjects into the randomized Treatment 
Period. This study will be conducted at approximately 250 sites in the United States with 
each site enrolling approximately 4 to 6 subjects.
Test Product, Dose, Strength, and Mode of Administration
All study drugs will be administered by oral inhalation.
Study Drug (Active and Placebo)
Product Name 
and Dose
Product Strength
Manufacturer
Dosage Form/
Fill Count
Administration
GP MDI 28.8 μg
GP MDI 14.4 μg 
per actuation
Pearl
MDI/
120 inhalations
Taken as 
2 inhalations BID
GP MDI 14.4 μg
GP MDI 7.2 μg 
per actuation
Pearl
MDI/
120 inhalations
Taken as 
2 inhalations BID
GP MDI 7.2 μg
GP MDI 3.6 μg 
per actuation
Pearl
MDI/
120 inhalations
Taken as 
2 inhalations BID
Placebo MDI 
No active 
ingredient
Pearla
MDI/
120 inhalations
Taken as 
2 inhalations BID
Spiriva®
Respimat® 2.5 μg
tiotropium 
bromide 1.25 μg 
per actuation
Boehringer 
Ingelheim 
Pharmaceuticals, 
Inc.
Inhalation spray, 
metered/ 
60 inhalations
Taken as 
2 inhalations QD
a
Placebo MDIs are manufactured in the image of the active test product.
Duration of Treatment: 24 weeks
Duration of Study: The entire study is scheduled to take approximately 27 to 30 weeks 
for each subject. The study is anticipated to run for approximately 12 months.
Efficacy Endpoints
Primary Efficacy Endpoint:
•
Change from baseline in FEV1 area under the curve from 0 to 4 hours (AUC0-4) at 
Week 24
Secondary Efficacy Endpoints
•
Change from baseline in morning pre-dose trough FEV1 at Week 24
•
Rate of moderate/severe asthma exacerbations 
•
Change from baseline in ACQ-7 at Week 24


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•
Change from baseline in ACQ-5 at Week 24
•
Change from baseline in Asthma Quality of Life Questionnaire for 12 years and older 
(AQLQ +12) at Week 24
Safety Endpoints
•
Adverse events
•
Clinical laboratory values
•
Vital signs
•
12-lead safety electrocardiograms (ECGs)
24-Hour Holter Monitoring Sub-Study Endpoint (Assessed at Week 12)
Primary Endpoint
•
Change from baseline in mean heart rate over 24 hours
Statistical Methods
Primary Efficacy Analysis
Change from baseline in FEV1 AUC0-4 will be analyzed using a linear repeated measures 
analysis of covariance model for the Efficacy Estimand. The model will include 
treatment, visit, background ICS/LABA, and treatment by-visit interaction as categorical 
covariates and baseline FEV1, percentage reversibility to ipratropium, and blood 
eosinophil count at screening as continuous covariates.
Sample Size
A sample size of 1125 subjects (250 subjects per double-blind treatment group, 
125 subjects in the open-label Spiriva Respimat treatment group) will provide 
approximately 93% power to detect a 120 mL difference between the GP MDI treatment 
groups and Placebo MDI in the analysis of change from baseline in FEV1 AUC0-4 at 
Week 24. The assumed standard deviation is 348 mL at each visit. The 2-sided alpha for 
each pairwise comparison is 0.05. This sample size assumes that approximately 20% of 
randomized subjects will have discontinued study drug prior to Week 24.
Comparisons of GP MDI to Spiriva Respimat will be focused on estimation as the study 
is not formally powered to demonstrate non-inferiority or superiority.
Data Monitoring Committee:
An independent, external Data Monitoring Committee (DMC) will be set up to review all 
serious adverse events (including deaths and all hospitalizations) and cardiovascular 
events. Members of the DMC will review summaries of these safety data generated 
externally and independently of the Sponsor in a semi-blinded or unblinded manner at 
predetermined intervals. If significant safety issues arise in between scheduled meetings, 
ad hoc meetings will be scheduled to review the data. Based on the safety implications of 
the data, the DMC may recommend modification or termination of the study.
Date of Original Approved Protocol: 13 October 2017
Date of Protocol Amendment 1 (Version 2.0): 13 April 2018


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Date of Protocol Amendment 2 (Version 3.0): 07 June 2018
Date of Protocol Amendment 3 (Version 4.0): 22 August 2018
Date of Protocol Amendment 4 (Version 5.0): 08 March 2018


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TABLE OF CONTENTS
SUMMARY OF CHANGES TO AMENDED PROTOCOL PT001102-04 (VERSION 
5.0), DATED 08 MARCH 2019 ....................................................................................2
SYNOPSIS............................................................................................................................5
TABLE OF CONTENTS ....................................................................................................10
LIST OF IN-TEXT TABLES..............................................................................................15
LIST OF IN-TEXT FIGURE...............................................................................................15
LIST OF APPENDICES .....................................................................................................15
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS........................................17
1
INTRODUCTION.......................................................................................................20
1.1
Background Information on the Treatment of Asthma........................................20
2
STUDY OBJECTIVES................................................................................................22
2.1
Primary Objective ..............................................................................................22
2.2
Secondary Objective ..........................................................................................22
2.3
Safety Objective.................................................................................................22
2.4
24-Hour Holter Monitoring Sub-Study Objective...............................................22
3
STUDY ENDPOINTS.................................................................................................23
3.1
Primary Efficacy Endpoint.................................................................................23
3.2
Secondary Efficacy Endpoints............................................................................23
3.3
Other Efficacy Endpoints...................................................................................23
3.4
Safety Endpoints................................................................................................24
3.5
24-Hour Holter Monitoring Sub-Study Endpoints ..............................................24
3.5.1
Primary Holter Monitoring Sub-Study Endpoint.......................................24
3.5.2
Secondary Holter Monitoring Sub-Study Endpoints..................................24
4
INVESTIGATIONAL PLAN ......................................................................................26
4.1
Study Design......................................................................................................26
4.2
Rationale............................................................................................................28
4.2.1
Population................................................................................................28
4.2.2
Choice of Study Doses .............................................................................28
4.2.3
Choice of Comparators/Control Groups....................................................29
4.2.4
Study Duration .........................................................................................29
5
STUDY POPULATION SELECTION ........................................................................30
5.1
Inclusion Criteria ...............................................................................................30
5.2
Exclusion Criteria ..............................................................................................31
5.3
Randomization Criteria ......................................................................................33
5.4
Re-Screening Criteria.........................................................................................33
5.5
Holter Monitoring Sub-Study Exclusion Criteria................................................33


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5.6
Subject Identification .........................................................................................34
5.7
Prior, Concomitant, and Prohibited Medications and Vaccinations.....................34
5.7.1
Prior Medications .....................................................................................34
5.7.2
Concomitant Medications and Vaccinations .............................................35
5.7.2.1
Vaccinations...................................................................................35
5.7.2.2
Allowed Medications......................................................................35
5.7.3
Prohibited Medications and Washout Periods...........................................37
5.7.3.1
Prohibited Asthma and Allergy Medications and Washout Periods .37
5.7.3.2
Prohibited Non-Asthma and Non-Respiratory Medications and 
Washout Periods.............................................................................37
5.8
Other Restrictions, Illicit Drugs, and Drugs of Abuse.........................................39
5.8.1
Illicit Drugs or Drugs of Abuse.................................................................39
5.8.2
Dietary Restrictions..................................................................................39
5.9
Reasons for Study Drug Discontinuation or Study Withdrawal...........................39
5.9.1
Reasons for Study Drug Discontinuation ..................................................39
5.9.2
Reasons for Study Withdrawal .................................................................40
6
CLINICAL SUPPY LABELING, PACKAGING, STORAGE, DISPENSING, AND
RETURN.....................................................................................................................41
6.1
Description of Study Drugs................................................................................41
6.2
Other Sponsor-Provided Medications Used in the Study ....................................42
6.3
Packaging and Labeling .....................................................................................43
6.3.1
Primary Packaging and Labeling ..............................................................43
6.3.2
Secondary Packaging and Labeling ..........................................................43
6.4
Storage Requirements ........................................................................................43
6.5
Instructions for Dispensing and Preparation of Study Drugs for 
Administration...................................................................................................44
6.6
Emergency Unblinding ......................................................................................45
6.7
Drug Accountability/Return of Clinical Supplies................................................45
7
STUDY PROCEDURES .............................................................................................47
7.1
Efficacy Assessments.........................................................................................47
7.1.1
Pulmonary Function Tests ........................................................................47
7.1.1.1
Spirometry Standardization.............................................................47
7.1.1.2
Spirometry Schedule.......................................................................48
7.1.1.3
Reversibility to Albuterol and Ipratropium......................................49
7.1.2
Subject’s eDiary Data Collection..............................................................49
7.1.2.1
eDiary Compliance Requirement ....................................................50
7.1.2.2
Rescue Medication Use...................................................................50
7.1.2.3
PEFR..............................................................................................50
7.1.2.4
Asthma Symptoms..........................................................................51
7.1.2.5
Study Drug and Other Study Medication Compliance .....................52
7.1.2.6
Symptom Worsening Assessment and eDiary Alert System............52


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7.1.3
Asthma Exacerbations..............................................................................52
7.1.3.1
Definitions and Treatments.............................................................52
7.1.3.2
Onset and Duration of Asthma Exacerbations .................................54
7.1.3.3
Approach for Capturing Asthma Exacerbations...............................54
7.1.4
Subject Questionnaires .............................................................................55
7.1.4.1
ACQ...............................................................................................55
7.1.4.2
AQLQ +12 .....................................................................................55
7.1.5
FENO .........................................................................................................56
7.2
Safety Assessments............................................................................................56
7.2.1
Medical/Surgical/Asthma Exacerbation History and Physical 
Examination .............................................................................................56
7.2.2
Vital Sign Measurements..........................................................................57
7.2.3
12-Lead ECG ...........................................................................................57
7.2.4
Holter Monitoring: 24-Hour Continuous Electrocardiography ..................58
7.2.4.1
Visit 3 Holter Monitoring Procedures .............................................58
7.2.4.2
Visit 7 Holter Monitoring Procedures .............................................59
7.2.4.3
Data for Analysis............................................................................59
7.2.5
Clinical Laboratory Tests .........................................................................59
7.3
AEs....................................................................................................................62
7.3.1
Performing AE Assessments.....................................................................62
7.3.2
AE 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
Asthma Exacerbations and Associated Symptoms of Asthma ...................63
7.3.7
AEs of Special Interest .............................................................................64
7.3.7.1
LAMA Effects................................................................................64
7.3.7.2
Paradoxical Bronchospasm .............................................................64
7.3.8
Clinical Laboratory AEs...........................................................................64
7.3.9
SAEs........................................................................................................65
7.3.9.1
Reporting SAEs..............................................................................65
7.3.9.2
Supplemental Investigations of SAEs..............................................66
7.3.9.3
Notification of Post-Study SAEs.....................................................66
7.3.9.4
Institutional Review Board/Independent Ethics Committee 
Notification of SAEs.......................................................................66
7.3.9.5
Health Authority Safety Reports .....................................................67
7.3.10
Post-Study Follow-Up of AEs and SAEs ..................................................67
7.3.11
Overdose..................................................................................................67
7.3.12
Pregnancy.................................................................................................67
7.3.13
Paternal Exposure.....................................................................................67
7.3.14
Hy’s Law .................................................................................................68


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7.3.15
Data Monitoring Committee.....................................................................68
7.4
Termination of Study .........................................................................................68
8
STUDY ACTIVITIES.................................................................................................69
8.1
General Study Considerations ............................................................................69
8.2
Visit 1 (Day –28 to –9).......................................................................................78
8.3
Visit 2 (Day –21 to Day –2) ...............................................................................79
8.4
Visit 3 (Day –20 to Day –1) ...............................................................................80
8.5
Visit 4 (Randomization, Day 1)..........................................................................81
8.6
Visits 5, 6, 8, and 9 (Weeks 4, 8, 16, and 20)......................................................83
8.7
Visit 7 (Week 12)...............................................................................................84
8.8
Final Visit (Visit 10, Week 24)...........................................................................86
8.9
Procedures for Treatment Discontinuation and Study Withdrawal Visits............87
8.9.1
Treatment Discontinuation .......................................................................87
8.9.2
Study Withdrawal.....................................................................................87
8.9.3
Study Visit Procedures .............................................................................87
8.10
Repeat Assessments and Treatment Discontinuation and/or Study Withdrawal 
Visits .................................................................................................................88
8.11
Follow-Up Telephone Call.................................................................................88
8.12
Completion of the Study ....................................................................................88
9
STATISTICAL METHODS........................................................................................90
9.1
Introduction .......................................................................................................90
9.2
Protocol Variables..............................................................................................90
9.3
Analysis Sets and Estimands..............................................................................90
9.3.1
Analysis Sets............................................................................................90
9.3.2
Estimands.................................................................................................91
9.4
Demographic and Baseline Characteristics.........................................................92
9.5
Efficacy Analysis...............................................................................................92
9.5.1
Primary Efficacy Analysis........................................................................92
9.5.1.1
Change From Baseline in FEV1 AUC0-4..........................................92
9.5.2
Secondary Efficacy Analysis ....................................................................93
9.5.2.1
Change From Baseline in Morning Pre-Dose Trough FEV1 ............93
9.5.2.2
Rate of Moderate/Severe Asthma Exacerbations.............................93
9.5.2.3
Change From Baseline in ACQ-7, ACQ-5, and AQLQ +12 ............93
9.5.3
Other Efficacy Analyses...........................................................................93
9.5.3.1
Percentage of Responders in ACQ-5, ACQ-6, ACQ-7, and 
AQLQ +12 .....................................................................................93
9.5.3.2
Change from Baseline in ACQ-6.....................................................94
9.5.3.3
Time to First Asthma Exacerbation.................................................94
9.5.3.4
Rate of Severe Asthma Exacerbations or Exacerbations of Any 
Severity ..........................................................................................94


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9.5.3.5
Peak FEV1 ......................................................................................94
9.5.3.6
Percentage of Symptom-Free Days, Rescue-Free Days, and 
Asthma Control Days......................................................................94
9.5.3.7
Rescue Medication Usage...............................................................95
9.5.3.8
Change From Baseline in Morning PEFR and Evening PEFR.........95
9.5.3.9
FENO ...............................................................................................95
9.5.3.10
CompEx .........................................................................................96
9.5.4
Subgroup Analyses...................................................................................96
9.5.5
Type I Error Control.................................................................................96
9.6
Safety Analysis ..................................................................................................97
9.6.1
AEs ..........................................................................................................97
9.6.2
AESIs.......................................................................................................97
9.6.3
Clinical Laboratory Measurements ...........................................................97
9.6.4
Vital Signs................................................................................................97
9.6.5
ECGs........................................................................................................97
9.6.6
24-Hour Holter Monitoring ......................................................................97
9.7
Sample Size Consideration.................................................................................98
9.8
Data Validation and Transformation...................................................................98
9.9
Analysis Plan .....................................................................................................99
9.10
Blinded Sample Size Re-Estimation...................................................................99
9.11
Interim Analysis.................................................................................................99
9.12
Handling of Missing Data ..................................................................................99
9.13
Statistical Software ............................................................................................99
10
ADMINISTRATIVE CONSIDERATIONS...............................................................100
10.1
Regulatory Authority Approval........................................................................100
10.2
Ethical Conduct of the Study and IRB or IEC Approval...................................100
10.3
Subject Informed Consent................................................................................100
10.4
Laboratory Accreditation .................................................................................101
10.5
Confidentiality.................................................................................................101
10.5.1
Confidentiality of Data...........................................................................101
10.5.2
Confidentiality of Subject Records .........................................................101
10.6
Quality Control and Assurance.........................................................................101
10.7
Data Management ............................................................................................102
10.8
Study Monitoring.............................................................................................102
10.9
Retention of Data.............................................................................................103
10.10 Financial Disclosure.........................................................................................103
10.11 Investigator’s Final Report...............................................................................103
10.12 Publication and Disclosure Policy ....................................................................103
11
REFERENCE LIST...................................................................................................105


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12
APPENDICES...........................................................................................................107
LIST OF IN-TEXT TABLES
Table 5-1
Permitted ICS Dosages in Fixed-Dose Combination Products 
With LABA…… .....................................................................................................35
Table 5-2 
Allowed Asthma Medications With Required Holding Periods Prior 
to Visit 2 and All Subsequent Visits.........................................................................36
Table 5-3 
Allowed Asthma and Allergy Medications..........................................36
Table 5-4 
Prohibited Asthma and Allergy Medications and Required Washout 
Period Prior to Visit 2 ..............................................................................................37
Table 5-5 
Prohibited Non-Asthma and Non-Respiratory Medications and 
Required Washout Period Prior to Visit 1 ................................................................38
Table 6-1 
Randomized Study Drugs ...................................................................42
Table 6-2 
Other Sponsor-Provided Study Medications........................................42
Table 7-1 
Definition and Severity of Asthma Exacerbations ...............................53
Table 7-2 
List of Clinical Safety Laboratory Tests..............................................61
Table 8-1 
Schedule of Events..............................................................................71
Table 8-2 
Sequence and Timing for Selected Assessments at Treatment 
Visits 4 through 10 …..............................................................................................75
Table 8-3 
Schedule of Events for 24-hour Holter Monitoring Sub-Study at 
Visits 3 and 7...........................................................................................................77
LIST OF IN-TEXT FIGURE
Figure 4-1 
Study Design Overview ......................................................................26
LIST OF APPENDICES
Appendix 1
Body Mass Index Calculators............................................................108
Appendix 2
Spirometry Assessment Criteria ........................................................109
Appendix 3
Spirometry Performance Recommendations......................................111
Appendix 4
Dose-Indicator Reading for GP MDI and Placebo MDI.....................117
Appendix 5
Instructions for Use of GP MDI and Placebo MDI............................118
Appendix 6
Instructions for Use of Spiriva® Respimat® (tiotropium) Inhalation 
Spray ………….....................................................................................................127
Appendix 7
Instructions for Use of Ventolin® HFA (albuterol) Inhaler ................133
Appendix 8
Instructions for Use of Atrovent® HFA (ipratropium) Inhaler............144


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Appendix 9
Asthma Control Questionnaire (ACQ) ..............................................149
Appendix 10
Asthma Quality of Life Questionnaire for 12 Years and Older 
(AQLQ +12) ….. ...................................................................................................152
Appendix 11
Fractional Nitric Oxide in Inhaled Breath..........................................158
Appendix 12
Rules for Evaluation of Abnormal Liver Laboratory Values..............159
Appendix 13
Sponsor Signatory.............................................................................162
Appendix 14
Investigator’s Agreement and Signature Page ...................................163


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ACQ
Asthma Control Questionnaire
ACQ-5
ACQ questions 1 through 5, which measure the frequency, intensity or 
limitations from asthma symptoms using 1-week recall
ACQ-6
ACQ questions 1 through 6, which is the ACQ-5 plus 1 item that scores 
the average number of daily puffs needed from rescue medication using 
1-week recall
ACQ-7
ACQ questions 1 through 7, which is the ACQ-6 plus1 item that scores
lung function (FEV1 percent predicted)
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AQLQ +12
Asthma Quality of Life Questionnaire for 12 years and older
AST
Aspartate aminotransferase
ATS
American Thoracic Society
AUC0-4
Area under the curve from 0 to 4 hours
BID
Twice daily
CFR
Code of Federal Regulations
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CompEx
A composite endpoint comprising clinically relevant deteriorations and 
severe exacerbations in asthma
DBP
Diastolic blood pressure
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
eDiary
Electronic diary
ER
Emergency room
ERS 
European Respiratory Society
FDA
Food and Drug Administration
FENO
Fractional nitric oxide concentration in exhaled breath


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FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
GP MDI
Glycopyrronium Inhalation Aerosol
hCG
Human chorionic gonadotropin
HFA
Hydrofluoroalkane
HR
Heart rate
IB
Investigator brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation 
ICMJE
International Committee of Medical Journal Editors
ICS
Inhaled corticosteroid
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISMPP
International Society for Medical Publication Professionals
ITT
Intent-to-Treat
IWRS
Interactive web response system
LABA
Long-acting β2-agonist
LAMA
Long-acting muscarinic antagonist
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-Treat 
NSVT
Non-sustained ventricular tachycardia
PEFR
Peak expiratory flow rate
PFT
Pulmonary function test
PIN
Personal identification number
PVC
Premature ventricular contraction
QD
Once daily


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QID
Four times daily
QTcF
Fridericia-corrected QT interval
SABA
Short-acting β2-agonist
SAE
Serious adverse event
SAMA
Short-acting muscarinic antagonist
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Standard deviation
TBL
Total bilirubin
ULN
Upper limit of normal
US
United States


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1
INTRODUCTION
The Sponsor is developing a family of orally inhaled drug products containing budesonide, 
glycopyrronium, and/or formoterol fumarate as single agents, dual combinations, and a triple 
combination product. These drug products are metered dose inhalers (MDIs) formulated as a 
suspension with micronized active pharmaceutical ingredients and Co-Suspension™ 
Delivery Technology. The Co-Suspension Delivery Technology consists of spray-dried 
porous particles comprised of the phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine 
and calcium chloride suspended in a hydrofluoroalkane (HFA) propellant. When used in 
combination MDI products, these particles form strong non-specific associations with the 
active pharmaceutical ingredients, preventing the drugs from interacting with each other in 
the suspension and providing reproducible drug delivery and long-term stability.
The test formulation to be evaluated in this study is an MDI containing Glycopyrronium 
Inhalation Aerosol (henceforth referred to as GP MDI), a long-acting muscarinic antagonist 
(LAMA). Further details about the to-be-tested formulations are provided in Table 6-1 and 
the current version of the PT001 investigator brochure (IB).
1.1
Background Information on the Treatment of Asthma
Asthma is a heterogeneous disease that is characterized by chronic airway inflammation and 
bronchial hyperreactivity. It is defined by a history of respiratory symptoms such as wheeze, 
shortness of breath, chest tightness, and cough that vary over time and in intensity, together 
with variable expiratory airflow obstruction. The variations in symptoms and airflow 
obstruction are often triggered by factors such as exercise, allergen or irritant exposure, 
changes in weather, noxious fumes, or viral respiratory infections. Symptoms and airflow 
obstruction may resolve spontaneously or in response to therapy. Importantly, worsening 
asthma symptoms/airway obstruction can be severe, resulting in an asthma exacerbation that 
may be life-threatening. Such events pose a significant burden to patients and result in 
significant direct and indirect economic costs (Global Initiative for Asthma [GINA] 2017).
The main objective of asthma treatment is to maintain asthma control (GINA 2017). The 
concept of ‘asthma control’ is not synonymous with ‘asthma severity’ and is defined as ‘the 
extent to which the various manifestations of asthma have been reduced or removed by 
treatment’. This concept encompasses 2 components: the patient’s recent clinical 
status/current disease impact (symptoms, night awakenings, use of rescue medication, and 
lung function) and future risk (exacerbations, decline in lung function, or treatment-related 
side effects). According to the GINA guidelines, asthma is controlled when a patient has 
daytime symptoms twice or less per week, no limitation of daily activities, no nocturnal 
symptoms, no exacerbations, the need for rescue medication use is twice or less per week, 
and normal or near normal lung function.
The GINA guidelines specify 5 treatment steps for asthma, each step outlining options for 
higher levels of treatment for controlling asthma in patients 5 years of age and older 
(GINA 2017). Within this stepwise approach, GINA proposes a classification of asthma 
severity based on the type and intensity of controller medication required for the control of 


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the disease (Steps 1 to 5). The GINA guidelines also propose a classification in 3 categories 
(mild, moderate, and severe asthma) assessed retrospectively once the patient is on regular 
controller treatment for several months.
Per GINA guidelines, the goal of the stepwise approach to treatment is to achieve and 
maintain control. In this regard, the level of asthma control obtained with treatment 
determines the need to step up or step down to the next treatment step in order to achieve 
optimum control with the minimum amount of medication. The majority of asthma patients 
can achieve and maintain clinical control with standard treatment regimens that generally 
include inhaled corticosteroids (ICSs) with or without inhaled long-acting β2-agonists 
(LABAs) as well as short-acting β2-agonists (SABAs). However, some patients with asthma 
have inadequately controlled disease despite the use of an ICS with or without a LABA. 
Treatment options that may be considered in these patients include adding a LAMA such as 
tiotropium and, in certain subsets of patients, biologic agents (eg, omalizumab, 
mepolizumab), bronchial thermoplasty, and low-dose oral corticosteroids (GINA 2017).
This information indicates that LAMAs have a significant role in the management of asthma 
when used in combination with other controller medications (Barnes 2011). The goal of the 
current study is to evaluate the safety and efficacy of 3 doses of GP MDI in comparison to 
Placebo MDI and Spiriva® Respimat® over 24 weeks in subjects whose asthma is not 
optimally controlled despite treatment with an ICS/LABA or an ICS/LABA plus tiotropium.


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2
STUDY OBJECTIVES
2.1
Primary Objective
•
To assess the effect of 3 doses of GP MDI compared to Placebo MDI and Spiriva®
Respimat® on lung function over 24 weeks in subjects with persistent asthma
2.2
Secondary Objective
•
To assess the effect of 3 doses of GP MDI compared to Placebo MDI and Spiriva 
Respimat on exacerbations, quality of life, and symptoms over 24 weeks in subjects with 
persistent asthma
2.3
Safety Objective
•
To assess the safety of 3 doses of GP MDI compared to Placebo MDI and Spiriva 
Respimat over 24 weeks in subjects with persistent asthma
2.4
24-Hour Holter Monitoring Sub-Study Objective
•
To assess the cardiovascular safety of 3 doses of GP MDI compared to Placebo MDI and 
Spiriva Respimat as evaluated by 24-hour Holter monitoring


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3
STUDY ENDPOINTS
3.1
Primary Efficacy Endpoint
•
Change from baseline in forced expiratory volume in 1 second (FEV1) area under the 
curve from 0 to 4 hours (AUC0-4) at Week 24
3.2
Secondary Efficacy Endpoints
•
Change from baseline in morning pre-dose trough FEV1 at Week 24
•
Rate of moderate/severe asthma exacerbations 
•
Change from baseline in Asthma Control Questionnaire (ACQ)–7 at Week 24
•
Change from baseline in ACQ-5 at Week 24
•
Change from baseline in Asthma Quality of Life Questionnaire for 12 years and older 
(AQLQ +12) at Week 24
3.3
Other Efficacy Endpoints
With the exception of rate of moderate/severe asthma exacerbation, all of the primary and 
secondary endpoints shown above will also be assessed over the Treatment Period and at 
each clinic visit as other efficacy endpoints. 
In addition, the following endpoints will be assessed over the Treatment Period, by visit for 
measures assessed at clinic visits (with the exception of responder endpoints, which will be 
assessed at Week 24 and over the Treatment Period), and over each 4-week interval for 
measures assessed by electronic diary (eDiary) unless specified otherwise below. 
•
Percentage of responders in ACQ-5 (≥0.5 change equals response) 
•
Change from baseline in ACQ-6
•
Percentage of responders in ACQ-6 (≥0.5 change equals response) 
•
Percentage of responders in ACQ-7 (≥0.5 change equals response) 
•
Percentage of responders in AQLQ +12 (≥0.5 change equals response) 
•
Time to first moderate/severe asthma exacerbation (assessed over the Treatment Period 
only)
•
Time to first severe asthma exacerbation (assessed over the Treatment Period only)
•
Rate of severe asthma exacerbations (assessed over the Treatment Period only)
•
Time to first asthma exacerbation of any severity (assessed over the Treatment Period 
only)


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•
Rate of asthma exacerbations of any severity (assessed over the Treatment Period only)
•
Peak FEV1
•
Percentage of symptom-free days (24-hour period without symptoms) 
•
Percentage of rescue-free days (24-hour period without rescue medication use) 
•
Change from baseline in the mean number of puffs of rescue medication use (puffs/day) 
•
Percentage of asthma control days (24-hour period without rescue medication or 
symptoms) 
•
Change from baseline in morning peak expiratory flow rate (PEFR)
•
Change from baseline in evening PEFR 
•
Change from baseline in fractional nitric oxide concentration in exhaled breath (FENO) 
•
Percentage of clinically meaningful changes from baseline in FENO
•
Time to first CompEx event 
3.4
Safety Endpoints
•
Adverse events (AEs)
•
Clinical laboratory values
•
Vital signs
•
12-lead safety electrocardiograms (ECGs)
3.5
24-Hour Holter Monitoring Sub-Study Endpoints
3.5.1
Primary Holter Monitoring Sub-Study Endpoint
•
Change from baseline in mean heart rate (HR) over 24 hours
3.5.2
Secondary Holter Monitoring Sub-Study Endpoints
•
Change from baseline in mean nighttime (22:00 to 06:00) and daytime (06:00 to 22:00) 
HR
•
Change from baseline in the maximum 24-hour HR
•
Change from baseline in the minimum 24-hour HR
•
Change from baseline in the frequency of isolated ventricular events (premature 
ventricular contractions [PVCs])


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•
Change from baseline in the frequency of ventricular couplets (defined as 2 PVCs 
preceded or followed by regular beats)
•
Change from baseline in the frequency of ventricular runs (defined as 3 or more PVCs 
preceded or followed by regular beats)
•
Change from baseline in the frequency of supraventricular couplets
•
Change from baseline in frequency of isolated supraventricular events
•
Change from baseline in the frequency of supraventricular ectopic beats
•
Change from baseline in the frequency of supraventricular runs
•
Incidence of atrial fibrillation with rapid ventricular response (>100 bpm)
•
Proportion of subjects with maximum HR >180, >160 to 180, >140 to 160, >120 to 140, 
>100 to 120, and 100 bpm or less
•
Proportion of subjects with minimum HR >60, >50 to 60, >40 to 50, and <40 bpm
•
Proportion of subjects in each category of change from baseline in the number of PVCs 
per hour (no change; increase of >0 to <60, 60 to <120, and ≥120; and decrease of >0 to 
<60, 60 to <120, and ≥120)


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4
INVESTIGATIONAL PLAN
4.1
Study Design
This is a Phase II/III randomized, double-blind, parallel group, multi-center dose 
confirmation study comparing 3 doses of GP MDI (28.8, 14.4, and 7.2 μg) to Placebo MDI 
and open-label Spiriva Respimat (2.5 μg) in subjects with persistent asthma who are 
symptomatic despite treatment with an ICS/LABA or ICS/LABA + tiotropium. The 3 doses 
of GP MDI and the Placebo MDI will be administered twice daily (BID) and Spiriva 
Respimat will be administered once daily (QD), each for 24 weeks. The subject will also 
continue on their own ICS/LABA regimen during the Screening Period and throughout the 
Treatment Period.
Figure 4-1 displays the overall study design.
Figure 4-1
Study Design Overview
This study will be conducted at approximately 250 sites, contributing approximately 4 to 6 
subjects per site. It is planned that approximately 2250 prospective subjects will be screened, 
with approximately 1125 subjects randomized to provide approximately 900 subjects who 
complete the study.


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At Visit 1, subjects (or the parents or legal guardians of subjects <18 years of age) will sign 
an informed consent form (ICF); subjects <18 years of age will sign an assent form. All 
eligible subjects must be taking a stable regimen of an inhaled corticosteroid (ICS)/long-
acting !2-agonist (LABA) for at least 4 weeks; this ICS/LABA regimen will be continued 
throughout the Screening and randomized Treatment Periods. Subjects who are also taking 
tiotropium will discontinue its use at Visit 1 and replace tiotropium with Sponsor-provided 
ipratropium bromide HFA MDI (hereafter referred to as ipratropium) taken as 2 inhalations 
4 times daily (QID) during the Screening Period. Beginning with Visit 1, subjects will use an 
eDiary BID to record ICS/LABA use (Screening Period only), albuterol sulfate HFA MDI 
(hereafter referred to as albuterol) use, asthma symptom scores, PEFR, and study drug use 
(Treatment Period only).
Subjects must demonstrate an FEV1 >40% and <85% of predicted (>40% and <90% of 
predicted for subjects 12 to <18 years of age) at Visit 1, Visit 2 (if applicable) and Visit 4.  
Reversibility to albuterol must be demonstrated at either Visit 1 or Visit 2. A subject will be 
considered reversible to albuterol if the improvement in FEV1 from pre-albuterol to post-
albuterol is ≥12% and ≥200 mL (Section 7.1.1.3).
Subjects will return for Visit 2 after adequate washout of prohibited asthma medications. 
There will be a minimum of 7 days between Visit 1 and Visit 2. At Visit 2, the ACQ will be 
administered along with multiple other assessments including FENO. Spirometry will only be 
performed at Visit 2 if reversibility to albuterol was not demonstrated at Visit 1.
A subset of approximately 562 subjects (125 subjects from the GP MDI groups and Placebo 
MDI group and 62 subjects from the Spiriva Respimat group) will participate in the 24-hour 
Holter monitor sub-study. In these subjects, a 24-hour Holter monitor will be collected 
between Visit 3 and Visit 4 (Holter Monitor Baseline) and at Visit 7 (Week 12). Those 
subjects who have clinically significant abnormal findings defined as (but not limited to) 
criteria in Section 5.5 during the baseline 24-hour Holter monitor MUST be screen failed 
from the full study. Subjects unable to provide a minimum of 18 hours of acceptable quality 
recording in a 24-hour period after 2 attempts will not be eligible for the Holter monitoring 
sub-study, but DO NOT need to be screen failed from the full study.
Reversibility to ipratropium will be assessed at Visit 3 for characterization and randomization 
stratification purposes. For subjects participating in the Holter monitoring sub-study, a 24-
hour Holter monitor will also be placed at Visit 3 (Section 7.2.4) and removed the following 
day.
Subjects meeting randomization criteria at Visit 4 (Section 5.3) will continue to take their 
same ICS/LABA regimen throughout the randomized Treatment Period, discontinue 
ipratropium (if applicable), and be randomized in a 2:2:2:2:1 scheme to 1 of the following 
5 treatment groups for 24 weeks:
•
GP MDI 28.8 μg BID (n=250)
•
GP MDI 14.4 μg BID (n=250)


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•
GP MDI 7.2 μg BID (n=250)
•
Placebo MDI BID (n=250)
•
Spiriva Respimat 2.5 μg QD (n=125)
Randomization will be stratified by baseline percent predicted FEV1 (≤60% or >60%), 
reversibility to ipratropium (<12% or <200 mL vs ≥12% and ≥200 mL improvement in 
FEV1), and by the ICS included in their fixed-dose ICS/LABA combination product 
(budesonide [eg, Symbicort®, with formoterol fumarate dihydrate], mometasone furoate [eg, 
Dulera®, with formoterol fumarate dihydrate], fluticasone furoate [eg, Breo® Ellipta®, with 
vilanterol trifenatate], or fluticasone propionate [eg, Advair® or AirDuo™ RespiClick®, with 
salmeterol]).
Following randomization, subjects will undergo 6 additional treatment visits over 24 weeks. 
For subjects participating in the Holter monitoring sub-study, a Holter monitor will be placed 
at Visit 7 (Section 7.2.4) and removed the following day.
Note: The end of study is defined as the date on which data are collected 14 (+2) days after 
the last dose of study drug. Data collection can occur via a follow-up telephone call 
(Section 8.11) or a study visit, whichever provides 14 (+2) days of follow-up.
4.2
Rationale
GP MDI is being developed for use in the treatment of asthma. This study will characterize 
the efficacy and safety of GP MDI, evaluating multiple doses in order to determine the most 
appropriate GP MDI dose(s) to treat subjects with asthma who remain symptomatic despite 
treatment with an ICS/LABA.
4.2.1
Population
The primary intended use of GP MDI in asthma will be as add-on therapy to ICS/LABA in 
line with GINA guidelines (GINA 2017). This study will include subjects with persistent 
asthma who remain symptomatic, as demonstrated by an ACQ-5 (see Section 7.1.4.1) total 
score ≥1.5, despite treatment with an ICS/LABA. Symptomatic subjects receiving tiotropium 
in addition to an ICS/LABA are also included in order to cover the spectrum of asthma 
severity for which the addition of a LAMA to an ICS/LABA may be appropriate.
4.2.2
Choice of Study Doses
Efficacy and safety data from Phase I and II studies indicate that GP MDI 28.8, 14.4, and 
7.2 μg administered BID may be appropriate doses to evaluate in a Phase III study in subjects 
with uncontrolled persistent asthma despite treatment with an ICS/LABA. In a Phase II 
study, GP MDI 28.8 μg was most similar to salmeterol, the active comparator, for all 
outcome measures, and the GP MDI 14.4 and 7.2 μg doses were similar to salmeterol for 
some endpoints. GP MDI doses below 7.2 μg were appreciably less effective than salmeterol. 
The previous GP MDI Phase II study included subjects with asthma who were either on a 


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low dose of an ICS or not on an ICS. Therefore, confirmation of the optimal GP MDI dose in 
subjects with uncontrolled persistent asthma despite treatment with an ICS/LABA is 
warranted.
Doses above 28.8 μg have not been evaluated in subjects with asthma, and thus, the 28.8 μg 
dose is the highest dose planned for evaluation in this study. Furthermore, based on data from 
prior Phase I and Phase II studies, doses below 7.2 μg are not expected to have appreciable 
efficacy, and thus, the 7.2 μg dose is the lowest dose planned for inclusion in the study.
Refer to the current PT001 IB for further details on the Phase I and Phase II GP MDI studies. 
The dose chosen for Spiriva Respimat, 2.5 μg QD, is the approved dose in the current 
prescribing information for the treatment of asthma in individuals 6 years of age and older 
(Spiriva Respimat 2017).
4.2.3
Choice of Comparators/Control Groups
Spiriva Respimat will be included in this study as an active comparator to benchmark the 
GP MDI results. Placebo MDI will serve as the control arm. 
4.2.4
Study Duration
The specified study duration of 24 weeks will provide sufficient time to observe lung 
function changes in the chosen subject population. This is based on previous studies with 
tiotropium in asthma demonstrating that lung function changes plateau in 6 to 8 weeks and 
do not increase further in studies of up to 48 weeks in duration (Kerstjens 2015, 
Kerstjens 2012).


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5
STUDY POPULATION SELECTION
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 (and assent as appropriate) to participate
2. Are at least 12 years of age and no older than 80 years
3. Have a documented history of physician-diagnosed asthma
4. Require inhaled asthma maintenance therapy: has been regularly using an ICS/LABA on 
a stable regimen, with the ICS doses allowed in Table 5-1, for at least 4 weeks prior. 
Subjects may be included if also receiving tiotropium 2.5 μg QD for at least 4 weeks 
prior.
5. ACQ-5 total score ≥1.5 at Visit 2
6. Based on the average of 2 assessments, pre-bronchodilator FEV1 >40% and <85% of 
predicted normal value for subjects 18 to 80 years of age or >40% and <90% of predicted 
for subjects 12 to <18 years of age at Visits 1, 2 (if applicable), and 4
7. Documented reversibility to albuterol (defined as a post-albuterol increase in FEV1 of 
≥12% and ≥200 mL) at either Visit 1 or Visit 2
8. At Visits 1, 2 (if applicable), and 4 (pre-randomization), demonstrate both:
-
Acceptable spirometry performance (ie, meet American Thoracic Society 
[ATS]/European Respiratory Society [ERS] acceptability criteria; Appendix 3) 
-
FEV1 repeatability at one of the pre-dose measurements
9. Willing and, in the opinion of the Investigator, able to adjust current asthma therapy, as 
required by the protocol
10. Demonstrate acceptable MDI administration technique
Note: Use of a spacer device during the Screening and randomized Treatment Periods is 
not permitted.
11. Body mass index <40 kg/m2 (see calculators in Appendix 1)
12. Agree to 1 of the following to prevent pregnancy:
-
Non-childbearing potential (ie, physiologically incapable of becoming pregnant, 
including any female who is 2 years post-menopausal, or surgically sterile [defined as 
having a bilateral oophorectomy, hysterectomy, or tubal ligation])
Note: For purposes of this protocol, menopausal women are defined as women 
≥50 years old who are amenorrheic for 12 consecutive months or more following 
cessation of all exogenous hormonal treatment
-
Practice abstinence
-
If a heterosexual female of childbearing potential and sexually active, agrees to 
prevent pregnancy by using 1 of the following methods of birth control from the date 
the ICF is signed until 2 weeks after the final dose of study drug is taken:


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◦
Hormonal contraception (eg, oral contraceptive, contraceptive implant, or 
injectable hormonal contraceptive)
◦
Double-barrier birth control (eg, condom plus intrauterine device, diaphragm plus 
spermicide, or condom plus spermicide)
◦
Maintenance of a monogamous sexual relationship with a male partner who has 
been surgically sterilized by vasectomy
-
If a female of childbearing potential, have a negative serum pregnancy test
13. Screening clinical laboratory tests must be acceptable to the Investigator
14. Screening ECG must be acceptable to the Investigator
15. Compliance: must be willing to remain at the study center as required per protocol to 
complete all 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. Oral corticosteroid use (any dose) within 4 weeks
2. Received any marketed (eg, omalizumab) or investigational biologic within 3 months or 
5 half-lives, whichever is longer, or any other medication specifically prohibited by the 
protocol within the indicated exclusionary time periods (Table 5-4 and Table 5-5)
3. Current smokers, former smokers with >10 pack-years history, or former smokers who 
stopped smoking <6 months previously (including all forms of tobacco, e-cigarettes, and 
marijuana)
4. Life-threatening asthma as defined as a history of significant asthma episode(s) requiring 
intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or 
asthma-related syncopal episode(s)
5. Completed treatment for lower respiratory infection or asthma exacerbation within 
4 weeks
6. Upper respiratory infection not resolved within 7 days
7. Hospitalizations for asthma within 3 months
8. Historical or current evidence of a clinically significant disease including, but not limited 
to: cardiovascular (eg, congestive heart failure, known aortic aneurysm, clinically 
significant cardiac arrhythmia, coronary heart disease), hepatic, renal, hematological, 
neurological, endocrine (eg, uncontrolled diabetes mellitus, uncontrolled thyroid disorder, 
Addison’s disease, Cushing’s syndrome), gastrointestinal (eg, poorly controlled peptic 
ulcer, gastroesophageal reflux disease), or pulmonary (eg, chronic bronchitis, 
emphysema, bronchiectasis with the need of treatment, cystic fibrosis, bronchopulmonary 
dysplasia, chronic obstructive pulmonary disease). Significant is defined as any disease 
that, in the opinion of the Investigator, would put the safety of the subject at risk through 
participation, or that could affect the efficacy or safety analysis if the disease/condition 
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9. Pacemaker or implantable cardioverter-defibrillator/cardiac resynchronization 
therapy/cardiac resynchronization therapy-defibrillator devices
10. Narrow angle glaucoma not adequately treated. All medications approved for control of 
intraocular pressures are allowed, including topical ophthalmic non-selective β-blockers
11. Symptomatic prostatic hypertrophy that in the opinion of the Investigator is clinically 
significant and not adequately controlled with appropriate therapy
Note: Subjects with a trans-urethral resection of prostate or full resection of the prostate 
within 6 months prior to Visit 1 are excluded from the study.
12. Bladder neck obstruction or urinary retention that is clinically significant in the opinion 
of the Investigator
13. Calculated creatinine clearance ≤30 mL/minute using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula for subjects >18 to 80 years of age or 
the Schwartz formula for subjects 12 to ≤18 years of age at Visit 1 and on repeat testing 
prior to Visit 4; where ≤18 years of age is defined as anyone less than 18 years up to and 
including their 18th birthday and >18 years of age is defined as 18 years +1 day and older
14. Abnormal liver function tests, defined as aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), or total bilirubin (TBL) ≥1.5 times the upper limit of normal 
(ULN) at Visit 1 and on repeat testing prior to Visit 2 (Note: Chronic stable hepatitis B or 
C is acceptable)
15. Cancer not in complete remission for at least 5 years
Note: Subjects with squamous cell carcinoma of the skin, basal cell carcinoma of the 
skin, in situ carcinoma of the cervix, or localized prostate cancer are eligible if, in the 
opinion of the Investigator, the condition has been adequately worked up and clinically 
controlled and the subject’s participation in the study would not represent a safety 
concern.
16. Hospitalized for psychiatric disorder or attempted suicide within 1 year
17. History of psychiatric disease, intellectual deficiency, poor motivation, or other 
conditions limiting informed consent validity
18. Hypersensitivity to β2-agonists, corticosteroids, anticholinergics, or any component of 
the investigational MDI, Spiriva Respimat (tiotropium), or ipratropium
19. Significant, in the opinion of the Investigator, abuse of alcohol or drugs
20. Unable to abstain from protocol-defined prohibited medications during Screening and 
Treatment Periods
21. Using any herbal products by inhalation or nebulizer within 2 weeks and does not agree 
to stop during the study duration
22. Received a live attenuated vaccination within 7 days
23. Study investigators, sub-investigators, coordinators, and their employees or immediate 
family members
24. Treatment with investigational study drug (or device) in another clinical study within the 
last 30 days or 5 half-lives, whichever is longer
25. Previously randomized in any PT001 study


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5.3
Randomization Criteria
Each subject must meet the following criteria on the morning of Visit 4 to be randomized:
1. Subjects of childbearing potential only: have a negative urine pregnancy test prior to 
administration of the study drug
2. Received no asthma medication other than ICS/LABA (plus ipratropium, if previously 
receiving tiotropium at Visit 1) and Sponsor-provided albuterol from Visit 1 to Visit 4, 
except for allowable asthma and allergy medications defined in Table 5-2 and Table 5-3
3. Fulfillment of at least 1 of the following conditions for ≥3 days over the 7 days 
immediately prior:
•
Daytime or nighttime symptom score ≥1
•
Rescue albuterol use
4. Pre-dose FEV1 >40% and <85% of predicted normal value for subjects 18 to 80 years of 
age or >40% and <90% of predicted for subjects 12 to <18 years of age
5. Demonstrate acceptable MDI administration technique
6. Able to comply with study procedures, including compliance with eDiary completion (ie,
≥70% subject completion of diary assessments in the last 7 days)
7. No upper respiratory infection, lower respiratory infection, or moderate or severe asthma 
exacerbation during the Screening Period
8. No clinically significant findings on baseline 24-hour Holter monitoring conducted 
between Visits 3 and 4 (See Section 5.5)
5.4
Re-Screening Criteria
Subjects who have an upper respiratory tract infection during Screening may re-screen 
following resolution and completion of treatment for at least 2 weeks.
Subjects who have a lower respiratory tract infection during Screening may re-screen 
following resolution and completion of treatment for at least 4 weeks.
Subjects 18 to 80 years of age may re-screen one time if they were screen failed because they 
had an FEV1 ≥80% and <85% of predicted normal value at V1, V2 (if applicable), or V4.
Subjects who have been on a stable regimen of an ICS/LABA for at least 4 weeks may re-
screen if they were screen failed because they were not on an ICS/LABA for at least 3 
months prior to Visit 1.
5.5
Holter Monitoring Sub-Study Exclusion Criteria
Subjects with clinically significant abnormal findings during the baseline Holter monitor 
recording defined as (but not limited to) any of the following will be excluded from the full 


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study. Subjects unable to provide a minimum of 18 hours of acceptable quality recording in a 
24-hour period after 2 attempts will be excluded from the Holter monitoring sub-study, but 
DO NOT need to be excluded from the full study:
1. Average HR ≤40 bpm for any 1 hour
2. Second-degree atrioventricular block (Type 2) or third-degree atrioventricular block
3. Sinus pause of EITHER:
•
2.5 seconds duration during daytime 
•
3.0 seconds duration during nighttime
4. Any episode of ventricular flutter and/or ventricular fibrillation
5. Any episode of non-sustained ventricular tachycardia (NSVT) with symptoms of 
hypotension or syncope or asymptomatic NSVT >15 ventricular premature beats in a row
6. Sustained ventricular tachycardia (>30 seconds in duration)
7. Five or more episodes of NSVT over 24 hours
8. Greater than 500 ventricular premature beats/hour
5.6
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 criteria 
and randomization criteria at Visit 4 will be assigned a unique subject randomization number. 
Randomization will be centralized with an Interactive Web Response System (IWRS).
5.7
Prior, Concomitant, and Prohibited Medications and Vaccinations
5.7.1
Prior Medications
All prescription and over-the-counter 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 route and dates of drug administration should be captured to the best of the 
subject’s and site’s ability.
Subjects eligible for this study are required to be on a stable regimen of an inhaled asthma 
maintenance therapy defined as an ICS/LABA for at least 4 weeks prior to Visit 1. The 
permitted total daily ICS dosage to qualify ICS usage for the 4 weeks prior to Visit 1 is 
defined in Table 5-1. Subjects also receiving tiotropium 2.5 μg QD for at least 4 weeks prior 
to Visit 1 may be included.


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Table 5-1
Permitted ICS Dosages in Fixed-Dose Combination Products 
With LABA……
Asthma Inhaled 
Corticosteroid
Total Daily Dose 
(μg/day)
Example Fixed-Dose Combination Products
Budesonide 
320 to ≤640
Budesonide and formoterol fumarate dihydrate 
(Symbicort®)
Fluticasone furoate
100 to ≤200
Fluticasone furoate and vilanterol trifenatate 
(Breo® Ellipta®)
Fluticasone propionate 
176 to ≤1000
Fluticasone propionate and salmeterol xinafoate 
(Advair® or AirDuo™ RespiClick®)
Mometasone furoate 
400 to ≤800
Mometasone furoate and formoterol fumarate dihydrate 
(Dulera®)
5.7.2
Concomitant Medications and Vaccinations
Any current ongoing medications, including over-the-counter medications, herbal 
supplements, and vaccinations, will be allowed provided they are not explicitly prohibited by 
the protocol (Table 5-4 or Table 5-5). All concomitant medications taken during the study 
will be recorded on the concomitant medications eCRF page with indication, total daily dose, 
route of administration, 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.
5.7.2.1
Vaccinations
All subjects should be vaccinated with annual influenza vaccine per local policies, 
availability, and affordability (GINA 2017). If a subject has egg intolerance or refuses to be 
vaccinated, the vaccination may be omitted. The 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.
5.7.2.2
Allowed Medications
5.7.2.2.1
ASTHMA AND ALLERGY MEDICATIONS
Table 5-2 lists asthma and allergy medications that are allowed during the study as long as 
the subject does not take these medications for the specified time periods prior to Visit 2 and 
all subsequent in-clinic visits.


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Table 5-2
Allowed Asthma Medications With Required Holding Periods Prior 
to Visit 2 and All Subsequent Visits
Allowed Medication
Minimum Holding Period
Sponsor-provided SABAa
6 hours
LABAsb
24 hours: indacaterol, olodaterol, vilanterol
12 hours: salmeterol, formoterol
Sponsor-provided ipratropiumc
6 hours
Abbreviation: SAMA=short-acting muscarinic antagonist.
a
All other SABAs and SAMAs besides Sponsor-provided albuterol and ipratropium (as appropriate) must be 
discontinued at Visit 1 and may not be used throughout the remainder of the Screening and randomized 
Treatment Periods.
b
In combination with an ICS
c
This washout only applies to subjects who are switched from tiotropium at Visit 1 to ipratropium. The 
ipratropium will be discontinued at Visit 4 for the remainder of the randomized Treatment Period.
Table 5-3 lists asthma and allergy medications that are allowed as long as the subject has 
been on a stable dose for at least 4 weeks prior to Visit 1 and remains on a stable dose 
throughout the study.
Table 5-3
Allowed Asthma and Allergy Medications
Non-sedating long-acting antihistaminesa
Allergen immunotherapy
Intranasal corticosteroids
Intranasal antihistamines or combination products of intranasal antihistamines/corticosteroids
Montelukast sodiumb
Intranasal ipratropium bromide
a
Short-acting antihistamines (eg, diphenhydramine) are also permitted for use as needed, but not regularly.
b
Leukotriene modifiers other than montelukast sodium are prohibited within 7 days prior to Visit 2 and 
throughout the Screening and randomized Treatment Periods.
5.7.2.2.2
TREATMENT OF AN ASTHMA EXACERBATION
If a subject experiences an asthma exacerbation, they should continue dosing with study 
drug, if possible. During the randomized Treatment Period, asthma exacerbations should be 
treated at the discretion of the Investigator, taking into consideration that the use of certain 
medications are prohibited for use during the study in conjunction with study drug (see 
Section 5.7.3.1). 
Definitions of a mild, moderate, and severe asthma exacerbation are provided in 
Section 7.1.3.1, as are the recommended treatments for moderate and severe asthma 


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exacerbations. New or increased dose ICS treatment is permitted for treatment of a moderate
asthma exacerbation, to help avoid progression to a severe exacerbation; oral corticosteroids 
are permitted for treatment of a severe asthma exacerbation.
Details regarding the collection of data concerning asthma exacerbations are provided in 
Section 7.3.6.
5.7.2.2.3
MEDICAL MARIJUANA
Edible medical marijuana is not an exclusionary drug if used for medical purposes and there 
is no change in the dose or frequency of consumption during study participation. Subjects 
who use medical marijuana by smoking or vaping are excluded (see also Section 5.8.1).
5.7.3
Prohibited Medications and Washout Periods
5.7.3.1
Prohibited Asthma and Allergy Medications and Washout Periods
Specific prohibited asthma and allergy medications and their required washout periods prior 
to Visit 2 are displayed in Table 5-4. Minimum washout periods for oral, intravenous (IV), 
intramuscular (IM), and depot steroids are shown in Section 5.7.3.2.
Table 5-4
Prohibited Asthma and Allergy Medications and Required 
Washout Period Prior to Visit 2
Medication
Minimum Washout Period Prior to Visit 2
Tiotropiuma
2 weeks
Oral β2-agonists
2 days
Theophylline
2 days
Cromoglycate
7 days
Nedocromil
7 days
Ketotifenb
7 days
Zileuton
7 days
SAMA and/or SABA other than Sponsor providedc
7 days
Monoclonal antibodies (eg, anti-immunoglobulin E, 
anti-interleukin-5)
3 months or 5 half-lives, whichever is longer
a
Subjects currently on a LAMA other than tiotropium are excluded from study participation.
b
Ketotifen eye drops are allowed; no washout required.
c
Administered as fixed or loose combinations.
5.7.3.2
Prohibited Non-Asthma and Non-Respiratory Medications and Washout Periods
Subjects requiring medications presented in Table 5-5 are prohibited from participating in 
this study. Subjects who recently discontinued use of these medications may be considered 


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for study enrollment provided they have met the minimum cessation period prior to Visit 1. 
These medications are prohibited throughout the course of the study. If subjects require any 
of the prohibited medications listed in Table 5-5, the Investigator should discuss with the 
Medical Monitor the suitability of the subject continuing study drug.
Note: The minimum washout period prior to Visit 1 for oral, IV, and IM steroids is 4 weeks, 
and for depot (intra-articular and intraocular) steroids is 12 weeks. Use of systemic 
corticosteroids (eg, oral, parenteral, intraocular, intra-articular) to treat conditions other than 
a severe asthma exacerbation is prohibited for the duration of the study, including both the 
Screening and randomized Treatment Periods.
Table 5-5
Prohibited Non-Asthma and Non-Respiratory Medications and 
Required Washout Period Prior to Visit 1
Class of Medication
Minimum Cessation Period Prior to Visit 1 and 
Prohibited Throughout the Study
Any drug with potential to significantly prolong the
QT intervala,b
14 days or 5 half-lives, whichever is longer
Other investigational drugs
30 days or 5 half-lives, whichever is longer
Non-selective non-ocular β-blocking agents
7 days
Cardiac anti-arrhythmics (Class Ia, III)
7 days, unless amiodarone, then 3 months
Anticonvulsants for seizure disorderc
Allowed if stable dose for 12 months and free of 
seizures for 1 year
Antipsychotic drugsd
30 days
Tricyclic antidepressantsd
14 days
Monoamine oxidase inhibitors
14 days
Anti-tumor necrosis factor α antibodies (eg, infliximab 
and any other members of this class of drugs)
30 days or 5 half-lives, whichever is longer
Monoclonal antibodiese
30 days or 5 half-lives, whichever is longer
Cytochrome P450 enzyme inhibitors (eg, systemic 
calcineurin inhibitors, systemic antifungal agents, 
cimetidine)
30 days
Protease inhibitors (eg, ritonavir)
30 days
Systemic anticholinergicsf
7 days
Chinese complementary and alternative 
bronchodilatory medicines, ie, herbal therapies (eg, 
Astragalus membranaceus [huáng qí], Panax ginseng
[ginseng products] and Cordyceps sinensis, A. 
membranaceus [ghost moth caterpillar fungus])g
To be determinedg
Note: Benzodiazepines are not exclusionary. Serotonin norepinephrine reuptake inhibitors and selective 
serotonin reuptake inhibitors are not excluded as long as the subject has been on a stable dose for at least 
4 weeks prior to Visit 1 and throughout the Screening and randomized Treatment Periods, and the dose does not 
exceed the maximum recommended.


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a
Subjects 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 Screening and randomized
Treatment Periods.
b
Short courses of macrolide and quinolone antibiotics to treat infections are permitted.
c
Anticonvulsants for conditions other than seizures may be started and stopped at any time prior to the study 
and throughout the Screening and randomized Treatment Periods.
d
Antipsychotic 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 subject has been on a stable dose for at least 6 weeks.
e
Investigators should contact the Medical Monitor to determine the appropriateness and safety of continuing 
study drug in consultation with the Medical Monitor on a case-by-case basis (eg, Prolia® [denosumab] for 
osteoporosis, may be allowed after consultation).
f
If systemic anticholinergics are used for the treatment of irritable bowel syndrome or overactive bladder 
and the treatment has been constant for at least 1 month, they are allowed.
g
Requires case-by-case review by the Investigator to determine appropriate washout period, if needed.
5.8
Other Restrictions, Illicit Drugs, and Drugs of Abuse
5.8.1
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 
telephone call 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 from randomized study drug and 
withdrawn from the study at the discretion of the Investigator. 
Edible medical marijuana is not an exclusionary drug if used for medical purposes and there 
is no change in the dose or frequency of consumption during study participation (see also 
Section 5.7.2.2.3). Subjects who use medical marijuana by smoking or vaping are excluded.
5.8.2
Dietary Restrictions
Subjects must not ingest xanthine and/or xanthine analogue (caffeine)-containing foods or 
beverages or 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.
5.9
Reasons for Study Drug Discontinuation or Study Withdrawal
5.9.1
Reasons for Study Drug Discontinuation
Subjects who discontinue study drug should be encouraged to continue in the study and 
complete all study visits and procedures.


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If a subject experiences either of the below, the subject must be discontinued from study 
drug:
•
An asthma exacerbation requiring inpatient hospitalization
•
More than 2 severe asthma exacerbations requiring oral corticosteroid treatment
If a subject experiences any of the changes of concern listed below, a repeat assessment 
should be obtained, and if confirmed, the subject must be discontinued from study drug:
•
Calculated Fridericia-corrected QT interval (QTcF) of either >500 msec and a ≥30 msec 
change  from pre-dose baseline value obtained at Visit 4 OR a ≥60 msec change  from 
pre-dose baseline value obtained at Visit 4
•
Hepatic impairment, defined as an AST, ALT, or TBL concentration ≥3×ULN
If a subject experiences any of the following changes of concern, a repeat assessment should 
be obtained, and if confirmed, the Investigator needs to determine the suitability of 
continuing the subject on study drug:
•
A HR >120 bpm and in which there is an increase of >40 bpm from the pre-dose baseline 
value at Visit 4
•
A systolic blood pressure (SBP) >160 mmHg and an increase of >40 mmHg from the 
pre-dose baseline value at Visit 4
•
Either a decrease in creatinine clearance to a value ≤30 mL/minute using the CKD-EPI 
formula for subjects >18 to 80 years of age or the Schwartz formula for subjects 12 to 
≤18 years of age at Visit 1 (where ≤18 years of age is defined as anyone less than18 years 
up to and including their 18th birthday and >18 years of age is defined as 18 years +1 day 
and older) OR a clinically relevant change from pre-dose baseline obtained at Visit 4 as 
determined by the Investigator
Procedures for study drug discontinuation and study withdrawal are provided in Section 8.9.
5.9.2
Reasons for Study Withdrawal
If a subject becomes pregnant during the course of the study, she will discontinue study drug, 
and must be withdrawn from the study and followed until delivery or final outcome (see 
Section 7.3.12 for additional procedures).
Subjects may be withdrawn from the study at their own request or upon the request of the 
Investigator or the Sponsor at any time and for any reason (see Section 8.9 for additional 
procedures).


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6
CLINICAL SUPPY LABELING, PACKAGING, STORAGE, 
DISPENSING, AND RETURN
Study personnel will have access to an IWRS to allocate subjects, assign study-related 
medication to subjects, and manage the distribution of clinical supplies. Each person 
accessing the IWRS system will be assigned a unique personal identification number (PIN) 
to use for their access. The assigned PIN must not be shared with anyone, even another 
colleague involved with the study.
Clinical supplies will be packaged according to a component schedule generated by the 
Sponsor or their designee. Subjects receiving tiotropium prior to Visit 1 will be supplied 
ipratropium in an open-label fashion during the Screening Period. Study drug for all 
treatments other than Spiriva Respimat will be packaged to support enrollment of the study in 
a blinded fashion for the 24-week Treatment Period; treatment with Spiriva Respimat will be 
open-label. 
The study drug and other medications provided by the Sponsor are described in Section 6.1
(randomized study drugs) and Section 6.2 (other medications). Medications to treat asthma 
exacerbations or other AEs will not be provided by the Sponsor. 
6.1
Description of Study Drugs
In this protocol, “study drug” refers to an active ingredient or placebo being tested or used as 
a reference in the study. Study drugs used in this study are described in Table 6-1. 
Subjects meeting all randomization criteria (Section 5.3) will be randomized at Visit 4 to 
receive study drug QD (Spiriva) or BID (GP MDI or Placebo MDI) during the randomized 
Treatment Period. Instructions for reading the dose indicator for the GP MDI and 
Placebo MDI and for priming, use, and cleaning of the GP MDI and Placebo MDI are 
provided in Appendix 4 and Appendix 5, respectively. Instructions for the priming, use, and 
cleaning of the Spiriva Respimat are provided in Appendix 6. 


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Table 6-1
Randomized Study Drugs
Product Name 
and Dose
Product Strength
Manufacturer
Dosage Form/
Fill Count
Administration
GP MDI 28.8 μg
GP MDI 14.4 μg per 
actuation
Pearl
MDI/
120 inhalations
Taken as 
2 inhalations BID
GP MDI 14.4 μg
GP MDI 7.2 μg per 
actuation
Pearl
MDI/
120 inhalations
Taken as 
2 inhalations BID
GP MDI 7.2 μg
GP MDI 3.6 μg per 
actuation
Pearl
MDI/
120 inhalations
Taken as 
2 inhalations BID 
Placebo MDIa
No active ingredient
Pearl
MDI/
120 inhalations
Taken as 
2 inhalations BID
Spiriva Respimat 
2.5 μgb
tiotropium 1.25 μg per 
actuationb
Boehringer Ingelheim 
Pharmaceuticals, Inc.
IS metered/
60 inhalations
Taken as 
2 inhalations QD
Abbreviation: IS=inhalation spray; MDI=metered dose inhaler.
Note: All study drugs will be administered by oral inhalation.
a
All Placebo MDIs are manufactured by the Sponsor in the image of the active test product.
b
Each actuation contains 1.25 μg tiotropium corresponding to 1.562 μg of tiotropium bromide monohydrate.
6.2
Other Sponsor-Provided Medications Used in the Study
Other Sponsor-provided medications used open-label during the study are shown in 
Table 6-2. These medications will be commercial MDIs with dose counters and 
manufacturer’s instructions for use. Instructions for use of the albuterol and ipratropium 
MDIs are provided in Appendix 7 and Appendix 8, respectively. 
Table 6-2
Other Sponsor-Provided Study Medications
Product Name and 
Dose
Product Strength
Dosage Form/
Fill Count
Administration
Albuterol sulfate 
inhalation aerosol 
(Ventolin® HFA)
albuterol sulfate 
90 μg/actuationa
MDI/
60 or 200 actuations
Taken as directed for reversibility 
testing (Visits 1 and/or 2)b and as 
rescue during the Screening and 
randomized Treatment Periods
Ipratropium bromide 
inhalation aerosol 
(Atrovent® HFA)c
ipratropium bromide 
17 μg/actuation
MDI/
200 actuations
Taken during the Screening Period as 
2 inhalations QID (selected subjectsc) 
and as 4 inhalations for reversibility 
testing at Visit 3 (all subjects)
a
Each inhalation contains 108 μg albuterol sulfate corresponding to 90 μg albuterol base per actuation.
b
Reversibility to albuterol is a requirement that may be met at either Visit 1 or 2.
c
Only for subjects receiving tiotropium 2.5 mg QD for at least 4 weeks prior to Visit 1.


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6.3
Packaging and Labeling
6.3.1
Primary Packaging and Labeling
All clinical trial supplies will be packaged by the Sponsor.
Blinded study drug (GP MDI and Placebo MDI) will be packaged 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 drug.
Open-label medications (albuterol, ipratropium, and Spiriva Respimat) will be provided as 
individually labeled inhalers with a single label on the actuator.
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 and dosage form
Visit # (Space for entry of Interval ID)
Storage Conditions
Protocol #
Country regulatory requirements
Sponsor address
Abbreviations: #=number; ID=identification
6.3.2
Secondary Packaging and Labeling
All clinical trial supplies will be packaged in individual visit boxes containing 1 MDI each. 
Box configuration is subject to change as a result of packaging constraints.
Each box will be labeled with a 2-part label printed with black ink and may include the 
following text:
Packaging Lot ID #
Space for entry of screening #
Component ID #
Space for entry of randomization #
Kit contents (1 MDI)
Space for entry of Interval ID
Re-evaluation/Expiration date (if applicable)
Dosing instructions (if applicable)
Storage conditions
Compound ID - Protocol #
Country regulatory requirements
Sponsor address (if applicable)
Abbreviations: #=number; ID=identification
6.4
Storage Requirements
All clinical drug supplies should be kept in a locked cabinet or room with limited access. The 
temperature of the site’s storage area for study drugs must be monitored by site staff for 
temperature ranges consistent with those specified for each product as outlined below. 
Documentation of temperature monitoring should be maintained at the site and available for 
review. 


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•
All clinical drug supplies contain contents under pressure. Do not use or store near heat 
or open flame. Exposure to temperatures above 49°C (120°F) may cause bursting. Never 
throw clinical drug canisters into a fire or incinerator. Avoid spraying in eyes.
•
Albuterol MDI (Ventolin HFA) should be stored at room temperature between 20°C and 
25°C (68°F-77°F); excursions permitted from 15°C to 30°C (59°F-86°F). Store the 
inhaler with the mouthpiece down. For best results, the inhaler should be at room 
temperature before use. SHAKE WELL BEFORE EACH SPRAY. 
•
GP MDI and Placebo MDI should be stored below 25°C (77°F); excursions permitted up 
to 30°C (86°F). Do not freeze.
•
Ipratropium inhalers (Atrovent HFA) should be stored at 25°C (77°F); excursions 
permitted to 15°C to 30°C (59°F to 86°F). For optimal results, the canister should be at 
room temperature before use.
•
Spiriva Respimat inhaler (tiotropium) should be stored at 25°C (77°F); excursions 
permitted to 15°C to 30°C (59°F to 86°F). Avoid freezing. 
6.5
Instructions for Dispensing and Preparation of Study Drugs for 
Administration
Before dispensing the study drug to the subject, authorized study staff must confirm the 
identifier given by the IWRS and the component identification number written on the label 
are the same. To document dispensing of the study drug, the authorized study staff will write 
the subject number and treatment visit number on each of the 2-part labels and affix the ‘tear 
off’ part of the label onto the IWRS confirmation report.
All GP MDIs and Placebo MDIs must be primed before the first use. To prime the inhaler, 
gently shake the inhaler for 5 to 10 seconds and then spray once into the air away from 
yourself and others. Wait approximately 30 seconds and repeat the process 3 more times (see 
Appendix 5 for complete instructions). 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. 
Priming should occur in a separate room from the subject treatment area.
Similarly, the Spiriva Respimat inhaler must be primed before the first use. To prime the 
inhaler, in brief, point the inhaler toward the ground and press the dose-release button. If a 
mist is seen, repeat for 3 more actuations; if a mist is not seen, follow the manufacturer’s 
instructions (see Appendix 6 for complete instructions).
Once the inhalation device is primed, the first dose (2 puffs) of study drug should be taken by 
the subject in the clinic under site personnel supervision. The date and time of the second 
puff should be recorded as the time of dose administration (ie, in iDataFax for in-clinic doses 
and in the e-Diary for at-home dosing). Subjects should be instructed to inhale 2 puffs in the 
morning and, unless randomized to Spiriva Respimat, 2 puffs in the evening approximately 
12 hours apart. The timing of the morning administration should match ±1 hour of in-clinic 
study drug administration.


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Refer to Appendix 5 for additional instructions on the administration and cleaning of the GP 
MDI and Placebo MDI, and to Appendix 6 for instructions on the administration and 
cleaning of the Spiriva Respimat inhaler. Instructions for the albuterol MDI and ipratropium 
inhaler are provided in Appendix 7 and Appendix 8, respectively.
6.6
Emergency Unblinding
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 Sponsor’s Medical 
Monitor or other appropriate study personnel from the Sponsor before unblinding the 
subject’s treatment assignment. If this is impractical, the Investigator must notify the Sponsor 
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.
6.7
Drug Accountability/Return of Clinical Supplies
Under no circumstances will the Investigator(s) allow the study drug to be used other than as 
directed by this protocol.
Investigational clinical supplies must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secure location to which only the 
Investigator and designated study personnel have access. Clinical supplies should be 
dispensed only in accordance with the protocol.
The Investigator or designee is responsible for keeping accurate records of the clinical 
supplies received from the Sponsor, 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 (eg, gloves should always be worn by study 
personnel if directly handling study drug that is returned). The Sponsor’s 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 the Sponsor.
Sites should check with the Sponsor representative for appropriate documentation that needs 
to be completed for drug accountability.


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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 
Sponsor’s 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 the Sponsor or 
designee. Used study drug must be stored separately from unused study drug.
All product complaints (including device malfunctions) must be reported to the Sponsor or 
the Sponsor’s representative using the Product Complaints Form provided in each site’s 
regulatory binder. The Sponsor 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. A detailed visit 
schedule for all pre- and post-dose assessments is described in Table 8-2. A summary of 
24-hour Holter monitoring sub-study procedures is in Table 8-3.
7.1
Efficacy Assessments
7.1.1
Pulmonary Function Tests
7.1.1.1
Spirometry Standardization
All pulmonary function tests (PFTs) including FEV1, forced vital capacity, and forced 
expiratory flow in the midpoint as defined in ATS/ERS guidelines will be performed in 
accordance with ATS criteria (Appendix 2; Miller 2005) and will be assessed using a 
spirometer that meets or exceeds minimum performance recommendations of the ATS 
(Appendix 3).
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 PFTs on 
each test day.
The volume accuracy of the spirometer is checked using a 3 L syringe across 3 flow ranges 
(ie, 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% (ie, 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 (see Appendix 2). 
All study staff responsible for performing PFTs 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 PFTs will 
be stored electronically. After completion of testing, the study staff will electronically 
transmit the spirometry measurements for centralized quality assurance review 
 
 Feedback on the quality of the measurements will be provided to the 
investigational site and to the Sponsor or designee for central data management.
As spirometry results are primary and secondary efficacy endpoints for this study, it is 
important for the medication withholding conventions and timing of spirometry to be 
consistently managed throughout the study (Section 8.1).


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7.1.1.2
Spirometry Schedule
Spirometry collection is briefly outlined below. For exact spirometry collection and 
specifications, please refer to Table 8-1 and Section 8.
•
Visit 1: 
-
Spirometry, including reversibility to albuterol, will be performed at Visit 1 only if 
the subject did not take their morning doses of inhaled asthma maintenance 
medications and if albuterol was not administered within 6 hours. If the subject has 
not withheld their dose(s) of regular asthma medications (Section 8.1) or albuterol, 
Visit 1 should be rescheduled no sooner than the following day.
-
Spirometry will be conducted at 60 and 30 minutes prior to bronchodilator (albuterol) 
administration and 30 minutes post-bronchodilator (Section 7.1.1.3). If subjects are 
not reversible to albuterol at 30 minutes post-dose, the post-dose PFTs can be 
repeated at 60 minutes post-dose. 
-
The average of the 2 pre-bronchodilator FEV1 values will be calculated to determine 
if the subject meets the inclusion criterion (ie, FEV1 >40% and <85% of predicted 
normal value for subjects 18 to 80 years of age or FEV1 >40% and <90% of predicted 
normal value for subjects 12 to <18 years of age).
-
FEV1 repeatability must be demonstrated at one of the pre-dose measurements.
•
Visit 2:
-
Spirometry will only be conducted in those subjects who did not demonstrate 
reversibility to albuterol at Visit 1.
-
Subjects who did not meet albuterol reversibility criteria at Visit 1 must meet these 
criteria at Visit 2.
-
When spirometry is conducted at Visit 2, the procedures will be the same as those 
described above for Visit 1 (eg, FEV1 inclusion criterion must be met). 
•
Visit 3: spirometry will be conducted 60 and 30 minutes prior to ipratropium 
administration and 30 minutes post-ipratropium (Section 7.1.1.3).
•
At Visits 4, 7, and 10/Final Visit or the Treatment Discontinuation Visit: spirometry will 
be conducted 60 minutes and 30 minutes prior to study drug and ICS/LABA 
administration and 15 minutes, 30 minutes, and 1, 2, and 4 hours post-dosing with study 
drug and ICS/LABA (if a subject discontinues taking study drug but agrees to continue in 
the study and complete all remaining study visits, the subject’s usual inhaled asthma 
maintenance medication(s) will be administered for spirometry testing instead of study 
drug). At Visit 4, the average of the 2 pre-dose FEV1 values will be calculated to 
determine if the subject meets the inclusion criterion.
•
At Visits 5, 6, 8, and 9: spirometry will be conducted 60 minutes and 30 minutes prior to 
study drug and ICS/LABA administration.
Subjects will be required to return to the clinic at approximately the same time of day for all 
treatment visits. All in-clinic dosing must occur prior to 10 am with consistent in-clinic dose 


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timing throughout the randomized Treatment Period; visits must be planned accordingly 
(Section 8.1). The subjects will be required to remain at the clinic until completion of all 
protocol-defined assessments.
7.1.1.3
Reversibility to Albuterol and Ipratropium
Reversibility to albuterol will be evaluated for subject qualification purposes, and 
reversibility criteria must be met at either Visit 1 or Visit 2 (Section 5.1). If reversibility 
criteria are met at Visit 1, reversibility testing will not be repeated at Visit 2. If reversibility 
criteria are not met at Visit 1, subjects may continue to Visit 2; however, reversibility criteria 
must be met at Visit 1 or Visit 2 to continue to Visit 3.
Reversibility to ipratropium will be evaluated at Visit 3 for characterization and 
randomization stratification purposes.
The procedures for determining reversibility to albuterol and ipratropium are as follows:
1. Determine if morning doses of all maintenance asthma medications were withheld and 
that short-acting bronchodilators were not administered within 6 hours of testing
2. Perform prebronchodilator PFTs at 60 and 30 minutes prior to administration of 
bronchodilator
3. Administer 4 puffs of albuterol (Visit 1 and, if needed, Visit 2) or 4 puffs ipratropium 
(Visit 3).
4. Perform postbronchodilator PFTs 30 minutes after the administration of either albuterol 
or ipratropium (as appropriate per visit). If subjects are not reversible to albuterol at 
30 minutes, the post-dose PFT can be repeated at 60 minutes post-dose. Repeat 
spirometry at 60 minutes post-dose is not necessary for reversibility testing to 
ipratropium.
Reversibility will be a comparison of the average best FEV1 effort obtained at 60 and 
30 minutes prebronchodilator to the best FEV1 effort obtained at 30 minutes (or up to 
60 minutes, if repeated for albuterol) postbronchodilator following administration of either 
albuterol or ipratropium. A subject is considered reversible to albuterol if the improvement in 
FEV1 at 30 minutes (or up to 60 minutes) post-albuterol is ≥12% and ≥200 mL.
7.1.2
Subject’s eDiary Data Collection
At Visit 1, subjects will be trained on and receive their eDiary. Prior to issuing the eDiary to 
the subject, site personnel are responsible for programming the eDiary and training subjects 
on its use. Subjects will enter the following information into the eDiary BID beginning with 
Visit 1 and for the duration of the study during both Screening and Treatment Periods: 
daytime and nighttime asthma symptom scores, and use of rescue albuterol. During the 
Screening Period, time of ICS/LABA administration will also be entered (this will be QD for 
ICS/LABAs that are only administered QD and BID otherwise); ipratropium use, if 
applicable, will be recorded as a concomitant medication. During the Treatment Period, time 


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of study drug administration will also be entered; time of ICS/LABA administration will then 
be recorded as a concomitant medication.
7.1.2.1
eDiary Compliance Requirement
Between Visits 1 and 4, 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 4 will be considered a screen failure
•
Chronic failure in the judgment of the Investigator (eg. noncompliance with the eDiary), 
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. The Sponsor may also instruct a site to discontinue a subject 
based on consistent noncompliance.
7.1.2.2
Rescue Medication Use
Use of rescue medication will be recorded in the eDiary each morning (reflecting nighttime 
albuterol use) and each evening (reflecting daytime albuterol use). The subject will record the 
total number of “puffs” of albuterol used over the time period as the number of actuations on 
the canister. For example, when rescue medication is required and 2 actuations are inhaled, 
this should be recorded as 2 “puffs.” If the subject requires 4 actuations, this should be 
recorded as 4 “puffs.”
7.1.2.3
PEFR
The PEFR is to be assessed using the Sponsor-provided PEFR meter, which will be paired 
with the eDiary via Bluetooth. Subjects will be dispensed and trained on the device at Visit 1. 
The eDiary will remind the subject BID when it is time to obtain their peak flow. Once the 
subject has completed the peak flow assessment, the data will be automatically transmitted 
from the PEFR to the eDiary. The best (highest) of 3 PEFR efforts BID will be captured in 
the eDiary.
Subjects will complete the PEFR maneuver at home once in the morning and once in the 
evening before dosing with ICS/LABA (and ipratropium, if applicable) during the Screening 
Period, and once in the morning and once in the evening before dosing with study drug and 
ICS/LABA during the Treatment Period. In addition, PEFR should be measured before use 
of rescue albuterol. 
On the morning of all clinic visits, PEFR will be assessed at home prior to coming to the 
clinic. Subjects do not need to bring their peak flow meter to clinic visits, except to their final 
visit.


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At Visit 4, a PEFR stability limit will be automatically calculated by the eDiary. The stability 
limit is defined as the average of the available morning PEFR eDiary recordings during at 
least 4 of the last 7 days before Visit 4 (ie, the baseline PEFR), multiplied by 0.8. The PEFR 
stability limit will be used to help identify moderate asthma exacerbation as described in 
Section 7.1.3.
7.1.2.4
Asthma Symptoms
The subject will record their asthma symptom scores in the eDiary each morning (reflecting 
nighttime symptoms) and each evening (reflecting daytime symptoms). This symptom 
assessment should occur before determining PEFR and before administration of any 
medications during the Screening Period or randomized Treatment Period.
Subjects will assess the symptoms of cough, wheeze, shortness of breath, and chest tightness 
and enter a single score that is inclusive of all symptoms for their daytime and nighttime 
symptom scores. Symptom scores will be used to help identify moderate asthma 
exacerbations as described in Section 7.1.3.
The following symptoms will be assessed:
Daytime Symptom Score (determined in the evening)
0=No symptoms during the day
1=Symptoms for 1 short period during the day
2=Symptoms for 2 or more short periods during the day
3=Symptoms for most of the day that did not affect my normal daily activities
4=Symptoms for most of the day that did affect my normal daily activities
5=Symptoms so severe that I could not go to work or perform normal daily activities
Nighttime Symptom Score (determined in the morning)
0=No symptoms during the night
1=Symptoms causing me to wake once (or wake early)
2=Symptoms causing me to wake twice or more (including waking early)
3=Symptoms causing me to be awake for most of the night
4=Symptoms so severe that I did not sleep at all
On clinic visit mornings, the nighttime symptom score will be determined and recorded at 
home prior to the clinic visit.


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7.1.2.5
Study Drug and Other Study Medication Compliance
During the Screening Period, subjects will record the times of ICS/LABA dosing in the
eDiary for practice. Rescue medication (albuterol) use will also be recorded as described in 
Section 7.1.2.2. 
During the Treatment Period, subjects will record the times of study drug dosing (morning 
and evening for BID treatments, morning only for the QD treatment) in the eDiary, except on 
the mornings of in-clinic dosing. 
ICS/LABA dosing during the Screening Period and during the Treatment Period will be 
recorded as concomitant medications.
Study drug compliance will be checked at all visits. Any issues identified will be documented 
in the appropriate study file and reinstruction will be completed as necessary.
7.1.2.6
Symptom Worsening Assessment and eDiary Alert System
The eDiary will be programmed to monitor for signs of a potential asthma exacerbation by 
monitoring decreases from baseline in morning or evening PEFR, increases from baseline in 
the number of puffs of albuterol used per day, and/or increases in daytime or nighttime 
asthma symptom scores (Section 7.1.3). If any of these parameters meet the pre-defined 
thresholds for a moderate asthma exacerbation (Table 7-1), the eDiary will generate an alert 
to the subject and the clinical site. This alert is intended to generate a contact between the 
subject and the Investigator to assess the status of the subject’s asthma.
7.1.3
Asthma Exacerbations
7.1.3.1
Definitions and Treatments
The definitions of mild, moderate, and severe asthma exacerbations to be used in this study 
are shown in Table 7-1. These definitions are based on the ATS/ERS Statement “Asthma 
Control and Exacerbations, Standardizing Endpoints for Clinical Asthma Trials and Clinical 
Practice” (Reddel 2009).


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Table 7-1
Definition and Severity of Asthma Exacerbations 
Severity of 
Asthma 
Exacerbation
Definition
Criteria for Study Drug 
Discontinuationc
Severea
Use of systemic corticosteroids (tablets, suspension, 
or injection) for at least 3 days OR a hospitalization or 
ER visit because of asthma
There are 2 criteria for 
discontinuing study drug based on 
asthma exacerbations 
(Section 5.9.1):
•
Inpatient hospitalization
•
Requirement for >2 courses of 
oral corticosteroids to treat an 
exacerbation during the course 
of the study
Moderateb
A deterioration of asthma requiring a new or 
increased dose of ICS for at least 3 days.
Deterioration of asthma is defined by the occurrence 
of 1 or more of the following for ≥2 consecutive days: 
•
PEFR: a decline of ≥20% from baseline 
(see Section 7.1.2.3 for baseline PEFR stability 
limit calculation)
•
Rescue albuterol use: >4 puffs/day and 
≥2×baseline
•
Symptoms: nighttime score that is >baseline and 
≥2 OR a daytime score that is >baseline and ≥3
Mild
A deterioration of asthma (as defined above) 
•
Not requiring treatment OR 
•
Requiring treatment with a systemic 
corticosteroid or a new or increased dose of ICS 
for <3 days
Abbreviation: ER=emergency room.
a
Subjects who have died because of asthma will be considered to have had a severe asthma exacerbation 
regardless of whether they received systemic corticosteroids or were hospitalized.
b
Will be captured via the eDiary.
c
For subjects who discontinue study drug, the Investigator will place subjects on appropriate asthma 
medications and the subjects will be encouraged to stay in the study and complete all remaining study visits 
and procedures.
In cases where the subject meets the criteria for a moderate or severe asthma exacerbation, 
the Investigator or designee will enter the information into the eCRF on the asthma 
exacerbation page (refer to Section 7.1.3.3). A mild exacerbation will be captured by the 
eDiary.
The recommended treatment for a moderate asthma exacerbation is a short course (5-7 days) 
of an increased dose of ICS or an additional ICS as outlined below, to help avoid progression 
to a severe exacerbation:
•
Budesonide 400 ∀g BID for 5 to 7 days


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Note: Each actuation of Pulmicort Turbuhaler 200 ∀g delivers 160 ∀g budesonide from the 
mouthpiece, which is the same amount as delivered by an actuation of Pulmicort Flexhaler 
180 ∀g.
For an individual subject, the same increased dose of ICS or additional ICS should be used 
throughout the study when possible.
The recommended (GINA 2017) treatment for a severe asthma exacerbation is a short course 
of oral corticosteroids as outlined below:
•
Prednisolone (1 mg/kg/day up to 50 mg for adults and adolescents) QD (preferably in the 
morning) for 5 to 7 days
•
Tapering the prednisolone dose is not needed if the treatment has been given for 
<2 weeks
Additional information about treatment of asthma exacerbations is provided in 
Section 5.7.2.2.2.
7.1.3.2
Onset and Duration of Asthma Exacerbations
For a severe asthma exacerbation, the start date is defined as the start date of prescribed 
treatment with a systemic corticosteroid or the date of ER visit or hospitalization for asthma. 
The stop date is defined as the last day on which systemic corticosteroids were used, or the 
discharge date from the ER or hospital for asthma, whichever is later.
For a moderate asthma exacerbation, the start date is defined as the first day of the increased 
dose of ICS or new ICS treatment (for example, adding inhaled budesonide) and the end date 
is defined as the last day of this treatment.
For a mild asthma exacerbation, the start date is defined as the first day of 2 consecutive days 
of deterioration and the end date is defined as the first day the subject no longer meets the 
deterioration criteria OR the last day of treatment, whichever is later. Treatment must be for 
less than 3 days to meet the criteria for a mild exacerbation.
In order to ensure that the same event is not counted twice, consecutive exacerbations with 
start and stop dates ≤7 days apart will be considered to be the same event of the highest 
severity.  Any exceptions and clarifications to this rule will be provided in detail in the
statistical analysis plan.
7.1.3.3
Approach for Capturing Asthma Exacerbations
Asthma exacerbations occurring prior to Visit 1 will be considered part of the subject’s 
medical history and will be captured in the medical history eCRF.


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All moderate and severe asthma exacerbations occurring after Visit 4 must be captured on the 
asthma exacerbation eCRF page. Mild exacerbations will be identified and captured by the 
eDiary alert system. 
Asthma exacerbations will be considered expected study endpoints and will not be reported 
as AEs unless they meet the criteria for a serious adverse event (SAE). The start date for an 
SAE of severe asthma exacerbation should be the start date of systemic corticosteroids or the 
date of ER visit or hospitalization for asthma as stated in Section 7.1.3.2.
7.1.4
Subject Questionnaires
Subject questionnaires (ACQ and the AQLQ +12) will be completed on site utilizing study-
supplied electronic questionnaire devices (not the subject’s eDiary) at specified visits 
throughout the study.
7.1.4.1
ACQ 
The ACQ will be completed at Visits 2 and 4 through 10/Final Visit, or if the subject 
withdraws consent/discontinues study drug, at the Treatment Discontinuation or Study 
Withdrawal Visit, before any other study procedures are performed.
The ACQ (Appendix 9; Juniper 1999a) was developed to measure asthma control and has 
been fully validated for use in adults and in children 6 to 17 years of age. International 
guidelines for the treatment of asthma have identified that the primary clinical goal of asthma 
management is to optimize asthma control (minimization of symptoms, activity limitation, 
bronchoconstriction, and rescue bronchodilator use) and thus reduce the risk of life-
threatening exacerbations and long-term morbidity. The ACQ was developed to meet these 
criteria by measuring both the adequacy of asthma control and change in asthma control, 
which occurs either spontaneously or as a result of treatment.
The ACQ, comprising 7 questions, is completed in the clinic and requires subjects to recall 
their experiences during the previous week (7 days) prior to the study visit. The ACQ-5, -6, 
and -7 (questions 1-5, 1-6, and 1-7, respectively) have all been validated. The ACQ-5 
measures 5 symptoms (woken at night by symptoms, wake in the morning with symptoms, 
limitation of daily activities, shortness of breath, and wheeze); the ACQ-6 is these symptom 
measurements plus daily rescue medication use as recalled by the subject; and the ACQ-7 is 
the ACQ-6 plus airway caliber as measured by pre-bronchodilator FEV1 percent predicted.
Each question is scored on a 7-point scale (generally, 0=no impairment, 6=maximum 
impairment), the questions are equally weighted, and the ACQ score is the mean of the item 
responses and therefore ranges from 0 (totally controlled) to 6 (severely uncontrolled).
7.1.4.2
AQLQ +12
The AQLQ +12 will be completed at Visits 4 through 10/Final Visit, or at the Treatment 
Discontinuation or Study Withdrawal Visit, after the ACQ and before any other study 
procedures are performed.


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The AQLQ +12 is a 32-item validated subject-administered questionnaire that was developed 
to measure the functional problems (physical, emotional, social and occupational) that are 
most troublesome to adults (≥18 years of age) and adolescents (12 to 17 years of age) with 
asthma (Juniper 2005, Juniper 1999b, Juniper 1994, Juniper 1993, Juniper 1992). The 
32 questions in the AQLQ +12 are in 4 domains (symptoms, activity limitation, emotional 
function, and environmental stimuli). All 4 domains contain standard specific questions 
relating to each domain.
Subjects are asked to think about how they have been during the previous 2 weeks and to 
respond to each of the 32 questions on a 7-point scale (7=no impairment to 1=severe 
impairment). The overall AQLQ +12 score is the mean of all 32 responses and the individual 
domain scores are the means of the items in those domains. A change in score of 0.5 on the 
7-point scale is the smallest change that can be considered clinically important, known as the 
minimal clinically important difference. Additional information about the AQLQ +12 is 
provided in Appendix 10.
7.1.5
FENO
The FENO will be collected at Visits 2, 4, 5, 7, and 10/Final Visit, or at the Treatment 
Discontinuation or Study Withdrawal Visit, prior to spirometry. The procedure is described 
in Appendix 11.
Measurement of FENO is a noninvasive and established clinical biomarker for airway 
inflammation that is recommended by the ATS to monitor eosinophilic airway inflammation 
in subjects with asthma (Dweik 2011). Each site will be provided with a FENO device (Niox 
Vero® [Circassia Pharmaceuticals Inc., Chicago, Illinois, US]) and all required accessories 
(eg, test kits) and receive training on its use and care (Appendix 11). Clinically meaningful 
increases and decreases in FENO are defined in Section 9.5.3.9.
7.2
Safety Assessments
Safety assessments for this study are AEs, physical examinations, vital signs, 12-lead ECGs, 
24-hour Holter monitoring, and clinical laboratory tests.
7.2.1
Medical/Surgical/Asthma Exacerbation History and Physical Examination
Medical history will be collected at Visit 1 and updated during the Screening Period, if 
necessary. The number of asthma exacerbations requiring systemic corticosteroids, 
emergency room visits, and/or hospitalizations within the previous 12 months will be 
collected at Visit 1.
A complete physical examination will be performed at Visits 1 and 10/Final Visit. The 
complete physical examination will include the following:
•
Weight, general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), 
lymph nodes, chest, heart, abdomen, extremities, and nervous system


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•
Height will be measured at Visit 1 for subjects who have had their 18th birthday and at 
Visits 1, 4, 5, 7, and 10 for subjects 12 years of age up to and including their 18th
birthday, at the visit.
7.2.2
Vital Sign Measurements
Vital sign measurements (HR, SBP, and diastolic blood pressure [DBP]) will be obtained 
after the subject has rested for at least 5 minutes in either the supine or seated position. A 
single measurement of vital signs will be obtained as follows: 
•
Visit 1: before PFTs
•
Visit 2: before pre-bronchodilator (albuterol) PFT for reversibility testing
•
Visit 3: before pre-bronchodilator (ipratropium) PFT for reversibility testing
•
Visits 4, 7, and 10/Final Visit: approximately 60 minutes pre-dose and 4 hours post-dose
•
Visits 5, 6, 8, and 9: approximately 60 minutes pre-dose
For subjects who discontinue study drug or withdraw consent, a single measurement of vital 
signs will be obtained at the Treatment Discontinuation Visit or Study Withdrawal Visit, 
respectively.
7.2.3
12-Lead ECG
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 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.
A single ECG will be obtained as follows:
•
At Visit 1
•
At Visits 4, 5, 7, and 10/Final Visit within 60 minutes prior to dosing 
For subjects who discontinue study drug or withdraw consent, a single ECG will be obtained 
at the Treatment Discontinuation or Study Withdrawal Visit.


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The ECG parameters to be assessed include HR, PR interval, QRS axis, QRS interval, and 
QT/QTcF interval. The QT intervals and calculated QTcF intervals will be reviewed and 
checked for gross inaccuracies by the Investigator or designated ECG reviewer. Subjects who 
experience a change from their baseline ECG may need to discontinue study drug per criteria 
specified in Section 5.9.1.
7.2.4
Holter Monitoring: 24-Hour Continuous Electrocardiography
The following information applies only to those subjects participating in the 24-hour Holter 
monitoring sub-study.
Continuous Holter monitoring will be conducted over 24 hours at Visit 3 and at Visit 7. 
Holter monitor recordings are to be initiated in the morning at approximately the same time 
(±2 hours) for these visits and 15 to 30 minutes before administration of the morning dose of 
ICS/LABA and, at Visit 7, study drug. Holter monitor procedures are summarized in 
Table 8-3.
Continuous Holter monitor recording will be collected for 24 hours. Holter monitor 
recordings must contain a minimum of 18 hours of acceptable quality recording in a 24-hour 
period to be deemed a successful Holter monitor assessment.
The designated service provider for Holter monitoring will be 
 
All Holter monitor recordings will be assessed for cardiac arrhythmias by an independent 
cardiologist appointed by 
.
7.2.4.1
Visit 3 Holter Monitoring Procedures
The Visit 3 (screening/baseline) Holter monitoring will be initiated following reversibility 
testing to ipratropium and 15 to 30 minutes before administration of the morning dose of 
ICS/LABA.
When the subject returns to the clinic the following day, the quality of the Holter monitor 
recordings will be assessed at the site. If the first Holter monitoring attempt is not successful 
(ie, <18 hours of acceptable quality recording), the Holter monitor will be reconnected for 
another 24 hours using a new Holter monitor hook-up kit. The subject will be instructed to 
continue his/her medications as per study protocol. The subject will return the following day 
for removal of the Holter monitor. This second attempt should be scheduled so that the 
Holter monitoring will be completed at least 24 hours before administration of the morning 
dose of study drug and ICS/LABA at Visit 4.
If the Holter monitoring recording remains inadequate on the second attempt, the subject will 
not be eligible to participate in the Holter monitoring sub-study, but DOES NOT need to be 
excluded from the full study. If clinically significant findings (as defined in Holter monitor 
exclusion criteria [Section 5.5]) are noted on any of the Holter monitor recordings, there will 
be no further attempts; the subject will be considered a screen failure and will not be eligible 
to enroll in the full study.


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7.2.4.2
Visit 7 Holter Monitoring Procedures
At Visit 7, Holter monitoring will be initiated 15 to 30 minutes before administration of the 
morning dose of study drug and ICS/LABA in the clinic. Subjects will be instructed to return 
to the clinic the following day for removal of the Holter monitor.
When the subject returns to the clinic the following day, the quality of the Holter monitor 
recordings will be assessed at the site. If the first Holter monitoring attempt is not successful 
(ie, <18 hours of acceptable quality recording), the Holter monitor will be reconnected for 
another 24 hours using a new Holter monitor hook-up kit. The subject will be instructed to 
continue his/her medications as per study protocol. The subject will return the following day 
for removal of the Holter monitor. This second attempt should be scheduled so that the 
Holter monitoring will be placed on or before Visit 8. 
If the Holter monitoring recording remains inadequate on the second attempt, there will be no 
further attempts. 
7.2.4.3
Data for Analysis
Data for analysis will include the following:
•
General trends including HR
•
Hourly rhythm assessments
•
Ventricular ectopy summary
•
Ventricular run summary
•
Supraventricular ectopy summary
•
Supraventricular run summary
•
Any other clinically relevant arrhythmias, including atrial fibrillation and pronounced 
bradycardia
Manual summary interpretation of the data will be sent as a report to the site and to the 
Sponsor.
7.2.5
Clinical Laboratory Tests
Subjects will be in a seated or supine position during blood collection. 
Clinical safety laboratory tests will be analyzed by a central laboratory according to 
standardized, validated assays with the exception of urine pregnancy tests. The laboratory 
will supply detailed procedures for the preparation and collection of blood and urine samples 
along with all containers needed for their collection. Urine pregnancy tests will be performed 
at the clinical site using a commercially available test product.
Clinical laboratory tests performed during this study are shown in Table 7-2.


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Samples for clinical safety laboratory testing will be obtained at the following times:
•
Blood 
-
For hematology and clinical chemistry: Visit 1 (Screening) and prior to dosing at 
Visits 4, 5, 7, and 10/Final Visit, and the Treatment Discontinuation/Study
Withdrawal Visit
-
For pregnancy (women of childbearing potential only): Visit 1 (Screening) and prior 
to dosing at Visit 10/Final Visit, and the Study Withdrawal Visit
•
Urine 
-
For urinalysis: Visits 1 (Screening), 4, and 10/Final Visit, and the Treatment 
Discontinuation/Study Withdrawal Visit. 
-
For pregnancy (women of childbearing potential only): prior to dosing at Visits 2 
through 9 


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Table 7-2
List of Clinical Safety 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 
Eosinophil count
Platelet count 
Clinical Blood Chemistry
Liver Enzyme and Other Liver Function Tests
Other Clinical Blood Chemistry
Alanine aminotransferase 
Albumin
Aspartate aminotransferase
Blood urea nitrogen 
Alkaline phosphatase
Calcium
Bilirubin, total 
Chloride
Gamma-glutamyl transferase
Cholesterol, total 
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 for women of childbearing potential only: Serum human chorionic gonadotropin (hCG) at 
Visits 1 and 10/Final Visit or Treatment Discontinuation/Study Withdrawal Visit; urine hCG at all other 
visits. 
Creatinine clearance will be estimated by the central laboratory using the CKD-EPI formula (Levey et al 
2009) for subjects >18 to 80 years of age or the Schwartz formula for subjects 12 to ≤18 years of age; where 
≤18 years of age is defined as anyone less than 18 years of age up to and including their 18th birthday and 
>18 years of age is defined as 18 years +1 day and older (Schwartz et al 1987).


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7.3
AEs
7.3.1
Performing 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 the Sponsor. In addition, 
certain AEs are classified as ‘serious’ (as described in Section 7.3.9) and must be reported no 
later than 24 hours after the Investigator recognizes/classifies the event as an SAE to the 
Sponsor 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 study drug.
7.3.2
AE Definitions
The following definitions of terms are guided by the International Conference on 
Harmonisation (ICH) Technical Requirements for Registration of Pharmaceuticals for 
Human Use, the US Code of Federal Regulations (21 CFR 312.32) and European Union 
Directive 2001/83/EC and are included herein.
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE (also referred to as an adverse experience) 
can be any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a drug, without any judgment about 
causality. An AE can arise from any use of the drug (eg, off-label use, use in combination 
with another drug) and from any route of administration, formulation, or dose, including an 
overdose.
Adverse events include, but are not limited to the following:
•
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
•
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 the following:
•
Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, blood 
transfusion); the condition that leads to the procedure is an AE (eg, bleeding esophageal 
varices, dental caries)


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•
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
Any AE 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 7.3.9.
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. Note that for SAEs that could be associated with any study procedure, the causal 
relationship is implied as ‘yes’.
7.3.6
Asthma Exacerbations and Associated Symptoms of Asthma
Asthma exacerbations may occur as a manifestation of asthma despite using standardized 
drug treatment or treatment(s) with combination therapies. As a result, the Sponsor has 
classified an asthma exacerbation as a protocol-specified expected event, and it is not to be 
reported as an AE unless considered an SAE. Moderate and severe asthma exacerbations 
must be captured on the asthma exacerbations eCRF; mild asthma exacerbations will be 
captured by the eDiary.


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Since asthma exacerbations are expected events in this study, any individual case safety 
reports received related to an exacerbation of asthma will not be submitted on an expedited 
basis as a suspected unexpected serious adverse reaction unless further assessment is required 
by the Sponsor.
Associated symptoms of asthma (eg, wheeze, breathlessness, cough), the disease under study, 
will not be reported as AEs, unless considered an SAE. 
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 statistical analysis plan (SAP). Some 
events are described below but this is not a comprehensive list of all AESIs.
7.3.7.1
LAMA Effects
Known effects of LAMAs include dry mouth, cardiovascular effects, ocular disorders, 
urinary retention, and gastrointestinal disorders.
7.3.7.2
Paradoxical Bronchospasm
Monitoring for paradoxical bronchospasm will occur at Visits 4, 5, 7, and 10/Final Visit at 
15 and 30 minutes post-dose. 
In this study, paradoxical bronchospasm is defined as a reduction in FEV1 of >20% from 
baseline with associated symptoms of wheezing, shortness of breath, or cough that occur 
within 30 minutes post-dosing. Baseline is defined as the mean of the FEV1 values obtained 
60 and 30 minutes prior to study drug and ICS/LABA administration at that visit. 
7.3.8
Clinical Laboratory AEs
Many laboratory abnormalities observed during the course of a study will be included under 
a reported AE describing a clinical syndrome (eg, 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 the following:
•
A laboratory abnormality that leads to a dose-limiting toxicity (eg, an abnormality that 
results in study drug dose suspension or treatment discontinuation)
•
A laboratory abnormality that results in any therapeutic intervention (ie, concomitant 
medication or therapy)
•
Other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (eg, significant fall in hemoglobin not requiring transfusion)


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•
For laboratory abnormalities that do not meet the above criteria, but are outside of normal 
range (eg, < or > normal reference range), the Investigator should indicate whether the 
value is clinically significant or not clinically significant for the subject.
7.3.9
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
•
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) that 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 
IB or is not listed at the specificity or severity that has been observed.
7.3.9.1
Reporting SAEs
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 the Sponsor’s Pharmacovigilance Department or designee. All SAEs 
must be reported to the Sponsor Pharmacovigilance Department 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 


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Investigator’s judgment of causality must be provided at the time of the initial report using 
the appropriate form (eg, SAE report form). After the initial report, as necessary, the 
Investigator must provide any additional information on an SAE to the Sponsor’s 
Pharmacovigilance Department or designee within 2 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 who complete the entire study, all AEs/SAEs will be collected through 14 
(+2) days after the last dose of study drug via a follow-up telephone call (see Section 8.11).
For subjects who discontinue randomized study drug but are planning to continue study 
participation (ie, planning to complete all remaining study visits and procedures), see 
Section 8.9.1, Treatment Discontinuation.
For subjects who withdraw from the study, see Section 8.9.2, Study Withdrawal.
Post-treatment SAEs following the last dose of study drug must be reported to the Sponsor’s 
Pharmacovigilance Department as described in Section 7.3.9.3.
The Investigator is responsible for continuing to report any new or relevant follow-up 
information that s/he learns about the SAE.
7.3.9.2
Supplemental Investigations of SAEs
The Investigator and supporting personnel responsible for subject care should discuss with 
the Sponsor Medical Monitor or designee any need for supplemental investigations of SAEs. 
If additional assessments are conducted, results must be reported to the Sponsor. If a subject 
dies during study participation and if a postmortem examination is performed, a copy of the 
autopsy report should be submitted to the Sponsor.
7.3.9.3
Notification of Post-Study SAEs
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, the SAE must be reported to the Sponsor, whether or not the 
event is attributable to study drug. All SAEs must be reported to the Sponsor no later than 
24 hours after the Investigator recognizes/classifies the event as an SAE.
7.3.9.4
Institutional Review Board/Independent Ethics Committee Notification of SAEs
The Investigator is responsible for promptly notifying her/his Institutional Review Board 
(IRB)/Independent Ethics Committee (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 the Sponsor. Documentation of IRB/IEC submission must be retained 
for each safety report. The Investigator is also responsible for notifying the Sponsor if their 
IRB/IEC requires revisions to the ICF or other measures based on its review of an SAE 
Report.


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7.3.9.5
Health Authority Safety Reports
The Sponsor 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.
The Sponsor 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.
7.3.10
Post-Study Follow-Up of AEs and SAEs
Any AEs/SAEs 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. The Sponsor retains the right to request additional information for 
any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
7.3.11
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 
Sponsor’s 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 are not limited to the IB for GP 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 the Sponsor 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 the Sponsor’s 
Pharmacovigilance Department 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
Paternal Exposure
If a male subject's partner becomes pregnant during the course of the study, it must be 
reported to the Sponsor within 24 hours of the Investigator learning of its occurrence.


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7.3.14
Hy’s Law
Cases where a subject shows an AST or ALT ≥3×ULN with TBL ≥2×ULN may need to be 
reported as SAEs. Please refer to Appendix 12 for further instructions in cases of combined 
increase of aminotransferase and TBL.
7.3.15
Data Monitoring Committee
An independent, external Data Monitoring Committee (DMC) will be set up to review all 
SAEs (including deaths and all hospitalizations) and cardiovascular events. Members of the 
DMC will review summaries of these safety data generated externally and independently of 
the Sponsor in a semi-blinded or unblinded manner at predetermined intervals. If significant 
safety issues arise in between scheduled meetings, ad hoc meetings will be scheduled to 
review the data. Based on the safety implications of the data, the DMC may recommend 
modification or termination of the study.
7.4
Termination of 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 the Sponsor.
The Sponsor reserves the right to terminate 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 the Sponsor, in a timeframe that is compatible with the subjects’ 
welfare.


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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. The overall schedule of events is provided in Table 8-1. A detailed 
schedule is provided for the timing of assessments of all post-randomization visits in 
Table 8-2. A detailed schedule of events for 24-hour Holter monitoring sub-study at Visits 3 
and 7 is provided in Table 8-3.
8.1
General Study Considerations
•
In order to minimize diurnal variance, sites should make every effort to assess subjects in 
clinic at the same time throughout the study. The first dose of study drug administered in 
the clinic should be planned to occur at approximately the same time the subject will 
typically administer study drug in the morning at home. However, sites should also make 
every effort to ensure that the morning study drug dosing occurs before 10 am.
•
The subject should then be advised that subsequent morning study drug dosing should 
occur at approximately the same time every day and that evening study drug dosing 
should occur as close as possible to 12 hours from the time of morning study drug dosing.
•
Sites should discuss the importance of study drug dosing at a consistent time linked to the 
time of study drug dosing at randomization. For example, if the study drug dose at 
randomization is administered at 8 am, all subsequent doses should be administered as 
close as possible to 8 am and 8 pm. In this case, all visits should be scheduled to support 
in-clinic dosing as close to 8 am (the timing of the initial dose at Visit 4) as possible.
•
Subjects will be required to return to clinic at approximately the same time as Visit 1 for 
all treatment visits (±1 hour) and dosing time should not exceed 10 am. Subjects will be 
required to remain at the clinic until completion of all protocol-defined assessments.
•
The day before study visits, sites should contact subjects to confirm timing of the evening 
study drug dose and the expected timing of the in-clinic study drug dose. If the in-clinic 
dose will occur later than the subject typically takes their morning dose, the subject must 
be instructed to take their evening dose 12 hours prior to the expected in-clinic dosing 
time. Sites should instruct each subject as follows during this reminder phone call:
-
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
•
Subjects who inadvertently took asthma medication(s) within 6 hours of the start of study 
procedures must have their clinic visit delayed (but not to exceed study drug dosing by 
10 am) or rescheduled within the specified visit window.
•
Subjects must not ingest xanthine and/or xanthine analogue (caffeine)-containing foods 
or beverages or caffeine-containing medications 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.


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•
Site personnel will instruct subjects not to take any asthma medications without site 
personnel permission during a clinic visit until all study procedures have been completed, 
and the subject is discharged. Site personnel should take every precaution to prevent 
subject use of asthma medications during the study visit. Subjects will be asked to abstain 
wherever possible from using rescue albuterol during study clinic visits. If a subject is 
experiencing severe symptoms and requires albuterol for relief of asthma symptoms at 
any time during a study visit, site personnel must note the time and justification of use in 
the subject’s chart and all subsequent spirometry assessments should be stopped. 
However, safety assessments should be continued at the discretion of the Investigator.


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Table 8-1
Schedule of Events
Procedures
Screeninga
Treatment Period
Follow-Up 
TC
Visit 1
Visit 2b
Visit 3
Visit 4
Rand
Visit 5
Week 4
Visit 6
Week 8
Visit 7
Week 12
Visit 8
Week 16
Visit 9
Week 20
Visit 10/ 
Final Visit 
Week 24o
14 (+2)
days after 
last dose
Study Dayc:
Day
-28 to -9
Day
-21 to -2
Day
-20 to -1
Day
1
Day
28±2
Day 
56±5
Day 
84±5
Day 
112±5
Day 
140±5
Day
168±5
Day
182±2
Informed consent/assent
X
Inclusion/exclusion criteria
X
X
X
X
Verify continuing eligibility
X
X
X
X
X
X
Randomization criteria
X
Calculate PEFR stability limits
X
Demographics and medical/surgical 
historyd
X
X
X
Prior/concomitant medications 
reviewe
X
X
X
X
X
X
X
X
X
Xo
X
Discontinue tiotropium (if 
applicable)
X
Dispense/collect Sponsor-provided 
albuterol (as needed)
X
X
X
X
X
X
X
X
X
Xo
Dispense/collect Sponsor-provided 
ipratropium bromide HFAf
X
X
Spirometry/PFTsg
Xh
Xh
Xh
X
X
X
X
X
X
X
FENO
X
X
X
X
Xo
Vital signsi
X
X
X
X
X
X
X
X
X
Xo
Blood collected for laboratory 
testing
X
X
X
X
Xo


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Table 8-1
Schedule of Events
Procedures
Screeninga
Treatment Period
Follow-Up 
TC
Visit 1
Visit 2b
Visit 3
Visit 4
Rand
Visit 5
Week 4
Visit 6
Week 8
Visit 7
Week 12
Visit 8
Week 16
Visit 9
Week 20
Visit 10/ 
Final Visit 
Week 24o
14 (+2)
days after 
last dose
Study Dayc:
Day
-28 to -9
Day
-21 to -2
Day
-20 to -1
Day
1
Day
28±2
Day 
56±5
Day 
84±5
Day 
112±5
Day 
140±5
Day
168±5
Day
182±2
Urine collected for laboratory 
testing
X
X
Xo
Pregnancy testingj
X
X
X
X
X
X
X
X
X
Xo
12-lead ECG
X
X
X
X
Xo
Holter monitor placement/removalk
X
X
Physical examinationl
Xl
Xo
ACQ
X
X
X
X
X
X
X
Xo
AQLQ +12 
X
X
X
X
X
X
Xo
Asthma exacerbations and AEs
X
X
X
X
X
X
X
X
X
Xo
X
Inhalation device trainingp
X
X
X
X
X
X
X
X
X
Inhalation device dose indicator 
training
X
X
X
X
X
X
Study drug dispensing/collection
X
X
X
X
X
X
Xo
Administer subject’s ICS/LABA 
(in-clinic)g
X
X
X
X
X
X
X
X
X
Administer study drug in-clinicg
X
X
X
X
X
X
X
eDiary: dispense/collectm
X
Xo
eDiary: training/review
X
X
X
X
X
X
X
X
X
X


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Table 8-1
Schedule of Events
Procedures
Screeninga
Treatment Period
Follow-Up 
TC
Visit 1
Visit 2b
Visit 3
Visit 4
Rand
Visit 5
Week 4
Visit 6
Week 8
Visit 7
Week 12
Visit 8
Week 16
Visit 9
Week 20
Visit 10/ 
Final Visit 
Week 24o
14 (+2)
days after 
last dose
Study Dayc:
Day
-28 to -9
Day
-21 to -2
Day
-20 to -1
Day
1
Day
28±2
Day 
56±5
Day 
84±5
Day 
112±5
Day 
140±5
Day
168±5
Day
182±2
Peak flow meter: 
training/dispense/collectm
X
Xo
Return to maintenance asthma 
medication
Xn
Xn
Xn
X
Abbreviations: ACQ= Asthma Control Questionnaire; AEs=adverse events; AQLQ +12=Asthma Quality of Life Questionnaire for 12 years and older; 
ECG=electrocardiogram; eDiary=electronic diary; FENO= fractional nitric oxide concentration in exhaled breath; HFA=hydrofluoroalkane; ICS/LABA=inhaled 
corticosteroid/long-acting β2-agonist; PEFR=peak expiratory flow rate; PFTs=pulmonary function tests; Rand=randomization; TC=telephone call.
a
Screening Period of 11 to 28 days. Site should make every effort to maintain subjects within the scheduled visit windows. Subjects who fall outside the visit 
window will be placed in the appropriate window at the next scheduled visit.
b
Subjects will return for Visit 2 at least 7 days after Visit 1 to allow for eDiary compliance review and re-training as necessary.
c
Sites should call subjects 1 to 2 days before each scheduled visit to remind the subject of the visit and the required medication washouts and to bring all 
study-assigned medications and eDiary.
d
Collect medical history information at Visit 1 and update during the Screening Period if necessary.
e
Determine timing of last doses of short-acting bronchodilators, ICS/LABA, and study drug (Visits 5 through 10). Short-acting bronchodilators must be held 
for at least 6 hours prior to spirometry, and morning doses of ICS/LABA and study drug need to be withheld. With the exception of Visit 1, if these timelines 
have not been met, visits must be rescheduled and must occur within the specified windows. With the exception of reversibility testing, all other procedures 
at Visit 1 may take place if subjects did not withhold these medications.
f
Subjects taking tiotropium will discontinue this medication and be provided ipratropium to take 2 puffs QID until 6 hours prior to spirometry on the morning 
of Visit 4. All subjects will continue taking their regular ICS/LABA and will use Sponsor-provided albuterol as needed for rescue.
g
All pre-dose (trough) spirometry and all in-clinic dosing must occur between 7 am and 10 am and within ±1 hour of the Visit 1 time and approximately 
12 hours after the evening dose of BID study treatments (see Section 8.1). Subjects will be required to return to the clinic at approximately the same time as 
Visit 1 for all treatment visits (±1 hour).
h
Subjects will be tested for reversibility at 30 minutes following 4 puffs of albuterol (Visit 1 and, if needed, Visit 2) and ipratropium (Visit 3). If subjects are 
not reversible at 30 minutes, the post-dose PFT can be repeated at 60 minutes post-dose for qualification for albuterol (Section 7.1.1.3). Spirometry is not 


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required at Visit 2 unless the subject does not demonstrate reversibility to albuterol at Visit 1. If pre-dose spirometry is performed at Visit 2 due to the 
subject not demonstrating reversibility to albuterol at Visit 1, the pre-dose FEV1 should be >40% and <85 % of predicted normal for subjects 18 to 80 years 
of age or >40% and <90% for subjects 12 to <18 years of age. Repeat spirometry at 60 minutes post-dose is not necessary for reversibility testing to 
ipratropium.
i
Vital signs include HR and blood pressure only.
j
Serum pregnancy test at Visits 1 and 10/Final Visit or Study Withdrawal Visit; urine pregnancy test at all other visits.
k
Holter monitor will be placed on subjects participating in the Holter monitoring sub-study at Visits 3 and 7 and removed the following day. If Holter data are 
unacceptable, the Holter monitor will be reconnected for another 24 hours. The repeat Holter monitor following Visit 3 must be removed at least 24 hours 
prior to scheduled Visit 4 and the repeat Holter monitor following Visit 7 must be placed on or before Visit 8. Refer to Section 7.2.4 and Table 8-3 for 
additional details.
l
Includes evaluation of weight at Visit 1 and Visit 10/Final Visit for all subjects and height at Visit 1 for subjects who have had their 18th birthday and at 
Visits 1, 4, 5, 7, and 10 for subjects 12 years of age up to and including their 18th birthday, at the visit.
m
Issue and train subjects on eDiary and peak flow meter use only after subject has been found eligible to proceed to Visit 2. Subjects will use the eDiary to 
maintain a record of their rescue medication use, morning and evening asthma symptoms, ICS/LABA administration (Screening Period only; this will be QD 
for ICS/LABAs that are only administered QD and BID otherwise), and study drug dosing (Treatment Period only) (refer to Section 7.1.2 for specifics). 
Daily morning and evening pre-dose PEFRs will automatically be recorded in the eDiary.
n
Screening failure subjects only
o
These are minimum procedures that should be completed for Treatment Discontinuation and/or Study Withdrawal Visits (refer to Section 8.9 for additional 
details).
p
If MDI training is needed, Ventolin MDI or Atrovent MDI can be used; no Placebo MDI will be provided for training purposes.


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Table 8-2
Sequence and Timing for Selected Assessments at Treatment Visits 4 through 10 …
Pre-dose
Post-dose
Assessment
Visit(s)
Not Timed
At -60 min
At -30 min
15 min / 30 min / 1 hr /2 hr
4 hr
Determine if asthma drugs were withhelda
All
Xa
Perform ACQ and AQLQ +12b
All
Xb
Record vital signs (HR, DBP, and SBP)c
Pre-dose
All
Xb,c
Post-dose
4, 7, and 10/FV
Xc
Record 12-lead ECGb
4, 5, 7, and 10/FV
Xb
Collect blood and urine for clinical laboratory testingd
Hematology and chemistryd
4, 5, 7, and 10/FV
Xd
Urinalysisd
4 and 10/FV
Xd
Pregnancy testd
4-9 and 10/FV
Xd
Measure FENO
4, 5, 7, and 10/FV
Xb
Review eDiary including PEFR
All
Xa,b
Perform spirometry
Pre-dosee
All
Xe
Xe
Post-dosef
4, 7, and 10/FV
Xf
Xf
Xf
Xf
Collect study drug
5 through 10/FV
Xb
Dispense study drugg
All
Xb,g
Schedule next visith
4 through 9
Xb,h
Abbreviations: ACQ= Asthma Control Questionnaire; AQLQ +12=Asthma Quality of Life Questionnaire for 12 years and older; DBP=diastolic blood pressure; 
ECG=electrocardiogram; eDiary=electronic diary; FENO= fractional nitric oxide concentration in exhaled breath; HR=heart rate; PEFR=peak expiratory flow rate; 
SBP=systolic blood pressure. (Footnotes continued on next page.)


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Note: Time point for study drug and ICS/LABA dosing is regarded as “0 minutes” and pre- and post-dose are relative to study drug and ICS/LABA dosing. 
When data collection time points are concurrent, variables should be collected in the following order: ACQ, AQLQ +12, vital signs, ECG, clinical laboratory 
samples, FENO, eDiary review, and spirometry.
a
At the start of the Treatment Visit, subjects must have withheld morning doses of study drug and ICS/LABA (and ipratropium, as applicable, for Visit 4) and 
rescue albuterol for at least 6 hours prior to start of test day procedures.
b
This assessment should be performed pre-dose, at an appropriate time to allow for collection of timed pre-dose spirometry.
c
Vital signs (HR, DBP, and SBP only) should be started approximately 5 to 10 minutes ahead of the specified time point to ensure spirometry will be 
conducted as close as possible to the specified time points. 
d
Samples for clinical laboratory tests will be collected within 60 minutes prior to dosing. Pregnancy tests will be performed on urine (on site) before study 
drug and ICS/LABA dosing at Visits 4 through 9, and on serum at Visit 10/Final Visit. 
e
Pre-dose spirometry must be performed between 7 am and 10 am, within ±1 hour of the time of the Visit 1 spirometry, ±15 minutes of the specified time 
before study drug and ICS/LABA administration and, for subjects randomized to BID study drug treatment, approximately 12 hours after the evening study 
drug dose. 
f
Post-dose spirometry should be conducted ±5 minutes of the specified time for the first 60 minutes after study drug and ICS/LABA administration, and 
±15 minutes of the specified time point for assessments obtained thereafter.
g
Dispense study drug to subjects for at-home use. At Visit 10, study drug will be dispensed for the final in-clinic dose only.
h
Schedule next visit following completion of all post-dose assessments.


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Table 8-3
Schedule of Events for 24-hour Holter Monitoring Sub-Study at Visits 3 and 7
Procedures
Screening Period
Treatment Period
Visit 3
Visit 3
+1 Day
Visit 3
+2 Days
Visit 7
Visit 7
+1 Day
On or Before 
Visit 8
On or Before 
Visit 8 +1 Day
Begin 24-hour Holter monitoring (1st attempt)
Xa
Xb
Remove Holter monitor (1st attempt)
Xc
Xc
Begin 24-hour Holter monitoring (2nd attempt)
Xd
Xe
Remove Holter monitor (2nd attempt)
Xf
Xf
Note: Subjects who discontinue treatment before Week 12 will NOT be eligible for Visit 7 Holter assessment.
a
Attach Holter monitoring device and initiate 24-hour recording following the post-ipratropium spirometry assessment and 15 to 30 minutes before 
administration of the morning dose of ICS/LABA.
b
Attach Holter monitoring device and initiate 24-hour recording following the pre-dose spirometry assessments and 15 to 30 minutes before administration of 
the morning dose of study drug and ICS/LABA.
c
Site personnel determine the acceptability of the Holter monitor recording.
d
If the Visit 3 Holter monitor recordings are not successful (acceptable recordings for ≥18 hours) on the first attempt, a second attempt will be made using a 
new Holter monitor hook-up kit. The repeat Holter monitor must be removed at least 24 hours prior to scheduled Visit 4. Subjects can continue in the Holter 
monitoring sub-study provided an acceptable recording for ≥18 hours has been obtained and no clinically significant findings (as defined in Section 5.5) are 
reported by 
 following review of the Holter monitor recordings. Refer to Section 7.2.4 for additional details.
e
If the Visit 7 Holter monitor recordings are not successful (acceptable recordings for ≥18 hours) on the first attempt, a second attempt will be made using a 
new Holter monitor hook-up kit. The repeat Holter monitor must be placed on or before Visit 8. Refer to Section 7.2.4 for additional details.
f
No further attempts will be allowed if the second attempt is unsuccessful.


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8.2
Visit 1 (Day –28 to –9)
•
Obtain informed consent (and assent if applicable)
•
Register subject in IWRS to obtain subject screening number
•
Obtain demographic data, including age, race, and smoking and medical/surgical 
histories
•
Obtain prior and concurrent medication history, including all asthma medications
•
If the subject withheld morning dose(s) of regular asthma medications and has not 
administered albuterol within at least 6 hours prior to testing, conduct spirometry 
assessments (Section 7.1.1) between 7 am and 10 am including reversibility to albuterol 
(see Section 7.1.1.3). If the subject meets reversibility to albuterol criteria (defined in 
Section 7.1.1.3), reversibility testing will not be repeated at Visit 2. If the subject has not 
withheld their dose(s) of regular asthma medications (Section 8.1) or albuterol, Visit 1 
should be rescheduled no sooner than the following day.
•
Obtain vital signs (HR, SBP, and DBP) after the subject has been seated or supine for at 
least 5 minutes
•
Conduct a complete physical examination (ie, height, weight, general appearance, skin, 
head, eyes, ears, nose, throat, neck [including thyroid], lymph nodes, chest, heart, 
abdomen, extremities, and nervous system)
•
Confirm subject’s ability to use inhalation device correctly (provide coaching as needed)
•
Obtain a 12-lead ECG
•
Verify that the subject meets inclusion/exclusion criteria.
•
Once the subject has completed the above assessments and after determining that the 
subject is eligible to continue to Visit 2, complete the following:
-
Obtain blood and urine for hematology, chemistry, and urinalysis tests
-
Obtain blood for a serum pregnancy (hCG) test for all female subjects unless it is 
documented in the medical history that the subject has been irreversibly surgically 
sterilized (hysterectomy, bilateral oophorectomy, or bilateral tubal ligation), is at least 
2 years post-menopausal, or has not started menses
•
Instruct subjects taking tiotropium to discontinue this medication and begin ipratropium 
2 puffs QID during the Screening Period. The first dose should be taken in the clinic after 
all spirometry and reversibility testing has been completed. Ipratropium should not be 
taken the morning of study clinic Visit 2.
•
Dispense albuterol for use as rescue medication
•
Review required minimum washout criteria for other asthma medications (Table 5-2)
•
Dispense and train subjects on eDiary and PEFR meter use


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•
Schedule Visit 2: the timing of Visit 2 should coincide with the timing of Visit 1 in order 
to obtain pre-dose spirometry data between 7 am and 10 am and within ±1 hour of the 
time of the Visit 1 spirometry assessment 
•
Instruct the subject to do the following:
-
continue treatment with their ICS/LABA (and ipratropium, if applicable) along with 
Sponsor-provided albuterol for rescue
-
withhold ICS/LABA and albuterol (and ipratropium, if applicable) on the morning of 
Visit 2
◦
albuterol (and ipratropium, if applicable) should be withheld for a minimum of 
6 hours before Visit 2
-
bring their eDiary, ICS/LABA (and ipratropium, if applicable), and Sponsor-provided 
rescue albuterol to the next scheduled clinic visit …
•
Record asthma exacerbations and AEs (if any). AEs must be reported in the eCRF as part 
of medical history (unless they meet seriousness criteria, which will be recorded as an 
SAE) during the Screening Period from the time of signing informed consent.
Note: It is recommended that sites call subjects the day BEFORE their scheduled Visit 2 to 
remind them of all expectations.
8.3
Visit 2 (Day –21 to Day –2) 
•
Determine if subjects have withheld their morning doses ICS/LABA (and ipratropium, if 
applicable) and meet required washout timing of all prior asthma medications 
(Table 5-2). The date and time of last dose of rescue albuterol should be documented. If it 
has been <6 hours since the time of the last dose of short-acting bronchodilators, or if the 
morning dose of ICS/LABA dose was not held or the washout periods were not met, the 
clinic visit must be rescheduled.
•
Re-assess eligibility for the study by reviewing inclusion and exclusion criteria
•
Complete ACQ-5
•
If not previously reviewed, review clinical laboratory testing results from Visit 1 and 
record any clinically significant findings
•
Review/update concomitant medication history
•
Perform urine pregnancy test for all females of child-bearing potential
•
Obtain vital signs (HR, SBP, and DBP only)
•
Perform reversibility testing to albuterol (Section 7.1.1.3) if not completed at Visit 1 or if 
albuterol reversibility criteria were not met at Visit 1
•
Confirm subject’s ability to use inhalation device correctly (provide coaching as needed)
•
Review the eDiary; re-train if subject has not met the eDiary compliance requirement


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•
Record asthma exacerbations and AEs (if any). AEs must be reported in the eCRF as part 
of medical history (unless they meet seriousness criteria, which will be recorded as an 
SAE) during the Screening Period from the time of signing informed consent.
•
Obtain FENO (see Section 7.1.5)
•
Dose with subject’s ICS/LABA
•
Dispense additional albuterol for use as rescue medication, if needed
•
Schedule Visit 3. The timing of Visit 3 should coincide with the timing of Visit 1 in order 
to obtain spirometry data between 7 am and 10 am and within ±1 hour of the time of the 
Visit 1 spirometry assessment.
•
Instruct the subject to continue to do the following:
-
continue treatment with their ICS/LABA (and ipratropium, if applicable) along with 
Sponsor-provided albuterol for rescue
-
withhold ICS/LABA and albuterol (and ipratropium, if applicable) on the morning of 
Visit 3
◦
albuterol (and ipratropium, if applicable) should be withheld for a minimum of 
6 hours before Visit 3
-
bring their eDiary, ICS/LABA (and ipratropium, if applicable), and Sponsor-provided 
rescue albuterol 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 all expectations
Note: If the subject screen fails, then return the subject to their maintenance asthma 
medications.
8.4
Visit 3 (Day –20 to Day –1)
•
Determine if subjects have withheld their morning doses ICS/LABA (and ipratropium, as 
appropriate). The date and time of last dose of rescue albuterol should be documented. If 
there has been <6 hours since the time of the last dose of rescue albuterol, or if the 
morning dose of ICS/LABA dose was not held (and ipratropium, if applicable), the clinic 
visit must be rescheduled.
•
Re-assess eligibility for the study by reviewing inclusion and exclusion criteria
•
Review/update concomitant medication history
•
Record asthma exacerbations and AEs (if any). AEs must be reported in the eCRF as part 
of medical history (unless they meet seriousness criteria, which will be recorded as an 
SAE) during the Screening Period from the time of signing informed consent.
•
Confirm subject’s ability to use inhalation device correctly (provide coaching as needed)
•
Review eDiary with subject; re-train if subject has not met eDiary compliance 
requirement


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•
Perform urine pregnancy test for all females of child-bearing potential
•
Obtain vital signs (HR, SBP, and DBP)
•
Perform spirometry before and after ipratropium administration to determine reversibility 
(see Section 7.1.1.3 for instructions)
•
If a subject is participating in the 24-hour Holter monitoring sub-study, attach Holter
monitor and initiate 24-hour Holter monitor recording following the post-ipratropium 
spirometry assessment and 15 to 30 minutes before ICS/LABA dosing (see Section 7.2.4
and Table 8-3 for further instructions)  
•
Dose with subject’s ICS/LABA
•
Dispense additional albuterol for rescue use, if needed
•
Schedule a visit on the following day to remove Holter (see Section 7.2.4)
•
Schedule Visit 4. The timing of Visit 4 should coincide with the timing of Visit 1 in order 
to obtain spirometry data between 7 am and 10 am and within ±1 hour of the time of the 
Visit 1 spirometry assessment.
Note: For the remainder of the study, the timing of pre-dose clinic spirometry at all 
subsequent visits must occur between 7 am and 10 am and be within ±1 hour of the time 
of the spirometry conducted at Visit 1 
•
Instruct the subject to continue to do the following:
-
continue treatment with their ICS/LABA (and ipratropium, if applicable) along with 
Sponsor-provided albuterol for rescue
-
return the following day for removal of the Holter monitor
-
withhold ICS/LABA and albuterol (and ipratropium, if applicable) on the morning of 
Visit 4
◦
albuterol (and ipratropium, if applicable) should be withheld for a minimum of 
6 hours before Visit 4
-
bring their eDiary, ICS/LABA (and ipratropium, if applicable), and Sponsor-provided 
rescue albuterol to Visit 4
Note: It is recommended that sites call subjects the day BEFORE their scheduled Visit 4 to 
remind them of all expectations
Note: If the subject screen fails, then return the subject to their maintenance asthma 
medications.
8.5
Visit 4 (Randomization, Day 1)
There are timed and untimed assessments at Visit 4 (see Table 8-1 and Table 8-2). All pre-
dose assessments are to be completed within 30 to 60 minutes before dosing.


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•
Determine if subject has withheld their morning dose of ICS/LABA (and ipratropium, as 
appropriate). The date and time of last dose of rescue albuterol should be documented. If 
it has been <6 hours since the time of the last dose of rescue albuterol, or if the morning 
dose of ICS/LABA dose (and ipratropium, if applicable) was not held, the clinic visit 
must be rescheduled.
•
Review subject eDiary including peak flow values. Screen fail subject if subject has not 
met eDiary compliance requirement (See Section 5.2).
•
Review/update concomitant medication history
•
Re-assess eligibility for the study by reviewing inclusion and exclusion criteria
•
Obtain height for subjects 12 years of age up to an including their 18th birthday, at the 
visit
•
Complete all pre-dose assessments (refer to Table 8-2) in recommended order
-
Conduct -60 and -30 minute pre-dose spirometry. Pre-dose spirometry must be 
completed between 7 am and 10 am and within ±1 hour of the spirometry conducted 
at Visit 1.
•
Provide inhalation device and dose indicator training (for GP MDI and Placebo MDI use, 
see Appendix 5; for Spiriva Respimat use, see Appendix 6; for dose-indicator instructions 
for GP MDI and Placebo MDI, see Appendix 4)
•
Record asthma exacerbations and AEs (if any). 
•
Discontinue and collect ipratropium supplies from screening
•
Determine eDiary-calculated PEFR stability limit (Section 7.1.2.3)
•
Confirm eligibility for randomization (Section 5.3)
•
Subjects who are not eligible for randomization will be considered screen failures. The 
reason for the subject’s failure to qualify for randomization will be collected. Subjects 
who have not qualified for randomization will be instructed to restart their previous 
asthma maintenance medications before being discharged from the study.
•
Obtain subject randomization number and treatment assignment information from IWRS
•
Dispense study drug. To allow for proper preparation of study drug, it is recommended 
that the seal around the study day treatment box is opened 15 to 30 minutes prior to 
dosing and the instructions for administration of study drug followed:
-
See Section 6.5 for detailed instructions for preparation of study drugs for 
administration. These instructions are to be adhered to and are relevant to all study 
treatment visits.
-
Record/document the dose indicator reading. The dose indicator count recorded by 
the site staff will be the dose indicator count observed after priming but prior to 
subject dosing.
•
Once study drug is primed and ready for use, provide assigned study drug to subject. 


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•
Administer study drug and ICS/LABA at the clinic
•
Complete post-dose spirometry and vital signs (refer to Table 8-2)
•
Upon completion of post-dose spirometry and vital signs, dispense additional albuterol 
for rescue use, if needed
•
Schedule Visit 5: the timing of Visit 5 should coincide with the timing of Visit 1 in order 
to obtain spirometry data between 7 am and 10 am and within ±1 hour of the time of the 
Visit 1 spirometry assessment and, if randomized to a BID study drug, be approximately 
12 hours after the evening dose of study drug.
•
Instruct subject to do the following:
-
continue treatment with ICS/LABA and study drug at home, along with Sponsor-
provided albuterol for rescue
-
withhold their ICS/LABA, study drug, and albuterol on the morning of Visit 5
◦
albuterol should be withheld for a minimum of 6 hours before Visit 5
-
bring their eDiary, ICS/LABA, and Sponsor-provided rescue albuterol to Visit 5
Note: It is recommended that sites call subjects the day BEFORE their scheduled 
Visit 5 to remind them of all expectations.
Note: It is recommended that sites call subjects the day BEFORE their next scheduled visit to 
remind them of all expectations. 
8.6
Visits 5, 6, 8, and 9 (Weeks 4, 8, 16, and 20)
The following procedures will be completed: 
•
Determine if subjects have withheld their morning doses of ICS/LABA and study drug. 
The date and time of last dose of rescue albuterol should be documented. If it has been 
<6 hours since the time of the last dose of albuterol, or if the morning doses of 
ICS/LABA and/or study drug were not held, the clinic visit must be rescheduled.
•
Review/update concomitant medication history
•
Re-assess eligibility for the study by reviewing inclusion and exclusion criteria
•
Obtain height for subjects 12 years of age up to an including their 18th birthday, at the 
visit (Visit 5 only)
•
Complete all pre-dose assessments (refer to Table 8-2) in recommended order
•
Conduct -60 and -30 minute pre-dose spirometry. Pre-dose spirometry must be completed 
between 7 am and 10 am and within ±1 hour of the spirometry conducted at Visit 1 and, 
if randomized to a BID study drug, be approximately 12 hours after the evening dose of 
study drug.
•
Record asthma exacerbations and AEs (if any)
•
Provide inhalation device and dose indicator training (see Section 8.5)


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•
Perform urine pregnancy test for all females of child-bearing potential
•
Dispense study drug. To allow for proper preparation of study drug, it is recommended 
that the seal around the study day treatment box is opened 15 to 30 minutes prior to 
dosing and the instructions for administration of study drug followed:
-
See Section 6.5 for detailed instructions for preparation of study drugs for 
administration. These instructions are to be adhered to and are relevant to all study 
treatment visits.
-
Record/document the dose indicator reading. The dose indicator count recorded by 
the site staff will be the dose indicator count observed after priming but prior to 
subject dosing.
•
Administer study drug and ICS/LABA at the clinic
•
Dispense additional albuterol for rescue use, if needed
•
Schedule the next visit: the timing of each visit should coincide with the timing of Visit 1 
in order to obtain spirometry data between 7 am and 10 am and within ±1 hour of the 
time of the Visit 1 spirometry assessment and, if randomized to a BID study drug, be 
approximately 12 hours after the evening dose of study drug. 
•
Instruct subject to do the following:
-
continue treatment with ICS/LABA and study drug at home, along with Sponsor-
provided albuterol for rescue
-
withhold their ICS/LABA, study drug, and albuterol on the morning of the next visit
◦
albuterol should be withheld for a minimum of 6 hours before the next visit 
-
bring their eDiary, ICS/LABA, and Sponsor-provided rescue albuterol to the next 
visit
Note: It is recommended that sites call subjects the day BEFORE their next scheduled visit to 
remind them of all expectations. 
8.7
Visit 7 (Week 12)
The following procedures will be completed: 
•
Determine if subjects have withheld their morning doses of ICS/LABA and study drug. 
The date and time of last dose of rescue albuterol should be documented. If it has been 
<6 hours since the time of the last dose of albuterol, or if the morning doses of 
ICS/LABA and/or study drug were not held, the clinic visit must be rescheduled.
•
Review/update concomitant medication history
•
Re-assess eligibility for the study by reviewing inclusion and exclusion criteria
•
Obtain height for subjects 12 years of age up to an including their 18th birthday, at the 
visit


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•
Complete all pre-dose assessments (refer to Table 8-2) in recommended order
•
Conduct -60 and -30 minute pre-dose spirometry. Pre-dose spirometry must be completed 
between 7 am and 10 am and within ±1 hour of the spirometry conducted at Visit 1 and, 
if randomized to a BID study drug, be approximately 12 hours after the evening dose of 
study drug.
•
Record asthma exacerbations and AEs (if any)
•
Provide inhalation device and dose indicator training (see Section 8.5)
•
If a subject is participating in the 24-hour Holter monitoring sub-study, attach Holter 
monitor and initiate 24-hour Holter monitoring. The Holter monitor will be removed the 
following day (see Section 7.2.4, Table 8-1, and Table 8-3 for further instructions)
•
Dispense study drug. To allow for proper preparation of study drug, it is recommended 
that the seal around the study day treatment box is opened 15 to 30 minutes prior to 
dosing and the instructions for administration of study drug followed:
-
See Section 6.5 for detailed instructions for preparation of study drugs for 
administration. These instructions are to be adhered to and are relevant to all study 
treatment visits.
-
Record/document the dose indicator reading. The dose indicator count recorded by 
the site staff will be the dose indicator count observed after priming but prior to 
subject dosing.
•
Administer study drug and ICS/LABA at the clinic; at Visit 7 (15 to 30 minutes after 
Holter monitoring is initiated, if applicable)
•
Complete post-dose spirometry and vital signs (refer to Table 8-2)
•
Upon completion of post-dose spirometry and vital signs, dispense additional albuterol 
for rescue use, if needed
•
Schedule the next visit: the timing of each visit should coincide with the timing of Visit 1 
in order to obtain spirometry data between 7 am and 10 am and within ±1 hour of the 
time of the Visit 1 spirometry assessment and, if randomized to a BID study drug, be 
approximately 12 hours after the evening dose of study drug. 
•
Instruct subject to do the following:
-
continue treatment with ICS/LABA and study drug at home, along with Sponsor-
provided albuterol for rescue
-
withhold their ICS/LABA, study drug, and albuterol on the morning of the next visit
◦
albuterol should be withheld for a minimum of 6 hours before the next visit 
-
bring their eDiary, ICS/LABA, and Sponsor-provided rescue albuterol to the next 
visit
Note: It is recommended that sites call subjects the day BEFORE their next scheduled visit to 
remind them of all expectations. 


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8.8
Final Visit (Visit 10, Week 24)
•
Determine if subjects have withheld their morning dose of ICS/LABA. The date and time 
of last dose of rescue albuterol should be documented. If it has been <6 hours since the 
time of the last dose of short-acting bronchodilators, or if the morning dose of ICS/LABA 
was not held, the clinic visit must be rescheduled.
•
Re-assess eligibility for the study by reviewing inclusion and exclusion criteria
•
Review/update concomitant medication history 
•
Obtain height for subjects 12 years of age up to an including their 18th birthday, at the 
visit
•
Complete all pre-dose assessments (refer to Table 8-2) in recommended order
•
Conduct -60 and -30 minute pre-dose spirometry. Pre-dose spirometry must be completed 
between 7 am and 10 am and within ±1 hour of the spirometry conducted at Visit 1 and, 
if randomized to a BID study drug, be approximately 12 hours after the evening dose of 
study drug.
•
Record asthma exacerbations and AEs (if any)
•
Conduct a complete physical examination …
•
Obtain FENO (see Section 7.1.5)
•
Dispense study drug for this final visit. To allow for proper preparation of study drug, it 
is recommended that the seal around the study day treatment box is opened 15 to 
30 minutes prior to dosing and the instructions for administration of study drug followed:
-
See Section 6.5 for detailed instructions for preparation of study drugs for 
administration. These instructions are to be adhered to and are relevant to all study 
treatment visits.
-
Record/document the dose indicator reading. The dose indicator count recorded by 
the site staff will be the dose indicator count observed after priming but prior to 
subject dosing.
•
Administer study drug and ICS/LABA at the clinic
•
Complete post-dose spirometry and vital signs (refer to Table 8-2)
•
Upon completion of post-dose procedures, complete the following:
-
Collect dispensed study drug and Sponsor-provided albuterol
-
Collect dispensed peak flow meter and eDiary
-
Instruct subject to resume treatment with maintenance asthma medications per 
Investigator’s judgment
-
Schedule the follow-up telephone call if needed (see Section 8.11)


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8.9
Procedures for Treatment Discontinuation and Study Withdrawal 
Visits
Subjects who discontinue study drug (treatment) before the end of the study will be 
encouraged to remain in the study to complete all remaining study visits and procedures 
during the randomized Treatment Period. Procedures for subjects who agree to be followed 
after treatment discontinuation are described in Section 8.9.1 and procedures for subjects 
who withdraw from study participation are described in Section 8.9.2.
8.9.1
Treatment Discontinuation 
Subjects who agree to continue to be followed beyond discontinuation of only study 
treatment will sign an ICF/assent addendum and complete a Treatment Discontinuation Visit 
(see Section 8.9.3) before transitioning back to regularly scheduled study visits. No 14-day 
follow-up phone call is needed if the subject completes a study visit ≥ 14 days after the 
Treatment discontinuation visit. After the Treatment Discontinuation Visit, subjects will 
return to appropriate maintenance asthma medications at the Investigator's discretion, and the 
prohibited medications in Section 5.7 will no longer apply. 
For subjects who discontinue randomized study drug (ie, Treatment Discontinuation) but are 
planning to continue study participation (ie, planning to complete all remaining study visits 
and procedures), all AEs/SAEs will be collected through the last study visit or early 
termination visit.
8.9.2
Study Withdrawal
If a subject discontinues study treatment and chooses not to continue with study assessments, 
the subject should complete at least the minimum procedures for Visit 10/Final Visit at the 
Study Withdrawal Visit (see Section 8.9.3). After that visit, subjects will return to 
appropriate maintenance asthma medications at the Investigator's discretion. 
All AEs/SAEs will be collected through 14 (+2) days after the last dose of study drug. This 
can occur via a follow-up telephone call (Section 8.11) or a study visit, whichever follow-up 
type provides 14 (+2) days of AE/SAE follow-up.
8.9.3
Study Visit Procedures
Unless otherwise indicated, the following minimum procedures will be completed for either a 
Treatment Discontinuation Visit or a Study Withdrawal Visit:
•
Complete ACQ and AQLQ +12
•
Record asthma exacerbations and AEs (if any)
•
Review/update concomitant medication history
•
Conduct a physical examination and assess vital signs (HR, SBP, and DBP only)


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•
Perform ECG and collect blood and urine samples for clinical laboratory testing 
(hematology, chemistries, urinalysis, pregnancy test; see Section 7.2.5)
•
Obtain FENO (see Section 7.1.5)
•
Collect study drug and Sponsor-provided albuterol
•
Collect subject eDiary and peak flow meter (for Study Withdrawal Visit only)
•
Return subject to pre-study or appropriate maintenance asthma medications
•
Inform subject about reporting all SAEs for 14 (+2) days following the last dose of study 
drug
•
Capture the reason for subject discontinuation
8.10
Repeat Assessments and Treatment Discontinuation and/or Study 
Withdrawal Visits
Repeat assessments, if needed, will be captured as Unscheduled Visits in the eCRF. 
Treatment Discontinuation Visits and Study Withdrawal Visits will also be captured as 
Unscheduled Visits in the eCRF.
Procedures for the Treatment Discontinuation Visit and Study Withdrawal Visit are shown in 
Section 8.9.
8.11
Follow-Up Telephone Call
For subjects that complete 24 weeks of study drug, use of concomitant medications and 
AEs/SAEs (if any) will be collected through 14 (+2) days after the last dose of study drug. 
Previously ongoing asthma exacerbations will also be reviewed. This can occur via a follow-
up telephone call or a study visit, whichever follow-up type provides 14 (+2) days of 
concomitant medication and AE/SAE follow-up.
8.12
Completion of the Study
The Investigator will document study completion or the reason for early study drug 
discontinuation or study withdrawal by a subject in the eCRF.
The following categories should be used to describe these events in the eCRF:
•
Subject discretion (document reason)
•
Investigator considers it to be in the best interest of the subject
•
AEs/SAEs
•
Administrative reasons (eg, early termination of the study)
•
Subject lost to follow-up


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•
Lack of efficacy
•
Major protocol deviation
•
Death
•
Completion of the study
•
Protocol-specified criteria (Section 5.9)


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9
STATISTICAL METHODS
9.1
Introduction
This is a double-blind, parallel group study evaluating the efficacy and safety of 3 doses of 
GP MDI compared to Placebo MDI and open-label Spiriva Respimat over a 24-week 
Treatment Period in approximately 1125 subjects with persistent asthma who are 
symptomatic despite treatment with an ICS/LABA or ICS/LABA + tiotropium. During the 
Screening and Treatment Periods, subjects will remain on their ICS/LABA regimen. At 
randomization, subjects will be randomized in a 2:2:2:2:1 ratio to 1 of the following 
5 treatment groups:
•
GP MDI 28.8 μg BID (n=250)
•
GP MDI 14.4 μg BID (n=250)
•
GP MDI 7.2 μg BID (n=250)
•
Placebo MDI BID (n=250)
•
Spiriva Respimat 2.5 μg QD (n=125) 
The primary objective of this study is to assess the effect of 3 doses of GP MDI compared to 
Placebo MDI and Spiriva Respimat on lung function over 24 weeks.
9.2
Protocol Variables
The study endpoints are found in Section 3.
9.3
Analysis Sets and Estimands
9.3.1
Analysis Sets
The following analysis sets are defined in this study: 
•
The Intent-to Treat (ITT) analysis set is defined as the data from all subjects who are 
randomized to treatment and use 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 in the ITT analysis set.
•
The Modified Intent-to-Treat (mITT) analysis set is a subset of the ITT analysis set and is 
defined as the data from 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 set but will 
still be included in the ITT analysis set. Subjects will be analyzed according to 
randomized treatment group. It is noted that a subject who used a study treatment, but 
took less than 1 full dose of treatment, will qualify for this analysis set. The mITT 


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analysis set will be the primary analysis set for all efficacy analyses. Note: The 
knowledge that a subject did not have an exacerbation constitutes an efficacy assessment.
•
The Safety analysis set is defined as data from all subjects who are randomized to 
treatment and receive any amount of the study treatment. However, subjects will be 
analyzed according to treatment received rather than randomized. If a subject receives 
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. Note: The 
statement that a subject has no AEs also constitutes a safety assessment.
•
The Holter Monitoring analysis set is defined as all subjects in the Safety analysis set 
who had at least 18 hours of acceptable quality Holter monitoring data at both Visit 3 
(Holter Baseline) and Visit 7 (Week 12). Data judged to be impacted by major protocol 
deviations will be determined prior to database lock and excluded per the statistical 
protocol deviation plan.
9.3.2
Estimands
Three estimands are of interest in this trial:
•
The primary estimand of interest is the Efficacy Estimand, defined as 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 second estimand of interest is the Attributable Estimand, defined as the effect of 
treatment in subjects attributable to the randomized treatment. For this estimand, 
discontinuation of randomized treatment for reasons such as tolerability or lack of 
efficacy is considered a bad outcome. 
•
The third estimand of interest is the Treatment Policy Estimand, defined as the effect of 
randomized treatment over the study period regardless of whether randomized treatment 
is continued. 
Analysis of the Efficacy Estimand will be conducted using the mITT analysis set 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. 
Analysis of the Attributable Estimand will be conducted in the mITT analysis set, but data 
that are missing due to treatment discontinuation will be imputed based on the 95th or the 5th
percentile of the reference arm’s distribution if the reason is reasonably attributable to 
tolerability or lack of efficacy. The 95th percentile would apply to an endpoint for which a 
higher value is a worse outcome, while the 5th percentile would apply to an endpoint for 
which a higher value is a better outcome. More detail about the computation of the 
Attributable Estimand will be provided in the SAP. 


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Analysis of the Treatment Policy Estimand will be conducted in the ITT analysis set, in 
which all observed data will be utilized regardless of whether subjects remain on randomized 
treatment.
9.4
Demographic and Baseline Characteristics
Demographic and baseline characteristics data will be summarized by treatment for the mITT 
and Safety analysis sets.
9.5
Efficacy Analysis
All efficacy assessments are relative to baseline. Baseline for spirometry endpoints will be 
defined as the mean of the 60- and 30-minute pre-dose values at the randomization visit. 
Though all possible comparisons will be performed, the key comparisons will be those 
between each dose of GP MDI with Placebo MDI and, for benchmarking purposes, Spiriva 
Respimat.
9.5.1
Primary Efficacy Analysis
The primary analysis will be conducted for the Efficacy Estimand where only data obtained 
prior to subjects discontinuing from study drug will be utilized. Analyses will also be 
conducted for the Attributable and Treatment Policy Estimands. 
For the primary comparisons, the null hypothesis for each pair-wise comparison will be that 
the mean treatment difference is zero (mean treatment effects are equal). The alternative 
hypothesis is that the mean treatment difference is not zero (mean treatment effects are not 
equal). All p-values will be reported as 2-sided. 
9.5.1.1
Change From Baseline in FEV1 AUC0-4
Change from baseline in FEV1 AUC0-4 will be analyzed using a linear repeated measures 
analysis of covariance (ANCOVA) model. The model will include treatment, visit, 
background fixed-dose ICS/LABA combination product, and treatment-by-visit interaction 
as categorical covariates and baseline FEV1, percentage reversibility to ipratropium, and 
blood eosinophil count at screening as continuous covariates. An unstructured matrix will be 
used to model the variance-covariance structure. If this model fails to converge, an 
alternative structure will be employed as pre-specified in the SAP. Contrasts will be used to 
obtain estimates of the treatment differences at Week 24. Two-sided p-values and point 
estimates with 2-sided 95% confidence intervals will be produced for each treatment 
difference.
The FEV1 AUC0-4 will be calculated for the changes from baseline using the trapezoidal rule 
and will be normalized by dividing by the time (in hours) from dosing to the last 
measurement included (ie, 4 hours). For the Efficacy Estimand analysis, only 1 non-missing, 
post-dose value is required for the calculation of FEV1 AUC0-4. Actual time from dosing will 
be used in the calculation if available; otherwise, scheduled time will be used.


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9.5.2
Secondary Efficacy Analysis
Similar to the primary efficacy analysis, the secondary efficacy analyses will be conducted 
for the Efficacy Estimand. Analyses will also be conducted for the Attributable and 
Treatment Policy Estimands.
9.5.2.1
Change From Baseline in 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 be similar to the one used for FEV1
AUC0-4. Contrasts will be used to obtain estimates of the treatment differences at Week 24. 
Two-sided p-values and point estimates with 2-sided 95% confidence intervals will be 
produced for each treatment difference
9.5.2.2
Rate of Moderate/Severe Asthma Exacerbations
The ratio of the rates of moderate/severe asthma exacerbations will be analyzed with 
negative binomial regression. Asthma exacerbations will be considered separate events if 
more than 7 days are between the recorded stop date of the earlier event and start date of the 
later event. Time at risk of experiencing an exacerbation will be used as an offset variable in 
the model. Time during an exacerbation or in the 7 days following an exacerbation will not 
be included in the calculation of exposure. Treatments will be compared adjusting for 
baseline post-bronchodilator percent predicted FEV1, baseline asthma exacerbation history, 
blood eosinophil count at screening, background ICS/LABA, and reversibility to 
ipratropium.
The number and percentage of subjects with exacerbations in each treatment group will be 
tabulated.
9.5.2.3
Change From Baseline in ACQ-7, ACQ-5, and AQLQ +12
Change from baseline in ACQ-7, ACQ-5, and AQLQ +12 will be analyzed using a linear 
repeated measures ANCOVA model. The model will include treatment, visit, background 
fixed-dose ICS/LABA combination product, and treatment-by-visit interaction as categorical 
covariates and baseline post-bronchodilator FEV1 percent predicted, baseline score for the 
patient-reported outcome instrument, percentage reversibility to ipratropium, and blood 
eosinophil count at screening as continuous covariates. Contrasts will be used to obtain 
estimates of the treatment differences at Week 24. Two-sided p-values and point estimates 
with 2-sided 95% confidence intervals will be produced for each treatment difference.
9.5.3
Other Efficacy Analyses 
Other efficacy analyses will be conducted for the Efficacy Estimand only.
9.5.3.1
Percentage of Responders in ACQ-5, ACQ-6, ACQ-7, and AQLQ +12
Responder analyses will be performed for ACQ-5, ACQ-6, ACQ-7, and AQLQ +12 at 
Week 24 and over the Treatment Period. Responders are defined as subjects with an 


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improvement of ≥0.5 points over baseline. Subjects who discontinue treatment for any reason 
will be classified as non-responders.
Logistic regression will be used to compare the treatment groups with background 
ICS/LABA as categorical covariates and baseline instrument score, blood eosinophil count at 
screening, percentage reversibility to ipratropium, and baseline post-bronchodilator percent 
predicted FEV1 as continuous covariates. P-values and odds ratios with 95% confidence 
intervals will be produced for each treatment comparison.
9.5.3.2
Change from Baseline in ACQ-6
Change from baseline in ACQ-6 will be analyzed using a linear repeated measures 
ANCOVA model. The model will include treatment, visit, background fixed-dose 
ICS/LABA combination product, and treatment-by-visit interaction as categorical covariates 
and baseline post-bronchodilator FEV1 percent predicted, baseline score for the patient-
reported outcome instrument, percentage reversibility to ipratropium, and blood eosinophil 
count at screening as continuous covariates. Contrasts will be used to obtain estimates of the 
treatment differences at Week 24. Two-sided p-values and point estimates with 2-sided 95% 
confidence intervals will be produced for each treatment difference.
9.5.3.3
Time to First Asthma Exacerbation 
Time to first moderate or severe asthma exacerbation will be analyzed with a Cox regression 
model to compare the treatment groups, adjusted for asthma exacerbation history, 
background ICS/LABA, reversibility to ipratropium, blood eosinophil count at screening, 
and baseline post-bronchodilator FEV1 percent predicted.
Time to first severe asthma exacerbation and time to first exacerbation of any severity will 
each be analyzed in a manner similar to the analysis of time to first moderate or severe 
asthma exacerbation.
9.5.3.4
Rate of Severe Asthma Exacerbations or Exacerbations of Any Severity
Severe asthma exacerbations and asthma exacerbations of any severity will each be analyzed 
in a manner similar to the analysis of the rate of moderate/severe asthma exacerbations.
9.5.3.5
Peak FEV1
Change from baseline in peak FEV1 will be analyzed at each clinic visit using a linear 
repeated measures ANCOVA model. The model will be similar to the one used for the 
primary analyses.
9.5.3.6
Percentage of Symptom-Free Days, Rescue-Free Days, and Asthma Control 
Days
The percentages of symptom-free days, rescue-free days, and asthma control days will each 
be analyzed over the entire Treatment Period. Additionally, analyses will be conducted over 
each 4-week interval in the study. An ANCOVA model will be used with treatment, the 


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number of the relevant 4-week interval (interval 1 to 6), asthma exacerbation history, 
background ICS/LABA, and the treatment-by-4-week interval interaction as categorical 
covariates. Baseline percentage of endpoint days (where endpoint is symptom free, rescue 
free, or asthma control per model), baseline post-bronchodilator FEV1 percent predicted, 
percentage reversibility to ipratropium, and blood eosinophil count at screening will be 
continuous covariates.
9.5.3.7
Rescue Medication Usage
The mean daily number of puffs of rescue medication use will be calculated overall and for 
each of the 4-week intervals during the Treatment Period. For every period of time for which 
the mean number of puffs of rescue medication 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 albuterol use. The model will include treatment, the number of the 
relevant 4-week interval (interval 1 to 6), asthma exacerbation history, background 
ICS/LABA, and the treatment-by-4-week interval interaction as categorical covariates and 
blood eosinophil count at screening, baseline daily rescue albuterol use, percentage 
reversibility to ipratropium, and baseline post-bronchodilator FEV1 percent predicted as 
continuous covariates. 
An unstructured variance-covariance matrix will be fit. If this model fails to converge, an 
alternative structure will be employed as pre-specified in the SAP. Contrasts will be used to 
obtain estimates of the treatment differences over 24 weeks. Two-sided p-values and point 
estimates with 2-sided 95% confidence intervals will be produced for each treatment 
difference.
9.5.3.8
Change From Baseline in Morning PEFR and Evening PEFR
Change from baseline in morning PEFR and evening PEFR will be analyzed over 4-week 
intervals using a linear repeated measures ANCOVA model.
9.5.3.9
FENO
Change from baseline in FENO will be analyzed using a linear repeated measures ANCOVA 
model. The model will be similar to the one used for the primary analyses.
Clinically meaningful increases and decreases from baseline in FENO will be summarized 
descriptively by visit. The clinically meaningful changes are defined below:
•
A clinically meaningful increase in FENO is defined as an increase of 20% or more from 
baseline if the baseline is 50 parts per billion (ppb) or more or an increase of more than 
10 ppb from baseline if the baseline is less than 50 ppb.


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•
A clinically meaningful decrease in FENO is defined as a decrease of 20% or more from 
baseline if the baseline value is 50 ppb or more or a decrease of more than 10 ppb from 
baseline if the baseline value is less than 50 ppb.
At each visit, the percentage of subjects with FENO less than 25 ppb, between 25 and less than 
50 ppb, and at least 50 ppb will be summarized descriptively by treatment.
9.5.3.10
CompEx
Time to first CompEx event will be analyzed with a Cox regression model to compare the 
treatment groups adjusted for asthma exacerbation history, background ICS/LABA, 
reversibility to ipratropium, blood eosinophil count at screening, and baseline post-
bronchodilator FEV1 percent predicted. Subjects who do not experience a CompEx event will 
be censored at their Week 24 Visit. 
9.5.4
Subgroup Analyses
Analyses of the primary, secondary, and other endpoints may be performed by various 
subgroups. In addition to baseline and demographic subgroups, other factors (T-helper cell 
type 2 high or low, GINA classification, etc) will be used to create subgroups of interest. All 
subgroup analyses will be described fully in the SAP.
9.5.5
Type I Error Control
The Type I error rate will be controlled within the primary and secondary efficacy analyses. 
As a general strategy, the Type I error rate will be strongly controlled within the primary 
analysis. The Type I error rate will also be controlled within the family of secondary analyses 
within a GP MDI treatment group.
Primary analysis testing will be conducted in descending dose order, with the highest dose of 
GP MDI tested against placebo at the nominal alpha. Testing will continue through the 
GP MDI doses as long as the results are successful. Testing will stop if any comparison of 
GP MDI versus placebo fails to meet statistical significance. Through this strategy, the 
Type I error rate of the primary analyses of all 3 GP MDI doses versus placebo will be 
strictly controlled to the nominal alpha.
The secondary analyses for each dose of GP MDI versus placebo will proceed only if the 
primary analysis for that GP MDI dose is successful. The Type I error rate within the 
secondary analyses of each GP MDI dose versus placebo will be controlled with a multiple 
comparison procedure as specified in the SAP.


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9.6
Safety Analysis
9.6.1
AEs
Adverse events during the Treatment Period will be summarized by the number of subjects 
experiencing an event. Adverse events will be tabulated at the level of the Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. The 
version of MedDRA current at the time of database lock will be used in the tabulations and 
listings. Tabulations will be broken down by severity, seriousness, AEs leading to 
discontinuation, and by relationship to study drug. No hypothesis tests will be performed.
9.6.2
AESIs
The AESIs will be tabulated by treatment group. Additional analyses may be performed and 
will be detailed in the SAP.
9.6.3
Clinical Laboratory Measurements
Summary statistics (mean, median, standard deviation [SD], and range) of change from 
baseline values will be tabulated for each treatment and each assessment time. For clinical 
laboratory measurements, baseline will be defined as the last available value prior to 
randomization. Potentially clinically significant values will be identified and summarized.
9.6.4
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.
9.6.5
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 last value obtained prior to 
randomization. In addition, potentially clinically significant values will be identified and 
summarized.
9.6.6
24-Hour Holter Monitoring
Holter monitoring endpoints are listed in Section 3.5.
Change from baseline in the ventricular and supraventricular variables will be analyzed with 
nonparametric methods. The Wilcoxon Rank Sum Test will be used to produce p-values for 
the pairwise comparison of treatments. The median treatment differences will be presented 
with 95% confidence intervals based on the Hodges-Lehmann approach. The number of 


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subjects experiencing a ventricular couplet, ventricular run, supraventricular couplet, and 
supraventricular run at Week 12 will be analyzed with a logistic regression model. 
Alternative analysis methods may be employed if found to be appropriate and will be pre-
specified in the SAP.
Additionally, for the endpoints that involve incidences and proportions of events, those 
values will be summarized by treatment.
9.7
Sample Size Consideration
A sample size of 1125 subjects (250 subjects per double-blind treatment group, 125 subjects 
in the open-label Spiriva Respimat treatment group) will provide approximately 93% power 
to detect a 120 mL difference between the GP MDI treatment groups and Placebo MDI in the 
analysis of change from baseline in FEV1 AUC0-4 at Week 24. The assumed SD is 348 mL at 
each visit. The 2-sided alpha for each pairwise comparison is 0.05. 
Comparisons of GP MDI to Spiriva Respimat will be focused on estimation as the study is 
not formally powered to demonstrate non-inferiority or superiority.
For the secondary endpoint of change from baseline in morning pre-dose trough FEV1 at 
Week 24, it is assumed that the difference between GP MDI and Placebo MDI is 90 mL, with 
each treatment group having an SD of 317 mL at each visit. Under these assumptions, the 
study will have 80% power to declare GP MDI superior to Placebo MDI in the analysis of 
change from baseline in morning pre-dose trough FEV1 at Week 24. 
The Type I error rate will be strongly controlled for the primary analyses. The Type I error 
control strategy for the primary and secondary analyses are described in Section 9.5.5. This 
sample size assumes that approximately 20% of randomized subjects will have discontinued 
study drug prior to Week 24.
9.8
Data Validation and Transformation
In general, the distribution of spirometry measures is well approximated by a normal 
distribution. Under some circumstances, however, 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 prior to unblinding. 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 transformation or by removal of the outlier. 
Transformations to be considered may include the logarithmic transformation, or normal rank 
transformations. Any changes will be documented prior to unblinding and, 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. 


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9.9
Analysis Plan
All analyses will be specified in a detailed SAP that will include table and data listing shells 
with mock graphical representations. The SAP will be signed before database lock and 
unblinding.
9.10
Blinded Sample Size Re-Estimation
No blinded sample size re-estimation is currently planned for this study.
9.11
Interim Analysis
No interim analysis is currently planned for this study.
9.12
Handling of Missing Data
Sensitivity analyses will evaluate the robustness of findings to missing data. Details will be 
provided in the SAP.
9.13
Statistical Software
Data processing, statistical screening, descriptive reporting and analysis of the efficacy and 
safety data will be performed using SAS® (Version 9.2 or higher). Graphs may also be 
produced using R® (R. Development Core Team, 2003).


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10 ADMINISTRATIVE CONSIDERATIONS
10.1
Regulatory Authority Approval
The Sponsor will obtain approval to conduct this study from the appropriate regulatory 
agency in accordance with any applicable country-specific regulatory requirements prior to 
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 Good Clinical Practice E6 (R1): Consolidated Guideline (ICH, 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) 
•
Any additional regulatory requirements.
The Investigator (or the Sponsor, where applicable) is responsible for ensuring that this 
protocol, the site’s ICF, and any other information that will be presented to potential subjects 
(eg, advertisements or information that supports or supplements the ICF) are reviewed and 
approved by the appropriate IRB/IEC. The Investigator agrees to allow the IRB/IEC direct 
access to all relevant documents. The IRB/IEC must be constituted in accordance with all 
applicable regulatory requirements.
The Sponsor 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. The approval of 
an amended ICF/other information by an IRB/IEC must be promptly forwarded to the 
Sponsor or its designee.
10.3
Subject Informed 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/IEC and the Sponsor 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 procedures. For subjects <18 years of age, an 


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assent form will be signed by the subject, and a parent or legal guardian will sign the ICF. A 
copy of the signed ICF and assent form (where applicable) will be provided to the subject 
and the original will be retained by the Investigator.
10.4
Laboratory Accreditation
Any laboratory facility intended to be used for analysis of clinical laboratory samples 
required by this protocol must provide evidence of adequate licensure or accreditation 
according to the prevailing regulations in that state and/or country. Reference values and/or 
normal ranges for the test results must be provided to the Sponsor. The Sponsor must be 
notified promptly in writing of any changes occurring in reference values during the course 
of the study.
10.5
Confidentiality
10.5.1
Confidentiality of Data
By signing this protocol, the Investigator affirms that information furnished to the 
Investigator by the Sponsor 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.
10.5.2
Confidentiality of Subject Records
By signing this protocol, the Investigator agrees that the Sponsor (or its representative), 
IRB/IEC, or regulatory agency representatives may consult and/or copy study documents in 
order to verify worksheet/eCRF data. By signing the ICF, the subject (or parent or legal 
guardian, as applicable) agrees to this process. If study documents are photocopied during the 
process of verifying worksheet/eCRF information, the subject will be identified by a unique 
code; full names/initials will be masked prior to transmission to the Sponsor. 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 (ie, Health Insurance Portability and 
Accountability Act), rules and regulations.
10.6
Quality Control and Assurance
The Sponsor is responsible for implementing and maintaining quality control and quality 
assurance systems with written Standard Operating Procedures 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.


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10.7
Data Management
Data management procedures and information for this protocol will be provided by the 
Sponsor.
10.8
Study Monitoring
In accordance with applicable regulations, GCP, and the Sponsor’s 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
•
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 the Sponsor
•
Data queries
•
Accountability, reconciliation, and arrangements for unused investigational product(s)
•
Review of site study records for completeness
After the final review of the study files, the files should be secured for the appropriate time 
period as specified in Section 10.9. The Investigator will also permit inspection of the study 


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files by the Sponsor’s Quality Assurance auditors, or designees, including other 
representatives from the Sponsor, and authorized representatives of the Food and Drug 
Administration (FDA) or other applicable regulatory agencies.
10.9
Retention of Data
Documents that individually and collectively permit evaluation of the conduct of the study 
and the quality of the data produced must be maintained for review by the Sponsor 's Quality 
Assurance auditors and by all applicable regulatory authorities. The period of time these 
documents must be maintained is governed by county-specific regulations. The Sponsor or 
its designee will inform the Investigator when these documents may be destroyed. The 
Sponsor 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 the Sponsor to make alternate 
storage arrangements.
10.10 Financial Disclosure
The Principal Investigator or sub-Investigators named on FDA Form 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.
10.11 Investigator’s Final Report
Following completion of the study, the Investigator will submit a final written report to the 
Sponsor.
10.12 Publication and Disclosure Policy
The Sponsor intends to publish the results of all the clinical studies that it sponsors in 
compliance with the Declaration of Helsinki. 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 sponsored studies should fairly 
recognize the activities of those that have made a significant contribution to the study. In 
addition, the Sponsor 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 the Sponsor’s 
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, the Sponsor 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. The Sponsor (or its representatives) is 


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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: The Sponsor, 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 first 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 the 
Sponsor for review, approval, and to ensure consistency with the policy in this protocol. 
The Sponsor 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 the Sponsor 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 the Sponsor to publish the 
study in a fair and accurate manner, the Sponsor supports diligence in the publication 
review process of medical journals. Accordingly, upon request, all pertinent study data 
and information will be made available as supplemental information for journal editors 
and reviewers to evaluate and audit, eg, protocol and amendments, data tabulations, etc. 
The journal and reviewers will need to make arrangements to maintain the confidentiality 
of such supplemental information, where relevant, and the Sponsor 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, the Sponsor reports clinical findings based on the 
guidance of The CONsolidated Standards of Reporting Trials Statement (Moher 2012) 
and a 25-item checklist that 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, the Sponsor 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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Kerstjens HA, Casale TB, Bleecker E, et al. Tiotropium or salmeterol as add-on therapy to 
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Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard 
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Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration 
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2005;26(2):319-338.


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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. 
Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European 
Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for 
clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59-99.
Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating 
glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am. 
1987;34(3):571-590.
SPIRIVA RESPIMAT (tiotropium bromide) inhalation spray, for oral inhalation [package 
insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; Feb 2017.


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12 APPENDICES


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Appendix 1
Body Mass Index Calculators 
The online calculators below should be used to determine a subject’s body mass index (BMI) 
from their height and weight. Height and weight can be measured in either English units 
(feet, inches, pounds) or metric units (centimeters, kilograms).
•
For children/teens aged 2 to <20 years:
https://nccd.cdc.gov/dnpabmi/Calculator.aspx
•
For adults 20 years of age and older:
https://www.cdc.gov/healthyweight/assessing/bmi/adult_BMI/english_bmi_calculator
/bmi_calculator.html


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Appendix 2
Spirometry Assessment Criteria 
Acceptable Versus Usable Tests
Acceptable Tests must meet the following 7 Criteria:
1. Acceptable start of exhalation with brisk upstroke, no hesitation or false start, and back 
extrapolation volume (EV) <5% of forced vital capacity (FVC) or 0.150 L, whichever is 
the greater. (Refer to example in Figure A1-1)
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 
≥1 second, and the patient has tried to exhale for at least 6 seconds.
An acceptable test meets all 7 criteria listed. This is to be considered the “gold standard”.
Usable spirometry tracings are those that only meet criteria 1 and 2 (Figure A1-1). When this 
occurs, repeat testing up to 8 attempts in an effort to obtain 3 acceptable spirograms. If only 
usable tests are obtained, report results based on the 3 best usable results with observed 
limitations.
Figure A1-1. Example of a Usable Spirogram
The expanded version of the early part of a subject’s volume-time spirogram, illustrating back-extrapolation 
through the steepest part of the curve, where flow is peak expiratory flow (PEF), to determine the new “time 
zero”. Forced vital capacity (FVC) -4.291 L; back-extrapolated volume (EV) – 0.123 L (2.9% FVC): back-
extrapolation line through PEF.


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Between-Maneuver Repeatability Criteria
After 3 acceptable spirograms have been obtained, apply the following tests
•
The 2 largest values of FVC must be within 0.150 L of each other
•
The 2 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 
repeatability tracings), will be collected. 
If acceptability criteria are not met, continue testing until they are met or the patient cannot/ 
should not continue (maximum of 8 attempts).


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Appendix 3
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. 
The following instructions are supported by ATS/ERS defined criteria (Miller 2005).
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-1 1s -1
(0.15 kPa L-1 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 8 successive forced vital capacity (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 vs. 
volume provide more detail for the initial portion (first 1 s) of the FVC maneuver. Since this 
portion of the maneuver, particularly the peak expiratory flow rate, 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 (Table A2-1).
Table A2-1. Recommended Minimal Scale Factors for Time, Volume and 
Flow on Graphical Output
Parameter
Instrument Display
Hardcopy Graphical 
Output
Resolution Required
Scale Factor
Resolution Required
Volume*
0.050 L
5 mm-L-1
0.050 L
Flow*
0.200 L-s-1
2.5 mm L-1 s-1
0.200 L-s-1
Time
0.2 s
10 mm-s-1
0.2 s
*The correct aspect ratio for flow versus volume display is two units of flow per one unit of volume
The time scale should be ≥20 mm-s -1, and larger time scales are preferred (≥30 mm-s -1) 
when manual measurements are made. When the volume–time plot is used in conjunction 
with a flow–volume curve (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 A2-1). 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 A2-2.


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Table A2-2. 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 new calibration procedure or 
equipment maintenance is required. Calibration checks must be undertaken daily, or more 
frequently, if specified by the manufacturer. The syringe used to check the volume 
calibration of spirometers must have an accuracy of ±15 mL or ±0.5% of the full scale (15 
mL for a 3 L syringe), and the manufacturer must provide recommendations concerning 
appropriate intervals between syringe calibration checks. Users should be aware that a 
syringe with an adjustable or variable stop may be out of calibration if the stop is reset or 
accidentally moved. Calibration syringes should be periodically (eg, monthly) leak tested at 
more than one volume up to their maximum; this can be done by attempting to empty them 
with the outlet corked. A dropped or damaged syringe should be considered out of calibration 
until it is checked.
With regard to time, assessing mechanical recorder time scale accuracy with a stopwatch 
must be performed at least quarterly. An accuracy of within 2% must be achieved.
Quality Control for Volume Measuring Devices
The volume accuracy of the spirometer must be checked at least daily, with a single 
discharge of a 3 L calibrated syringe. Daily calibration checking is highly recommended so 
that the onset of a problem can be determined within 1 day and also to help define day to day 
laboratory variability. More frequent checks may be required in special circumstances, such 
as: 1) during industrial surveys or other studies in which a large number of subject 
maneuvers are carried out, the equipment’s calibration should be checked more frequently 
than daily; and 2) when the ambient temperature is changing (eg, field studies), volume 
accuracy must be checked more frequently than daily and the BTPS correction factor 
appropriately updated. 


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The accuracy of the syringe volume must be considered in determining whether the measured 
volume is within acceptable limits. For example, if the syringe has an accuracy of 0.5%, a 
reading of ±3.5% is appropriate.
The calibration syringe should be stored and used in such a way as to maintain the same 
temperature and humidity of the testing site. This is best accomplished by keeping the 
syringe in close proximity to the spirometer, but out of direct sunlight and away from heat 
sources.
Volume type spirometer systems must be evaluated for leaks every day. The importance of 
undertaking this daily test cannot be overstressed. Leaks can be detected by applying a 
constant positive pressure of ≥3.0 cmH2O (0.3 kPa) with the spirometer outlet occluded 
(preferably at or including the mouthpiece). Any observed volume loss of 0.30 mL after 
1 minute indicates a leak and needs to be corrected.
At least quarterly, volume spirometers must have their calibration checked over their entire 
volume range using a calibrated syringe or an equivalent volume standard. The measured 
volume should be within ±3.5% of the reading or 65 mL, whichever is greater. This limit 
includes the 0.5% accuracy limit for a 3-L syringe. The linearity check procedure provided 
by the manufacturer can be used if it is equivalent to one of the following procedures: 
1) consecutive injections of 1-L volume increments while comparing observed volume with 
the corresponding cumulative measured volume (eg, 0–1,1–2, 2–3,…6–7 and 7–8 L, for an 
8-L spirometer); and 2) injection of a 3-L volume starting at a minimal spirometer volume, 
then repeating this with a 1-L increment in the start position (eg, 0–3, 1–4, 2–5, 3–6, 4–7, and 
5-8 L, for an 8-L spirometer). The linearity check is considered acceptable if the spirometer 
meets the volume accuracy requirements for all volumes tested.
Quality Control for Flow Measuring Devices
With regards to volume accuracy, calibration checks must be undertaken at least daily, using 
a 3-L syringe discharged at least three times to give a range of flows varying between 0.5 and 
12 L-s -1 (with 3-L injection times of 6 s and 0.5 s). The volume at each flow should meet the 
accuracy requirement of ±3.5%. For devices using disposable flow sensors, a new sensor 
from the supply used for subject 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 AND INSPIRATORY CAPACITY MANEUVERS
Equipment
For measurements of vital capacity (VC) and inspiratory capacity, 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 


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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.
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 (ie, 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 A2-3, but must meet the recommendations for those that 
are measured. Accuracy and repeatability recommendations apply over the entire volume 
range of the instrument.
Table A2-3. Range and Accuracy Recommendations Specified for Forced 
Expiratory Maneuvers
Test
Range/Accuracy 
(BTPS)
Flow 
Range
(L-s-1)
Resistance and 
Back Pressure
Test Signal
VC
0.5–8 L, ±3% of reading or 
±0.050 L, whichever is greater
0-14
3-L Calibration syringe
FVC
0.5–8 L, ±3% of reading or 
±0.050 L, whichever is greater
0-14
<1.5 cmH2O L-1 s-1
(0.15 kPa L-1s-1)
24 ATS waveforms, 3-L 
Cal Syringe
FEV1
0.5–8 L, ±3% of reading or 
±0.050 L, whichever is greater
0-14
<1.5 cmH2O L-1 s-1
(0.15 kPa L-1s-1)
24 ATS waveforms
Time 
Zero
The time point from which all 
FEVt measurements are taken
Back extrapolation
FEVt: forced expiratory volume in t seconds
BTPS Correction
All spirometry values should be reported at BTPS by any method (measuring temperature 
and barometric pressure) proven effective by the manufacturer. For volume-type spirometers, 
the temperature inside the spirometer should be measured for each breathing maneuver. 


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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 4
Dose-Indicator Reading for GP MDI and Placebo MDI
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 5
Instructions for Use of GP MDI and Placebo MDI
How do I store the inhaler?
•
The inhaler should be stored below 25°C (77°F) in a dry place. Excursions permitted up 
to 30°C (86°F). 
•
The contents of the canister are under pressure. Do not puncture or throw the canister into 
a fire or incinerator. Do not use or store it near heat or open flame. Storage above 120ºF 
may cause the canister to burst.
•
Keep the product and all medicines out of the reach of children.
For Oral Inhalation Only
Parts of the Inhaler:
•
The parts of your inhaler are seen in Figure A4-1.
Figure A4-1
•
The Dose indicator lets you know about how many puffs are left in your inhaler and is 
the part of the inhaler that is pressed to dispense a puff of medication. See Figure A4-1.
•
The Dose indicator should be pointing just to the right of 120 when your inhaler is new. 
See Figure A4-1.
•
The Dose indicator has numbers for every 20 puffs. The Dose indicator display will 
move after every tenth puff. 


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•
For example, if the Dose indicator is pointing to 120 (see Figure A4-2a) and you take 
10 puffs it will move between 120 and 100. This means that there are 110 puffs of 
medicine left (see Figure A4-2b). 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 A4-2c).
•
The Dose indicator number will continue to change after every 20 puffs.
•
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 A4-2d.
Figure A4-2
Figure A4-2a
Figure A4-2b
Figure A4-2c
Figure A4-2d
120 puffs
110 puffs
100 puffs
Preparing the Inhaler for Use:
The inhaler comes in a foil pouch that contains a drying packet (desiccant).
•
Take the inhaler out of the foil pouch.
•
Throw away the pouch and the drying packet. Do not eat or inhale the contents of the 
drying packet. 
•
Remove the Cap from the Mouthpiece as shown in Figure A4-3. 
Figure A4-3


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Prime the inhaler before you use it for the first time.
Priming the Inhaler:
•
Check inside the Mouthpiece for objects before use.
•
Hold the Actuator with the Mouthpiece pointing away from you and others as shown in 
Figure A4-4a.
•
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 (see Figure 1) until the Canister stops moving in the Actuator to release a 
puff from the Mouthpiece as shown in Figure A4-4b. Note: It is normal to hear a soft 
click from the dose indicator as it counts down during use.
•
Repeat this priming step 3 more times for a total of 4 times, shaking the inhaler each time 
before you press it.
•
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.
Figure A4-4
Figure A4-4a
Figure A4-4b
Using the Inhaler:
Your dose of medicine comes from 2 puffs from the inhaler.
Refer to Figure A4-5 for Step 1 through Step 8.
•
Step 1: Remove the Cap from the Mouthpiece.
•
Step 2: Shake the inhaler well before each puff.


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•
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.
•
Step 4: Close your lips around the Mouthpiece and tilt your head back slightly to make 
sure your tongue is away from the Mouthpiece.
•
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. 
•
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. 
•
Step 7: Then, breathe out normally. 
Take your second puff of medicine by repeating Step 2 through Step 7. 
•
Step 8: Replace the Cap back on the Mouthpiece.


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Figure A4-5
How to clean the inhaler:
It is very important to keep your inhaler clean so medicine will not build-up and block the 
spray through the Mouthpiece. See Figure A4-6.


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Figure A4-6
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.
•
Step 1: Pull the Canister out of the Actuator as shown in Figure A4-7.


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Figure A4-7
•
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 A4-8).
Figure A4-8
•
Step 5: Shake all of the water droplets out of the Actuator.
•
Step 6: Look in the Actuator and the Mouthpiece to make sure it is clean and clear.


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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 A4-9. 
Do Not put the Canister back into the Actuator if it is still wet.
Figure A4-9
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 A4-10. It is not necessary to press down on the Canister hard enough to 
cause a puff to be released.


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Figure A4-10
•
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 A4-4.
•
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 6
Instructions for Use of Spiriva® Respimat® (tiotropium) 
Inhalation Spray …………


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Appendix 7
Instructions for Use of Ventolin® HFA (albuterol) 
Inhaler 


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Appendix 8
Instructions for Use of Atrovent® HFA (ipratropium) 
Inhaler


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Appendix 9
Asthma Control Questionnaire (ACQ) 
The ACQ-5, ACQ-6, and ACQ-7 comprise questions 1 through 5, questions 1 through 6, and 
all 7 questions, respectively.
(The sample provided here is for illustrative purposes only)


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Appendix 10
Asthma Quality of Life Questionnaire for 12 Years and 
Older (AQLQ +12) …..
(The sample provided here is for illustrative purposes only)


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Appendix 11
Fractional Nitric Oxide in Inhaled Breath
Fractional nitric oxide in inhaled breath (FENO) data of high and consistent quality must be 
obtained for proper interpretation of the results of this protocol. To these ends, a standard 
measurement device will be used, and training provided on its use and care; specific 
operating instruction will also be provided. 
Equipment 
The 
device 
 and all 
required accessories (eg, test kits) will be provided by Pearl and used by all sites. The 
 
 device is suitable for children, approximately 7 to 17 years of age, and adults 18 years 
and older.
A User Manual will also be provided (electronically, printed, or both) which includes 
detailed information for installation, use, troubleshooting, and preventive care for the Niox 
Vero device.
Procedures
Two valid, reproducible FENO measurements are required, in accordance with testing 
procedures recommended by the manufacturer and similar to those published by the 
American Thoracic Society and European Respiratory Society (ATS/ERS 2005). If either or 
both of the first 2 valid FENO measurements is < 30 ppb and the measurements are within 
2 ppb of each other, or if both measurements are > 30 ppb and within 10% of each other, then 
the test is considered reproducible and complete. 
Two values below or above the measurement range (5-300 ppb) are also considered 
reproducible. If the reproducibility criteria are not met within the first 2 exhalations, a 
participant has 2 additional exhalations to satisfy the criteria (up to a total of 4 trials). The 
examinee's exhalations for which the device does not display a valid reading, ie, exhalations 
that are either too strong or too weak, or any other reasons for failing to achieve a successful 
exhalation, will be recorded as attempts. Examinees may not always able to meet the criteria 
for a reproducible measurement. 
The results of each attempt will be recorded in the appropriate eCRF.
Reference
American Thoracic Society, European Respiratory Society. ATS/ERS recommendations for 
standardized procedures for the online and offline measurement of exhaled lower respiratory 
nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005;171(8):912-930.


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Appendix 12
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 the Sponsor 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 ≥3×ULN with TBL ≥ 2×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 ≥3×ULN with TBL ≥ 2×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 ≥3×ULN
•
AST ≥3×ULN
•
TBL ≥2×ULN
When a subject meets any of the identification criteria in combination, the central laboratory 
will immediately send an alert to the Investigator and the Sponsor 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 by reviewing all laboratory reports 
including previous visits
•
Notify the Sponsor representative
FOLLOW-UP
Potential Hy’s Law Criteria not met
If the subject does not meet PHL criteria the Investigator will:
•
Inform the Sponsor 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 Sponsor 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 Sponsor Medical Monitor.
•
If at any time (in consultation with the Sponsor 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 Sponsor 
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 Sponsor 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 an AE/SAE, record the AE /SAE in the eCRF according 
to the Sponsor’s standard reporting procedures.
•
If the alternative explanation is not an AE, record the alternative explanation on the 
comment form within the eCRF.
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 Sponsor 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 13
Sponsor Signatory


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Appendix 14
Investigator’s Agreement and Signature Page
Study Title:
A Randomized, Double-Blind, Parallel Group, Multi-Center 
24-Week Study Comparing the Efficacy and Safety of Three 
Doses of PT001 to Placebo and Open-label Spiriva® Respimat® 
in Subjects With Persistent Asthma
Study Number:
PT001102-04  
Final Date:
08 March 2019
I agree:
a.
To assume responsibility for the proper conduct of the study at this site.
b.
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).
c.
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).
d.
That I am aware of, and will fully comply with GCP and all applicable regulatory requirements.
e.
That I am thoroughly familiar with the appropriate use of the investigational product(s), and other 
information provided by the Sponsor including, but not limited to, the following: the protocol and the 
current Investigator Brochure (IB).
f.
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.
g.
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.
h.
I agree to report all information or data in accordance with the protocol and any other study conduct 
procedures provided by Pearl.
i.
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.
j.
To accurately transfer all required data from each subject’s source document to the eCRFs. The eCRFs will 
be provided to the Sponsor in a timely manner at the completion of the study, or as otherwise specified by 
the Sponsor.
k.
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:
Site Name:

SAP_001.pdf: 
 
Statistical Analysis Plan 
 
Study Code 
PT001102  
NCT #  
NCT03358147 
Date 
12 August 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Double-Blind, Parallel Group, Multi-Center 24 
Week Study Comparing the Efficacy and Safety of Three Doses of 
PT001 to Placebo and Open-label Spiriva® Respimat® in Subjects 
With Persistent Asthma 


Statistical Analysis Plan
Study:  PT001102 
12 August 2019
Version 1.0
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STATISTICAL ANALYSIS PLAN FOR
STUDY PT001102
Protocol Number:
PT001102-04 (Version 5.0)
Investigational Drug 
and Drug Number:
Glycopyrronium Inhalation Aerosol (GP MDI; PT001)
Spiriva® Respimat®
Indication:
Asthma
Dosage Form/Dose:
x
GP MDI 28.8 μg BID
x
GP MDI 14.4 μg BID
x
GP MDI 7.2 μg BID
x
Placebo MDI BID
x
Spiriva Respimat 2.5 μg QD
PT001102 Protocol Title: A Randomized, Double-Blind, Parallel Group, Multi-Center 24-
Week Study Comparing the Efficacy and Safety of Three Doses of PT001 to Placebo and Open-
label Spiriva Respimat in Subjects With Persistent Asthma
Date of Issue:
12 August 2019
Version:
Version 1.0




Statistical Analysis Plan
Study:  PT001102 
12 August 2019
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Change Log
Version No.
Effective Date
Reason for the Change / Revision
Supersedes


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12 August 2019
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TABLE OF CONTENTS 
1. 
INTRODUCTION ..................................................................................................................................... 11 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................ 11 
2.1 
STUDY OBJECTIVES............................................................................................................................11 
 
Primary Objective...............................................................................................................11 
 
Secondary Objective...........................................................................................................11 
 
Safety Objective .................................................................................................................11 
 
24-Hour Holter Monitoring Sub-Study Objective ..............................................................11 
2.2 
STUDY ENDPOINTS.............................................................................................................................11 
 
Primary Efficacy Endpoints................................................................................................11 
 
Secondary Efficacy Endpoints............................................................................................11 
 
Other Efficacy Endpoints ...................................................................................................12 
 
Safety Endpoints.................................................................................................................13 
 
24-Hour Holter Monitoring Sub-Study Endpoints..............................................................13 
Primary Holter Monitoring Sub-Study Endpoint................................................................13 
Secondary Holter Monitoring Sub-Study Endpoints ..........................................................13 
3. 
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS ............................................................. 14 
3.1 
STUDY DESIGN...................................................................................................................................14 
 
Overall Study Design and Plan...........................................................................................14 
 
Prior, Concomitant, Post-Treatment, Prohibited Medications, and Other Restrictions ......16 
3.2 
HYPOTHESIS TESTING ........................................................................................................................16 
3.3 
INTERIM ANALYSIS ............................................................................................................................17 
3.4 
SAMPLE SIZE......................................................................................................................................17 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE ........................................................................ 17 
5. 
ANALYSIS SETS AND ESTIMANDS .................................................................................................... 18 
5.1 
ANALYSIS SETS..................................................................................................................................18 
 
Intent-to-Treat (ITT) Analysis Set......................................................................................18 
 
Modified Intent-to-Treat (mITT) Analysis Set...................................................................18 
 
Safety Analysis Set.............................................................................................................18 
 
Holter Monitoring Analysis Set..........................................................................................18 
5.2 
ANALYSIS SETS FOR PRIMARY AND SENSITIVITY ANALYSES.............................................................18 
5.3 
ESTIMANDS ........................................................................................................................................19 
 
Efficacy Estimand...............................................................................................................19 
 
Attributable Estimand.........................................................................................................19 
 
Treatment Policy Estimand.................................................................................................20 
6. 
STATISTICAL ANALYSIS ..................................................................................................................... 20 
6.1 
DATA HANDLING RULES AND DEFINITIONS, INCLUDING HANDLING OF MISSING DATA....................20 
6.2 
SUBJECT DISPOSITION AND ANALYSIS SETS.......................................................................................21 
6.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS AND EXTENT OF EXPOSURE.................................22 
 
Demography, Physical Characteristics ...............................................................................22 
 
Asthma History, Screening/Baseline Spirometry, and Reversibility ..................................24 
 
Asthma Exacerbation, Medical and Surgical History at Screening, Reproductive Status 
and Pregnancy Testing........................................................................................................25 
 
Prior, Concomitant, and Post-Treatment Medications/Treatments.....................................25 
 
Extent of Exposure to Study Medication and Compliance .................................................26 
6.4 
EFFICACY ANALYSES.........................................................................................................................27 
 
Baselines and Baseline Covariates for Analysis.................................................................27 


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Visits and Time Windows for Visit-Based Efficacy Assessments .....................................29 
 
Asthma Exacerbations ........................................................................................................29 
 
Primary Efficacy Analysis..................................................................................................32 
FEV1 AUC0-4.......................................................................................................................32 
Assumptions Checks and Possible Removal of Outliers.....................................................33 
 
Secondary Efficacy Analysis..............................................................................................33 
Change from Baseline in Morning Pre-Dose Trough FEV1................................................33 
Rate of Moderate/Severe Asthma Exacerbations................................................................34 
Change from Baseline in ACQ-7, ACQ-5, and AQLQ+12 ................................................35 
 
Other Efficacy Analysis......................................................................................................36 
Percentage of Responders in ACQ-5, ACQ-6, ACQ-7, and AQLQ+12.............................36 
Change from Baseline in ACQ-6........................................................................................37 
Rate of Asthma Exacerbations............................................................................................37 
Time to First Moderate/Severe Asthma Exacerbation, Severe Asthma Exacerbation, or 
Asthma Exacerbation of Any Severity...............................................................37 
Peak Change from Baseline in FEV1 ..................................................................................38 
Percentage of Symptom-Free Days, Rescue-Free Days, and Asthma Control Days ..........38 
Rescue Medication Usage...................................................................................................39 
Change from Baseline in Morning PEFR and Evening PEFR............................................40 
FENO
41 
CompEx 42 
 
Subgroup Analyses .............................................................................................................44 
Subgroup Cut Point Exploration.........................................................................................45 
 
Control of Type I Error.......................................................................................................46 
 
Correlation Analysis...........................................................................................................47 
6.5 
SAFETY ANALYSIS .............................................................................................................................47 
 
Adverse Events...................................................................................................................47 
Adverse Events of Special Interest .....................................................................................50 
Paradoxical Bronchospasm.................................................................................................50 
 
Clinical Laboratory Measurements.....................................................................................52 
 
Vital Signs ..........................................................................................................................55 
 
12-Lead Electrocardiogram Measurements ........................................................................57 
 
24-Hour Holter Monitoring Sub-Study...............................................................................58 
Primary Analysis.................................................................................................................58 
Secondary and Other Holter Monitoring Data Safety Analyses .........................................59 
 
Physical Examination .........................................................................................................60 


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7. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL .................................................... 60 
8. 
STATISTICAL SOFTWARE ................................................................................................................... 60 
9. 
REFERENCES .......................................................................................................................................... 60 
APPENDIX 1: DATA HANDLING RULES .................................................................................................... 62 
APPENDIX 2: ANALYSIS DATASET SPECIFICATIONS .......................................................................... 70 
APPENDIX 3: SAS CODE FOR STATISTICAL ANALYSES ..................................................................... 70 
APPENDIX 4: CTCAE LABORATORY TEST CRITERIA FOR SHIFT TABLES AND CENTRAL 
LABORATORY REFERENCE RANGES FOR USE IN FLAGGING ABNORMAL VALUES .... 70 
APPENDIX 5: STANDARD MEDDRA QUERIES (SMQ) ............................................................................ 70 
APPENDIX 6: STATISTICAL DETAILS ....................................................................................................... 70 
APPENDIX 7: TABLE OF CONTENTS END-OF-TEXT TLFS .................................................................. 71 
List of Tables
Table 1 
GINA Classification of Asthma Treatment ...........................................................24 
Table 2 
Analysis Study Time Window for Spirometry Assessments .................................29 
Table 3 
4-Week Intervals....................................................................................................39 
Table 4 
Asthma Deterioration Criteria................................................................................43 
Table 5 
Adverse Events of Special Interest ........................................................................50 
Table 6 
Lab Parameters.......................................................................................................52 
Table 7 
Potentially Clinically Significant Laboratory Parameter Criteria..........................54 
Table 8 
Potentially Clinically Significant Criteria for Systolic and Diastolic Blood 
Pressure Parameters ...............................................................................................56 
Table 9 
Potentially Clinically Significant Criteria for Heart Rate Parameters ...................56 
Table 10 
Analysis Study Time Windows for Vital Signs Assessments................................57 
Table 11 
Criteria for PCS ECG Values.................................................................................58 
List of Figures
Figure 1  
Study Design Overview .........................................................................................14 
Figure 2 
Order of Hypothesis Testing for Type I Error Control ..........................................46 


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12 August 2019
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ACQ
Asthma Control Questionnaire
ACQ-5
ACQ questions 1 through 5, which measure the frequency, intensity or 
limitations from asthma symptoms using 1-week recall
ACQ-6
ACQ questions 1 through 6, which is the ACQ-5 plus 1 item that scores 
the average number of daily puffs needed from rescue medication using 1-
week recall
ACQ-7
ACQ questions 1 through 7, which is the ACQ-6 plus 1 item that scores 
lung function (FEV1 percent predicted)
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AQLQ+12
Asthma Quality of Life Questionnaire for 12 years and older
AR(1)
Autoregressive order 1
AST
Aspartate aminotransferase
ATS
American Thoracic Society
AUC0-4
Area Under the Curve From 0 to 4 Hours
BID
Twice daily
BDRM
Blinded Data Review Meeting
BPM
Beats Per Minute
BMI
Body mass index
CI
Confidence Interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CompEx
A composite endpoint comprising clinically relevant deteriorations and 
severe exacerbations in asthma
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data monitoring committee
ECG
Electrocardiogram


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eCRF
Electronic case report form
eDiary
Electronic Diary
e.g.
Exempli Gratia, For Example
FENO
Fractional nitric oxide concentration in exhaled breath
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
H0
Null Hypothesis
H1
Alternative Hypothesis
GINA
Global Initiative for Asthma
GP MDI
Glycopyrronium Inhalation Aerosol
hCG
Human chorionic gonadotropin
HFA
Hydrofluoroalkane
HLGT
High Level Group Term
HLT
High Level Term
ICF
Informed consent form
ICS
Inhaled corticosteroid
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
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
μg
Microgram
mITT
Modified intent-to-treat 


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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
PFT
Pulmonary function test
ppb
Parts per billion
PT
Preferred Term
PVC
Premature ventricular contraction
QTcF
QT corrected using Fridericia’s formula
SABA
Short-acting β2-agonist
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SMQ
Standard MedDRA Query
sPDP
Statistical Protocol Deviation Plan
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
UN
Unstructured
US
United States


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Trademark Information
Trademarks Not Owned By Pearl
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Statistical Analysis Plan
Study:  PT001102 
12 August 2019
Version 1.0
(Page 11 of 87)
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 PT001102. 
The SAP should be read in conjunction with the study protocol. This version of the SAP has 
been developed using the PT001102-04 Amended Protocol (Version 5.0 dated 08 March 2019) 
and the PT001102 case report form (CRF) (Version 07 dated 05 April 2018).
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1
Study Objectives 
The overall objective is to assess the efficacy and safety of 3 doses of GP MDI (glycopyrronium 
inhalation aerosol meter dose inhaler) compared to Placebo MDI and Spiriva Respimat over 24 
weeks in subjects with persistent asthma. 
Primary Objective
x
To assess the effect of 3 doses of GP MDI compared to Placebo MDI and Spiriva Respimat 
on lung function over 24 weeks in subjects with persistent asthma
Secondary Objective
x
To assess the effect of 3 doses of GP MDI compared to Placebo MDI and Spiriva Respimat 
on exacerbations, quality of life, and symptoms over 24 weeks in subjects with persistent 
asthma
Safety Objective
x
To assess the safety of 3 doses of GP MDI compared to Placebo MDI and Spiriva Respimat 
over 24 weeks in subjects with persistent asthma
24-Hour Holter Monitoring Sub-Study Objective
x
To assess the cardiovascular safety of GP MDI compared to Placebo MDI and Spiriva 
Respimat as evaluated by 24-hr Holter monitoring
2.2
Study Endpoints
Primary Efficacy Endpoints 
x
Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 
from 0 to 4 hours (AUC0-4) at Week 24
Secondary Efficacy Endpoints
x
Change from baseline in morning pre-dose trough FEV1 at Week 24
x
Rate of moderate/severe asthma exacerbations


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x
Change from baseline in Asthma Control Questionnaire (ACQ)-7 at Week 24
x
Change from baseline in ACQ-5 at Week 24
x
Change from baseline in Asthma Quality of Life Questionnaire for 12 years and older 
(AQLQ+12) at Week 24
Other Efficacy Endpoints
With the exception of rate of moderate/severe asthma exacerbation, all of the primary and 
secondary endpoints shown above will also be assessed over the Treatment Period and at each 
clinic visit as other efficacy endpoints. 
In addition, the following endpoints will be assessed over the Treatment Period, by visit for 
measures assessed at clinic visits (with the exception of responder endpoints, which will be 
assessed at Week 24 and over the Treatment Period), and over each 4-week interval for measures 
assessed by electronic diary (eDiary) unless specified otherwise below. 
x
Percentage of responders in ACQ-5 (≥0.5 decrease equals response) 
x
Change from baseline in ACQ-6
x
Percentage of responders in ACQ-6 (≥0.5 decrease equals response) 
x
Percentage of responders in ACQ-7 (≥0.5 decrease equals response) 
x
Percentage of responders in AQLQ +12 (≥0.5 change equals response) 
x
Time to first moderate/severe asthma exacerbation (assessed over the Treatment Period only)
x
Time to first severe asthma exacerbation (assessed over the Treatment Period only)
x
Rate of severe asthma exacerbations (assessed over the Treatment Period only)
x
Time to first asthma exacerbation of any severity (assessed over the Treatment Period only)
x
Rate of asthma exacerbations of any severity (assessed over the Treatment Period only)
x
Peak FEV1
x
Percentage of symptom-free days (24-hour period without symptoms) 
x
Percentage of rescue-free days (24-hour period without rescue medication use) 
x
Change from baseline in the mean number of puffs of rescue medication use (puffs/day) 
x
Percentage of asthma control days (24-hour period without rescue medication use or 
symptoms) 
x
Change from baseline in morning peak expiratory flow rate (PEFR)
x
Change from baseline in evening PEFR 
x
Change from baseline in fractional nitric oxide concentration in exhaled breath (FENO)
x
Percentage of clinically meaningful changes from baseline in FENO
x
Time to first CompEx event 


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12 August 2019
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Safety Endpoints
The safety endpoints for this study include:
x
Adverse events (AEs)
x
Clinical laboratory values
x
Vital signs
x
12-lead electrocardiograms (ECGs)
24-Hour Holter Monitoring Sub-Study Endpoints
Primary Holter Monitoring Sub-Study Endpoint
x
Change from baseline in mean heart rate (HR) over 24 hours
Secondary Holter Monitoring Sub-Study Endpoints
x
Change from baseline in mean nighttime (22:00 to 06:00) and daytime (06:00 to 22:00) HR
x
Change from baseline in the maximum 24-hour HR
x
Change from baseline in the minimum 24-hour HR
x
Change from baseline in the frequency of isolated ventricular events (premature ventricular 
contractions [PVCs])
x
Change from baseline in the frequency of ventricular couplets (defined as 2 PVCs preceded 
or followed by regular beats)
x
Change from baseline in the frequency of ventricular runs (defined as 3 or more PVCs 
preceded or followed by regular beats)
x
Change from baseline in the frequency of supraventricular ectopic beats
x
Change from baseline in the frequency of isolated supraventricular events
x
Change from baseline in the frequency of supraventricular couplets
x
Change from baseline in the frequency of supraventricular runs
x
Incidence of atrial fibrillation with rapid ventricular response (>100 beats per minute (bpm))
x
Proportion of subjects with maximum HR >180, >160 to 180, >140 to 160, >120 to 140, 
>100 to 120, and 100 bpm or less
x
Proportion of subjects with minimum HR >60, >50 to 60, >40 to 50, and <40 bpm
x
Proportion of subjects in each category of change from baseline in the number of PVCs per 
hour (no change; increase of >0 to <60, 60 to <120, and ≥120; and decrease of >0 to <60, 60 
to <120, and ≥120)


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12 August 2019
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3.
STUDY DESIGN AND ANALYTICAL CONSIDERATIONS
3.1
Study Design
Overall Study Design and Plan
This is a Phase II/III randomized, double-blind, parallel group, multi-center dose confirmation 
study comparing 3 doses of GP MDI (28.8, 14.4, and 7.2 μg) to Placebo MDI and open-label 
Spiriva Respimat (2.5 μg) in subjects with persistent asthma who are symptomatic despite 
treatment with an ICS/LABA or ICS/LABA + tiotropium. The 3 doses of GP MDI and the 
Placebo MDI will be administered twice daily (BID) and Spiriva Respimat will be administered 
once daily (QD), each for 24 weeks. The subjects will also continue on their own ICS/LABA 
regimen during the Screening Period and throughout the Treatment Period.
Figure 1 displays the overall study design.
Figure 1
Study Design Overview 
This study will be conducted at approximately 250 sites, contributing approximately 4 to 6 
subjects per site. It is planned that approximately 2250 prospective subjects will be screened, 
with approximately 1125 subjects randomized to provide approximately 900 subjects who 
complete the study.


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12 August 2019
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At Visit 1, subjects (or the parents or legal guardians of subjects <18 years of age) will sign an 
informed consent form (ICF); subjects <18 years of age will sign an assent form. All eligible 
subjects must be taking a stable regimen of an inhaled corticosteroid (ICS)/long-acting E2-
agonist (LABA) for at least 4 weeks; this ICS/LABA regimen will be continued throughout the 
Screening and randomized Treatment Periods. Subjects who are also taking tiotropium will 
discontinue its use at Visit 1 and replace tiotropium with Sponsor-provided ipratropium bromide 
HFA MDI (hereafter referred to as ipratropium) taken as 2 inhalations 4 times daily (QID) 
during the Screening Period. Beginning with Visit 1, subjects will use an eDiary BID to record 
ICS/LABA use (Screening Period only), albuterol sulfate HFA MDI (hereafter referred to as 
albuterol) use, asthma symptom scores, PEFR, and study drug use (Treatment Period only).
Subjects must demonstrate an FEV1 >40% and <85% of predicted (>40% and <90% of predicted 
for subjects 12 to <18 years of age) at Visit 1, Visit 2 (if applicable) and Visit 4.  Reversibility to 
albuterol must be demonstrated at either Visit 1 or Visit 2. A subject will be considered 
reversible to albuterol if the improvement in FEV1 from pre-albuterol to post-albuterol is ≥12% 
and ≥200 mL.
Subjects will return for Visit 2 after adequate washout of prohibited asthma medications. There 
will be a minimum of 7 days between Visit 1 and Visit 2. At Visit 2, the ACQ will be 
administered along with multiple other assessments including FENO. Spirometry will only be 
performed at Visit 2 if reversibility to albuterol was not demonstrated at Visit 1.
A subset of approximately 562 subjects (125 subjects from the GP MDI groups and Placebo 
MDI group and 62 subjects from the Spiriva Respimat group) will participate in the 24-hour
Holter monitor sub-study. In these subjects, a 24-hour Holter monitor will be collected between 
Visit 3 and Visit 4 (Holter Monitor Baseline) and at Visit 7 (Week 12). Those subjects who have 
clinically significant abnormal findings defined as (but not limited to) criteria in protocol Section 
5.5Error! Reference source not found. during the baseline 24-hour Holter monitor MUST be 
screen failed from the full study. Subjects unable to provide a minimum of 18 hours of 
acceptable quality recording in a 24-hour period after 2 attempts will not be eligible for the 
Holter monitoring sub-study, but DO NOT need to be screen failed from the full study.
Reversibility to ipratropium will be assessed at Visit 3 for characterization and randomization 
stratification purposes.
Subjects meeting randomization criteria at Visit 4 will discontinue ipratropium (if applicable), 
and be randomized in a 2:2:2:2:1 scheme to 1 of the following 5 treatment groups for 24 weeks:
x
GP MDI 28.8 μg BID (n=250)
x
GP MDI 14.4 μg BID (n=250)
x
GP MDI 7.2 μg BID (n=250)
x
Placebo MDI BID (n=250)
x
Spiriva Respimat 2.5 μg QD (n=125)


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Randomization will be stratified by baseline percent predicted FEV1 (≤60% or >60%), 
reversibility to ipratropium (<12% or <200 mL vs ≥12% and ≥200 mL improvement in FEV1),
and by the ICS included in their fixed-dose ICS/LABA combination product (budesonide [e.g., 
Symbicort®, with formoterol fumarate dihydrate], mometasone furoate [e.g., Dulera®, with 
formoterol fumarate dihydrate], fluticasone furoate [e.g., Breo® Ellipta®, with vilanterol 
trifenatate], or fluticasone propionate [e.g., Advair® or AirDuo™ RespiClick®, with salmeterol]).
Following randomization, subjects will undergo 6 additional clinic visits over 24 weeks. For 
subjects participating in the Holter monitoring sub-study, a Holter monitor will also be placed at 
Visit 7 and removed the following day.
Note: The end of study is defined as the date on which data are collected 14 (+2) days after the 
last dose of study drug. Data collection can occur via a follow-up telephone call or a study visit, 
whichever provides 14 (+2) days of follow-up.
The Schedule of Events and Timed Assessments are available in the study protocol.
Prior, Concomitant, Post-Treatment, Prohibited Medications, and Other 
Restrictions
All prescription and over-the-counter (OTC) medications, as well as any herbal or vitamin
supplements, 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 route 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 
Placebo MDI dose 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 not zero 
(mean treatment effects are not equal). All p-values will be reported as 2-sided.
The primary null (H0) and alternative (H1) hypotheses, with μ representing the mean, are 
presented below:
H0: μGP xx = μPlacebo
H1: μGP xx ≠ μPlacebo
Secondary and other efficacy analyses will involve the above hypotheses applied to secondary 
and other efficacy endpoints. Other pairwise comparisons will be evaluated in a similar manner; 
comparison to Spiriva Respimat will focus on estimation.




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Appendix 1 of this SAP. The quality of all PFT’s obtained at each time point will be graded 
independently at 
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 SETS AND ESTIMANDS
5.1
Analysis Sets
Intent-to-Treat (ITT) Analysis Set
The Intent-To-Treat analysis set is defined as the data from all subjects who are randomized to
treatment and use 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 in the ITT analysis set.
Modified Intent-to-Treat (mITT) Analysis Set 
The Modified Intent-to-Treat analysis set is a subset of the ITT analysis set, and is defined as the 
data from 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 set but will still be included in the ITT 
analysis set. Subjects will be analyzed according to randomized treatment group. It is noted that 
a subject who used a study treatment, but took less than 1 full dose of treatment will qualify for 
this analysis set. The mITT analysis set will be the primary analysis set for all efficacy analyses. 
Note: The knowledge that a subject did not have an exacerbation constitutes an efficacy 
assessment.
Safety Analysis Set
The Safety analysis set is defined as data from all subjects who are randomized to treatment and 
receive any amount of the study treatment. However, subjects will be analyzed according to 
treatment received rather than randomized. If a subject receives 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. Note: the statement that a subject has no AEs also 
constitutes a safety assessment.
Holter Monitoring Analysis Set
The Holter Monitoring analysis set is defined as all subjects in the Safety analysis set who had at 
least 18 hours of acceptable quality Holter monitoring data at both Visit 3 (Holter Baseline) and 
Visit 7 (Week 12). Data judged to be impacted by major protocol deviations will be determined 
prior to database lock and excluded per the Statistical Protocol Deviation Plan (sPDP).
5.2
Analysis Sets for Primary and Sensitivity Analyses 
Demographics will be summarized for the mITT, Safety, and Holter Monitoring analysis sets.


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Extent of exposure will be summarized for the Safety analysis set. The Safety analysis set will be 
used to summarize safety endpoints.
Holter monitoring data will be summarized for the Holter Monitoring analysis set.
Efficacy analyses will be performed for the ITT and mITT analysis sets. The mITT analysis set 
will be considered the primary analysis set for the efficacy analyses, with the ITT analysis set 
being considered supportive. Rescue medication endpoints will be analyzed with mITT and ITT 
analysis sets.
5.3
Estimands
Efficacy Estimand
The Efficacy Estimand, the primary estimand of interest, is defined as the effect of the 
randomized treatments in all subjects assuming continuation of randomized treatments for the 
duration of the study, regardless of actual compliance. 
Analysis of the Efficacy Estimand will be conducted using the mITT analysis set 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. 
Attributable Estimand
The Attributable Estimand, the second estimand of interest, is defined as the effect of treatment 
in subjects attributable to the randomized treatment. For this estimand, discontinuation of 
randomized treatment for reasons of tolerability or lack of efficacy is considered a bad outcome. 
Analysis of the Attributable Estimand will be conducted in the mITT analysis set, but data that 
are missing due to treatment discontinuation will be imputed based on the 95th or the 5th
percentile of the reference arm’s distribution if the reason is reasonably attributable to 
tolerability or lack of efficacy. The 95th percentile would apply to an endpoint for which a higher 
value is a worse outcome, while the 5th percentile would apply to an endpoint for which a higher 
value is a better outcome. For this purpose, the Placebo MDI treatment arm is considered the 
reference arm. 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 Appendix 6 of this SAP.
Treatment discontinuations reasonably attributable to tolerability or lack of efficacy will be 
identified during the blinded data review meeting (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 


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the remaining discontinuation categories, where specific reasons or criteria frequently need to be 
considered, decisions will be made and documented at the BDRM.
Treatment Policy Estimand
The Treatment Policy Estimand, the third estimand of interest, is defined as the effect of 
randomized treatment over the study period regardless of whether randomized treatment is 
continued. 
Analysis of the Treatment Policy Estimand will be conducted in the ITT analysis set, in which all 
observed data will be utilized regardless of whether subjects remain on randomized treatment.
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.


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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.
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.
On-treatment Asthma 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 Sets
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 group who 
received the study treatment, who were not treated, who completed treatment through Week 24, 
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, 
ITT, Safety, and Holter Monitoring analysis sets will also be tabulated (Table 1.1.1). Informed 
consent/assent (yes or no) and study day of informed consent/assent is listed in Listing 2.1.
The number of subjects randomized and in the analysis sets will be provided by center, and 
treatment in Table 1.1.2. The number of subjects randomized by stratification factor will be 
tabulated (Table 1.1.4), including baseline percent predicted FEV1 (≤60% or >60%), reversibility 
to ipratropium (<12% or <200 mL vs ≥12% and ≥200 mL improvement in FEV1), and by the 
ICS included in their fixed-dose ICS/LABA combination product (budesonide, mometasone 
furoate, fluticasone furoate, or fluticasone propionate). The stratification factors will be based on 
the actual data rather than on IWRS values. If there are any subjects who took study treatment 


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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 1.6).
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, Safety, and Holter Monitoring 
analysis sets will be listed (Listing 1.5) for all subjects randomized. Reasons for premature 
discontinuation from study treatment will be summarized for the Safety Analysis Set (Table 
1.2.1). Similarly, reasons for subjects’ withdrawal from the study will be summarized for the ITT 
Analysis Set (Table 1.2.2).
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 attributable status for premature discontinuation from the study will be tabulated by 
treatment for the mITT Analysis Set (Table 1.2.5).
A Per Protocol population is not defined in this study. However, important protocol deviations 
will be identified according to the sPDP and blinded data review meeting (BDRM) process. 
These deviations will be summarized (Table 1.3.1) and listed (Listing 1.7).
A listing of subjects who did not comply with restrictions on illicit drugs or drugs of abuse, use 
of rescue medication, and xanthine-containing products 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).
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
Subject demographics, use of inhaled corticosteroids (ICSs)/long-acting β2-agonists (LABAs) 
and the use of tiotropium (at least 4 weeks prior) at Screening, and smoking status/history will be 
summarized for the mITT, Safety and Holter Monitoring Analysis Sets and for Non-Randomized 
subjects (Tables 1.4.1 through 1.4.4, respectively, and Listing 1.2). The ITT analysis set does not 
need to be tabulated because it is the same as the mITT analysis set for demographics and 
baseline characteristics. If the Safety Analysis Set has the same treatment assignment as the 
mITT, then these summaries will be identical as well and hence not produced.


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Demographic and baseline characteristic variables summarized will include the following:
x
Age
x
Age Group (12 to <18, and 18 to 80 years)
x
Age of onset of Asthma
x
Gender
x
Race
x
Ethnicity (Hispanic or Non-Hispanic)
x
PEFR stability limit at Visit 4
x
ICS/LABA + tiotropium use (at least 4 weeks prior) at Screening (by the ICS type and use of 
tiotropium, Yes vs. No)
x
GINA Classification (Steps 3 and 4/5, per GINA)
x
ACQ-5 at Visit 2 (continuous and <1.5, ≥1.5, ≥2, ≥3, ≥4, ≥5)
x
Baseline eosinophil count, calculated as the average of Visit 1 and Visit 4 values (<300 cells 
per mm3 vs.  ≥300 cells per mm3)
x
Number of severe asthma exacerbations in the 12 months prior to Visit 1 (Group as 0, 1 and 
≥2)
x
Baseline FENO (continuous and <40 ppb vs. ≥40 ppb)
x
T-helper Cell Type 2 Status (Low: FENO < 40 ppb AND Baseline eosinophil count < 300 
cells per mm3; High (1): FENO ≥ 40 ppb OR Baseline eosinophil count ≥ 300 cells per mm3;
High (2): FENO ≥ 40 ppb AND Baseline eosinophil count ≥ 300 cells per mm3)
x
Smoking status (former smoker vs. non-smoker)
x
Number of years smoked
x
Average number of cigarettes smoked per day
x
Number of pack years smoked, calculated as (number of cigarettes per day/20) x number of 
years smoked
x
Weight
x
Height
x
Body mass index (BMI)
For this study, GINA classification will be determined by the total daily dose of ICS used at 
study entry and use of a concurrent LABA and/or tiotropium. Table 5-1 of the protocol provides 
the permissible ranges of ICS total daily doses. It is anticipated that all subjects will fall into 
GINA 3, 4, or 5.  The table below presents how subjects will be categorized into GINA 
classifications. To account for subjects randomized in error, the table includes ICS doses that fall 
outside what is permissible in this study and definitions for GINA 1 and 2.


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Table 1
GINA Classification of Asthma Treatment
Drug at Study Entry
GINA Classification
1
2
3
4 and 5
Controller Regimen
None
Low dose 
ICS
Low dose 
ICS/LABA
Med/high dose 
ICS/LABA
Tiotropium
ICS (μg/day)
Budesonide
Fluticasone Furoate
Fluticasone
Propionate
Mometasone
Furoate
0
0
0
0
200-400
100-199
100-250
110-220
200-400
100-199
100-250
110-220
>400
≥200
>250
>220
LABA
No
No
Yes
Yes
Tiotropium*
No
No
No
Yes or No
* Tiotropium is the only LAMA permitted in the study. Doses for MDIs are ex-valve doses.
Unusual combination therapies not included in the above table will be adjudicated on a case-by-
case basis prior to database lock.
Asthma History, Screening/Baseline Spirometry, and Reversibility
Duration of asthma, the number of years prior to the start of study medication that asthma was 
first diagnosed (calculated as [Date of First Dose of Study treatment in the study – Date Asthma 
First Diagnosed] /365.25), will be summarized by treatment and all subjects for the mITT and 
Safety Analysis Sets and listed (Tables 1.5.1, 1.5.2 and Listing 4.1). A summary for the Safety 
Analysis Set will only be performed if the Safety Analysis Set is different from the mITT/ITT 
Analysis Set. Asthma control (GINA classifications) (GINA2018) will also be included in these 
summaries. History of severe asthma exacerbations will be listed (Listing 4.2).
Descriptive statistics will be provided for Screening period pre-bronchodilator and 
post-bronchodilator and baseline spirometry parameters (Table 1.6.1 and Listing 2.2) for the 
mITT analysis set. Spirometry data will be listed (Listing 6.2).
Characterization of Reversibility:
Reversibility to albuterol (Ventolin HFA) will be evaluated at either Visit 1 or Visit 2. 
Reversibility to ipratropium (Atrovent HFA) will be evaluated at Visit 3 and used as a 
stratification variable at randomization to ensure an even distribution of reversibility across the 
treatment arms.


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Reversibility will be a comparison of the average of all best FEV1 efforts obtained at -60 min and 
-30 min pre-bronchodilator to the best FEV1 effort obtained at 30 minutes post-bronchodilator. 
However, if the subject fails the reversibility criteria at 30 minutes post-dose, any other available 
post-dose timepoint will be used instead to determine if reversibility was achieved. A subject is 
considered reversible to albuterol if the improvement in FEV1 at 30 minutes (or up to 60 
minutes) is ≥ 12% and ≥ 200 mL. A subject is considered reversible to ipratropium if the 
improvement in FEV1 at 30 minutes is ≥ 12% and ≥ 200 mL.
Reversibility to albuterol at Screening Visits 1 or 2, with the latest value collected, will be 
summarized for the mITT Analysis Set and listed (Table 1.7.1, Listing 2.2 and Listing 5.2 for 
Ventolin HFA dispensing). Reversibility to ipratropium at Screening Visit 3 based on actual data 
will be summarized for the mITT Analysis Set and listed (Table 1.7.2, Listing 2.2 and Listing 5.2 
for Atrovent 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.
Additionally, the number and percentage of subjects meeting each of the following response 
criteria will be summarized for Ventolin HFA and Atrovent HFA bronchodilators:
x
≥12% improvement post-bronchodilator in FEV1 from pre-bronchodilator
x
≥15% improvement post-bronchodilator in FEV1 from pre-bronchodilator
x
≥200 mL improvement post-bronchodilator in FEV1 from pre-bronchodilator
Asthma Exacerbation, Medical and Surgical History at Screening, Reproductive 
Status and Pregnancy Testing
Severe asthma exacerbation history in the 12 months prior to Screening will be summarized for 
the Safety Analysis Set and listed for all randomization subjects (Table 1.8.1 and Listing 4.2).
Medical and Surgical History at Screening will be summarized for the Safety Analysis Set and 
listed for all randomized subjects (Table 1.8.2 and Listing 4.3).
Reproductive Status and Pregnancy Testing Results will be listed (Listing 4.4).
Prior, Concomitant, and Post-Treatment Medications/Treatments
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 
 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: 
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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 any 
time between the date of first study treatment and the date that is one day before the date of 
discontinuation from or completion of study medication. Any medication that was used at any 
time on or after the day of treatment completion or treatment discontinuation 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.
Concomitant asthma, asthma-exacerbation, and non-asthma related medications/treatments will 
be summarized by preferred term and actual treatment received for the Safety Analysis Set 
(Tables 1.10.1 to 1.10.3). Asthma-related concomitant medication summaries will not include the 
asthma-exacerbation medications. Prior, concomitant/post-treatment asthma, asthma-
exacerbation, and non-asthma medications will be displayed in separate listings (Listings 4.5 to 
4.7, respectively).
Reported prior medications for asthma, asthma-exacerbation, and non-asthma-related 
medications will be tabulated for the Safety Analysis Set (Tables 1.9.1, 1.9.3 to 1.9.4) and listed 
separately (Listings 4.5 to 4.7, respectively).
Prior asthma medications will be tabulated (for the Safety Analysis Set) 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 1.9.2). 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.
Reported post-treatment medications for asthma, asthma-exacerbation, and non-asthma-related 
medications will be tabulated for the Safety Analysis Set (Tables 1.10.4, 1.10.6-1.10.7) and listed 
separately (Listings 4.5-4.7, respectively). 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 1.10.5).
Extent of Exposure to Study Medication and Compliance
Subject’s exposure to a study treatment will be determined by the duration of time (days) for 
which the doses were administered, defined as “([End date of treatment – Date of first dose of 


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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.
For the blinded MDI treatments, 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. For Spiriva Respimat, the expected 
number of puffs of study medication will be 2.
The number of days of exposure to study treatment will be summarized for each treatment for the 
Safety Analysis Set. 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 1.11). 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 9.4).
6.4
Efficacy Analyses
Three estimands of interest are defined for this study: efficacy estimand, attributable estimand, 
and treatment policy estimand. They have been introduced in Section 5.3.
There are three primary pairwise comparisons of treatments of interest, namely, GP MDI (3 
doses: 28.8 μg, 14.4 μg and 7.2 μg) vs. Placebo MDI. Comparisons of GP MDI to Spiriva 
Respimat will be focused on estimation as the study is not formally powered to demonstrate non-
inferiority or superiority. Estimation results will be provided by randomized treatment and for 
each treatment difference for all comparisons, in each estimand, and will be available in the post-
text tables.
Baselines and Baseline Covariates for Analysis
The mean of all evaluable 60- and 30-minute pre-dose spirometry assessments conducted at 
Day 1 (Visit 4) will be used to establish baseline for FEV1 AUC0-4, trough and peak.
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 morning and evening PEFR. The PEFR stability limit at Visit 4 will be 
calculated as the average of the available morning PEFR eDiary recordings during at least 4 of the 
last 7 days before Visit 4 (i.e., the baseline PEFR), multiplied by 0.8.


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For severe asthma exacerbation history in the past 12 months before Visit 1, baseline is the 
number of severe asthma exacerbations reported on the History of Asthma Exacerbation CRF 
page. It will be grouped as 0 and ≥1 exacerbations for the purpose of modeling.
Identification of the fixed combinations of ICS/LABA taken within 4 weeks prior to Visit 1 will 
be based on a medical review of entries in the Prior and Concomitant Medications CRF page.
The type of ICS in the fixed combination of ICS/LABA that the subject is taking prior to Visit 1 
will be a covariate (budesonide, mometasone furoate, fluticasone furoate, or fluticasone 
propionate).
Baseline blood eosinophil count is the average of non-missing blood eosinophil count values at 
Visit 1 and Visit 4.
Baseline age is the age in years at the time of Informed Consent/Assent.
Baseline post-albuterol FEV1 is the highest available value of FEV1 obtained after dosing with 
albuterol (Ventolin HFA) at Visit 2 if reversibility to albuterol was performed at Visit 2; 
otherwise, it is the highest value of FEV1 obtained after dosing with albuterol at Visit 1. Baseline
percent reversibility to albuterol 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 albuterol at Visit 2 (or 
Visit 1), and POST is the post-albuterol FEV1 value defined above. 
Baseline post-ipratropium FEV1 is the highest available value of FEV1 obtained after dosing with 
ipratropium (Atrovent HFA) at Visit 3. Baseline percent reversibility to ipratropium 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 ipratropium at Visit 3, and POST is the post-ipratropium FEV1 value 
defined above.
Baseline for the ACQ and AQLQ+12 questionnaire scores is the last available result at Visit 4.
For ACQ, if there is no result at Visit 4, then the result at Visit 2 is used as the baseline.
Baseline FENO is defined taking into account the FENO testing procedures, which are outlined in 
protocol Appendix 11. Two valid, reproducible FENO measurements are required in order for the
FENO test to be considered complete. The test is considered reproducible if ANY of these 
conditions is met:
x
Either or both of 2 valid FENO measurements is < 30 ppb and the measurements are within 2 
ppb of each other.
x
Both measurements are > 30 ppb and within 10% of each other.
x
Both values are below or above the measurement range (5-300 ppb). 
If the reproducibility criteria are met within the first 2 exhalations, baseline FENO is defined the
average of these 2 measurements. Otherwise, the participant has up to 2 additional exhalations to 
satisfy the reproducibility criteria (up to a total of 4 trials). Any pair of the completed attempts 


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can be assessed for reproducibility. If successful, the baseline is defined as the average of the last
2 reproducible measurements. For example, if attempts 1 and 2 do not meet reproducibility 
conditions, attempt 3 is performed. If pairs (1,3) and (2,3) both satisfy reproducibility, the pair 
(2,3) will be used to derive the baseline. If the reproducibility criteria are still not met for any 
pair of attempts after taking 4 measurements at Visit 4, then FENO measurements at Visit 2 will 
be considered, using the same rules. If no reproducible pair exists either at Visit 4 or Visit 2, 
baseline FENO will be missing.
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.
As of protocol amendment v4.0, post-dose spirometry data are no longer collected at Week 4 
(Visit 5). Any data available at Week 4 will be assigned to the corresponding analysis week 
(Week 4) in the analysis dataset.
Although no efficacy analysis based on time points were planned for spirometry, the change 
from baseline in PFT assessments will be allocated to derived nominal collection time windows 
using the time intervals specified below. This derivation is consistent with other Pearl studies. It 
will in particular ensure that no post-dose assessments are used in the calculation of trough, and 
no assessments later than 5 hours post-dose are used in the calculation of AUC0-4 and peak.
Table 2
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 15 min.
>0 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 
Note: The minutes are rounded to the nearest whole number before applying time windows.
Asthma Exacerbations
The definitions of mild, moderate, and severe asthma exacerbations to be used in this study are 
shown below. These definitions are based on the ATS/ERS Statement “Asthma Control and 
Exacerbations, Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice” (Reddel
2009).
Exacerbations will be considered severe if they result in:


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x
Use of systemic corticosteroids (tablets, suspension or injection) for at least 3 days or 
x
A hospitalization or ER visit because of asthma or
x
Death due to asthma
Exacerbations will be considered moderate if they result in: 
x
A deterioration of asthma requiring a new or increased dose of ICS for at least 3 days.
Deterioration of asthma is defined by the occurrence of 1 or more of the following for ≥ 2 
consecutive days:
o
PEFR: a decline of ≥ 20% from baseline
o
Rescue albuterol use: >4 puffs/day and ≥ 2 x baseline
o
Symptoms: nighttime score that is > baseline and ≥ 2 or a daytime score that is > baseline 
and ≥ 3
Exacerbations will be considered mild if they result in: 
x
A deterioration of asthma (as defined above)
o
Not requiring treatment or
o
Requiring treatment with a systemic corticosteroid or a new or increased dose of ICS for 
< 3 days
The conditions for moderate and severe asthma exacerbations will be captured in the eCRF. Mild 
exacerbations will be captured programmatically using data from the eDiary (Listing 6.1.4).
Additionally, the investigator may identify certain events (recorded on the same CRF page) 
which don’t entirely meet the criteria above as exacerbations (for example, in the judgment of 
the investigator, severe symptoms lasting less than 2 days but requiring systemic steroids); the 
justifications supporting the investigator’s judgment will be recorded on the same eCRF page.
For a severe asthma exacerbation, the start date is defined as the start date of prescribed 
treatment with a systemic corticosteroid or the date of ER visit or hospitalization for asthma or 
the date of death due to asthma. The stop date is defined as the last day on which systemic 
corticosteroids were used, or the discharge date from the ER or hospital for asthma, whichever is 
later.
For a moderate asthma exacerbation, the start date is defined as the first day of the increased 
dose of ICS or new ICS treatment (for example, adding inhaled budesonide). The end date is 
defined as the last day of this treatment. For moderate exacerbations that are longer than 14 days, 
a review will be done during the BDRM to confirm if this duration is justified. This review may 
result in a programmatic adjustment to the duration of the event.
For a mild asthma exacerbation, the start date is defined as the first day of 2 consecutive days of 
deterioration and the end date is defined as the first day the subject no longer meets the 


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deterioration criteria OR the last day of treatment, whichever is later. Treatment must be for less 
than 3 days to meet the criteria for a mild exacerbation.
There are three groups of asthma exacerbation severity analyzed in this study: severe, 
moderate/severe, and any severity.
For the severe and moderate/severe groups, in order to ensure that the same event is not counted 
twice, consecutive exacerbations with start and stop dates ≤7 days apart will be considered to be the 
same event of the highest severity. Any days of asthma deterioration where new or increased ICS or 
systemic CS were given, but which were not part of a moderate/severe event, will also be considered 
for this merger. Note: This means that if a mild asthma exacerbation required treatment with a 
systemic corticosteroid or a new or increased dose of ICS for < 3 days, then those days 
under treatment will be merged into an exacerbation of worse severity if they occurred ≤7 
days from another exacerbation. In the case where two mild events are within 7 days of each 
other, where ICS or systemic steroid treatment is required for each event, the merged event 
will be categorized as a moderate or severe event. Asthma 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.
Similarly, for asthma exacerbations of any severity, consecutive exacerbations with start and stop 
dates ≤7 days apart will be considered to be the same event.
For the efficacy estimand, the time at risk is defined for each severity group as time from the 
date of first dose until the last dosing date, minus the time during or within 7 days after all 
exacerbations from the given severity group. However, the start day of an asthma exacerbation 
will not be subtracted from the time at risk. Any days subsequent to the date of discontinuation 
from or completion of treatment will not be subtracted.
For the attributable estimand, the time at risk is defined as time from the date of first dose until 
the treatment completion date (for subjects who have completed treatment) or 24 weeks after the 
date of first dose (for subjects who have not completed treatment), minus the time during or 
within 7 days after all observed exacerbations from the given severity group. However, the start 
day of an asthma exacerbation will not be subtracted from the time at risk. For subjects who 
completed treatment, any days subsequent to the date of completion of treatment will not be 
subtracted. For subjects who discontinued treatment, all time between treatment discontinuation 
and 24 weeks after the date of first dose will be included into the time at risk.
For the treatment policy estimand, time at risk is defined as follow-up time up to the last 
recorded date (of any assessment or contact) for the subject (including telephone contact), minus 
the time during or within 7 days after all observed exacerbations from the given severity group.
However, the start day of an asthma exacerbation will not be subtracted from the time at risk. 
Any days subsequent to the date of completion of study will not be subtracted.
It is noted that the time at risk will be different for each severity.


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Analyses will be conducted on the efficacy estimand, on the attributable estimand, and on the 
treatment policy estimand. The primary analyses of the efficacy and treatment policy estimands 
will use only observed data. The attributable estimand will use the mITT Analysis Set but then 
impute missing data as described in Section 5.3.
Primary Efficacy Analysis
Analyses for the primary endpoint are presented in this section.
FEV1 AUC0-4
FEV1 AUC0-4 at Week 24 is the primary efficacy endpoint. FEV1 AUC0-4 at the other visits and 
over 24 weeks are “Other” endpoints.
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 computation of FEV1 AUC0-4 after the discontinuation of study treatment will be based on 
the actual time of administration of asthma maintenance medication if known and applicable or 
otherwise using the nominal time points (e.g., 1 hr pre-dose, 30 min pre-dose, 15 min post-dose, 
30 min post-dose, 1 hr post-dose, 2 hr post-dose, and 4 hr post-dose). The 1 hr pre-dose time 
point would be used as time zero for the computation of the AUC if the time of asthma 
maintenance medication is unknown.
The differences in change from baseline between treatment groups in FEV1 AUC0-4 at Week 24, 
over 24 weeks, and at each post-randomization visit will be evaluated using a linear repeated 
measures analysis of covariance (ANCOVA) model. The model will include treatment, visit, 
background ICS/LABA, and treatment by visit interaction as categorical covariates and baseline 
FEV1, percent reversibility to ipratropium, and logarithm of baseline blood eosinophil count as 
continuous covariates. An unstructured (UN) matrix will be used to model the variance-
covariance structure. 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.
Two-sided p-values and point estimates with two-sided 95% confidence intervals (CIs) will be 
produced for each treatment difference (Tables and Figures 2.1.1 to 2.1.3 for the efficacy 
estimand, attributable estimand, and treatment policy estimand, respectively).
For the attributable estimand of FEV1 AUC0-4, data that are missing due to treatment 
discontinuation will be imputed as described in Section 5.3.2. Imputation for missing values 
classified as “attributable” will use mean changes from baseline based on the 5th percentile of the 


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Placebo MDI arm’s distribution. The analysis of this endpoint with the attributable estimand is 
considered secondary.
Individual data will be listed (Listing 6.2).
Assumptions Checks and Possible Removal of Outliers 
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 to the CSR.
The assumption of normality for FEV1 AUC0-4 data will be checked by visually inspecting the 
distribution of the residuals. Also, model fit and the assumption of homogeneity of variance 
among treatments will be verified by inspection of scatter plots of predicted vs. residuals, 
residuals vs. treatment, residuals vs. screening ICS/LABA use, and by box plots of residuals for 
model variables with a potential effect on variance (treatment, visit, and ICS/LABA 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). If appropriate, the 
linear repeated measures model analysis may be conducted by allowing for heterogeneity of 
variance between treatments and ICS/LABA use categories. Note that the unstructured 
covariance structure allows for heterogeneity among the visits.
Further assumption checks are described in Appendix 6 to this SAP.
Secondary Efficacy Analysis
Similar to the primary efficacy analysis, the secondary efficacy analyses will be conducted for 
the efficacy estimand. Analyses will also be conducted for the attributable and treatment policy 
estimands.
Change from Baseline in Morning Pre-Dose Trough FEV1
Change from baseline in morning pre-dose trough FEV1 at Week 24 is a secondary endpoint. 
Change from baseline in morning pre-dose trough FEV1 at the other visits and over 24 weeks are 
“Other” endpoints.


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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. Baseline is defined in Section 6.4.1. In 
subjects missing one 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.
The 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, background 
ICS/LABA, and treatment by visit interaction as categorical covariates and baseline FEV1,
percent reversibility to ipratropium, and logarithm of baseline blood eosinophil count as 
continuous covariates. An unstructured (UN) matrix will be used to model the variance-
covariance structure. 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 24 
Weeks, and at each post-randomization visit. 
Two-sided p-values and point estimates with two-sided 95% confidence intervals (CIs) will be 
produced for each treatment difference (Tables and Figures 2.2.1 to 2.2.3 for the efficacy 
estimand, attributable estimand, and treatment policy estimand, respectively).
For the attributable estimand of change from baseline in morning pre-dose trough FEV1, data 
that are missing due to treatment discontinuation will be imputed as described in Section 5.3.2.
Imputation for missing values classified as “attributable” will use mean changes from baseline 
based on the 5th percentile of the Placebo MDI arm’s distribution.
Rate of Moderate/Severe Asthma Exacerbations
Only on-treatment exacerbations will be included for the analysis of rate of moderate/severe
asthma exacerbations for the efficacy estimand (see Section 6.1). 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 arm’s (Placebo 
MDI) 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 estimate for Placebo MDI 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 or missing completely at random. Further information about 
the computation of the attributable estimand is described in Appendix 6 to this SAP.
The rate of moderate/severe asthma exacerbations will be analyzed using negative binomial 
regression as implemented in SAS PROC GENMOD. Treatments will be compared adjusting for 
baseline post-albuterol FEV1 percent predicted, percent reversibility to ipratropium and logarithm 
of baseline blood eosinophil count as continuous covariates and baseline severe asthma 


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exacerbation history, and background ICS/LABA as categorical covariates. Time at risk of 
experiencing an exacerbation will be used as an offset variable in the model.
Moderate/severe asthma exacerbation data will be listed (Listing 6.1.3). For exacerbations that 
were identified apart from an eDiary alert, the symptom information will be listed.
The number of moderate/severe exacerbations and the percentage of subjects who experience 
exacerbations, observed and adjusted exacerbation rates, and rate ratios comparing treatments 
will be summarized for the efficacy estimand (Table 2.3.1) and treatment policy estimand (Table 
2.3.3); only adjusted rates and rate ratios will be presented for the attributable estimand (Table 
2.3.2).
Follow-up time at risk for moderate/severe asthma exacerbations will be summarized for the 
efficacy estimand (Table 2.3.1a) and treatment policy estimand (Table 2.3.3a).
Change from Baseline in ACQ-7, ACQ-5, and AQLQ+12
Change from baseline in ACQ-7, ACQ-5 and AQLQ +12 scores at Week 24 are secondary 
endpoints. Change from baseline in ACQ-7, ACQ-5 and AQLQ +12 scores at the other visits and 
over 24 weeks are “Other” endpoints. ACQ-6 at all visits and over 24 weeks is an “Other” 
endpoint.
The Asthma Control Questionnaire (ACQ), comprising 7 questions, is completed in the clinic 
and requires subjects to recall their experiences during the previous week (7 days) prior to the 
study visit. The ACQ-5, -6, and -7 are each calculated from the ACQ with each using a different 
subset of questions (questions 1-5, 1-6, and 1-7, respectively). All three instruments have been 
validated. The ACQ-5 measures 5 symptoms (woken at night by symptoms, wake in the morning 
with symptoms, limitation of daily activities, shortness of breath, and wheeze); the ACQ-6 is 
these symptom measurements plus daily rescue medication use as recalled by the subject; and the 
ACQ-7 is the ACQ-6 plus airway caliber as measured by pre-bronchodilator FEV1 percent 
predicted. Each question is scored on a 7-point scale (generally, 0=no impairment, 6=maximum 
impairment), the questions are equally weighted, and the ACQ score is the mean of the item 
responses and therefore ranges from 0 (totally controlled) to 6 (severely uncontrolled).
The Asthma Quality of Life Questionnaire (AQLQ +12) is a 32-item validated subject-
administered questionnaire. 32 questions in the AQLQ +12 are in 4 domains (symptoms, activity 
limitation, emotional function, and environmental stimuli). All 4 domains contain standard 
specific questions relating to each domain. Subjects are asked to think about how they have been 
during the previous 2 weeks and to respond to each of the 32 questions on a 7-point scale (7=no 
impairment to 1=severe impairment). The overall AQLQ +12 score is the mean of all 32 
responses, and the individual domain scores are the means of the items in those domains.
No imputation is planned for missing individual questionnaire items. Missing items will result in 
missing ACQ or AQLQ +12 score values for the visit.


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Change from baseline in ACQ-7, ACQ-5, and AQLQ +12 will be analyzed using a linear 
repeated measures ANCOVA model. The model will include treatment, visit, background 
ICS/LABA, and treatment-by-visit interaction as categorical covariates and baseline post-
albuterol FEV1 percent predicted, baseline score for the patient-reported outcome instrument, 
percent reversibility to ipratropium, and logarithm of baseline blood eosinophil count 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. 
Contrasts will be used to obtain estimates of the treatment differences at Week 24, over 24 
Weeks, and at each post-randomization visit. Two-sided p-values and point estimates with 2-
sided 95% confidence intervals will be produced for each treatment difference (Tables and 
Figures 2.4.1-2.4.3 for ACQ-7, 2.5.1-2.5.3 for ACQ-5, 2.7.1-2.7.3 for AQLQ+12) for the 
efficacy, attributable, and treatment policy estimands.
For the attributable estimand of change from baseline in ACQ and AQLQ +12 scores, data that 
are missing due to treatment discontinuation will be imputed as described in Section 5.3.2.
Imputation for missing values classified as “attributable” will use mean changes from baseline 
based on the 95th percentile of the Placebo MDI arm’s distribution for ACQ scores, and on the 5th
percentile for AQLQ +12 score.
Individual responses will be listed (Listing 6.1.5 for ACQ-5, ACQ-6 and ACQ-7, 6.1.6 for 
AQLQ+12, and 6.1.7 for AQLQ+12 Domain Scores).
Other Efficacy Analysis
Other efficacy analyses will be conducted for the efficacy estimand only.
Percentage of Responders in ACQ-5, ACQ-6, ACQ-7, and AQLQ+12
The ACQ and AQLQ +12 instruments were introduced in Section 6.4.5.
Responder analyses will be performed for ACQ-5, ACQ-6, ACQ-7, and AQLQ +12 at Week 24,
over 24 Weeks, and at each post-randomization visit. Responders are defined as subjects with an 
improvement of ≥0.5 points over baseline (decrease in ACQ scores, increase in AQLQ +12 
score). Subjects who discontinue treatment for any reason will be classified as non-responders. 
Subjects who have a missing result at Week 24 will also be classified as non-responders for that 
endpoint at Week 24.
Logistic regression will be used to compare the treatment groups with treatment and background 
ICS/LABA as categorical covariates and baseline instrument score, logarithm of baseline blood 
eosinophil count, percent reversibility to ipratropium, and baseline post-albuterol FEV1 percent 
predicted as continuous covariates. P-values and odds ratios with 95% confidence intervals will 
be produced for each treatment comparison (Table 2.4.4 for ACQ-7, 2.5.4 for ACQ-5, 2.7.4 for
AQLQ+12, and Table 2.6.2 for ACQ-6).


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Change from Baseline in ACQ-6
The ACQ instrument was introduced in Section 6.4.5, with ACQ-6 being one of the associated 
scores.
Change from baseline in ACQ-6 will be analyzed using a linear repeated measures ANCOVA 
model. The model will include treatment, visit, background ICS/LABA, and treatment-by-visit
interaction as categorical covariates and baseline post-albuterol FEV1 percent predicted, baseline 
score for the patient-reported outcome instrument, percent reversibility to ipratropium, and 
logarithm of baseline blood eosinophil count as continuous covariates. Contrasts will be used to 
obtain estimates of the treatment differences at Week 24, Over 24 weeks, and at each post-
randomization visit. Two-sided p-values and point estimates with 2-sided 95% confidence 
intervals will be produced for each treatment difference (Table and Figure 2.6.1).
Rate of Asthma Exacerbations
The rates of severe asthma exacerbations and asthma exacerbations of any severity over the 
treatment period are “Other” endpoints. For details on the collection and operational definition of
these events, and calculation of the time at risk, refer to Section 6.4.3.
The number and percentage of subjects with asthma exacerbations in each treatment group will 
be tabulated.
The rate of severe asthma exacerbations and asthma exacerbations of any severity will each be 
analyzed in the same way as the rate of moderate/severe asthma exacerbations. Treatments will 
be compared adjusting for baseline post-albuterol FEV1 percent predicted, percent reversibility to 
ipratropium and logarithm of baseline blood eosinophil count as continuous covariates and 
baseline severe asthma exacerbation history, and background ICS/LABA as categorical 
covariates. Time at risk of experiencing an exacerbation will be used as an offset variable in the 
model.
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 severe exacerbations (Table 2.3.4), and for exacerbations of any severity (Table 
2.3.5).
Follow-up time at risk will be summarized and displayed graphically for the efficacy estimand 
for severe exacerbations (Table 2.3.4a), and for exacerbations of any severity (Table 2.3.5a).
Time to First Moderate/Severe Asthma Exacerbation, Severe Asthma Exacerbation, or 
Asthma Exacerbation of Any Severity
Time to first moderate/severe asthma exacerbation is the time from the first dose of study 
medication to the time of onset of the first moderate/severe asthma exacerbation. Time to first 
severe asthma exacerbation and time to first asthma exacerbation of any severity are defined 
similarly.


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Only on-treatment exacerbations will be included for calculating the time to first asthma 
exacerbation for the efficacy estimand (see Section 6.1).
The time to first asthma 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 
severe asthma exacerbation history and background ICS/LABA as categorical covariates, and 
percent reversibility to ipratropium, logarithm of baseline blood eosinophil count, and baseline 
post-albuterol FEV1 percent predicted as continuous covariates. 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 2.3.6 to 2.3.8
for moderate/severe, severe, and any severity exacerbations). 
Time to first asthma exacerbation will also be displayed graphically for each treatment using 
Kaplan-Meier curves (Figures 2.3.6 to 2.3.8 for moderate/severe, severe, and any severity 
exacerbations). Subjects who complete the study (and the study treatment) and do not experience 
an asthma exacerbation over the treatment period will be censored at the Week 24 visit. Subjects 
who do not experience an asthma exacerbation and discontinue treatment early will be censored 
at the date of treatment discontinuation.
Peak Change from Baseline in FEV1
The differences in peak change from baseline in FEV1 within 4 hours post-dosing at Week 24, 
over 24 weeks, and at each post-randomization visit will be evaluated using a linear repeated 
measures analysis of covariance (ANCOVA) model. The model will include treatment, visit,
background ICS/LABA, and treatment by visit interaction as categorical covariates and baseline 
FEV1, percent reversibility to ipratropium, and logarithm of baseline blood eosinophil count as 
continuous covariates. An unstructured (UN) matrix will be used to model the variance-
covariance structure. 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.
Two-sided p-values and point estimates with two-sided 95% confidence intervals (CIs) will be 
produced for each treatment difference (Table and Figure 2.8.1) for the efficacy estimand.
Percentage of Symptom-Free Days, Rescue-Free Days, and Asthma Control Days
The percentages of symptom-free days, rescue-free days, and asthma control days over the 
treatment period are “Other” endpoints.
To calculate these percentages, the treatment period will be divided into 4-week intervals, as 
presented in Table 3. For each interval, the denominator will be the number of eDiary days in the 
interval, satisfying both conditions:
x
The day is before or on the day of completion or discontinuation of study treatment
x
eDiary data was collected on this day


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The numerator will be the number of days contributing to the denominator, and also meeting the 
specific endpoint criteria: no symptoms (symptom-free days), no rescue medication use (rescue-
free days), or no rescue medication use or symptoms (asthma control days).
If the treatment period extends beyond Day 168, the data from the days after Day 168 will not 
contribute to the calculation of these endpoints.
The percentages of symptom-free days, rescue-free days, and asthma control days will each be 
analyzed over the entire Treatment Period. Additionally, analyses will be conducted over each 4-
week interval in the study. An ANCOVA model will be used with treatment, the number of the 
relevant 4-week interval (interval 1 to 6), baseline severe asthma exacerbation history, 
background ICS/LABA, and the treatment-by-4-week interval interaction as categorical 
covariates. Baseline percentage of endpoint days (where endpoint is symptom free, rescue free, 
or asthma control per model), baseline post-albuterol FEV1 percent predicted, percent 
reversibility to ipratropium, and logarithm of baseline blood eosinophil count will be continuous 
covariates. An unstructured (UN) matrix will be used to model the variance-covariance structure. 
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 over 24 weeks.
Two-sided p-values and point estimates with two-sided 95% confidence intervals (CIs) will be 
produced for each treatment difference (Table and Figure 2.9.1 for percentage of symptom-free 
days, 2.9.2 for number of rescue-free days, and 2.9.3 for number of asthma control days) for the 
efficacy estimand.
Table 3
4-Week Intervals
Interval 
Time Period 
1
Day 1 to Day 28
2
Day 29 to Day 56
3
Day 57 to Day 84
4
Day 85 to Day 112
5
Day 113 to Day 140
6
Day 141 to Day 168
Rescue Medication Usage
The mean daily number of puffs of rescue medication use will be calculated overall and for each 
of the 4-week intervals during the Treatment Period (see Table 3). For every period of time for 
which the mean number of puffs of rescue medication 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. That is, the mean daily 
number of puffs of daytime rescue use (M_DT) will be set to the total number of daytime puffs 


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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.
A linear repeated measures ANCOVA model will be used to analyze change from baseline in 
average daily rescue albuterol use. The model will include treatment, the number of the relevant 
4-week interval (interval 1 to 6, see Table 3), baseline severe asthma exacerbation history, 
background ICS/LABA, and the treatment-by-4-week interval interaction as categorical 
covariates and logarithm of baseline blood eosinophil count, baseline daily rescue albuterol use, 
percent reversibility to ipratropium, and baseline post-albuterol FEV1 percent predicted as 
continuous covariates. 
An unstructured variance-covariance matrix will be fit. 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 24 weeks. 
Two-sided p-values and point estimates with two-sided 95% confidence intervals (CIs) will be 
produced for each treatment difference (Table and Figure 2.10.1) for the efficacy estimand.
Change from Baseline in Morning PEFR and Evening PEFR
Change from baseline in morning PEFR and evening PEFR over the treatment period are 
“Other” endpoints.
The PEFR is assessed using the Sponsor-provided PEFR meter, with the assessment data 
automatically transmitted from the PEFR to the eDiary. Subjects will complete the PEFR 
maneuver at home in the morning and in the evening before dosing with ICS/LABA (and 
ipratropium, if applicable) during the Screening Period, and in the morning and in the evening 
before dosing with study drug and ICS/LABA during the Treatment Period. In addition, PEFR 
should be measured before use of rescue albuterol.
The best (highest) of 3 PEFR efforts BID are to be captured in the eDiary. In case there is more 
than one assessment of PEFR available in the eDiary data, only the one with highest PEFR value 
will be retained for analysis (for the morning, and separately for the evening of a day). PEFR 
data with a “bad” vitalograph grade will not be used, where “Bad” is defined by the eDiary data 
vendor as unusable data. After this step, all morning and evening PEFR assessments will be 
allocated to 4-week intervals (see Table 3). Average morning and evening PEFR values will be 
calculated based on the data available within each interval.
Change from baseline in morning PEFR and evening PEFR will be analyzed using a linear 
repeated measures ANCOVA model. The model will include treatment, 4-week interval (interval 
1 to 6), background ICS/LABA, and treatment by 4-week interval interaction as categorical 
covariates and baseline PEFR (morning or evening, depending on endpoint), percent reversibility 
to ipratropium, and logarithm of baseline blood eosinophil count as continuous covariates. An 


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unstructured (UN) matrix will be used to model the variance-covariance structure. 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 over 24 weeks.
Two-sided p-values and point estimates with two-sided 95% confidence intervals (CIs) will be 
produced for each treatment difference (Table and Figure 2.11.1 for morning PEFR, and 2.11.2
for evening PEFR) for the efficacy estimand.
PEFR data will be listed (Listing 6.1.3).
FENO
Change from baseline in FENO over the treatment period and each clinic visit, percentage of 
subjects with a clinically meaningful increase in FENO from baseline, and percentage of subjects 
with a clinically meaningful decrease from baseline in FENO are “Other” endpoints.
Measurement of FENO is a noninvasive and established clinical biomarker for airway 
inflammation. Two valid, reproducible FENO measurements are required, in accordance with 
testing procedures recommended by the manufacturer and similar to those published by the 
American Thoracic Society and European Respiratory Society (American Thoracic Society, 
European Respiratory Society 2005). The test is considered reproducible if ANY of these 
conditions is met:
x
Either or both of 2 valid FENO measurements is < 30 ppb and the measurements are within 2 
ppb of each other.
x
Both measurements are > 30 ppb and within 10% of each other.
x
Both values are below or above the measurement range (5-300 ppb). 
If the reproducibility criteria are not met within the first 2 exhalations, a participant has up to 2
additional exhalations to satisfy the criteria (up to a total of 4 trials). The examinee's exhalations 
for which the device does not display a valid reading, i.e., exhalations that are either too strong 
or too weak, or any other reasons for failing to achieve a successful exhalation, will be recorded 
as attempts. Examinees may not always be able to meet the criteria for a reproducible 
measurement. The results of each attempt will be recorded in the appropriate eCRF. Any pair of 
the completed attempts can be assessed for reproducibility. If successful, the analysis value is 
defined as the average of the last 2 reproducible measurements. For example, if attempts 1 and 2 
do not meet reproducibility conditions, attempt 3 is performed. If pairs (1,3) and (2,3) both
satisfy reproducibility, the pair (2,3) will be used to derive the analysis value. If the 
reproducibility criteria are still not met, the value of FeNO will be missing.
Change from baseline in FENO will be analyzed using a linear repeated measures ANCOVA
model, similar to the one used for FEV1 AUC0-4. The model will include treatment, visit, 
background ICS/LABA, and treatment by visit interaction as categorical covariates and baseline 


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FENO, percent reversibility to ipratropium, and logarithm of baseline blood eosinophil count as 
continuous covariates. An unstructured (UN) matrix will be used to model the variance-
covariance structure. 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.
Two-sided p-values and point estimates with two-sided 95% confidence intervals (CIs) will be 
produced for each treatment difference (Table and Figure 2.12.1) for the efficacy estimand.
The percentage of subjects with clinically meaningful increases or decreases from baseline in 
FENO will be summarized descriptively by visit (Tables 2.12.2.1-2.12.2.2). The clinically 
meaningful changes are defined below:
x
A clinically meaningful increase in FENO is defined as an increase of 20% or more from 
baseline if the baseline is 50 parts per billion (ppb) or more or an increase of more than 10 
ppb from baseline if the baseline is less than 50 ppb.
x
A clinically meaningful decrease in FENO is defined as a decrease of 20% or more from 
baseline if the baseline value is 50 ppb or more or a decrease of more than 10 ppb from 
baseline if the baseline value is less than 50 ppb.
At each visit, the percentage of subjects with FENO less than 25 ppb, between 25 and less than 50 
ppb, and at least 50 ppb will be summarized descriptively by treatment (Table 2.12.2.3).
Missing FENO data will not be imputed and will not contribute to the summary statistics. 
Percentages will be calculated out of the available FENO data at each visit. FENO data will be 
listed (Listing 6.4).
CompEx
A CompEx event is defined as the first occurrence of either a diary event (clinically relevant 
asthma deterioration) or a severe asthma exacerbation (Fuhlbrigge 2017).
The definition of a diary event will consider 6 endpoints: PEFR (morning and evening), rescue 
medication use (morning and evening), and asthma symptoms (morning and evening). For each 
endpoint, the fulfilment of deterioration criteria will be calculated as follows:
Thresholds: The change from baseline is calculated, where baseline for eDiary endpoints is 
defined in Section 6.4.1. If two consecutive days fulfil the chosen threshold limit (Table 4), the 
deterioration criterion is met.
Slopes: A slope is calculated via univariate linear regression over 5 days (described further in the 
below paragraph). If the slope fulfils the chosen limit (Table 4), the deterioration criterion is met.


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Table 4
Asthma Deterioration Criteria
Variable 
Threshold 
Slope 
PEFR (AM)
PEFR (PM)
Decrease from BL ≥ 
15% for two 
consecutive days
Decrease ≥ 3% per day
Number of puffs of rescue medication (AM) 
Number of puffs of rescue medication (PM)
Increase from BL ≥ 
1.5 puffs for two 
consecutive days
Increase ≥0.3 puffs per 
day
Asthma symptoms score (Daytime)
Increase from BL ≥ 
1 unit, or absolute 
score 5 for two 
consecutive days
Increase ≥ 0.2 units per 
day
Asthma symptoms score (Nighttime)
Increase from BL ≥ 
1 unit, or absolute 
score 4 for two 
consecutive days
Increase ≥ 0.2 units per 
day
A diary event can occur when (i) the threshold deterioration criterion is met for at least two diary 
variables, or when (ii) the threshold deterioration criterion is met for one diary variable, and the 
slope criterion is fulfilled for all six variables. In case of (i), the diary event is defined to start on 
the first day of the two consecutive deterioration days (event days 0–1). Any missing data in this 
two-day window will make the event missing. In case of (ii), the event is defined to start on the 
first of the two days fulfilling the threshold criterion. This means that the slopes are calculated 
for days -4 to 0 of an event. At least two days with data are needed to calculate slopes, otherwise 
the event is considered missing. The occurrence of a diary event within a subject is defined 
as the first occasion when either (i) or (ii) above occurs.
Time to first CompEx event (i.e., a diary event or severe asthma exacerbation) will be analyzed 
with a Cox regression model to compare the treatment groups adjusted for baseline severe 
asthma exacerbation history, background ICS/LABA, percent reversibility to ipratropium, 
logarithm of baseline blood eosinophil count, and baseline post-bronchodilator FEV1 percent 
predicted. Subjects who complete the study (and the study treatment) and do not experience a 
CompEx event will be censored at their Week 24 visit. Subjects who discontinue study treatment 
will be censored at the time of treatment discontinuation.
Two-sided p-values and point estimates with two-sided 95% confidence intervals (CIs) will be 
produced for each treatment difference (Table and Figure 2.13.1) for the efficacy estimand.
Differences from Fuhlbrigge:
x
Fuhlbrigge defined baseline as “the mean over the 10 days ending just before the day of 
randomization for each of the diary variables. If no such data were available, the whole run-
in period was used, and if missing, the first 3 days after randomization were used.”  In this 


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study, baseline will be defined as the average of the non-missing values from the diary data 
collected in the last seven days of the Screening Period. This is consistent with Pearl analysis 
standards in which eDiary data are summarized as individual endpoints.
x
Fuhlbrigge developed the CompEx endpoint using a paper diary that collected asthma 
symptoms on a 4-point scale. In this study, asthma symptoms are collected in a eDiary with 
different scales for AM and PM symptoms. Daytime symptom scores are collected in the 
evening on a 6-point scale. Nighttime symptom scores are collected in the morning on a 5-
point scale. Although the scales are different, this study will retain the recommended 
thresholds and slopes for asthma symptoms score with a slight modification to account for
the different possible maximum symptoms scores. Exploration of the impact of adjusting the 
thresholds and slopes to account for the different symptom scales may be pursued as post-hoc 
analyses.
Subgroup Analyses
Subgroup analyses will be performed for FEV1 AUC0-4, change from baseline in morning pre-
dose trough FEV1, and rate of moderate/severe asthma exacerbations (efficacy estimand only). 
The following subgroups will be considered:
x
History of Severe Asthma Exacerbation in the last 12 Months:
o
None
o
One 
o
At Least Two
If there are fewer than 20% of patients in the “At Least Two” subgroup, combine “One” and “At 
Least Two” into “At Least One”.
x
Baseline Eosinophil Count:
o
<300 cells per mm3
o
≥300 cells per mm3
x
T-helper cell type 2:
o
Low (Baseline eosinophils count < 300 cells per mm3 AND baseline FENO < 40 ppb)
o
High (1) (Baseline eosinophils count ≥ 300 cells per mm3 OR baseline FENO ≥ 40 ppb)
o
High (2) (Baseline eosinophils count ≥ 300 cells per mm3 AND baseline FENO ≥ 40 ppb)
Other cut-off values for FENO in this definition will be explored (e.g. 50).
x
GINA Classification:
o
Step 3 
o
Step 4 or 5 


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x
Tiotropium Usage (Each subgroup must have ≥ 20% of study population):
o
Yes
o
No
The following subgroup analyses may also be performed in a post-hoc manner, where the cut 
point is to be determined based on the LOESS plots:
x
Baseline Eosinophil count, with a cut point different from 300 cells per mm3
x
Baseline FENO
x
T-helper cell type 2 with alternative cut points based on the LOESS plots of baseline 
eosinophils and FENO
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
4.3.5).
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 and 
4.4.1 for the efficacy estimand, for the planned and post hoc analyses, respectively).
Subgroup Cut Point Exploration
Subgroup analyses will be conducted in the baseline eosinophil count-high (≥300 cells per mm3)
and the baseline eosinophil count-low (<300 cells per mm3) subgroups. It is acknowledged 300 
cells per mm3 may not ultimately be the appropriate threshold for evaluation of treatment 
benefit. Thus, additional analyses will evaluate alternative thresholds. This exploration will use 
Locally Weighted Scatter-plot Smoothing (LOESS) models to assess the impact of baseline 
eosinophil counts on AUC0-4 FEV1 at Week 24 (Figures 4.5.1 to 4.5.10), on morning pre-dose 
trough FEV1 at Week 24 (Figures 4.6.1 to 4.6.10) and on the rate of moderate/severe asthma 
exacerbations (Figures 4.7.1 and 4.7.10). Details of constructing these LOESS curves are 
described in the Appendix 6 to this SAP.
Similarly, LOESS curves will be created to explore the cut point for the baseline FENO (Figures
4.5.11 to 4.5.20 for AUC, 4.6.11 to 4.6.20 for trough, and 4.7.11 to 4.7.20 for rate).
In addition, the cut point exploration for baseline eosinophils will be explored by general 
additive modeling (GAM) (Figures 4.8.1 to 4.8.10 for AUC, 4.9.1 to 4.9.10 for trough, and 
4.10.1 to 4.10.10 for rate). Details of performing GAM analysis are described in the Appendix 6 
to this SAP.


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Control of Type I Error
The Type I error rate will be controlled within the primary and secondary efficacy analyses. As a 
general strategy, the Type I error rate will be strongly controlled within the primary analysis. The 
Type I error rate will also be controlled within the family of secondary analyses within the GP 
MDI treatment groups. 
Primary analysis testing will be conducted in descending dose order, with the highest dose of GP 
MDI tested against placebo at the nominal alpha. Testing will continue through the GP MDI 
doses as long as the results are successful. Testing will stop if any comparison of GP MDI versus 
placebo fails to meet statistical significance. Through this strategy, the Type I error rate of the 
primary analyses of all 3 GP MDI doses versus placebo will be strictly controlled to the nominal 
alpha.
The secondary analyses for each dose of GP MDI versus placebo will proceed only if the 
primary analysis for that GP MDI dose is successful. The Type I error rate within the secondary 
analyses of each GP MDI dose versus placebo will be controlled with a combination of 
sequential testing and the Hochberg procedure.
The Type I error control strategy is displayed in the figure below:
Figure 2
Order of Hypothesis Testing for Type I Error Control


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Correlation Analysis
Pearson correlation coefficients will be generated between the primary and secondary continuous 
endpoints. The mITT Analysis Set will be used.
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 2.14.1), and also 
analyzed individually (Tables 2.14.2 to 2.14.6).
6.5
Safety Analysis
All safety analyses are based on the Safety Analysis Set. Descriptive statistics will be used for 
safety analyses. Hypothesis testing will not be performed for any safety analyses. Comparisons 
performed for Holter Monitoring endpoints will be interpreted descriptively.
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:
x
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.
x
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 period will be tabulated and listed.
Adverse Events
The version of the Medical Dictionary for Regulatory Activities (MedDRA) that is current at the 
time of database lock will be used to code verbatim terms for AEs for final analysis of the data. 
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 


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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/assent 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 Analysis Set 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 (Table 
3.1).
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.
General Summarization and Listing Strategy for Adverse Events
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 3.8.1 and Table 3.8.2.
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 3.8.1). Adverse events leading to permanent discontinuation of study 
treatment will be listed for the Safety Analysis Set (Table 3.6). A listing of any reported deaths 
during the study (prior to randomization, during the randomized-treatment period, or during the 
post- treatment discontinuation follow-up) will be provided (Table 3.12); study treatment taken 


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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:
x
The incidence of all treatment-emergent adverse events (Table 3.2.1.1)
x
The incidence of subjects with adverse events by SOC during the post- treatment 
discontinuation follow-up (Table 3.2.1.2)
x
The incidence of treatment-emergent adverse events occurring in AEs of special interest 
(Table 3.2.3)
x
The incidence of non-serious treatment-emergent adverse events occurring in ≥5% of 
subjects in a treatment (Table 3.2.4)
x
The incidence of all treatment-related treatment-emergent adverse events (Table 3.4)
x
The incidence of discontinuation from study treatment due to treatment-emergent adverse 
events (Table 3.5)
x
The incidence of discontinuation from study treatment due to treatment-related treatment-
emergent adverse events (Table 3.5.1)
x
The incidence of treatment-emergent serious adverse events (Tables 3.7.1)
x
The incidence of subjects with serious adverse events by SOC during the post-treatment 
discontinuation follow-up (Tables 3.7.2)
x
The incidence of all treatment-related treatment-emergent serious adverse events (Tables 3.9)
x
The incidence of all treatment-emergent adverse events by highest severity to treatment 
(Tables 3.11.1 through 3.11.5 for the five treatments)
x
The incidence of treatment-emergent adverse events occurring in at least 2% of subjects in 
any treatment (Table 3.2.2) sorted by descending frequency of events in a preferred term).
x
In addition, to control for possible differences in exposure between the treatments, the 
following AE and SAE summaries will be presented with the frequency and rate of 
occurrence (total number of events per 1000 person-years of exposure) by treatment, primary 
system organ class, and preferred term:
o
Frequency and rate of AEs (Table 3.3)


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o
Frequency and rate of SAEs (Table 3.8.3)
o
Frequency and rate of neoplasms (Tables 3.10.1 and 3.10.3 – All Cancer, 3.10.2 and
3.10.4 - Excluding Non-Melanoma Skin Cancer).
Adverse Events of Special Interest
Adverse events of special interest (AESIs) have been defined based on known effects of 
LAMAs. These include anticholinergic effects, cardiovascular effects, cerebrovascular 
conditions, ocular disorders, paradoxical bronchospasm, urinary retention, and gastrointestinal 
disorders.
Standard MedDRA queries (SMQs) will be utilized when possible, and a selection of high-level 
terms (HLTs) and preferred terms (PTs) will be utilized to represent other situations. The 
definitions of AESIs associated with LAMAs are listed in Table 5.
Table 5
Adverse Events of Special Interest
Medical Concept
Selection of MedDRA Terms
Anticholinergic effects
Anticholinergic syndrome SMQ
Dry mouth PT
Cardiovascular effects
Cardiac arrhythmias SMQ
Cardiac failure SMQ
Ischemic heart disease SMQ
Torsades de Pointe/QT prolongation SMQ
Cerebrovascular conditions
CNS haemorrhages and cerebrovascular conditions SMQ
Gastrointestinal disorders
Gastrointestinal obstruction SMQ
Ocular (disorders) effects
Visual disorders HLT  
Glaucoma SMQ
Paradoxical bronchospasm
PT Bronchospasm paradoxical
Urinary retention
Collection of PTs: urinary retention, urinary incontinence, 
pollakiuria, dysuria
Appendix 5 (which will be based on the latest version of MedDRA available at the time of 
database lock) provides detail on selection of PTs.
AESIs will be tabulated by medical concept, preferred term and treatment group (Table 3.2.3).
Paradoxical Bronchospasm
During Visits 4, 5 (if available), 7 and 10, a paradoxical bronchospasm event is defined as a 
reduction in FEV1 of >20% from baseline with associated symptoms of wheezing, shortness of 
breath, or cough that occur within 30 minutes post-dosing. Baseline is defined as the mean of the 
FEV1 values obtained 60 and 30 minutes prior to study drug and ICS/LABA administration at 
that visit. Spontaneous reporting of paradoxical bronchospasm will occur at Visits 5 (for subjects 
without post-dose spirometry), 6, 8, and 9.


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All paradoxical bronchospasm events will be captured on the AE CRF page. For those events 
that occurred during Visits 4, 5 (if available), 7 and 10, 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
Lab parameters collected include the following:
Table 6
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 
Eosinophil count
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, total 
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 10) or Treatment Discontinuation/Study Withdrawal Visit, urine hCG at all other visits
Creatinine clearance will be estimated by the CKD-EPI formula [Levey, 2009] for subjects >18 to 80 years of
age or the Schwartz formula for subjects 12 to ≤18years of age [Schwartz, 1987].
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:
x
A laboratory abnormality that leads to a dose-limiting toxicity (e.g., an abnormality that 
results in study drug dose reduction, suspension or discontinuation)
x
A laboratory abnormality that results in any therapeutic intervention (i.e., concomitant 
medication or therapy)
x
Other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (e.g., significant fall in hemoglobin not requiring transfusion)
x
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 subjects.
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, and Listing 8.3 for urinalysis). 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). These flags along with the reference 
ranges will be provided in the laboratory data listings.
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. 




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*CTCAE 4.03 criteria are based on fasting glucose values. However, subjects were not required to fast prior to 
obtaining blood glucose values.
# Only a 20% decrease from baseline is considered here: a 20% increase would not be of concern.
Clinically significant laboratory values will be tabulated for the Safety Analysis Set (Table 
3.13.8).
Since a reduction in potassium and an increase in blood glucose are known class effects of 
beta-agonists, all potassium or glucose assessments for subjects who experienced newly 
occurring or worsening potentially clinically significant values after start of the study treatment 
will be provided in separate listings (Tables 3.13.9 and 3.13.10). For all laboratory parameters 
other than glucose and potassium noted in Table 6, all laboratory data for the parameter 
identified as potentially clinically significant for a subject will be listed (Table 3.13.11 - Safety 
Analysis Set).
Vital Signs
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 
pre-dose measurement taken prior to the start of dosing at the Randomization Visit (Visit 4). If 
there are no Visit 4 pre-dose values, the baseline will be defined as the pre-bronchodilator values 
at Visit 3. 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 8
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 9
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, 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-
1.4.4) for the mITT, ITT and Safety Analysis Sets, and all subjects not randomized, respectively. 
Adolescent subjects (12-18 years of age) will have height measurements collected at Visits 1, 4, 
5, 7 and 10. A summary of height and change from baseline in height will be presented for the 
adolescent subjects in the mITT Analysis Set, by gender and treatment (Table 1.4.5).
Summary statistics (n, mean, median, standard deviation and range) of the absolute value and 
change from baseline for systolic blood pressure, diastolic blood pressure, and heart rate will be 
tabulated by treatment, visit, and time point. These summaries (Table 3.14.1) 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, and post-dose 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 10. No hypothesis tests will be performed.


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Table 10
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 4 hours
>0 to <6 hours post-dose
Note that minutes are rounded to the nearest whole number before applying time windows.
If there are multiple vital sign values for the same parameter at pre-dose assessments after Visit 4 
or within the same post-dose study time window at a visit, the last value will be chosen for 
analysis.
The percentage of subjects with potentially clinically significant values for vital signs at any time 
post-baseline at a visit will be summarized by treatment based on the criteria in Table 8 and 
Table 9 (Table 3.14.2).
All vital sign assessments for subjects with potentially clinically significant values will be listed 
(Tables 3.14.3 and 3.14.4).
12-Lead Electrocardiogram Measurements
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 pre-
dose measurement taken prior to the start of treatment at the randomization visit (Visit 4). If 
there are no Visit 4 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 msec. 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 Analysis Set 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 3.15.1). 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 ECG parameters will be plotted across post-baseline visits by 
treatment (Figures 3.15.1 – 3.15.5). ECG data from subjects with pacemakers will not be 
included in analyses, but will be listed.


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If there are multiple ECG values for the same parameter at pre-dose of a visit date (other than for 
Visit 4), the last value will be chosen for analysis.
Other than for the change from baseline analyses mentioned above, all available data after 
randomization including data from unscheduled visits will be used for ECG parameter analyses.
Table 11
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
(5) ≥ 500 msec and ≥60 msec change from study baseline 
Potentially clinically significant ECG parameter values will be identified based on criteria listed 
in Table 11. The number and percentage of subjects who had such values observed any time 
post-baseline will be tabulated for each treatment (Table 3.15.2) and listed (Tables 3.15.3 for 
QTcF prolongation). No hypothesis tests will be performed.
24-Hour Holter Monitoring Sub-Study
For subjects participating in the Holter monitoring sub-study, continuous Holter monitoring will 
be collected over 24 hours at Visit 3 and at Visit 7 (Week 12). If continuous Holter monitoring is 
unacceptable (less than 18 hours of acceptable quality), it may be repeated. If repeated, then the 
repeated values will be used in all analyses. However, any incidence of AEs indicated by the 
incomplete Holter findings will be captured. Holter monitoring data will be listed for subjects in 
the Holter Monitoring analysis set (Listing 9.3.1, 9.3.2 and 9.3.3). For subjects excluded from the 
Holter Monitoring analysis set, investigator’s assessment of Holter data will be listed where 
available (Listing 9.3.4).
Baseline for each endpoint will be defined using the acceptable 24-hour Holter assessment at 
Visit 3 (Screening).
Note that 
 will provide mean 24-hr heart rate, mean daytime heart rate, and mean 
nighttime heart rate, which will be an average across hourly estimates collected during the 
specific Holter monitoring period (24-hour, daytime, nighttime).
Primary Analysis
The change from baseline in mean 24-hour heart rate (HR) obtained using Holter monitoring at 
Week 12 will be analyzed using an ANCOVA model to evaluate treatment differences with 


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baseline mean 24-hour HR (obtained during 24-hour Holter monitoring at Screening) as a 
covariate. LS means and estimated treatment differences with 95% CIs will be provided (Table 
3.16.1 and Listing 9.3.1). The raw mean values and change from baseline values will also be 
summarized by treatment. A schematic box-plot will display the distribution of change from 
baseline in mean heart rate by treatment, with extreme values that are 1.5*IQR above/below the 
upper/lower quartiles identifiable, where IQR is the interquartile range (Figure 3.16.1).
Secondary and Other Holter Monitoring Data Safety Analyses
The changes from baseline at Week 12 (Visit 7) for the mean daytime (06:00 to 22:00) HR, mean 
nighttime (22:00 to 06:00) HR, maximum 24-hour HR, and minimum 24-hour HR will be 
summarized and analyzed in a similar manner to the primary Holter endpoint (Tables and
Figures 3.16.2, 3.16.3, 3.16.4.1, and 3.16.5.1 and Listing 9.3.1).
A frequency distribution of the following will be provided:
x
Proportion of subjects with maximum heart rate during treatment of >180, >160-≤180, >140-
≤160, >120-≤140, >100-≤120, and 100 or less (Table 3.16.4.2).
x
The number and percentage of subjects who had sustained ventricular tachycardia (defined as 
PVCs lasting>30 seconds) will be tabulated by treatment (Table 3.16.9).
x
Proportion of subjects with minimum heart rate during treatment of >60, >50-≤60, >40-≤50, 
and ≤40 (Table 3.16.5.2).
x
Proportion of subjects with change from baseline in mean heart rate of >5, >10, >20 bpm
(Table 3.16.1.1).
x
Proportion of subjects with change from baseline in maximum heart rate of >5, >10, >20 
bpm (Table 3.16.4.3).
x
Proportion of subjects with change from baseline in minimum heart rate of >5, >10, >20 bpm
(Table 3.16.5.3).
The change from baseline in the number of Holter ventricular and supraventricular events will be 
summarized descriptively (mean, median, range, etc.) and analyzed with nonparametric methods. 
The Wilcoxon Rank Sum test will be used to produce p-values for the pairwise comparison of 
treatments. The median treatment differences will be presented with 95% confidence intervals 
based on the Hodges-Lehmann approach for the location shift (median treatment difference).
This analysis will be performed for change from baseline for the following parameters 
(calculated per hour): number of isolated ventricular events (PVCs), number of ventricular 
couplets, number of ventricular runs, number of isolated supraventricular events, number of 
supraventricular couplets, number of supraventricular runs, and number of supraventricular 
ectopic beats (Tables and Figures 3.16.6.1, 3.16.7.1, 3.16.8.1, 3.16.10.1, 3.16.11.1, 3.16.12.1,
and 3.16.13.1, respectively, Listing 9.3.2 for ventricular and supraventricular events).
The number of subjects experiencing an isolated ventricular event, ventricular couplet, 
ventricular run, isolated supraventricular event, supraventricular couplet, supraventricular run 
and supraventricular ectopic beat at Week 12 will be analyzed with a logistic regression model 


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comparing across the treatment groups with baseline value of the Holter variable as a continuous 
covariate, and treatment and background ICS/LABA as categorical covariates.  P-values and 
odds ratios with 95% CIs will be produced for each treatment comparison (Tables 3.16.6.2, 
3.16.7.2, 3.16.8.2, 3.16.10.2, 3.16.11.2, 3.16.12.2, and 3.16.13.2, respectively).
Additionally, the following will be tabulated: 
x
The proportion of subjects in each category of change from baseline in the number of isolated 
PVCs per hour (no change, increase of >0-<60, ≥60-<120, and ≥120, and decrease of >0-<60, 
≥60-<120, and ≥120) (Table 3.16.6.3).
x
The number of subjects who had atrial fibrillation with a rapid ventricular response (>100 bpm) 
will be tabulated by treatment (Table 3.16.14).
x
Bradycardia and tachycardia episodes and Holter assessment will be listed (Listing 9.3.3).
Physical Examination
Any physical examination abnormality reported after the start of treatment for a subject is to be 
reported as an adverse event. Thus, these will be included in listings of adverse events and 
summarized in adverse event summaries. Abnormalities seen at the Screening physical 
examinations will be recorded as Medical History and listed.
7.
CHANGES FROM METHODS PLANNED IN THE PROTOCOL
None.
8.
STATISTICAL SOFTWARE
Data processing, statistical screening, descriptive reporting and analysis of the efficacy and 
safety data will be performed using SAS (Version 9.4 or higher). Graphs may also be produced 
using R (R Development Core Team, 2003).
9.
REFERENCES
American Thoracic Society, European Respiratory Society. ATS/ERS recommendations for 
standardized procedures for the online and offline measurement of exhaled lower respiratory nitric 
oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005;171(8):912-930.
Fuhlbrigge AL, Bengtsson T, Peterson S, et al. A novel endpoint for exacerbations in asthma to 
accelerate clinical development: a post-hoc analysis of randomized controlled trials. Lancet 
Respiratory Medicine 2017. DOI: 10.1016/S2213-2600(17)20218-7.
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention,
2017. http://ginasthma.org/. Accessed 17 September 2017.


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Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. 
Ann Intern Med. 2009;150(9):604-612.
Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European 
Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical 
asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59-99.
SAS Institute Inc. 2008. SAS/STAT 9.2 User’s Guide. Cary, NC: SAS Institute Inc.
Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular 
filtration rate in infants, children, and adolescents. Pediatr Clin North Am. 1987;34(3):571-590.