A Randomized, Double-blind, Single Dose, Placebo-controlled, 5-Period, 5-Treatment, Crossover, Multi-center, Dose-ranging Study to Compare PT007 to Placebo MDI and Open-Label Proventil® HFA in Adult and Adolescent Subjects With Mild to Moderate Asthma (ANTORA)
Phase: PHASE2
Conditions: Asthma
Sponsor: AstraZeneca

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Clinical Study Protocol (CSP) - ANGEL 
Version 18.0 
Template Form Doc ID: LDMS_001_00026737 
Parent Doc ID: SOP AZDoc0018580 
 
Clinical Study Protocol  
 
Drug Substance 
PT007 
 
Study Code 
D6930C00001 (PT007001) 
 
Version 
2.0 
 
Date 
12 January 2018 
 
 
A Randomized, Double-blind, Single dose, Placebo-controlled, 5-Period, 5-
Treatment, Crossover, Multi-center, Dose-ranging Study to Compare PT007 
to Placebo MDI and Open-Label Proventil® HFA in Adult and Adolescent 
Subjects With Mild to Moderate Asthma 
 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden 

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
 
 
Date 12 January 2018 
2 (97) 
VERSION HISTORY 
 
Version 2.0, 12 January 2018 
Post-dose spirometry will be collected at 180 and 300 minutes, in addition to the timepoints 
currently outlined in the protocol. The 180 and 300 minute timepoints were inadvertently 
not included. Table 2 and the protocol have been updated accordingly. 
Table 1 was updated to add the superscript “d” to spirometry. This footnote applies to 
spirometry as well as reversibility testing. 
Section 4.1.1 and 4.1.2, Visit 1 activities: clarifies that spirometry assessments should be 
performed only if subjects held their morning doses of asthma medications and SABA for 
≥6 hours, per Table 1 and inclusion criteria 5. The previous text was confusing to sites. 
Section 4.2.2: moved “conducting pre-dose spirometry” from an after randomization 
activity to a before randomization activity. A pre-bronchodilator FEV1 ≥40% percent 
predicted normal value is a randomization criterion. 
Version 1.0, 27 October 2017 
Initial creation. 
 

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
 
 
Date 12 January 2018 
3 (97) 
This clinical study protocol has been subject to a peer review according to the Sponsor’s 
Standard procedures. The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the Sponsor’s Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 
 

Clinical Study Protocol
Drug Substance PT007
Study Code D6930C00001 (PT007001)
Version 2.0
Date 12 January 2018
4 (97)
CLINICAL STUDY PROTOCOL SYNOPSIS
A Randomized, Double-blind, Single dose, Placebo-controlled, 5-Period, 5-
Treatment, Crossover, Multi-center, Dose-ranging Study to Compare 
PT007 to Placebo MDI and Open-Label Proventil® HFA in Adult and 
Adolescent Subjects With Mild to Moderate Asthma
Coordinating Investigator
Study site(s) and number of subjects planned
This study will be conducted at approximately 10 sites in the United States. Across these sites, 
it is planned that approximately 70 subjects with mild to moderate asthma will be randomized.
Phase of development
II
Study design
This is a randomized, double-blind, single-dose, placebo-controlled, 5-period, 5-treatment, 
crossover, multi-center study to assess the bronchodilatory effect and safety of 2 dose levels of 
Albuterol Sulfate Pressurized Inhalation Suspension (hereafter referred to as AS MDI), 90 μg 
and 180 μg, compared with placebo for AS MDI (hereafter referred to as Placebo MDI) and 
open-label Proventil® hydrofluoroalkane (HFA; hereafter referred to as Proventil) 90 μg and 
180 μg in adult and adolescent subjects with mild to moderate asthma. This study design 
utilizes 10 treatment sequences.

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
5 (97) 
Objectives 
Primary Objective 
Outcome Measures 
To confirm the dose of albuterol delivered 
from AS MDI that is comparable to Proventil 
Primary: Change from baseline in forced expiratory 
volume in 1 second (FEV1) area under the curve from 
0 to 6 hours (AUC0-6) 
Secondary efficacy endpoints: 
x 
Change from baseline in FEV1 AUC from 0 
to 4 hours (AUC0-4) 
x 
Peak change from baseline in FEV1 
Other efficacy endpoints: 
x 
Change from baseline in FEV1 at each post-
dose timepoint 
x 
Time to peak FEV1  
x 
Percentage of subjects achieving 12% 
improvement in FEV1 from baseline within 
30 minutes of dose  
x 
Percentage of subjects achieving 15% 
improvement in FEV1 from baseline within 
30 minutes of dose 
x 
Time to onset of response 
x 
Duration of response 
 
Secondary Objective 
Outcome Measures 
To assess the dose response of AS MDI versus 
Placebo MDI 
Primary: Change from baseline in FEV1 AUC0-6 
Secondary efficacy endpoints: 
x 
Change from baseline in FEV1 AUC0-4 
x 
Peak change from baseline in FEV1 
Other efficacy endpoints: 
x 
Change from baseline in FEV1 at each post-
dose timepoint 
x 
Time to peak FEV1  
x 
Percentage of subjects achieving 12% 
improvement in FEV1 from baseline within 
30 minutes of dose  
x 
Percentage of subjects achieving 15% 
improvement in FEV1 from baseline within 
30 minutes of dose 
x 
Time to onset of response 
x 
Duration of response 
 

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
6 (97) 
Safety Objective 
Outcome Measures 
To evaluate the safety and tolerability of 
AS MDI relative to Placebo MDI and 
Proventil. 
Adverse events (AEs)/serious adverse events (SAEs) 
Vital signs 
Clinical laboratory parameters 
Electrocardiograms 
 
Target subject population 
Adult and adolescent subjects (≥12 to ≤65 years old) with stable mild to moderate asthma 
(pre-bronchodilator FEV1 of ≥40 to <90% predicted normal value), with demonstrated FEV1 
reversibility to Ventolin® HFA (hereafter referred to as Ventolin). 
Subjects must be on either a short-acting β-agonist (SABA) as needed as their only asthma 
therapy or a low to medium inhaled corticosteroid (ICS) dose (either alone or in combination 
with a long-acting β2-agonist [LABA]) for at least 30 days as a consistent regimen before 
screening. 
Duration of treatment 
This is a 5-period crossover study. Each Treatment Period is 1 day. Subjects will receive a 
single dose of randomized study drug at each of the 5 Treatment Visits (Visits 2, 3, 4, 5, and 
6), with a 3- to 7-day Washout Period between Treatment Visits. 
All subjects in this study will discontinue their current asthma medications at Visit 1 and 
initiate Sponsor-provided asthma medication to be used during the Screening Period and 
throughout the duration of the study. Subjects who were using only SABA as needed before 
Visit 1 will discontinue their SABA and initiate Sponsor-provided Ventolin, to be used as 
needed throughout the study, up until 6 hours before each study visit. For these subjects, the 
minimum Screening Period will be 3 days. Subjects who were receiving regularly scheduled 
ICS or ICS/LABA before Visit 1 will discontinue their ICS or ICS/LABA and initiate 
Pulmicort Flexhaler™ 180 μg or 360 μg twice a day, in addition to the Sponsor-provided 
Ventolin as described above. For these subjects, the minimum Run-in Period will be 14 days. 
For all subjects, the maximum Screening/Run-in Period will be 28 days. 
Each subject will participate for a minimum of 23 days and up to a maximum of 68 days, 
including the 3- to 28-day Screening Period described above and a telephone call 3 to 7 days 
after the final dose of study drug. 
Investigational product, dosage, and mode of administration 
Test product: AS MDI; 45 μg albuterol base (equal to 54 μg albuterol sulfate) or 90 μg 
albuterol base (equal to 108 μg albuterol sulfate) per actuation 
Active comparator: Proventil; 90 μg albuterol base (equal to 108 μg albuterol sulfate) per 
actuation 

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
7 (97) 
Placebo: Placebo MDI manufactured in the image of AS MDI 
Each product is taken as follows during 1 of 5 Treatment Visits 
x AS MDI 90 μg (2 actuations of 45 μg/actuation) 
x AS MDI 180 μg (2 actuations of 90 μg/actuation) 
x Placebo MDI (2 actuations) 
x Proventil 90 μg (1 actuation of 90 μg/actuation) 
x Proventil 180 μg (2 actuations of 90 μg/actuation) 
Statistical methods 
All efficacy assessments will be compared with Placebo MDI and Proventil, and where 
appropriate, the AS MDI dose levels will be compared. Efficacy analyses will be performed 
for the Modified Intent-to-Treat analysis set (defined as subjects who received treatment and 
have post-treatment efficacy data from at least 2 Treatment Periods). As a sensitivity analysis, 
the Intent-to-Treat analysis set (defined as subjects who are randomized to treatment and 
receive at least 1 dose of the study treatment) will also be applied to the primary endpoint, 
change from baseline in FEV1 AUC0-6. 
The FEV1 AUC0-6 will be analyzed using a linear mixed model with a random subject effect. 
The fixed effects in the model will include treatment, treatment sequence, baseline FEV1, and 
period. 
Superiority comparisons of AS MDI relative to Placebo MDI and Proventil versus Placebo 
MDI will be conducted first using a dose-ordered approach. A 2-sided alpha level of 0.05 will 
be employed. Estimated treatment differences and 95% confidence intervals will be provided 
for the superiority comparisons. 
The secondary endpoints will be analyzed using a similar approach as that of the primary 
endpoint. 
Adverse events will be tabulated by treatment. No hypothesis tests will be performed. 
Sample size 
Power calculations were based on the properties of the primary endpoint, the change from 
baseline in FEV1 AUC0-6. Randomization of 70 subjects in order to achieve at least 
64 subjects completing the study will provide >95% overall probability to demonstrate 
superiority of each treatment relative to Placebo MDI assuming a minimum detectable 
difference (active – Placebo MDI) of 100 mL, within-subject standard deviation of 115 mL, 
and two-sided 5% level test. 

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
8 (97) 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1 
VERSION HISTORY .............................................................................................. 2 
CLINICAL STUDY PROTOCOL SYNOPSIS ....................................................... 4 
TABLE OF CONTENTS ......................................................................................... 8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 13 
1. 
INTRODUCTION ................................................................................................. 15 
1.1 
Background and rationale for conducting this study ............................................. 15 
1.2 
Rationale for study design, doses and control groups ............................................ 15 
1.3 
Benefit/risk and ethical assessment........................................................................ 16 
1.4 
Study design ........................................................................................................... 17 
1.5 
Study governance and oversight ............................................................................ 20 
2. 
STUDY OBJECTIVES .......................................................................................... 20 
2.1 
Primary objective ................................................................................................... 20 
2.2 
Secondary objectives ............................................................................................. 21 
2.3 
Safety objectives .................................................................................................... 21 
2.4 
Exploratory objectives – not applicable ................................................................. 21 
3. 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 21 
3.1 
Inclusion criteria .................................................................................................... 21 
3.2 
Exclusion criteria ................................................................................................... 23 
3.3 
Subject enrollment and randomization .................................................................. 25 
3.3.1 
Randomization criteria ........................................................................................... 25 
3.3.2 
Subject identification ............................................................................................. 25 
3.3.3 
Screen failures ........................................................................................................ 26 
3.4 
Procedures for handling incorrectly enrolled or randomized subjects ................... 26 
3.5 
Methods for assigning treatment groups ................................................................ 26 
3.6 
Methods for ensuring blinding ............................................................................... 27 
3.7 
Methods for unblinding .......................................................................................... 27 
3.8 
Restrictions ............................................................................................................ 28 
3.8.1 
Illicit drugs ............................................................................................................. 28 
3.8.2 
Dietary restrictions ................................................................................................. 28 

Clinical Study Protocol
Drug Substance PT007
Study Code D6930C00001 (PT007001)
Version 2.0
Date 12 January 2018
9 (97)
3.9 
Discontinuation of study drug................................................................................28 
3.10 
Discontinuation of the study ..................................................................................29 
4. 
STUDY PLAN AND TIMING OF PROCEDURES.............................................30 
4.1 
Screening period (Visit 1, and Visits 1a/1b if applicable) .....................................34 
4.1.1 
Visit 1.....................................................................................................................34 
4.1.2 
Visit 1a...................................................................................................................35 
4.1.3 
Visit 1b...................................................................................................................35 
4.2 
Treatment periods ..................................................................................................36 
4.2.1 
General guidance for Treatment Visits 2 through 6 (Treatment Periods 1 
through 5)...............................................................................................................36 
4.2.2 
Visit 2 (Randomization Visit, Treatment Period 1)...............................................37 
4.2.3 
Visits 3, 4, and 5 (Treatment Periods 2, 3, and 4)..................................................38 
4.2.4 
Visit 6 (Treatment Period 5) ..................................................................................39 
4.2.5 
Premature Study Withdrawal Visit ........................................................................40 
4.3 
Follow-up period....................................................................................................40 
4.3.1 
Follow-up telephone call........................................................................................40 
4.3.2 
Premature withdrawal from the study....................................................................41 
5. 
STUDY ASSESSMENTS .....................................................................................41 
5.1 
Efficacy assessments..............................................................................................41 
5.1.1 
Standardization of spirometry collections .............................................................41 
5.1.2 
Assessment of FEV1 ..............................................................................................42 
5.1.3 
Characterization of reversibility.............................................................................42 
 
 
5.2 
Safety assessments.................................................................................................43 
5.2.1 
Medical/surgical history and physical examination...............................................43 
5.2.2 
Vital signs ..............................................................................................................43 
5.2.3 
Clinical laboratory safety assessments...................................................................44 
5.2.4 
12-lead ECG...........................................................................................................45 
5.3 
Other assessments – not applicable........................................................................46 
5.4 
Pharmacokinetics – not applicable.........................................................................46 
5.5 
Pharmacodynamics – not applicable......................................................................46 
5.6 
Genetics – not applicable.......................................................................................46 
5.7 
Biomarker analysis - not applicable.......................................................................46 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................46 
6.1 
Definition of AEs...................................................................................................46 
6.2 
Definitions of SAE.................................................................................................47 
6.3 
Recording of AEs...................................................................................................48 
6.3.1 
Performing AE assessments...................................................................................48 

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
10 (97) 
6.3.2 
Pre-randomization AEs .......................................................................................... 48 
6.3.3 
AEs based on signs and symptoms ........................................................................ 48 
6.3.4 
AEs based on examinations and tests .................................................................... 48 
6.3.5 
Disease under study ............................................................................................... 49 
6.3.6 
Severity .................................................................................................................. 49 
6.3.7 
Relationship to study drug ..................................................................................... 50 
6.4 
Reporting of SAEs ................................................................................................. 50 
6.4.1 
Supplemental investigations of SAEs .................................................................... 50 
6.4.2 
Post-study follow-up of AEs .................................................................................. 51 
6.4.3 
Notification of post-treatment SAEs ...................................................................... 51 
6.4.4 
IRB notification of SAEs ....................................................................................... 51 
6.4.5 
Health Authority Safety Reports ............................................................................ 51 
6.5 
Overdose ................................................................................................................ 51 
6.6 
Pregnancy ............................................................................................................... 52 
6.6.1 
Maternal exposure .................................................................................................. 52 
6.6.2 
Paternal exposure ................................................................................................... 52 
6.7 
Medication Error .................................................................................................... 52 
6.8 
Management of study drug-related toxicities – not applicable .............................. 54 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 54 
7.1 
Identity of investigational products........................................................................ 54 
7.2 
Dose and treatment regimens ................................................................................. 55 
7.2.1 
Randomized study drug ......................................................................................... 55 
7.2.2 
Sponsor-provided background asthma therapies ................................................... 56 
7.3 
Labeling ................................................................................................................. 57 
7.3.1 
Primary packaging and labeling ............................................................................. 57 
7.3.2 
Secondary packaging and labeling information (box) ........................................... 57 
7.4 
Storage ................................................................................................................... 58 
7.5 
Compliance ............................................................................................................ 58 
7.6 
Accountability ........................................................................................................ 58 
7.7 
Concomitant and other treatments ......................................................................... 59 
7.7.1 
Prior medications ................................................................................................... 59 
7.7.2 
Concomitant medications ....................................................................................... 60 
7.7.2.1 
Required concomitant medications ........................................................................ 60 
7.7.2.2 
Allowed allergy medications ................................................................................. 61 
7.7.3 
Prohibited medications ........................................................................................... 61 
7.7.3.1 
Prohibited asthma and allergy medications and washout periods.......................... 61 
7.7.3.2 
Prohibited non-asthma and non-respiratory medications ...................................... 62 
7.7.4 
Other concomitant treatment .................................................................................. 63 
8. 
STATISTICAL ANALYSES ................................................................................ 64 

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
11 (97) 
8.1 
Statistical considerations ........................................................................................ 64 
8.2 
Sample size estimate .............................................................................................. 64 
8.3 
Definitions of analysis sets .................................................................................... 64 
8.4 
Outcome measures for analyses ............................................................................. 65 
8.5 
Methods for statistical analyses ............................................................................. 65 
8.5.1 
Primary efficacy analysis ....................................................................................... 65 
8.5.2 
Secondary efficacy analysis ................................................................................... 66 
8.5.3 
Other efficacy analysis ........................................................................................... 66 
8.5.4 
Type 1 error control ............................................................................................... 67 
8.5.5 
Data validation and transformation ........................................................................ 67 
8.5.6 
Safety analyses ....................................................................................................... 67 
8.5.6.1 
AEs ......................................................................................................................... 67 
8.5.6.2 
Vital signs .............................................................................................................. 68 
8.5.6.3 
Clinical laboratory measurements .......................................................................... 68 
8.5.6.4 
12-Lead ECGs ........................................................................................................ 68 
8.5.7 
Handling of missing data ....................................................................................... 68 
8.5.8 
Statistical software ................................................................................................. 68 
9. 
STUDY AND DATA MANAGMENT BY THE SPONSOR ............................... 68 
9.1 
Training of study site staff ..................................................................................... 68 
9.2 
Monitoring of the study ......................................................................................... 69 
9.2.1 
Source data ............................................................................................................. 69 
9.2.2 
Study agreements ................................................................................................... 69 
9.2.3 
Archiving of study documents ............................................................................... 69 
9.3 
Study timetable and end of study ........................................................................... 69 
9.4 
Data management ................................................................................................... 70 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 70 
10.1 
Ethical conduct of the study ................................................................................... 70 
10.2 
Subject data protection ........................................................................................... 70 
10.3 
Ethics and regulatory review.................................................................................. 70 
10.4 
Informed consent ................................................................................................... 71 
10.5 
Changes to the clinical study protocol and ICF/assent form ................................. 71 
10.6 
Audits and inspections ........................................................................................... 72 
11. 
LIST OF REFERENCES ....................................................................................... 73 
 

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
12 (97) 
LIST OF TABLES 
Table 1 
Schedule of Events ................................................................................... 31 
Table 2 
Timed Assessments at Visits 2, 3, 4 and 5 ............................................... 33 
Table 3. 
Timed Assessments at Visit 6 ................................................................... 33 
Table 4. 
List of Laboratory Tests ........................................................................... 45 
Table 5. 
Randomized Study Drugs ......................................................................... 54 
Table 6. 
Other Sponsor-provided Study Medications ............................................ 55 
Table 7 
Dose of Sponsor-provided Pulmicort Flexhaler to be Assigned 
Based on Pre-study ICS or ICS/LABA Dose ........................................... 60 
Table 8  
Allowed Allergy Medications .................................................................. 61 
Table 9  
Prohibited Asthma and Allergy Medications That Must be 
Discontinued at Visit 1 and Required Washout Period Prior to 
Visit 1a ...................................................................................................... 62 
Table 10 
Prohibited Non-Asthma and Non-Respiratory Medications .................... 63 
Table A1-1. 
Recommended Minimal Scale Factors for Time, Volume and Flow 
on Graphical Output ................................................................................. 77 
Table A1-2. 
Summary of Equipment Quality Control ................................................. 78 
Table A1-3. 
Range and Accuracy Recommendations Specified for Forced 
Expiratory Maneuvers .............................................................................. 80 
 
LIST OF FIGURES 
Figure 1 
Study Design Flow Chart ......................................................................... 19 
 
LIST OF APPENDICES 
Appendix A 
Spirometry Assessment Criteria ............................................................... 74 
Appendix B 
Spirometry Performance Recommendations ............................................ 76 
Appendix C 
Additional Safety Information .................................................................. 82 
Appendix D 
Instructions for Use of Inhaled Medications ............................................ 84 
Appendix E 
Sponsor Signatory .................................................................................... 96 
Appendix F 
Investigator’s Agreement and Signature Page.......................................... 97 

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
13 (97) 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study clinical study protocol. 
Abbreviation 
or special term 
Explanation 
AE 
Adverse event 
AS MDI 
Albuterol Sulfate Pressurized Inhalation Suspension 
ATS 
American Thoracic Society 
AUC 
Area under the curve 
AUC0-6 
Area under the curve from 0 to 6 hours 
AUC0-4 
Area under the curve from 0 to 4 hours 
β-hCG 
β-human chorionic gonadotropin 
BID 
Twice a day 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
Case Report Form (electronic/paper) 
ERS 
European Respiratory Society 
FEV1 
Forced expiratory volume in 1 second 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HFA 
Hydrofluoroalkane 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference for Harmonisation 
ICS 
Inhaled corticosteroid 
ID 
Identification 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LABA 
Long-acting β2-agonist 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDI 
Metered dose inhaler 

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
14 (97) 
Abbreviation 
or special term 
Explanation 
mITT 
Modified Intent-to-Treat 
PIN 
Personal ID number 
PFT 
Pulmonary function testing 
QTcF 
Fridericia-corrected QT interval 
SABA 
Short-acting β-agonist 
SAE 
Serious adverse event  
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
 

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
15 (97) 
1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
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. Worsening asthma symptoms/airway obstruction 
can be mild to severe (Global Initiative for Asthma 2017). Albuterol sulfate is a short-acting 
β-agonist (SABA) that has been used world-wide in the management of asthma symptoms 
across all severities of asthma for over 40 years (Global Initiative for Asthma 2017). 
The test formulation to be evaluated in this study is a metered dose inhaler (MDI) containing 
albuterol sulfate (Albuterol Sulfate Pressurized Inhalation Suspension; hereafter referred to as 
AS MDI). This study is designed to support the selection of the albuterol dose by comparing 
the bronchodilatory effect and safety of 2 dose levels of AS MDI (90 μg and 180 μg) with 
placebo for AS MDI (hereafter referred to as Placebo MDI) and open-label Proventil® 
hydrofluoroalkane (HFA; hereafter referred to as Proventil; 90 μg and 180 μg) as the reference 
product in adult and adolescent subjects with mild to moderate asthma. 
The drug product in clinical development is an MDI formulated as a suspension with a 
micronized active pharmaceutical ingredient and Co-Suspension™ Delivery Technology, 
which consists of spray-dried porous particles comprised of the phospholipid, 1,2-distearoyl-
sn-glycero-3-phosphocholine and calcium chloride suspended in a HFA propellant. When 
used in MDI products, these particles form strong non-specific associations with the active 
pharmaceutical ingredient, providing reproducible drug delivery and long-term stability. 
All references to doses of AS MDI and Proventil refer to the albuterol base (ie, 90 μg 
albuterol base, which equals 108 μg albuterol sulfate). 
1.2 
Rationale for study design, doses and control groups 
The primary goal of this study is to confirm the bronchodilatory effect of 2 dose levels of 
AS MDI relative to Placebo MDI and the active control, Proventil, in subjects with mild to 
moderate asthma. The study is based on a 5-period Williams (Williams 1949) crossover 
design to allow the comparison of 2 doses of AS MDI against Placebo MDI and Proventil. 
The crossover design was selected to ensure acceptable power with a limited subject exposure 
through within-subject treatment comparisons. 
The dose levels of AS MDI to be tested (90 μg and 180 μg) were selected based on over 
40 years of clinical experience with inhaled albuterol in asthma patients, and are likely to be 
efficacious doses with acceptable safety profiles. It is anticipated that the dose of albuterol 
delivered with AS MDI will be close to the approved dose in Proventil. The doses will allow 
evaluation of the bronchodilation effect of AS MDI relative to Placebo MDI and Proventil 
administered at 90 μg and 180 μg. The recommended dose of Proventil for the treatment or 
prevention of bronchospasm in adults and children aged 4 years and older is 2 actuations of 

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90 μg every 4 to 6 hours; for some patients, 1 actuation may be sufficient (PROVENTIL HFA 
package insert). 
In this double-blind, placebo-controlled study, AS MDI and Placebo MDI will be blinded to 
all subjects, study site staff, endpoint assessors, and Sponsor personnel. Proventil is open-
label. However, to reduce bias, dosing will be performed under the supervision of study staff, 
and spirometry assessments will be performed by different study personnel who will only 
enter the room after dosing is completed; thus, the study personnel conducting the spirometry 
assessments will be blinded to the identity of the study drug. 
Subjects enrolled in this study are selected to represent the intended patient population for an 
albuterol product to be used as needed for symptoms, ie, adults and adolescents 12 years of 
age or older currently treated and well controlled with appropriate background standard of 
care for their asthma severity. 
All subjects will use only Sponsor-provided medication for rescue as needed during the study. 
At Visit 1 (Screening), subjects will discontinue their SABA and initiate Sponsor-provided 
Ventolin, to be used as needed up until 6 hours before each study visit. 
Subjects who were previously on a low to medium dose of an inhaled corticosteroid (ICS) 
with or without a long-acting β2-agonist (LABA) before study entry will be required to 
discontinue their previous therapy and initiate Sponsor-supplied Pulmicort Flexhaler™ for at 
least 14 days to standardize therapy and to confirm asthma is adequately treated prior to 
randomization; these subjects will also use Sponsor-provided Ventolin as needed for 
symptoms as described above. 
Each dose of AS MDI will be compared with Placebo MDI and Proventil on the primary 
efficacy endpoint, change from baseline in forced expiratory volume in 1 second (FEV1) area 
under the curve (AUC) from 0 to 6 hours (AUC0-6), a commonly accepted endpoint for the 
assessment of bronchodilation. The duration of 6 hours was selected to capture the expected 
duration of the effect of albuterol. 
1.3 
Benefit/risk and ethical assessment 
This study has been designed to support the dose selection for a new formulation of albuterol 
in subjects with mild to moderate asthma. The product being tested in this study, AS MDI, is 
being compared with an approved inhaled albuterol product to confirm a pharmacologically 
appropriate dose. The subjects in this study will not gain any therapeutic benefit from the 
study as it is comprised of only 5 single-dose treatments. 
All subjects in this study will be switched at Visit 1 from their current asthma medication to 
Sponsor-provided asthma medication to be used during the Screening Period and throughout 
the duration of the study, as described in Section 1.2. Subjects requiring medications other 
than those specified in Section 1.2 to control or treat their asthma symptoms before Visit 1 
will be excluded from participation in this study. In addition, to be eligible for randomization, 
subjects must not have used more than 8 actuations per day (ie, 4 doses of 2 actuations per 

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day) of Sponsor-provided Ventolin for rescue on more than any 3 days during the previous 7 
days before randomization. 
Based on the well-established safety profile of inhaled albuterol, no new or specific risks 
beyond what is described in the PROVENTIL HFA package insert are anticipated with the 
doses and the dose regimens being used in this study. Investigators will ensure adequate 
medical care of the study participants at all times throughout the course of the study, including 
up to the follow-up telephone call 3 to 7 days after the last dose of study drug. 
1.4 
Study design 
This is a randomized, double-blind, single-dose, placebo-controlled, 5-period, 5-treatment, 
crossover, multi-center study to assess the bronchodilatory effect and safety of 2 dose levels of 
AS MDI (90 μg and 180 μg) compared with Placebo MDI and open-label Proventil (90 μg and 
180 μg) in adult and adolescent subjects with mild to moderate asthma (Figure 1). 
This study will be conducted at approximately 10 sites in the US, contributing approximately 
7 subjects per site. Across these sites, it is planned that approximately 70 subjects with mild to 
moderate asthma will be randomized to provide approximately 64 subjects to complete the 
study. Each subject will participate for a minimum of 23 days and up to a maximum of 
68 days, including a 3- to 28-day Screening Period and a telephone call 3 to 7 days after the 
final dose of study drug. The study is anticipated to run for approximately 4 months, including 
the recruitment period. 
This study consists of a Screening Period, which includes a Run-in Period for those subjects 
who will be switched from ICS and ICS/LABA to Sponsor-provided Pulmicort Flexhaler, a 
Treatment Phase, which includes 5 randomized Treatment Periods, and a follow-up telephone 
call. Each Treatment Period will be 1 day, with a Washout Period of 3 to 7 days between 
Treatment Periods. 
The Screening Period begins at Visit 1. At Visit 1, subjects will sign an informed consent 
form (ICF). If the subject is a minor, the parent or guardian will sign an ICF and the subject 
will sign an assent form. Inclusion/exclusion criteria will be assessed. To be eligible, subjects 
must be on either a SABA as needed as their only asthma therapy or a low to medium ICS 
dose (either alone or in combination with a LABA) for at least 30 days as a consistent regimen 
before screening. Subjects must have a pre-bronchodilator FEV1 between ≥40 and <90% 
predicted normal value. 
All subjects must demonstrate FEV1 reversibility to Ventolin (defined as improvement in 
FEV1 of ≥15% post Ventolin dosing) during the Screening Period; historical reversibility is 
not acceptable. For subjects who did not administer their morning asthma maintenance 
medications, as applicable, and/or SABA, reversibility will be measured at Visit 1. For 
subjects who received their morning asthma maintenance medications, as applicable, and/or 
SABA, reversibility will be measured at Visit 1a, which will occur within 10 days of Visit 1 
and after these medications have been held for the appropriate time period (Table 9). Subjects 
who do not meet reversibility criteria at Visit 1 or Visit 1a may be retested at a subsequent 

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Screening Visit (1a or 1b). Only 2 reversibility testing attempts are allowed. Subjects not 
meeting reversibility criteria after 2 attempts must be screen failed. 
Subjects meeting eligibility criteria at Visit 1 will continue in the Screening Period. All 
subjects in this study will discontinue their current asthma medications at Visit 1 and initiate 
Sponsor-provided asthma medication to be used during the Screening Period and throughout 
the duration of the study, as described in Section 1.2. For subjects who were using only SABA 
as needed before study entry, the minimum Screening Period will be 3 days. For subjects who 
were receiving regularly scheduled ICS or ICS/LABA before study entry, the minimum Run-
in Period (on Pulmicort Flexhaler) will be 14 days. For all subjects, the maximum 
Screening/Run-in Period will be 28 days. 
Randomization will take place at Visit 2. At Visit 2, before randomization, subjects must 
demonstrate a pre-bronchodilator FEV1 ≥40% predicted normal value (average of 2 pre-
bronchodilator assessments). Subjects who do not meet this randomization criterion will be 
screen failed. Randomization will be centralized through the use of an Interactive Web 
Response System (IWRS). Eligible subjects will be randomized to 1 of 10 pre-defined 
treatment sequences. Each sequence will contain AS MDI 90 μg, AS MDI 180 μg, Placebo 
MDI, Proventil 90 μg, and Proventil 180 μg, in a randomized order. Randomization is planned 
to be stratified by pre-study background asthma maintenance therapy, with approximately 
50% of subjects on an ICS and approximately 50% of subjects who are not on an ICS 
(receiving only a SABA as needed). 
Subjects will receive single doses of randomized study drug at each of the 5 Treatment Visits 
(Visits 2, 3, 4, 5, and 6), with a 3- to 7-day Washout Period between Treatment Visits. At each 
Treatment Visit, bronchodilation activity of the study drug will be assessed through 
pulmonary function testing (PFT). Subjects will be required to remain at the clinic until 
completion of all protocol-defined assessments up to and including the 6-hour post-dose 
timepoint (Table 1). Safety will be assessed by evaluation of adverse events (AEs), clinical 
laboratory tests, vital signs, and electrocardiograms (ECGs). 
Subjects who prematurely discontinue study drug for any reason before completing all study 
visits will undergo a Premature Discontinuation Visit. After the last Treatment Period or 
following a Premature Discontinuation Visit, subjects will be scheduled for a follow-up 
telephone call to occur 3 to 7 days from the date of the last study drug dose. 
The end of study is defined as the last subject’s follow-up telephone call. 
 

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Figure 1 
Study Design Flow Chart 
 
*Subjects on ICS or ICS/LABA prior to Visit 1 will be run-in on Pulmicort Flexhaler 180 or 360 μg BID for a minimum of 
14 days. 
Abbreviations: BID = twice a day; V=visit; R=randomization; Rx=treatment. 

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1.5 
Study governance and oversight 
No study governance or oversight committees will be used in this study. 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary Objective 
Outcome Measures 
To confirm the dose of albuterol delivered 
from AS MDI that is comparable to Proventil 
Primary: Change from baseline in FEV1 AUC0-6 
Secondary efficacy endpoints: 
x 
Change from baseline in FEV1 AUC from 0 
to 4 hours (AUC0-4) 
x 
Peak change from baseline in FEV1 
Other efficacy endpoints: 
x 
Change from baseline in FEV1 at each post-
dose timepoint 
x 
Time to peak FEV1  
x 
Percentage of subjects achieving 12% 
improvement in FEV1 from baseline within 
30 minutes of dose  
x 
Percentage of subjects achieving 15% 
improvement in FEV1 from baseline within 
30 minutes of dose 
x 
Time to onset of response 
x 
Duration of response 

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2.2 
Secondary objectives 
Secondary Objective 
Outcome Measures 
To assess the dose response of AS MDI versus 
Placebo MDI 
Primary: Change from baseline in FEV1 AUC0-6 
Secondary efficacy endpoints: 
x 
Change from baseline in FEV1 AUC0-4 
x 
Peak change from baseline in FEV1 
Other efficacy endpoints: 
x 
Change from baseline in FEV1 at each post-
dose timepoint 
x 
Time to peak FEV1 
x 
Percentage of subjects achieving 12% 
improvement in FEV1 from baseline within 
30 minutes of dose 
x 
Percentage of subjects achieving 15% 
improvement in FEV1 from baseline within 
30 minutes of dose 
x 
Time to onset of response 
x 
Duration of response 
2.3 
Safety objectives 
Safety Objective 
Outcome Measures 
To evaluate the safety and tolerability of 
AS MDI relative to Placebo MDI and Proventil 
AEs/serious adverse events (SAEs) 
Vital signs 
Clinical laboratory parameters 
ECGs 
 
2.4 
Exploratory objectives – not applicable 
3. 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject must meet all of the inclusion criteria and none of the exclusion criteria for this 
study. Under no circumstances will there be exceptions to this rule. 
3.1 
Inclusion criteria 
Each subject must meet the following criteria in relationship to Visit 1, unless otherwise 
noted, to be enrolled in this study: 
1. 
Give their signed written informed consent to participate (and assent, as applicable) 

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2. 
Are at least 12 years of age and no older than 65 years 
3. 
Have stable (for 6 months) physician-diagnosed asthma with historical 
documentation of the diagnosis 
4. 
Must be receiving 1 of the following required inhaled asthma therapies listed below 
for at least the last 30 days: 
x Only SABA, which is used as needed for rescue 
x Low to medium doses of ICS (alone or in combination with LABA), used 
regularly as maintenance asthma therapy, with the ICS doses allowed in 
Table 7, with a stable regimen 
5. 
Pre-bronchodilator FEV1 of ≥40 to <90% predicted normal value after withholding 
SABA for ≥6 hours (and/or Visit 1a and/or Visit 1b, if applicable) 
6. 
Confirmed FEV1 reversibility to Ventolin, defined as a post-Ventolin increase in 
FEV1 of ≥15% at either Visit 1, Visit 1a, or Visit 1b; only 2 reversibility testing 
attempts are allowed 
7. 
Demonstrate acceptable spirometry performance (ie, meet American Thoracic 
Society [ATS]/European Respiratory Society [ERS] acceptability/repeatability 
criteria; Appendix A) 
8. 
Willing and, in the opinion of the Investigator, able to adjust current asthma 
therapy, as required by the protocol 
9. 
Demonstrate acceptable MDI administration technique 
Note: Use of a spacer device during the Screening and randomized Treatment 
Periods is not permitted. 
10. 
Body mass index <40 kg/m2 
11. 
If a female of childbearing potential, have a negative serum pregnancy test 
12. 
Women of childbearing potential must agree to 1 of the following to prevent 
pregnancy: 
Note: Women are considered to be of non-childbearing potential if they are 
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. 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. 
x Practice abstinence 

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x If a 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: 
o Hormonal contraception (eg, oral contraceptive, contraceptive 
implant, or injectable hormonal contraceptive) 
o Double-barrier birth control (eg, condom plus intrauterine device, 
diaphragm plus spermicide, condom plus spermicide) 
o Maintenance of a monogamous sexual relationship with a male 
partner who has been surgically sterilized by vasectomy 
13. 
Male subjects who are sexually active must be surgically sterile or agree to use a 
double-barrier method of contraception (condom with spermicide) from the first 
dose of randomized study drug until 2 weeks after their last dose, and must not 
donate sperm during their study participation period 
14. 
Compliance: must be willing to remain at the study site as required per protocol to 
complete all visit assessments 
3.2 
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. 
Chronic obstructive pulmonary disease or other significant lung disease (eg, chronic 
bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, or 
bronchopulmonary dysplasia) 
2. 
Oral corticosteroid use (any dose) within 6 weeks 
3. 
Received any marketed (eg, omalizumab, mepolizumab, reslizumab) 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 9 and Table 10) 
4. 
Received tiotropium within 2 weeks 
5. 
Current smokers, former smokers with >10 pack-years history, or former smokers 
who stopped smoking <6 months (including all forms of tobacco, e-cigarettes 
[vaping], and marijuana) 
6. 
Life-threatening asthma as defined as any history of significant asthma episode(s) 
requiring intubation associated with hypercapnia, respiratory arrest, hypoxic 
seizures, or asthma-related syncopal episode(s) 

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7. 
Completed treatment for lower respiratory infection or asthma exacerbation within 
6 weeks 
8. 
Upper respiratory infection not resolved within 7 days 
9. 
Hospitalizations for asthma within 6 months 
10. 
Clinically significant laboratory abnormalities or ECG abnormalities, in the opinion 
of the Investigator 
Note: If laboratory tests have to be repeated, the results should be available for 
review before Visit 2 (Randomization). 
11. 
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, neuropsychological, endocrine (eg, uncontrolled diabetes mellitus, 
uncontrolled thyroid disorder, Addison’s disease, Cushing’s syndrome), or 
gastrointestinal (eg, poorly controlled peptic ulcer, gastroesophageal reflux disease). 
Significant is defined as any disease that, in the opinion of the Investigator, would 
put the safety of the subject at risk through study participation, or that could affect 
the efficacy or safety analysis if the disease/condition exacerbated during the study. 
12. 
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. 
13. 
Hospitalized for psychiatric disorder or attempted suicide within 1 year 
14. 
History of psychiatric disease, intellectual deficiency, poor motivation, or other 
conditions limiting informed consent validity 
15. 
Significant, in the opinion of the Investigator, abuse of alcohol or drugs 
16. 
Hypersensitivity to β2-agonists or any component of the investigational MDI or any 
component of Proventil or Ventolin (or Pulmicort Flexhaler, if applicable) 
17. 
Unable to abstain from protocol-defined prohibited medications during the study 
18. 
Using any herbal products by inhalation or nebulizer within 2 weeks and does not 
agree to stop during the study duration 
19. 
Received a live attenuated vaccination within 7 days 
20. 
Currently pregnant or nursing 

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21. 
Study investigators, sub-investigators, coordinators, and their employees or 
immediate family members, or employees of the Sponsor 
22. 
Treatment with investigational study drug (or device) in another clinical study 
within the last 30 days or 5 half-lives, whichever is longer 
23. 
Randomized in any PT007 study 
3.3 
Subject enrollment and randomization 
3.3.1 
Randomization criteria 
Each subject must meet the following criteria on the morning of Visit 2 to be randomized: 
1. 
Subjects of childbearing potential must have a negative urine pregnancy test 
2. 
Received no asthma medication other than Sponsor-provided Pulmicort Flexhaler 
180 μg or 360 μg BID as assigned and/or Sponsor-provided Ventolin from Visit 1 
to Visit 2, except for allowable allergy medications defined in Table 8 
3. 
The last dose of Pulmicort Flexhaler (if applicable) was the previous night (ie, 
morning dose of Pulmicort Flexhaler was not administered), and the last dose of 
Sponsor-provided Ventolin was no later than 6 hours before the study visit (if 
Ventolin is needed in the morning, the visit must be rescheduled) 
4. 
Pre-bronchodilator FEV1 ≥40% percent predicted normal value 
5. 
Has not used >8 actuations per day (ie, 4 doses of 2 actuations per day) of Sponsor-
provided Ventolin for rescue on more than any 3 days during the previous 7 days 
6. 
No upper respiratory infection, lower respiratory infection, or asthma exacerbation 
during the Screening Period 
7. 
Demonstrate acceptable MDI administration technique 
8. 
Able to comply with all study procedures 
For procedures for withdrawal of incorrectly randomized subjects see Section 3.4. 
3.3.2 
Subject identification 
All subjects who undergo screening will be assigned a unique screening identification number 
(ID) at Visit 1. Only subjects continuing to meet all inclusion criteria and none of the 
exclusion criteria at Visit 2 and who meet randomization criteria at Visit 2 will be assigned a 
unique subject randomization number. 

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3.3.3 
Screen failures 
Screening failures are subjects who do not fulfil the eligibility criteria for the study and 
therefore must not be randomized. 
3.4 
Procedures for handling incorrectly enrolled or randomized 
subjects 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled into the Screening Period or receive study drug. There can be no exceptions to this 
rule. Subjects who are enrolled into the Screening Period but subsequently found not to meet 
all the eligibility criteria must not be randomized or initiated on study drug. 
If a subject does not meet all the eligibility criteria and is randomized in error or is incorrectly 
started on study drug, the Investigator should inform the Sponsor immediately, and the 
Sponsor and the Investigator should discuss whether to continue or discontinue the subject 
from study drug and withdraw the subject from the study. The Sponsor must ensure all 
decisions are appropriately documented. 
3.5 
Methods for assigning treatment groups 
The randomization scheme will be generated by the Sponsor or designee using computer 
software incorporating a random number generator. Subjects will be randomly assigned to 1 
of 10 treatment sequences based on a Williams design (Williams 1949) using an IWRS. Each 
sequence will comprise all 5 of the treatments included in this study in a randomized order. 
All sequences will contain AS MDI 90 μg, AS MDI 180 μg, Placebo MDI, Proventil 90 μg, 
and Proventil 180 μg. 
The 10 treatment sequences are shown below. 

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Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
Period 5 
1 
A 
B 
E 
C 
D 
2 
B 
C 
A 
D 
E 
3 
C 
D 
B 
E 
A 
4 
D 
E 
C 
A 
B 
5 
E 
A 
D 
B 
C 
6 
D 
C 
E 
B 
A 
7 
E 
D 
A 
C 
B 
8 
A 
E 
B 
D 
C 
9 
B 
A 
C 
E 
D 
10 
C 
B 
D 
A 
E 
Note: A=Placebo; B=AS MDI 90 μg; C=AS MDI 180 μg; D= Proventil 90 μg; E= Proventil 180 μg. 
 
Randomization will be centralized and stratified by pre-study background therapy consisting 
of either ICS or non-ICS (subjects not previously treated with ICS). 
3.6 
Methods for ensuring blinding 
AS MDI and Placebo MDI will be blinded to all subjects, study site staff, endpoint assessors, 
and Sponsor personnel. Placebo MDI is designed to mimic the appearance, smell, and taste of 
AS MDI. No double-dummy will be used. Packaging and labeling of AS MDI and Placebo 
MDI will be designed to ensure blinding. 
Randomized Proventil is open-label. However, to reduce bias, dosing will be performed under 
the supervision of study staff, and spirometry assessments will be performed by different 
study personnel who will only enter the room after dosing is completed; thus, the study 
personnel conducting the spirometry assessments will be blinded to the identity of the study 
drug. 
3.7 
Methods for unblinding 
Individual treatment codes, indicating the treatment randomization for each randomized 
subject, will be available to the Investigator(s) or pharmacists from the IWRS. Routines for 
this will be described in the IWRS user manual that will be provided to each study site. 
The IWRS should be used in order to unblind subjects and to unmask drug identity. The 
Sponsor will not provide a disclosure envelope with the clinical supplies. The Investigator or 
treating Physician may unblind a subject’s treatment assignment only in the case of an 
emergency, when knowledge of the study drug treatment is essential for the appropriate 

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clinical management or welfare of the subject. Whenever possible, the Investigator must first 
discuss options with the Sponsor Medical Monitor or appropriate study personnel 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 subjects currently in 
the study. The date and reason for the unblinding must be recorded in the appropriate data 
collection tool. 
The Sponsor retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to a study drug and that potentially require expedited 
reporting to regulatory authorities. Treatment codes will not be broken for the planned 
analyses of data until all decisions on the evaluability of the data from each individual subject 
have been made and documented. 
3.8 
Restrictions 
Prohibited concomitant medications are described in Section 7.7.3. 
3.8.1 
Illicit drugs 
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 discontinues from the study drug and 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 
study drug and withdrawn from the study at the discretion of the Investigator. Medical 
marijuana (edibles and tinctures only; inhaled marijuana is excluded) is not an exclusionary 
drug if used for medical purposes and the dose or frequency of consumption does not change 
during the Screening Period or throughout the study. 
3.8.2 
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 before each study visit and 
throughout the duration of each study visit. Examples of such products include coffee, tea, 
chocolate, and cola. Decaffeinated beverages are acceptable. 
3.9 
Discontinuation of study drug 
All subjects who discontinue study drug will be withdrawn from the study. 
Subjects may be withdrawn from the study at their own request at any time for any reason. 
Subjects experiencing any of the changes of concern listed below should be discontinued from 
randomized study drug and withdrawn from the study. 
x 
Asthma worsening requiring change in asthma treatment, other than 
Sponsor-provided Pulmicort Flexhaler, if assigned, and as needed Sponsor-
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Note: Subjects experiencing an asthma exacerbation during the study will 
be evaluated by the Investigator and treated with medications for asthma 
deemed medically necessary and will be discontinued from study drug and 
withdrawn from the study.
x
x
Requirement for any of the prohibited medications listed in Section 7.7.3
x
Any safety reason as judged by the Investigator and/or Sponsor
x
Pregnancy
x
The subject’s treatment code is prematurely broken by the Investigator.
Subjects who discontinue study drug and withdraw from the study should be encouraged to 
complete the Premature Discontinuation Visit (see Section 4.2.5).
Withdrawal of the informed consent
Subjects are free to withdraw from the study at any time without prejudice to further 
treatment.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any AE. The Investigator will follow up AEs outside of the clinical study.
If a subject withdraws from participation in the study, then his/her enrollment and/or 
randomization code(s) cannot be reused. Withdrawn subjects will not be replaced.
3.10
Discontinuation of the study
The study may be stopped if, in the judgment of the Sponsor, study subjects are placed at 
undue risk because of clinically significant findings that:
x
meet individual stopping criteria or are otherwise considered significant
x
are assessed as causally related to study drug
x
are not considered to be consistent with continuation of the study
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 time frame that is compatible with the subjects’ well-being.
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation must be recorded in the electronic case report form (eCRF). All reasons for 
discontinuation of study drug must be documented.

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In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 
4. 
STUDY PLAN AND TIMING OF PROCEDURES 
Note: Before conducting any study-related procedures, subjects are required to provide their 
written informed consent using the Institutional Review Board (IRB)-approved ICF, and 
assent as appropriate. If the subject is a minor, the parent or guardian will sign an ICF and the 
subject will sign an assent form. The ICF and assent form should be signed during Visit 1. 
A time and events schedule is provided in Table 1. Detailed schedules are provided for timed 
assessments at Visits 1 through 5 (Table 2) and Visit 6 (Table 3). 
When data collection timepoints are concurrent, variables will be collected in the following 
order: vital signs, ECG, clinical laboratory assessments, and spirometry. 
 

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Table 1
Schedule of Events
Procedures
Screeninga
Treatment Phaseb
Follow-up
For details 
see Section
Visit 1
Visit 
1a/b
Visit 2
Rand.
(TP 1)
Day 1
Visit 3
(TP 2)
Visit 4
(TP 3)
Visit 5
(TP 4)
Visit 6
(TP 5)
PDV (if 
applicable)c
TC
3 to 7 days 
after final 
dose
Day -28 to Day -1
Informed consent (and 
assent, as appropriate)
X
Section 10.4
Eligibility criteria
X
Section 3
Verify randomization 
criteria
X
Section 3.3.1
Verified continued 
eligibility
X
X
X
X
X
Section 3
MDI 
demonstration/training
X
X
X
X
X
X
Section 4.1
Ventolin reversibility testd
X
X
Section 5.1.3
Medical/surgical history
X
Section 5.2.1
Demographics
X
Section 4.1
Concomitant medicationse
X
X
X
X
X
X
X
X
Section 7.7
Spirometryd
X
X
X
X
X
X
X
Section 5.1.2
Physical examinationf
X
X
X
Section 5.2.1
Vital signs
X
X
X
X
X
X
X
Section 5.2.2
12-lead ECG
X
X
X
Section 5.2.4
Pregnancy testg
X
X
Section 5.2.3

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Table 1 
Schedule of Events 
Procedures 
Screeninga 
Treatment Phaseb 
Follow-up 
For details 
see Section 
Visit 1 
Visit 
1a/b 
Visit 2 
Rand. 
(TP 1) 
Day 1 
Visit 3 
(TP 2) 
Visit 4 
(TP 3) 
Visit 5 
(TP 4) 
Visit 6 
(TP 5) 
PDV (if 
applicable)c 
TC 
3 to 7 days 
after final 
dose 
Day -28 to Day -1 
Clinical laboratory testing 
X 
 
 
 
 
 
X 
X 
 
Section 5.2.3 
Adjust asthma medications 
per protocolh 
X 
X 
 
 
 
 
X 
X 
 
Section 7.2.2 
Randomization  
 
 
X 
 
 
 
 
 
 
Section 3.5 
Randomized study drug 
administered 
 
 
X 
X 
X 
X 
X 
 
 
Section 7.2.1 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 6.3 
Telephone contact 
 
 
 
 
 
 
 
 
X 
Section 4.3.1 
Abbreviations: AE=adverse event; β-hCG= β-human chorionic gonadotropin; ECG=electrocardiogram; FEV1=forced expiratory volume in 1 second; ICS=inhaled 
corticosteroid; LABA= long-acting β2-agonist; MDI=metered dose inhaler; PDV=Premature Discontinuation Visit; Rand.=randomization; SABA= short-acting 
β-agonist; TC=telephone call; TP=Treatment Period. 
Note: When data collection timepoints are concurrent, variables will be collected in the following order: vital signs, ECG, clinical laboratory assessments, and spirometry. 
a 
Screening Period will be 3 to 28 days for subjects on SABA only before study entry, and 14 to 28 days for subjects on ICS or ICS/LABA before study entry.  
b 
Subjects to return to clinic within 3 to 7 days following Visits 2, 3, 4, and 5. 
c 
Subjects who prematurely withdraw from the study will undergo a Premature Discontinuation Visit (see Section 4.2.5). 
d 
For subjects who received their regularly inhaled asthma medications and/or SABA on the morning of the visit, spirometry and reversibility will be measured at Visit 1a, 
which will occur within 10 days of Visit 1. For subjects who do not meet reversibility criteria at Visit 1a, Visit 1b will be scheduled for a second reversibility test, to 
occur within 7 days. Subjects who do not meet reversibility criteria after the second attempt will be screen failed. 
e 
At all visits beyond Visit 1, note time of the last dose of asthma medications. The visit must be rescheduled if the last dose of Ventolin was <6 hours before the visit. 
f 
Includes evaluation of height and weight at Visit 1. 
g 
A serum pregnancy test (β-hCG) will be performed at Visit 1; urine β-hCG test will be performed before randomization at Visit 2 (for women of child-bearing potential 
only). 
h 
At Visit 1, prohibited asthma medications are to be stopped and asthma medications changed as specified in Section 7.2.2. At the end of Visit 6 (or upon premature 
discontinuation or screen failure, if applicable), subjects will return to pre-study or other appropriate maintenance asthma medications. 

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Table 2 
Timed Assessments at Visits 2, 3, 4 and 5 
 
Pre-Dose 
(minutes) 
Post-Dose (minutes) 
Before 
leaving 
clinic 
For details see 
Section 
-60  
-30  
5  
15  
30  
45  
60  
120  
180 
240  
300 
360 
Vital signs 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Section 5.2.2 
Spirometry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 5.1.2 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 6.3 
Abbreviations: AE=adverse event. 
 
 
Table 3. 
Timed Assessments at Visit 6 
 
Pre-Dose 
(minutes) 
Post-Dose (minutes) 
Before 
leaving 
clinic 
For details see 
Section 
-60  
-30  
5  
15  
30  
45  
60  
120  
180 
240  
300 
360 
Vital signs 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Section 5.2.2 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Section 5.2.4 
Spirometry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 5.1.2 
Physical 
examination 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Section 5.2.1 
Clinical 
laboratory 
testing 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Section 5.2.3 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 6.3 
Abbreviations: AE=adverse event; ECG=electrocardiogram. 
 

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4.1 
Screening period (Visit 1, and Visits 1a/1b if applicable) 
For subjects who were receiving only SABA as needed before study entry, the minimum and 
maximum Screening Period will be 3 and 28 days, respectively. For subjects who were 
receiving regularly scheduled ICS or ICS/LABA before study entry, the minimum and 
maximum Run-in Period will be 14 and 28 days, respectively. The Screening Period should be 
as short as possible; however, the duration will be determined by the Investigator. 
4.1.1 
Visit 1 
The following activities will be performed at Visit 1: 
x 
Obtain informed consent 
x 
Register subject in IWRS to obtain subject screening number 
x 
Obtain demographic data, including age, race, smoking history, 
medical/surgical history, and age of onset of asthma 
x 
Obtain medication history, including prior and concomitant medications (see 
Section 7.7) 
x 
Obtain vital signs (see Section 5.2.2) 
x 
Conduct a complete physical examination (see Section 5.2.1) 
x 
Confirm acceptable MDI device technique and provide training as necessary 
x 
Confirm the subject satisfies inclusion/exclusion criteria (see Section 3.1 
and Section 3.2) 
x 
Obtain a 12-lead ECG (see Section 5.2.4) 
x 
Obtain clinical laboratory blood samples, including blood sample for serum 
β-hCG for all women of child-bearing potential (see Section 5.2.3) 
x 
Discontinue the subject’s baseline asthma medications and change to 
protocol-specified asthma medications as follows for both the Screening and 
randomized Treatment Periods (see Section 7.7.2.1): 
o For subjects receiving only SABA as needed: switch to Sponsor-
provided Ventolin as needed for symptoms 
o For subjects receiving regularly scheduled ICS or ICS/LABA: switch 
to Sponsor-provided Pulmicort Flexhaler (either 180 μg or 360 μg 
BID, based on the subject’s previous therapy; see Table 7). These 

Clinical Study Protocol
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subjects will also receive Sponsor-provided Ventolin as needed for 
symptoms.
x
Record AEs (if any)
Note: AEs must be recorded during the Screening Period, that is, from the 
time of signing the ICF (and assent form, as appropriate) to the start of 
randomized study drug. Adverse events that occur during the Screening 
Period will be recorded as medical history and not as study AEs unless they 
meet the definition of an SAE (see definition in Section 6.2).
For subjects who have not taken their regular morning doses of asthma maintenance 
medications and/or SABA within the previous 6 hours, the following activity will also be 
performed at Visit 1:
x
Conduct spirometry assessments (FEV1) (see Section 
x
Perform Ventolin reversibility test (described in Section 5.1.3).
Note: For subjects who complete this reversibility test at Visit 1 and do not meet Ventolin
reversibility criteria, Visit 1a will be scheduled for a second reversibility test.
For subjects who have taken their regular morning doses of inhaled asthma maintenance 
medications and/or SABA within the previous 6 hours before Visit 1 or any of the medications 
listed in Table 9 within the washout periods listed in Table 9, Visit 1a will be scheduled to 
allow for washout of asthma medications before spirometry and reversibility testing.
4.1.2
Visit 1a
The following activities will be performed at Visit 1a for subjects who did not complete 
spirometry at Visit 1 or do not have a reversibility test at Visit 1 or who fail to meet 
reversibility criteria at Visit 1. Visit 1a will be scheduled to occur within 10 days of Visit 1.
x
Review clinical laboratory results from Visit 1
x
Review concomitant medications (see Section 7.7)
x
Confirm the subject satisfies inclusion/exclusion criteria (see Section 3.1
and Section 3.2)
x
Perform Ventolin reversibility test (described in Section 5.1.3)
x
Record AEs (if any)
4.1.3
Visit 1b
Visit 1b may only be scheduled for subjects who did not perform Ventolin reversibility testing 
at Visit 1 and who did not meet Ventolin reversibility criteria at Visit 1a.

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For subjects who do not meet reversibility criteria at Visit 1a, Visit 1b will be scheduled to 
occur within 7 days of Visit 1a for a second reversibility test. Only 2 reversibility attempts 
will be allowed. Subjects who do not meet reversibility criteria after the second attempt will 
be screen failed.
The following activities will be performed at Visit 1b for subjects who do not meet 
reversibility criteria at Visit 1a:
x
Review concomitant medications (see Section 7.7)
x
Confirm the subject satisfies inclusion/exclusion criteria (see Section 3.1
and Section 3.2)
x
Perform Ventolin reversibility test (described in Section 5.1.3)
x
Record AEs (if any)
4.2
Treatment periods
4.2.1
General guidance for Treatment Visits 2 through 6 (Treatment Periods 1 
through 5)
x
At the start of each Treatment Visit, before any study procedures are
performed, site personnel must confirm the subject has withheld all asthma 
medications. The last Pulmicort Flexhaler dose should be no later than the 
previous night. The last dose of Ventolin should be no later than 6 hours 
before the visit. Confirm the last time of dosing.
Note: Subjects who did not withhold their Ventolin as described above 
before the start of study procedures must have their visit rescheduled as 
soon as is practical, but within the specified visit window (±2 days).
 
x
At Visit 2, the first dose of study drug will be administered before 10 am. At 
all subsequent Treatment Visits, the first dose of study drug will be 
administered before 10 am and within 1 hour of the time administered at 
Visit 2.
x
Sites should call the subject on the day before a scheduled visit to remind 
the subject of the following:

Pulmicort Flexhaler and Ventolin should be held for the time periods described 
above

Bring their Sponsor-provided Ventolin and Pulmicort Flexhaler, if assigned, 
with them to the clinic

Clinical Study Protocol 
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Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
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 
Refrain from ingesting xanthine-containing foods and beverages and 
caffeine-containing medications for at least 6 hours before each study visit and 
for the duration of each study visit (see Section 3.8.2) 
x 
Study drug should be dispensed as follows: 
 
At 15 to 30 minutes before dosing, the seal around the study day treatment box 
should be opened and the instructions for administration of study drug on the 
inner flap of the study day treatment box should be followed 
 
Refer to Section 7.2.1 for detailed instructions for preparation of treatments for 
administration. These instructions are to be adhered to and are relevant to all 
study treatment visits 
 
Subject will administer the dose of assigned study drug at the clinic 
x 
For doses consisting of 2 inhalations, the in-clinic dosing time will be 
recorded as the time of administration of the second actuation of study drug 
x 
Site personnel will instruct subjects not to take any non-study asthma 
medications without site personnel permission during a visit, until all study 
procedures have been completed and the subject is discharged. Site 
personnel should take every precaution to prevent use of non-study asthma 
medications during the test day. Site personnel may request the subject to 
surrender all non-study asthma medications at the start of the visit before 
performing any study procedures and return them to the subject at the end of 
the visit when all study procedures are completed. 
x 
If a subject is experiencing severe symptoms and requires Ventolin for relief 
of asthma symptoms at any time during a study visit, site personnel must 
note the time and justification for use in the subject’s chart and all 
spirometry assessments should be stopped during the current Treatment 
Visit. Safety assessments should be continued at the discretion of the 
Investigator. 
4.2.2 
Visit 2 (Randomization Visit, Treatment Period 1) 
The following activities should be performed before randomization: 
x 
Perform a urine pregnancy test 
x 
Confirm randomization criteria (see Section 3.3.1), including pre-dose 
spirometry assessments (see Section 5.1.2) 
x 
Review concomitant medications 
x 
Review clinical laboratory results from Visit 1 

Clinical Study Protocol 
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Study Code D6930C00001 (PT007001) 
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x 
Record AEs (if any) 
Note: Pre-randomization AEs are to be recorded as part of the medical 
history unless the event meets the definition of an SAE (see definition in 
Section 6.2). 
x 
Confirm acceptable MDI device technique 
x 
Register subject in IWRS to obtain subject randomization number. The 
subject is to be considered randomized after receiving a randomization 
number from the IWRS. 
The following activities are to be performed after randomization: 
x 
Perform all pre-dose vital signs assessments (see Section 5.2.2) 
x 
Dispense study drug (see Section 4.2.1) based on subject treatment 
assignment information from IWRS  
x 
Perform post-dose spirometry assessments (see Section 5.1.2) 
The following will be performed after the final (6-hour post-dose) spirometry test: 
x 
Record AEs (if any) 
x 
Schedule Visit 3, allowing for a Washout Period of 3 to 7 days 
x 
Assure that the subject has enough Sponsor-provided asthma medication to 
last until the next Treatment Visit (rescue Ventolin for all subjects, 
Pulmicort Flexhaler 180 μg or 360 μg for those subjects who were on ICS or 
ICS/LABA before study entry) 
x 
Perform post-dose vital signs assessments (see Section 5.2.2) before the 
subject leaves the clinic 
4.2.3 
Visits 3, 4, and 5 (Treatment Periods 2, 3, and 4) 
The following should be performed before any other activities: 
x 
Confirm eligibility criteria (see Section 3.1 and Section 3.2) 
x 
Review concomitant medications 
x 
Confirm acceptable MDI device technique 
Then the following activities are to be performed: 

Clinical Study Protocol
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x
Perform pre-dose vital signs assessments (see Section 5.2.2)
x
Perform pre-dose spirometry assessments (see Section 5.1.2), 
 
x
Dispense study drug (see Section 4.2.1) based on subject treatment 
assignment information from IWRS
x
Perform post-dose spirometry assessments (see Section 5.1.2)
The following will be performed after the final (6-hour post-dose) spirometry test:
x
Record AEs (if any)
x
Schedule the next Treatment Visit, allowing for a Washout Period of 3 to
7 days.
x
Assure that the subject has enough Sponsor-provided asthma medication to 
last until the next Treatment Visit (rescue Ventolin for all subjects, 
Pulmicort Flexhaler 180 μg or 360 μg for those subjects who were on ICS or 
ICS/LABA before study entry)
x
Perform post-dose vital signs assessments (see Section 5.2.2) before the 
subject leaves the clinic
4.2.4
Visit 6 (Treatment Period 5)
x
Confirm eligibility criteria (see Section 3.1 and Section 3.2)
x
Review concomitant medications
x
Confirm acceptable MDI device technique
x
Perform pre-dose vital signs assessments (see Section 5.2.2)
x
Perform pre-dose spirometry assessments (see Section 
)
x
Dispense study drug (see Section 4.2.1) based on subject treatment 
assignment information from IWRS
x
Perform post-dose spirometry assessments (see Section 5.1.2)
The following will be performed after the final (6-hour post-dose) spirometry test:
x
Conduct a complete physical examination (see Section 5.2.1)

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x 
Obtain a 12-lead ECG (see Section 5.2.4) 
x 
Obtain clinical laboratory blood samples (see Section 5.2.3) 
x 
Record AEs (if any) 
x 
Collect all unused Sponsor-provided asthma medication (Sponsor-provided 
Ventolin and Pulmicort Flexhaler, if applicable) 
x 
Schedule the follow-up telephone call (see Section 4.3.1) 
x 
Perform post-dose vital signs assessments (see Section 5.2.2) before the 
subject leaves the clinic 
x 
Return subjects to their pre-study asthma maintenance medication regimen 
or other appropriate asthma medications 
4.2.5 
Premature Study Withdrawal Visit 
See Section 4.3.2. The following activities should occur at the Premature Discontinuation 
Visit: 
x 
Review concomitant medications 
x 
Perform vital signs assessments (see Section 5.2.2) 
x 
Conduct a complete physical examination (see Section 5.2.1) 
x 
Obtain clinical laboratory blood samples (see Section 5.2.3) 
x 
Obtain a 12-lead ECG (see Section 5.2.4) 
x 
Record AEs (if any) 
x 
Collect all unused Sponsor-provided asthma medication (Sponsor-provided 
Ventolin and Pulmicort Flexhaler, if applicable) 
x 
Return subjects to their pre-study asthma maintenance medication regimen 
or other appropriate asthma medications  
x 
Schedule the follow-up telephone call (see Section 4.3.1) 
4.3 
Follow-up period 
4.3.1 
Follow-up telephone call 
Subjects will be contacted by study personnel through a telephone call 3 to 7 days after the 
last dose of study drug to assess AEs and SAEs, if any. 

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Study Code D6930C00001 (PT007001)
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4.3.2
Premature withdrawal from the study
Complete the end of treatment form of the eCRF and record the reason for premature study 
withdrawal. The following categories should be used to describe these events in the eCRF:
x
Subject discretion (document reason)
x
Investigator considers it to be in the best interest of the subject
x
AEs
x
Administrative reasons (eg, early termination of the study)
x
Subject lost to follow-up
x
Major protocol deviation
x
Death
x
Protocol-specified criteria such as use of prohibited medications (refer to 
Section 7.7.3).
5.
STUDY ASSESSMENTS
The iDatafax system will be used for data collection and query handling. The Investigator will 
ensure that data are recorded on the eCRFs as specified in the clinical study protocol and in 
accordance with the instructions provided.
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the clinical study agreement. The 
Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
5.1
Efficacy assessments
Efficacy will be assessed by PFTs. Forced expiratory spirometry for derivation of FEV1 as 
defined in ATS/ERS guidelines will be performed in accordance with ATS criteria 
(Appendix A) using a spirometer that meets or exceeds minimum performance 
recommendations of the ATS (Appendix B).
5.1.1
Standardization of spirometry collections
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.

Clinical Study Protocol
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Study Code D6930C00001 (PT007001)
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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 (Appendix B).
All study staff responsible for performing PFTs will receive standardized training at an
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 et al 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 (Appendix B). All PFT testing will 
be stored electronically. After completion of testing, the study staff will electronically transmit 
the spirometric measurements for centralized quality assurance review 
 
. Feedback on the quality of the measurements will be provided to the 
investigational site and to the Sponsor or designee for central data management.
5.1.2
Assessment of FEV1
Spirometry will be conducted at all visits except the Premature Discontinuation Visit (when 
applicable).
Spirometry at Visits 1, 1a and/or 1b, and 2 will be used to satisfy enrollment and 
randomization criteria. Multiple forced expiratory efforts (at least 3 but no more than 8) will 
be performed and the 2 best efforts that meet the ATS/ERS acceptability and reproducibility 
criteria will be recorded. The best efforts will be based on the highest FEV1. The average of 
these 2 assessments will be used to calculate the screening FEV1.
At all Treatment Visits (Visits 2, 3, 4, 5, and 6), spirometry will 
be conducted 60 minutes and 30 minutes before study drug administration. The average of 
these 2 assessments will be used to calculate morning pre-dose FEV1.
Following study drug administration at each visit, spirometry will be obtained at 5, 15, 30, 45, 
60, 120, 180, 240, 300, and 360 minutes post-dose. Three tests will be performed at each
timepoint. The highest value at each timepoint will be used for these post-dose assessments.
5.1.3
Characterization of reversibility
Reversibility to Ventolin will be evaluated at Visit 1, 1a, and/or 1b. Subjects must demonstrate 
reversibility to Ventolin to be randomized in the study; no more than 2 reversibility test 
attempts are allowed. Reversibility testing is performed as follows:
1.
Determine if morning doses of all maintenance asthma ICS/LABA, if applicable,
were withheld and that short-acting bronchodilators were not administered within 
6 hours of testing

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2.
Perform pre-bronchodilator PFTs at 30 minutes before administration of Ventolin
3.
Administer 2 actuations of Ventolin (90 μg per actuation; total 180 μg)
4.
Perform post-bronchodilator PFTs 30 minutes after the administration of Ventolin.
Reversibility will be a comparison of the best FEV1 effort obtained at 30 minutes pre-
bronchodilator to the best FEV1 effort obtained at 30 minutes post-bronchodilator following 
administration of Ventolin. A subject is considered reversible to Ventolin if the improvement 
in FEV1 at 30 minutes post-Ventolin is ≥15%.
5.2
Safety assessments
Safety will be assessed by vital signs, ECGs, and clinical laboratory tests, in addition to
recording AEs.
5.2.1
Medical/surgical history and physical examination
Medical and surgical history will be collected at Visit 1. A complete physical examination will 
be performed at Visits 1 and 6 or the Premature Discontinuation Visit, as applicable.
A complete physical examination will include the following: general appearance, skin, head, 
eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest, heart, abdomen, 
extremities, and nervous system. Additionally, weight, assessed in ordinary indoor clothing 
with shoes off, and height will be recorded at Visit 1 only (Table 1).
5.2.2
Vital signs
At all study visits (Visits 1 to 6 and the Premature Discontinuation Visit, if applicable), heart 
rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) will be assessed.
At all Treatment Visits, vital signs will be assessed pre-dose and post-dose before the subject 

Clinical Study Protocol 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
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leaves the clinic. Heart rate, SBP and DBP will be assessed after the subject is supine or 
seated for 5 minutes. If, in the opinion of the Investigator, a clinically significant vital sign 
change occurs, then the measurement should be repeated at medically appropriate intervals 
until the value returns to within an acceptable range. If the value does not return to baseline, 
the Investigator should determine if this is an AE (see Section 6.1). 
5.2.3 
Clinical laboratory safety assessments 
Blood will be collected for clinical laboratory testing at Visit 1, Visit 6 (post-dose), and during 
the Premature Discontinuation Visit, if applicable. 
Subjects will be in a seated or supine position during blood collection. Clinical laboratory tests 
for this study are listed in Table 4. 
Approximately 10 mL of blood will be collected per subject during the study. The exact blood 
volume collected may vary depending on laboratory procedures. However, it will not exceed 
15 mL per subject during the study. 
Clinical safety laboratory tests will be analyzed by a central laboratory according to 
standardized, validated assays. The laboratory will supply detailed procedures for the 
preparation and collection of blood samples along with all containers needed for their 
collection. Blood sample volumes will meet the laboratory’s specification. Sites must evaluate 
clinical laboratory data before the subject is randomized. 

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Table 4. 
List of Laboratory Tests 
Hematology 
Hemoglobin  
Platelet count 
Hematocrit  
Mean corpuscular hemoglobin 
White blood cell count with differential  
Mean corpuscular hemoglobin concentration 
Red blood cell count  
Mean corpuscular volume 
Clinical chemistry 
Liver enzyme and other liver function tests Other clinical chemistry 
Alanine aminotransferase 
Albumin 
Aspartate aminotransferase 
Blood urea nitrogen 
Alkaline phosphatase  
Calcium 
Bilirubin, total  
Chloride 
Gamma-glutamyl transferase  
Cholesterol  
 
Bicarbonate 
 
Creatinine 
 
Glucose 
 
Magnesium  
 
Potassium 
 
Phosphate 
 
Protein, total  
 
Sodium 
 
Triglycerides  
 
Urea  
Other tests: 
β-hCG test for pregnancya 
Creatinine clearance will be estimated at Screening only. The CKD-EPI formula will be used for 
subjects >18 years old, and the Schwartz equation will be used for subjects ≤18 years old 
(Schwartz et al 1976). 
Abbreviations: CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration. 
a 
Serum β-hCG will be assessed in all women of childbearing potential at Visit 1. Urine β-hCG test will be 
performed at Visit 2 before randomization. 
 
5.2.4 
12-lead ECG 
A single 12-lead ECG will be obtained at Visit 1, post-study drug dosing at Visit 6, and during 
the Premature Discontinuation Visit, if applicable.   

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To standardize ECG collection, all sites will be provided with identical ECG equipment 
with customized study-specific software on a laptop. All study staff responsible for 
performing ECG collection will receive identical, detailed training at the Investigator meeting 
as well as site-phone training sessions. Each site is required to demonstrate proficiency in the 
use of the equipment and the ability to perform technically acceptable ECGs before 
performing testing on study subjects. After each test is performed, the site will electronically 
transfer the ECG data for centralized quality assurance review 
Feedback on the quality of the ECGs will be provided to the investigational site via a site 
qualification form. Sites must evaluate a subject’s ECG data before the subject is randomized.
The ECG parameters to be assessed include HR, PR interval, QRS axis, QRS interval, and 
QT/Fridericia-corrected 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.
5.3
Other assessments – not applicable
5.4
Pharmacokinetics – not applicable
5.5
Pharmacodynamics – not applicable
5.6
Genetics – not applicable
5.7
Biomarker analysis - not applicable
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of AEs
The following definitions of terms are guided by the International Conference for
Harmonisation (ICH) and the US Code of Federal Regulations (CFR) (21 CFR 312.32) 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:

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x 
any symptom or condition not previously reported by the subject (medical 
history) 
x 
an exacerbation of a pre-existing symptom or condition 
x 
a significant increase in frequency or intensity of a pre-existing episodic 
event or condition 
x 
a drug interaction 
x 
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: 
x 
medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, 
blood transfusion); the condition that led to the procedure is an AE (eg, 
bleeding esophageal varices, dental caries) 
x 
overdose of either study drug or concurrent medication without any clinical 
signs or symptoms 
x 
non-clinically significant abnormal laboratory values (if accompanied by 
signs/symptoms, the signs or symptoms are considered an AE) 
6.2 
Definitions of SAE 
An AE is considered “serious” if, in the view of the Investigator or Sponsor, it results in any 
of the following outcomes: 
x 
death 
x 
a life-threatening AE 
x 
inpatient hospitalization or prolongation of existing hospitalization  
x 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
x 
a congenital anomaly/birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 

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dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Hospitalization for a pre-existing condition, including an elective procedure, which has not 
worsened, does not constitute an SAE. 
An AE is considered “life-threatening” if, in the view of the Investigator or Sponsor, its 
occurrence places the patient or subject at immediate risk of death. It does not include an 
adverse reaction or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death. 
For further guidance on the definition of a SAE, see Appendix C. 
6.3 
Recording of AEs 
6.3.1 
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 (as described in Section 6.2) are classified as ‘serious’ 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 randomized study drug. 
6.3.2 
Pre-randomization AEs 
Adverse events 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 6.2. 
6.3.3 
AEs based on signs and symptoms 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
6.3.4 
AEs based on examinations and tests 
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. 

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If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Criteria for a “clinically significant” laboratory abnormality are:
x
a laboratory abnormality that leads to study drug dose suspension or 
discontinuation
x
a laboratory abnormality that results in any therapeutic intervention (ie, 
concomitant medication or therapy)
x
Any other laboratory abnormality judged by the Investigator to be of any 
particular clinical concern (eg, significant fall in hemoglobin not requiring 
transfusion)
For laboratory abnormalities that do not meet the above criteria but are outside of the normal 
reference range, the Investigator should indicate whether the value is clinically significant or 
not clinically significant for the subject.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
Paradoxical bronchospasm will be monitored 
.
6.3.5
Disease under study 
Symptoms of the disease under study are those which might be expected to occur as a direct 
result of the subject’s asthmatic condition (eg, wheeze, breathlessness, cough). Events that are 
unequivocally due to the disease under study should not be reported as an AE during the study 
unless they meet SAE criteria or lead to discontinuation of study drug.
6.3.6
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.

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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. 
6.3.7 
Relationship to study drug 
The Investigator will assess causal relationship between the study drug and each AE, and 
answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that 
the event may have been caused by the study drug?’ 
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’. 
A guide to the interpretation of the causality question is found in Appendix C. 
6.4 
Reporting of 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 or designee. All SAEs must be reported to the Sponsor or 
designee no later than 24 hours after the Investigator recognizes/classifies the event as an 
SAE. All SAEs should be documented and reported using the eCRF. At a minimum, a 
description of the event and the Investigator’s judgment of causality must be provided at the 
time of the initial report using the appropriate form (eg, SAE Report Form). After the initial 
report, as necessary, the Investigator must provide any additional information on an SAE to 
the Sponsor 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 discontinuing study drug, all AEs/SAEs will be collected through the follow-up 
telephone call. 
Post-treatment SAEs following the last dose of study drug must be reported to the Sponsor as 
described in Section 6.4.3. 
The Investigator is responsible for continuing to report any new or relevant follow-up 
information that s/he learns about the SAE. 
6.4.1 
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 post mortem examination is performed, a copy of the 
autopsy report should be submitted to the Sponsor. 

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6.4.2 
Post-study follow-up of AEs 
Any AEs that are unresolved at the subject’s last AE assessment in the study are to be 
followed up by the Investigator for as long as medically indicated, but without further 
recording in the eCRF. 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. 
6.4.3 
Notification of post-treatment SAEs 
Investigators are not obligated to actively follow subjects after completion of the study. 
However, if the Investigator becomes aware of a post-treatment SAE occurring within 3 to 
7 days following the last dose of study drug, 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. 
6.4.4 
IRB notification of SAEs 
The Investigator is responsible for promptly notifying her/his IRB 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 submission must be 
retained for each safety report. The Investigator is also responsible for notifying the Sponsor if 
their IRB requires revisions to the ICF or other measures based on its review of an SAE 
Report. 
6.4.5 
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 the Sponsor’s clinical studies. Safety reports must also 
be submitted to the appropriate IRBs as soon as possible. Documentation of submission to the 
IRB must be retained for each safety report. 
6.5 
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 Investigator’s Brochure for AS MDI and approved product 
labeling for open-label products. 

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6.6 
Pregnancy 
Any pregnancy that occurs from Visit 1 until study completion must be reported to the 
Sponsor. The pregnancy must be followed up to determine the outcome (including premature 
termination) and status of mother and child. 
6.6.1 
Maternal exposure 
If a subject becomes pregnant during the course of the study, the study drug should be 
discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
subject was withdrawn from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate Sponsor representatives immediately but no later than 24 
hours of when he or she becomes aware of it. 
Pregnancy should be recorded on a paper Pregnancy Report Form and reported by the 
Investigator to the Sponsor or designee. Pregnancy follow-up should be recorded on the same 
Pregnancy Report 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. 
The same timelines apply when outcome information is available. 
6.6.2 
Paternal exposure  
Male subjects who are sexually active must agree to use a double barrier method of 
contraception (condom with spermicide) from the first dose of randomized treatment until 
2 weeks after their last dose, and must not donate sperm during their study participation 
period. 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. 
6.7 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for a study drug that either causes harm to the subject or has the 
potential to cause harm to the subject.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or subject. 

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Medication error includes situations where an error:  
x 
occurred 
x 
was identified and intercepted before the subject received the drug 
x 
did not occur, but circumstances were recognized that could have led to an 
error 
Examples of events to be reported in clinical studies as medication errors: 
x 
drug name confusion 
x 
dispensing error, eg, medication prepared incorrectly, even if it was not 
actually given to the subject 
x 
drug not administered as indicated, for example, wrong route or wrong site 
of administration 
x 
drug not taken as indicated, eg, tablet dissolved in water when it should be 
taken as a solid tablet  
x 
drug not stored as instructed, eg, kept in the refrigerator when it should be at 
room temperature  
x 
wrong subject received the medication (excluding IWRS errors) 
x 
wrong drug administered to subject (excluding IWRS errors) 
Examples of events that do not require reporting as medication errors in clinical studies: 
x 
errors related to or resulting from IWRS, including those which lead to one 
of the above listed events that would otherwise have been a medication error  
x 
subject accidentally missed drug dose(s) (eg, forgot to take medication) 
x 
accidental overdose (will be captured as an overdose) 
x 
subject failed to return unused medication or empty packaging 
x 
errors related to background and rescue medication, or standard of care 
medication in open label studies  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.   

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If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate Sponsor representatives immediately but no later than 
24 hours of when he or she becomes aware of it. 
6.8 
Management of study drug-related toxicities – not applicable 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational products 
In this protocol, “study drug” refers to an active ingredient or placebo being tested or used as a 
reference in this study. Study drugs used in this study are summarized in Table 5. Instructions 
for priming and use are provided in Appendix D. 
AS MDI and Placebo MDI are manufactured and supplied by the Sponsor. Placebo MDI is 
manufactured in the image of the active test product. For open-label Proventil (active control), 
MDIs will be provided from commercial supplies. Manufacturer’s instructions for study drug 
administration will be provided.  
Table 5. 
Randomized Study Drugs 
Product Name 
and Dose 
Product Strength 
Manufacturer 
Dosage Form/ 
Fill Count 
Administration 
AS MDI 90 μg 
AS MDI 45 μg/ 
actuationa 
Pearl 
MDI/ 
120 actuations 
Taken as 2 actuations 
AS MDI 180 μg 
AS MDI 90 μg/ 
actuationb 
Pearl 
MDI/ 
120 actuations 
Taken as 2 actuations 
Placebo MDI 
Formulation does 
not contain an 
active ingredient 
Pearl 
MDI/ 
120 actuations 
Taken as 2 actuations 
Proventil 90 μg 
Albuterol 
90 μg/actuationb 
Merck Sharp & 
Dohme Corp. 
MDI/ 
200 actuations 
Taken as 1 actuation 
Proventil 180 μg 
Albuterol 
90 μg/actuationb 
Merck Sharp & 
Dohme Corp. 
MDI/ 
200 actuations 
Taken as 2 actuations 
Note: All study drugs will be administered by oral inhalation. 
a 
Each inhalation contains 54 μg albuterol sulfate corresponding to 45 μg albuterol base per actuation 
b 
Each inhalation contains 108 μg albuterol sulfate corresponding to 90 μg albuterol base per actuation 
 
For the Sponsor-provided background asthma medication (Ventolin and Pulmicort Flexhaler) 
and Ventolin for reversibility testing, commercial dry powder inhalers/MDIs with dose 
counters and manufacturer’s instructions for use will be provided. These medications are 
listed in Table 6. 

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Table 6. 
Other Sponsor-provided Study Medications 
Product 
Name 
Product Strength 
Manufacturer 
Dosage Form/ 
Fill Count 
Administration 
Pulmicort 
Flexhaler 
Budesonide 
180 μg 
AstraZeneca 
DPI/ 
120 actuations 
1 or 2 inhalations BID, as 
directed at Visit 1 
Ventolin 
Albuterol 
90 μg/actuationa 
GlaxoSmithKline 
MDI/ 
200 actuations 
Taken as directed for 
reversibility testing (Visits 
1, 1a, or 1b) and as needed 
for symptoms during the 
Screening and randomized 
Treatment Periods 
Abbreviation: DPI=dry powder inhaler. 
Note: All study drugs will be administered by oral inhalation. 
a 
Each inhalation contains 108 μg albuterol sulfate corresponding to 90 μg albuterol base per actuation. 
 
7.2 
Dose and treatment regimens 
Each of the 5 Treatment Visits will include 1 of the following single-dose treatments, based 
on the subject’s randomized treatment assignment: 
x 
AS MDI 90 μg (2 actuations of 45 μg/actuation) 
x 
AS MDI 180 μg (2 actuations of 90 μg/actuation) 
x 
Placebo MDI (2 actuations) 
x 
Proventil 90 μg (1 actuation of 90 μg/actuation) 
x 
Proventil 180 μg (2 actuations of 90 μg/actuation) 
7.2.1 
Randomized study drug 
AS MDI and Placebo MDI 
Individual AS MDIs and Placebo MDIs will be packaged in a foil pouch and contained in an 
individual visit treatment box. Both the visit treatment box and the foil overwrap will have a 
label with a component ID number. Confirm that the identifier given by IWRS and the ID 
number written on the label are the same. The foil overwrap is labeled with a 2-part label. 
Write the subject number and treatment visit number on each part of the 2-part label. The tear-
off part of the label is to be placed onto the IWRS confirmation report. 
All MDIs must be primed by study personnel before the first use. Priming involves releasing 
4 sprays into the air before the first use of the inhaler. Shaking and priming the inhaler fills a 
chamber inside the canister with the correct dose and mix of medication so that it is ready to 
use.   

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AS MDI must be primed in a separate room from the subject treatment area. Since the MDI is 
primed in a separate room before dosing, there is a possibility that there may be a delay 
between priming and dosing, and therefore to ensure consistency in the administration for all 
subjects, the MDIs are to be gently shaken (5 to 10 seconds) immediately before each 
actuation (inhalation). 
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.   
Each dose will consist of 2 actuations from the MDI. See Appendix D for instructions on the 
administration of AS MDI and Placebo MDIs. 
Open-label Proventil 
Individual Proventil MDIs will be contained in an individual visit treatment box. The visit 
treatment box will have a 2-part label with a component ID number. Confirm that the 
identifier given by IWRS and the component ID number written on the label are the same. 
Write the subject number and treatment visit number on each part of the 2-part label. The tear-
off part of the label is to be placed onto the IWRS confirmation report. 
Proventil should be primed by study personnel (in a separate room from the subject treatment 
area) per manufacturer’s instructions before administering to subject. Since Proventil is 
primed in a separate room before dosing, there is a possibility that there may be a delay 
between priming and dosing, and therefore to ensure consistency in the administration for all 
subjects, the MDIs are to be gently shaken (5 to 10 seconds) immediately before each 
actuation (inhalation).  
Each dose will consist of 1 or 2 actuations from the MDI. See Appendix D for the 
manufacturer’s instructions on the administration of Proventil. 
7.2.2 
Sponsor-provided background asthma therapies 
Ventolin 
Open-label Ventolin will be provided by the Sponsor and stored in a secured location within 
the clinic or pharmacy facilities. Ventolin should be stored at room temperature by the subject. 
Ventolin should be primed per manufacturer’s instructions before dispensing to subject. See 
Appendix D for the manufacturer’s instructions on the administration of Ventolin. Study 
personnel will record the number on the dose counter at the time of dispensing (following 
priming) and upon return. 
Pulmicort Flexhaler 
Open-label Pulmicort Flexhaler will be provided by the Sponsor and stored in a secured 
location within the clinic or pharmacy facilities. Pulmicort Flexhaler should be stored at room 
temperature by the subject. Pulmicort Flexhaler should be primed per manufacturer’s 

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instructions before dispensing to subject. See Appendix D for the manufacturer’s instructions 
on the administration of Pulmicort Flexhaler. Study personnel will record the number on the 
dose counter at the time of dispensing (following priming) and upon return. 
7.3 
Labeling 
AS MDI and Placebo MDI will be packaged by the Sponsor. Open-label Proventil 
(randomized study drug), Ventolin for rescue and reversibility testing, and Pulmicort 
Flexhaler will be supplied as commercially sourced open-label MDIs. 
7.3.1 
Primary packaging and labeling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labeling. 
Blinded supplies (AS MDI and Placebo MDI) 
Each MDI will be labeled with a 1-part label. The foil pouch will be labeled with a 1-part 
label. A 2-part label will be affixed to the carton holding the foil. 
Open-label supplies (Proventil) 
Open-label Proventil will be provided as individually labeled MDIs. Each MDI will contain a 
single label.  
Both single and 2-part labels will be printed with black ink and may include the following 
text: 
• Packaging Lot Trace ID # 
• Space for entry of screening # 
• Component ID # 
• Space for entry of randomization # 
• Fill Count & Dosage Form 
• Space for entry of Interval ID (Visit # only) 
• Re-evaluation/Expiration date (if 
applicable) 
• Dosing Instructions 
• Storage Conditions 
• Compound ID - Protocol # 
• Country regulatory requirements 
• Sponsor address (if applicable) 
• Translation Key (if applicable) 
 
7.3.2 
Secondary packaging and labeling information (box) 
AS MDI, Placebo MDI, open-label Proventil, open-label Ventolin, and open-label Pulmicort 
Flexhaler supplies will be provided as 1 MDI per box. Box configuration is subject to change 
due to packaging constraints. 

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Each box will be labeled with a 2-part panel 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 date (if applicable) 
• Dosing Instructions (if applicable) 
• Storage Conditions 
• Compound ID - Protocol # 
• Country regulatory requirements 
• Sponsor address (If applicable) 
• Translation Key (If applicable) 
 
7.4 
Storage 
All study drugs and Sponsor-provided medication should be kept in a secure place under 
appropriate storage conditions. The investigational product label specifies the appropriate 
storage. Commercially sourced medications (Proventil, Ventolin, and Pulmicort Flexhaler) 
should be stored as indicated on the respective product label. 
Note: The clinical supplies storage area at the site must be monitored by the site staff for 
temperature consistency with the acceptable storage temperature range specified in the 
product label. Documentation of temperature monitoring should be maintained. 
7.5 
Compliance 
The time of administration of randomized study drug will be recorded in the appropriate 
sections of the eCRF. 
7.6 
Accountability 
Study personnel will have access to an IWRS to allocate subjects, to assign drug to subjects, 
and to manage the distribution of clinical supplies. Clinical supplies will be packaged 
according to a component schedule generated by the Sponsor or designee. Each person 
accessing the IWRS must be assigned an individual unique personal ID number (PIN). They 
must use only their assigned PIN to access the system and they must not share their assigned 
PIN with anyone. 
The study drug provided for this study will be used only as directed in the clinical study 
protocol. 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 secured location to which only the 
Investigator and designated assistants have access. Storage conditions for the clinical supplies 

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should be observed, monitored, and documented. Clinical supplies are to be dispensed only in 
accordance with the protocol. The Investigator is responsible for keeping accurate records of 
the clinical supplies received from the Sponsor, the amount dispensed to and returned by the 
subjects, and the amount remaining at the conclusion of the study. Study drug should be 
handled in accordance with Good Pharmacy Practices. The Clinical Monitor should be 
contacted with any questions concerning investigational products where special or protective 
handling is indicated. At the end of the study, all clinical supplies including partial and empty 
containers must be returned as directed by the Sponsor. 
Sites should check with the Sponsor representative for appropriate documentation that must be 
completed for drug accountability. 
The Investigator or designated assistant should not open individual clinical supply containers 
until all pre-dose assessments have been completed and the subject is eligible to be 
randomized/continue with the study. Any deviation from this must be discussed with the 
Clinical Monitor. 
For each subject, all used study drug materials will be collected. Used subject supplies will be 
kept at room temperature in a secure and locked cabinet until returned to the Sponsor or 
designee. Note: Used study drug will be stored separately from unused study drug. 
7.7 
Concomitant and other treatments  
7.7.1 
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 eCRF page; 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. 
Some subjects eligible for this study will be on regular inhaled asthma maintenance therapy 
defined as an ICS with or without a LABA with a stable dose for at least 30 days prior to 
Visit 1. The permitted total daily ICS dosage to qualify ICS usage for the 30 days prior to 
Visit 1, along with the assigned dose for Sponsor-provided Pulmicort Flexhaler, is defined in 
Table 7. 

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Table 7 
Dose of Sponsor-provided Pulmicort Flexhaler to be Assigned Based 
on Pre-study ICS or ICS/LABA Dose 
Pre-study Asthma Inhaled 
Corticosteroid 
Total Daily Dose of Pre-
study Inhaled 
Corticosteroid (μg/day) 
Dose of Sponsor-provided 
Pulmicort Flexhaler 
(μg/day) 
Beclomethasone 
100 to ≤200 
360  
Beclomethasone 
>200 to ≤400 
720 
Budesonide 
200 to ≤400 
360 
Budesonide 
>400 to ≤800 
720 
Ciclesonide 
80 to ≤160 
360 
Ciclesonide 
>160 to ≤320 
720 
Fluticasone furoate 
100  
360 
Fluticasone furoate 
200 
720 
Fluticasone propionate 
100 to ≤250 
360 
Fluticasone propionate 
>250 to ≤500 
720 
Mometasone furoate 
110 to ≤220 
360 
Mometasone furoate 
>220 to ≤440 
720 
Triamcinolone acetonide 
400 to ≤1000 
360 
Triamcinolone acetonide 
>1000 to ≤2000 
720 
 
7.7.2 
Concomitant medications 
Any current ongoing medications, including over-the-counter medications and herbal 
supplements, will be allowed provided they are not explicitly prohibited by the protocol 
(Table 9 or Table 10). 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. 
7.7.2.1 
Required concomitant medications 
Subjects who were receiving a regularly scheduled ICS or ICS/LABA before study entry will 
be switched to Pulmicort Flexhaler 180 μg or 360 μg BID, and LABA (if applicable) will be 
discontinued (Table 7). These subjects will continue to use Sponsor-provided Pulmicort 
Flexhaler 180 μg or 360 μg BID, as assigned at Visit 1, throughout the Screening Period and 
for the remainder of the study during both the randomized Treatment Periods and Washout 
Periods. 

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No other asthma medications are allowed for the remainder of the study, except for Sponsor-
provided Ventolin to be used as needed for rescue. 
7.7.2.2 
Allowed allergy medications 
Table 8 lists allergy medications that are allowed as long as the subject has been on a stable 
dose for at least 30 days before Visit 1 and remains on a stable dose throughout the study. 
Table 8  
Allowed Allergy Medications 
Non-sedating long-acting antihistaminesa 
Allergen immunotherapy 
Intranasal corticosteroids 
Intranasal antihistamines or combination products of intranasal antihistamines/corticosteroids 
a 
Short-acting antihistamines (eg, diphenhydramine) are also permitted for use as needed, but not regularly. 
 
7.7.3 
Prohibited medications 
7.7.3.1 
Prohibited asthma and allergy medications and washout periods 
Specific prohibited asthma and allergy medications are listed in Table 9. Subjects taking any 
of these prohibited medications are required to stop taking them at Visit 1 and are required to 
attend Visit 1a for reversibility testing. The required washout period for each medication 
before reversibility testing is shown in Table 9. 

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Table 9  
Prohibited Asthma and Allergy Medications That Must be 
Discontinued at Visit 1 and Required Washout Period Prior to 
Visit 1a 
Medication 
Minimum Washout Period Prior to Visit 1a 
Short-acting muscarinic antagonista 
8 hours 
Oral β2-agonists 
2 days 
Theophylline 
2 days 
Cromoglycate 
7 days 
Nedocromil 
7 days 
Ketotifenb 
7 days 
Zileuton 
7 days 
LABAsc 
 
Indacaterol, olodaterol, vilanterol 
7 days 
Salmeterol, formoterol 
48 hours 
Leukotriene receptor antagonist s (eg, Singulair™) 
7 days 
a 
Administered as fixed or loose combinations. 
b 
Ketotifen eye drops are allowed; no washout required. 
c 
In combination with an ICS. 
 
7.7.3.2 
Prohibited non-asthma and non-respiratory medications 
Subjects requiring medications presented in Table 10 are prohibited from participating in this 
study. Subjects who recently discontinued use of these medications may be considered for 
study enrollment provided they have met the minimum 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 10, the Investigator should discuss with the monitor the 
suitability of the subject continuing study drug. 
Note: Use of systemic corticosteroids (eg, oral, parenteral, intraocular, intraarticular) is 
prohibited for the duration of the study, including both the Screening and randomized 
Treatment Periods. If a subject requires a systemic corticosteroid to treat an asthma worsening 
or asthma exacerbation, the subject will be discontinued from study drug and withdrawn from 
the study. 

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Table 10 
Prohibited Non-Asthma and Non-Respiratory Medications 
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 
Antitumor 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 
Protease inhibitors (eg, ritonavir) 
30 days 
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 
30 days before Visit 1 and throughout the Screening and Treatment Phase, and the dose does not exceed the 
maximum recommended. 
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 before 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 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 before the study 
and throughout the Screening and 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 on a case-by-case basis (eg, Prolia® [denosumab] for osteoporosis, may be allowed after 
consultation). 
 
7.7.4 
Other concomitant treatment 
Medication other than that described above, which is considered necessary for the subject’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF. 

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8. 
STATISTICAL ANALYSES  
This study will be conducted as a 5-period, 5-treatment Williams (Williams 1949) crossover 
design evaluating the following 5 treatments: 
x 
AS MDI 90 μg (2 actuations of 45 μg/actuation) 
x 
AS MDI 180 μg (2 actuations of 90 μg/actuation) 
x 
Placebo MDI (2 actuations) 
x 
Proventil 90 μg (1 actuation of 90 μg/actuation) 
x 
Proventil 180 μg (2 actuations of 90 μg/actuation) 
The primary objective of this study is to determine the dose of albuterol delivered from 
AS MDI that is comparable to Proventil. This design utilizes 10 treatment sequences. 
8.1 
Statistical considerations 
Analyses will be performed by the Sponsor or its representatives. All analyses will be 
specified in a detailed statistical analysis plan (SAP) that will include table and data listing 
shells with mock graphical representations. The SAP will be signed before database lock and 
unblinding. 
8.2 
Sample size estimate 
Power calculations were based on the properties of the primary endpoint, the change from 
baseline in FEV1 AUC0-6. Randomization of 70 subjects in order to achieve at least 
64 subjects completing the study will provide >95% overall probability to demonstrate 
superiority of each treatment relative to Placebo MDI assuming a minimum detectable 
difference (active–Placebo MDI) of 100 mL, within-subject standard deviation of 115 mL, 
and 2-sided 5% level test. The estimate of the within-subject standard deviation was obtained 
from a 5-treatment, 5-period dose-ranging study to evaluate albuterol dry powder inhaler and 
HFA in subjects ages 12 and older with persistent asthma (NCT01058863). 
8.3 
Definitions of analysis sets 
The following analysis sets are defined in this study: 
x 
The Intent-To-Treat (ITT) analysis set is defined as all subjects who are 
randomized to treatment and receive at least 1 dose of the study treatment. 
Subjects will be analyzed in each period according to the treatment they 
were assigned to per the randomization scheme (Note that a subject who 
used a study treatment but took less than 1 full dose of treatment will qualify 
for this analysis set).  

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x 
A Modified ITT (mITT) analysis set is a subset of the ITT analysis set 
including subjects who received treatment and have post-treatment efficacy 
data from at least 2 Treatment Periods. Data judged to be impacted by major 
protocol deviations will be determined prior to unblinding and excluded per 
the statistical protocol deviation plan. Statistical tabulations and analyses 
will be by randomized treatment, but data obtained after subjects receive an 
incorrect treatment will be excluded from the affected periods. 
x 
The Safety analysis set is defined as all subjects who are randomized to 
treatment and receive at least 1 dose of the study treatment. Subjects will be 
analyzed according to treatment received rather than per the randomization 
scheme. 
x 
The Not Randomized analysis set is defined as subjects who did not 
receive a randomization number and therefore did not receive a dose of 
study treatment (eg, subjects who were screen failures or stopped 
participation before being randomized). 
Demographics and baseline characteristics will be summarized for the ITT, mITT, and Safety 
analysis sets. Extent of exposure will be summarized for the Safety analysis set. The Safety 
analysis set will be used to summarize safety. 
Efficacy analyses will be performed for the mITT analysis set. As a sensitivity analysis, the 
primary endpoint, change from baseline in FEV1 AUC0-6, will also be analysed using the ITT 
analysis set. 
8.4 
Outcome measures for analyses 
All efficacy assessments are relative to baseline and will be compared with Placebo MDI and 
Proventil, and where appropriate, the AS MDI dose levels will be compared. Since pre-dose 
values are known to be variable and an isolated timepoint may not accurately reflect the true 
baseline, the following baseline will be used for the statistical analyses of study assessments 
unless otherwise specified: the mean of available pre-dose values on the first day of each 
treatment cycle, ie., the mean of pre-dose values at Visits 2, 3, 4, 5, and 6, where the mean of 
the 60- and 30-minute pre-dose value for each visit is obtained and then the visit means are 
averaged. 
Refer to Section 2 for a complete delineation of efficacy and safety endpoints. 
8.5 
Methods for statistical analyses 
8.5.1 
Primary efficacy analysis  
The FEV1 AUC0-6 is the area under the curve for the change from baseline in FEV1 calculated 
using the trapezoidal rule. All observed data will be utilized with the trapezoidal rule to 
calculate AUC. To aid in interpretation, all AUC values will be normalized by dividing the 
AUC by the time from the first to the last non-missing value (typically 6 hours). 

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The FEV1 AUC0-6 will be analyzed using a linear mixed model with a random subject effect. 
The fixed effects in the model will include treatment, treatment sequence, baseline FEV1, and 
period. Analyses will be conducted on the overall study population, and may also be 
conducted separately within each of the 2 ICS use subgroups (previous ICS use and no 
previous ICS use before Visit 1). 
Superiority comparisons of AS MDI relative to Placebo MDI and Proventil versus Placebo 
MDI will be conducted first using a dose-ordered approach. A 2-sided alpha level of 0.05 will 
be employed. Estimated treatment differences and 95% confidence intervals (CIs) will be 
provided for the superiority comparisons. 
If both AS MDI 180 μg and Proventil 180 μg are statistically superior to Placebo MDI, as an 
exploratory endpoint, the non-inferiority of AS MDI 180 μg versus Proventil 180 μg for FEV1 
AUC0-6 will be assessed using a non-inferiority margin of 100 mL. If both AS MDI 90 μg and 
Proventil 90 μg are statistically superior to Placebo MDI, the non-inferiority of AS MDI 
90 μg versus Proventil 90 μg for FEV1 AUC0-6 will also be tested. 
Comparisons among the dose levels within a product will also be conducted for exploratory 
purposes. Estimated treatment differences and 95% CIs will be provided. 
8.5.2 
Secondary efficacy analysis 
The secondary endpoints will be analyzed using a similar approach as that of the primary 
endpoint. Linear mixed models will be fit with a random subject effect. The fixed effects will 
include baseline FEV1, treatment, treatment sequence, and period. 
The peak change from baseline in FEV1 will be calculated using the largest FEV1 value 
measured during the 6 hours post-dosing. 
The FEV1 AUC0-4 will be calculated in a similar manner as FEV1 AUC0-6; however, the 
trapezoidal rule will only be implemented through the 4-hour nominal timepoint. The AUC 
values will be normalized accordingly. 
8.5.3 
Other efficacy analysis 
Responders will be defined as subjects achieving ≥15% improvement in FEV1 within 
30 minutes after dosing. 
The time to onset of response for each individual subject will be defined as the first timepoint 
for which an increase from baseline FEV1 of at least 15% is observed within the first 
30 minutes post dose. 
The duration of response for each subject will be defined as the time from onset of a 15% or 
greater increase in FEV1 to the offset of the 15% increase in FEV1 relative to baseline. 
Change from baseline in FEV1 at each post-dose timepoint will be presented graphically by 
treatment. 

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The median values for time to peak FEV1, time to onset of response, and duration of response 
will be reported by treatment. The median differences and corresponding Hodges-Lehmann 
CIs will be presented for pairwise comparisons among the treatments. 
The percentages of subjects achieving a 12% and 15% improvement from baseline within 
30 minutes post dose will be tabulated by treatment. The odds of being a responder may also 
be estimated using a generalized mixed effects model. 
8.5.4 
Type 1 error control 
The Type I error rate will be controlled at the 5% level across the superiority comparisons of 
the primary endpoint, FEV1 AUC0-6. In general, the superiority of Proventil relative to Placebo 
MDI will be tested first using a dose-ordered approach. If Proventil 180 μg is superior to 
Placebo MDI, AS MDI 180 μg will be compared to Placebo MDI. If AS MDI 180 μg is 
superior to Placebo MDI, the superiority of the 90-μg dose relative to Placebo MDI will be 
tested. Full details of the procedure will be specified in the statistical analysis plan; however, 
the totality of the data including comparisons among AS MDI dose levels will be used to 
select an appropriate dose for AS MDI. 
8.5.5 
Data validation and transformation 
In general, the distribution of spirometry measures is well approximated by a normal 
distribution. Under some circumstances, however (eg, during an exacerbation unrelated to 
treatment), extreme and atypical values can arise. Such values have high influence on 
estimation of variance parameters and on standard errors of fixed effect estimates. The 
distribution of scaled marginal residuals, and influence statistics will be examined to identify 
such cases. In the event that a single or small number of such outlying values are found to 
exist and found to be highly influential, the effects may be ameliorated by either 
transformation or removal of the outlier. Transformations to be considered may include the 
logarithmic transformation or normal rank transformations. Where outliers are removed, 
sensitivity analyses including those values will be reported. 
Changes in spirometry measures from baseline, and from timepoint to timepoint will be 
examined graphically before database lock, and before unblinding, as part of data quality 
management. 
8.5.6 
Safety analyses 
No formal statistical analysis of safety data is planned. Safety data will be summarized by 
treatment and listed. 
8.5.6.1 
AEs 
Adverse events occurring during each Treatment Period will be summarized by the number of 
subjects experiencing an event and 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 for the final analysis of data. 
Tabulations will be broken down by severity, seriousness, AEs leading to discontinuation, and 

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by relationship to study drug. No hypothesis tests will be performed. Tables will show the 
overall incidence of AEs and the incidence for each treatment. 
8.5.6.2 
Vital signs 
Descriptive statistics (mean, median, standard deviation, and range) for 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. 
8.5.6.3 
Clinical laboratory measurements 
Subjects with out-of-range values will be listed. 
8.5.6.4 
12-Lead ECGs 
Subjects with out-of-range values will be listed. 
8.5.7 
Handling of missing data 
Pre-dose spirometry values will use the average of the non-missing -60 minute and -30 minute 
values. 
For the mITT analyses, FEV1 AUC0-6, FEV1 AUC0-4, and peak FEV1 will be calculated if 
there is at least 1 non-missing data point during the first 2 hours post-dose. 
8.5.8 
Statistical software 
Data processing, statistical screening, descriptive reporting, and analysis of the efficacy and 
safety data will be performed using SAS (SAS Institute, Cary, NC, US; Version 9.3 or 
higher). 
9. 
STUDY AND DATA MANAGMENT BY THE SPONSOR 
9.1 
Training of study site staff 
Before the first subject is entered into the study, a Sponsor representative will review and 
discuss the requirements of the clinical study protocol and related documents with the 
investigational staff and train them in any study specific-procedures and study system(s) used. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 

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9.2 
Monitoring of the study 
During the study, a Sponsor representative will have regular contacts with the study site, 
including visits to: 
x 
provide information and support to the Investigator(s) 
x 
confirm that facilities remain acceptable 
x 
confirm that the Clinical Study Team is adhering to the clinical study 
protocol, that data are being accurately and timely recorded in the eCRFs, 
that biological samples are handled in accordance with the laboratory 
manual, and that study drug accountability checks are being performed 
x 
perform source data verification (a comparison of the data in the eCRFs 
with the subject’s medical records at the hospital or practice, and other 
records relevant to the study) including verification of informed consent of 
participating subjects. This will require direct access to all original records 
for each subject (eg, clinic charts) 
The Sponsor representative will be available between visits if the Investigator(s) or other staff 
at the site needs information and advice about the study conduct. 
9.2.1 
Source data 
Refer to the Clinical Study Agreement for location of source data. 
9.2.2 
Study agreements 
The Principal Investigator at each site should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this clinical study protocol and the Clinical Study Agreement, the 
terms of clinical study protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail. 
Agreements between the Sponsor and the Principal Investigator should be in place before any 
study-related procedures can take place, or subjects are enrolled. 
9.2.3 
Archiving of study documents 
The Investigator should follow the principles outlined in the Clinical Study Agreement. 
9.3 
Study timetable and end of study 
The end of study is defined as the last subject’s follow-up telephone call. 
The study may be terminated at individual study sites if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow. 

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9.4 
Data management 
Data management of the study will be performed by the Sponsor or designee, and supervised 
by the Sponsor.  
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and the Sponsor’s policy on Bioethics and Human Biological Samples. 
10.2 
Subject data protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
10.3 
Ethics and regulatory review 
An IRB should approve the final clinical study protocol, the final version of the ICF, the 
assent form, and any other written information and/or materials to be provided to the subjects. 
The opinion of the IRB should be given in writing.  
The IRB should approve all advertising used to recruit subjects for the study. 
The Sponsor will approve any modifications to the ICF that are needed to meet local 
requirements. 
If required by local regulations, the clinical study protocol should be re-approved by the IRB 
annually. 
Before enrollment of any subject into the study, the final clinical study protocol, including the 
final version of the ICF and assent form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
Each Principal Investigator is responsible for providing the IRB with reports of any serious 
and unexpected adverse drug reactions from any other study conducted with the 
investigational product. The Sponsor will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements. 
The head of the study site should seek the opinion of the IRB with respect to the 
appropriateness of continuing the study at the study site at least once a year when the duration 
of the study exceeds 1 year. The Principal Investigator should submit progress reports to the 
IRB via the head of the study site at the time of the clinical study protocol re-approval. 

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Before enrollment of any subject into the study, the final clinical study protocol, including the 
final version of the ICF, should be approved by the national regulatory authority with 
notification provided, according to local regulations. The Sponsor will handle the distribution 
of any of these documents to the national regulatory authorities. 
The Sponsor will provide regulatory authorities, IRB, the head of the study site, and the 
Principal Investigator with safety updates/reports according to local requirements. 
10.4 
Informed consent 
The Principal Investigator(s) at each study site will: 
x 
ensure each subject is given full and adequate oral and written information 
about the nature, purpose, possible risk and benefit of the study 
x 
ensure each subject is notified that they are free to discontinue from the 
study at any time 
x 
ensure that each subject is given the opportunity to ask questions and 
allowed time to consider the information provided 
x 
ensure each subject provides signed and dated informed consent before 
conducting any procedure specifically for the study. If the subject is a 
minor, the parent or guardian will sign an ICF and the subject will sign an 
assent form. 
x 
ensure the original, signed ICF (and assent form, as appropriate) is/are 
stored in the Investigator’s study file 
x 
ensure a copy of the signed ICF (and assent form, as appropriate) is/are 
given to the subject (and the subject’s parent or guardian if the subject is a 
minor) 
x 
ensure that any incentives for subjects who participate in the study as well as 
any provisions for subjects harmed as a consequence of study participation 
are described in the ICF that is approved by an IRB 
10.5 
Changes to the clinical study protocol and ICF/assent form 
Study procedures will not be changed without the mutual agreement of the Coordinating 
Investigator and the Sponsor. 
If there are any substantial changes to the clinical study protocol, then these changes will be 
documented in a new version of the study protocol. 

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The new version of the clinical study protocol is to be approved by the relevant IRB and if 
applicable, also the national regulatory authority approval, before implementation. Local 
requirements are to be followed for new versions of clinical study protocols. 
The Sponsor will distribute any new versions of the clinical study protocol to each Principal 
Investigator(s). For distribution to the IRBs see Section 10.3. 
If a change to a clinical study protocol requires a change to a site’s ICF and assent form, the 
Sponsor and the site’s IRB are to approve the revised ICF and assent form before the revised 
forms are used. 
10.6 
Audits and inspections 
Authorized representatives of the Sponsor, a regulatory authority, or an IRB may perform 
audits or inspections at the study site, including source data verification. The purpose of an 
audit or inspection is to systematically and independently examine all study-related activities 
and documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the clinical study protocol, GCP, guidelines of 
the ICH, and any applicable regulatory requirements. The Investigator will contact the 
Sponsor immediately if contacted by a regulatory agency about an inspection at the site. 

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11. 
LIST OF REFERENCES 
ATS/ERS Task Force 2005 
ATS/ERS Task Force: Standardization of Lung Function Testing: Number 2 in Series. 
European Respiratory Journal. 2005;26(2):319-338. 
EPR-3 2007 
Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma–
Summary Report. J Allergy Clin Immunol. 2007;120(5 suppl):S94-138. 
Global Initiative for Asthma 2017 
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. 
Available from: www.ginasthma.org. Accessed 10 August 2017. 
Miller et al 2005 
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 
2005;26(2):319-338. 
PROVENTIL HFA package insert 
PROVENTIL HFA (albuterol sulfate) inhalation aerosol [package insert]. Whitehouse Station, NJ: 
Merck Sharp & Dohme Corp.; 2014. 
PULMICORT FLEXHALER package insert 
PULMICORT FLEXHALER (budesonide) Inhalation Powder [package insert]. Wilmington, 
DE: AstraZeneca; 2016. 
Schwartz et al 1976 
Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A. A simple estimate of glomerular 
filtration rate in children derived from body length and plasma creatinine. Pediatrics 
1976;58(2):259-263. 
Williams 1949 
Williams EJ. Experimental designs balanced for the estimation of residual effects of 
treatments. Australian Journal of Scientific Research. 1949;2(3):149-168. 
 
 

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

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

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Appendix B 
Spirometry Performance Recommendations 
Spirometry Performance Recommendations 
Spirometry data of the highest quality must be obtained for proper interpretation of the results 
of this protocol. To these ends, a standard spirometer will be used (provided by Pearl 
Therapeutics), central training provided, qualification will be required, and specific operating 
instruction will also be provided. 
Source: ATS/ERS Task Force 2005. 
FEV1, FVC, FEF25-75 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, BTPS) with an accuracy of at least ±3% of reading or 
±0.050 L, whichever is greater, with flows between 0 and 14 L-s-1. The total resistance to 
airflow at 14.0 L-s-1 must be <1.5 cmH2O L-1s-1 (0.15 kPa L-1s-1). The total resistance must be 
measured with any tubing, valves, pre-filter, etc. included that may be inserted between the 
subject and the spirometer. Some devices may exhibit changes in resistance due to water 
vapor condensation, and accuracy requirements must be met under BTPS conditions for up to 
8 successive FVC maneuvers performed in a 10-minute period without inspiration from the 
instrument. 
Display 
For optimal quality control, both flow–volume and volume–time displays are useful, and test 
operators should visually inspect the performance of each maneuver for quality assurance 
before proceeding with another maneuver. This inspection requires tracings to meet the 
minimum size and resolution requirements set forth in this standard. Displays of flow versus 
volume provide more detail for the initial portion (first 1 s) of the FVC maneuver. Since this 
portion of the maneuver, particularly the peak expiratory flow rate (PEFR), is correlated with 
the pleural pressure during the maneuver, the flow–volume display is useful to assess the 
magnitude of effort during the initial portions of the maneuver. The ability to overlay a series 
of flow–volume curves registered at the point of maximal inhalation may be helpful in 
evaluating repeatability and detecting sub-maximal efforts. However, if the point of maximal 
inhalation varies between blows, then the interpretation of these results is difficult because the 
flows at identical measured volumes are being achieved at different absolute lung volumes. In 
contrast, display of the FVC maneuver as a volume–time graph provides more detail for the 
latter part of the maneuver. A volume–time tracing of sufficient size also allows independent 
measurement and calculation of parameters from the FVC maneuvers. In a display of multiple 
trials, the sequencing of the blows should be apparent to the user. For the start of test display, 
the volume–time display should include >0.25 s, and preferably 1 s, before exhalation starts 
(zero volume). This time period before there is any change in volume is needed to calculate 
the back extrapolated volume (EV) and to evaluate effort during the initial portion of the 

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

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Key aspects of equipment quality control are summarized in Table A1-2. 
Table A1-2. 
Summary of Equipment Quality Control 
Test 
Minimal 
Interval 
Action 
Volume 
Daily 
Calibration check with a 3 L syringe 
Leak 
Daily 
2 cm H2O (0.3 kPa) constant pressure for 1 minute 
Volume 
Linearity 
Quarterly 
1 L increments with a calibrating syringe measured over 
the entire volume range 
Flow 
Linearity 
Weekly 
Test at least 3 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 1 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 

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are carried out, the equipment’s calibration should be checked more frequently than daily; and 
2) when the ambient temperature is changing (eg, field studies), volume accuracy must be 
checked more frequently than daily and the BTPS correction factor appropriately updated.  
The accuracy of the syringe volume must be considered in determining whether the measured 
volume is within acceptable limits. For example, if the syringe has an accuracy of 0.5%, a 
reading of ±3.5% is appropriate. 
The calibration syringe should be stored and used in such a way as to maintain the same 
temperature and humidity of the testing site. This is best accomplished by keeping the syringe 
in close proximity to the spirometer, but out of direct sunlight and away from heat sources. 
Volume-type spirometer systems must be evaluated for leaks every day. The importance of 
undertaking this daily test cannot be overstressed. Leaks can be detected by applying a 
constant positive pressure of >3.0 cmH2O (0.3 kPa) with the spirometer outlet occluded 
(preferably at or including the mouthpiece). Any observed volume loss of .30 mL after 
1 minute indicates a leak and needs to be corrected. 
At least quarterly, volume spirometers must have their calibration checked over their entire 
volume range using a calibrated syringe or an equivalent volume standard. The measured 
volume should be within ±3.5% of the reading or 65 mL, whichever is greater. This limit 
includes the 0.5% accuracy limit for a 3-L syringe. The linearity check procedure provided by 
the manufacturer can be used if it is equivalent to 1 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 3 times to give a range of flows varying between 0.5 and 12 L-
s-1 (with 3-L injection times of 6 s and 0.5 s). The volume at each flow should meet the 
accuracy requirement of ±3.5%. For devices using disposable flow sensors, a new sensor from 
the supply used for patient tests should be tested each day. 
For linearity, a volume calibration check should be performed weekly with a 3-L syringe to 
deliver 3 relatively constant flows at a low flow, then 3 at a mid-range flow, and finally 3 at a 
high flow. The volumes achieved at each of these flows should each meet the accuracy 
requirement of ±3.5%. 

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Equipment 
For measurements of VC and IC, the spirometer or flow meter must comply with the 
requirements for FVC (as described previously) and be capable of accumulating volume for 
>30 s. Expiratory maneuvers or, ideally, both inspiratory and expiratory maneuvers should be 
included in the display of VC maneuver. Regardless of whether the inspiratory or expiratory 
maneuver is used for deriving measurements, a display of the entire recorded VC maneuver 
must be provided. The maximal expiratory volume must be assessed to determine whether the 
subject has obtained a plateau in the expiratory effort. For display of the slow VC, the time 
scale may be reduced to 5 mm-s-1. 
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 1 time period to another. The 
accuracy of a spirometry system depends on characteristics of the entire system, from the 
volume or flow transducer and the use of an in-line filter, to the recorder, display or processor. 
Changes in any aspect of the equipment or errors at any step in the process can affect the 
accuracy of the results. For example, if the BTPS correction factor is wrong, an accurately 
measured FVC will be incorrectly reported. Spirometers are not required to measure all of the 
indices in Table A1-3, but must meet the recommendations for those that are measured. 
Accuracy and repeatability recommendations apply over the entire volume range of the 
instrument.  
Table A1-3. 
Range and Accuracy Recommendations Specified for Forced 
Expiratory Maneuvers 
Test 
Range/Accuracy 
(BTPS) 
Flow 
Range 
(L-s-1) 
Time (s) 
Resistance and 
Back Pressure 
Test Signal 
VC 
0.5–8 L, ± 3% of reading 
or ± 0.050 L, whichever 
is greater 
0-14 
30 
 
3-L Calibration 
syringe 
FVC 
0.5–8 L, ± 3% of reading 
or ±0.050 L, whichever is 
greater 
0-14 
15 
<1.5 cm H2O L-1 s-1 
(0.15 kPa L-1s-1) 
24 ATS 
waveforms,  
3-L Cal Syringe 

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Table A1-3. 
Range and Accuracy Recommendations Specified for Forced 
Expiratory Maneuvers 
Test 
Range/Accuracy 
(BTPS) 
Flow 
Range 
(L-s-1) 
Time (s) 
Resistance and 
Back Pressure 
Test Signal 
FEV1 0.5–8 L, ± 3% of reading 
or ± 0.050 L, whichever 
is greater 
0-14 
1 
<1.5 cm H2O L-1 s-1 
(0.15 kPa L-1s-1) 
24 ATS 
waveforms 
Time 
Zero 
The timepoint from 
which all FEVt 
measurements are taken.  
 
 
Back extrapolation 
 
FEVt: forced expiratory volume in t seconds 
 
Body temperature, ambient pressure, saturated with water vapor correction 
All spirometry values should be reported at BTPS by any method (measuring temperature and 
barometric pressure) proven effective by the manufacturer. For volume-type spirometers, the 
temperature inside the spirometer should be measured for each breathing maneuver. 
Regardless of the BTPS correction technique used, the ambient temperature must always be 
recorded with an accuracy of ±1°C. In situations where the ambient air temperature is 
changing rapidly (>3°C in <30 min), continuous temperature corrections may be necessary. 
Spirometer users should be aware of potential problems with testing performed at lower 
ambient temperatures:  17°C is the lower limit for ambient temperature, unless a manufacturer 
states that their spirometer will operate accurately at lower ambient temperatures. If 
barometric pressure is not used in calculating the BTPS correction factor, the range of 
barometric pressures over which the BTPS correction factor is valid must be published.  

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Appendix C 
Additional Safety Information 
Additional Safety Information 
Further Guidance on the Definition of a Serious Adverse Event (SAE) 
Life threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
x 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
x 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine 
x 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
x 
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization 
Development of drug dependency or drug abuse 
A Guide to Interpreting the Causality Question 

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When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
x 
Time Course.  Exposure to suspect drug.  Has the subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug? 
x 
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
x 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
x 
No alternative cause.  The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, other host or environmental factors. 
x 
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? The Sponsor would not normally recommend or support a 
re-challenge. 
x 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship. 
In difficult cases, other factors could be considered such as: 
x 
Is this a recognized feature of overdose of the drug? 
x 
Is there a known mechanism? 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 

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Appendix D 
Instructions for Use of Inhaled Medications 
Instructions for Use of Inhaled Medications 
Instructions for Use of the AS MDI and Placebo for AS MDI 
1. 
How do I store the inhaler? 
x 
The inhaler should be stored between 20°C-25°C (68°-77°F) as directed 
by the label. 
2. 
Preparation of the inhaler 
x 
Take the inhaler out of the pouch. Safely throw away the pouch and the 
desiccant packet that comes inside the pouch. 
x 
Take the cap off the inhaler by gently squeezing the sides of the dust-cap 
and pulling off. 
x 
Inspect the front of the inhaler and make sure there is nothing inside the 
mouthpiece of the inhaler. Make sure the canister is fully and firmly 
inserted into the actuator. 
x 
The inhaler must be primed before first use. Priming involves releasing a 
certain number of sprays (4) into the air before first use of the inhaler.  
Shaking and priming the inhaler fills a chamber inside the canister with 
the correct dose and mix of medication so that the inhaler is ready to use. 
x 
To prime the inhaler, gently shake the inhaler for 5-10 seconds and then 
spray once into the air away from yourself and others. 
NOTE:  an audible “click” may be heard which is advancement of the 
dose counter and considered normal. 
x 
Wait approximately 5-10 seconds and then repeat step #2.2.5, three more 
times.  
3. 
Using the inhaler 
x 
The inhaler should be held upright with the mouthpiece at the bottom and 
the canister at the top as pictured in Figure 1. 
x 
Shake the inhaler for 5 to 10 seconds. 
x 
Breathe out fully through your mouth, expelling as much air from your 
lungs as possible.  Tilt your head back slightly, place the mouthpiece into 
your mouth, holding the inhaler with the mouthpiece down, and closing 

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your lips around it.  To allow the medication to enter your lungs, keep 
your tongue flat on the bottom of your mouth. 
x 
While breathing in deeply and slowly through your mouth, fully depress 
the top of the dose counter with your index finger. Immediately after the 
spray is delivered, release your finger from the canister.  When you have 
breathed in fully, remove the inhaler from your mouth and close your 
mouth. 
x 
Hold your breath as long as possible, up to 10 seconds, and then breathe 
normally. 
x 
If more than one spray is necessary, repeat steps 2.3.2 to 2.3.5 the 
necessary number of times. 
x 
If the device will be used again, place the dust-cap back onto the device. 
 
Figure 1. 
Metered Dose Inhaler Diagram 
 
 
 
 
Actuator 
Dose Counter 
Dust 
C

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Instructions for Use of the PROVENTIL HFA 
 
Attention Health Care Professional:  
Detach Patient's Instructions for Use from package insert and dispense with the product 
PROVENTIL® HFA 
(albuterol sulfate) 
Inhalation Aerosol 
FOR ORAL INHALATION ONLY 
Patient's Instructions for Use 
 
Figure 1 
 
 
Figure 2 
Before using your PROVENTIL® HFA (albuterol sulfate) Inhalation Aerosol, read complete 
instructions carefully. Children should use PROVENTIL HFA Inhalation Aerosol under adult 
supervision, as instructed by the patient's doctor 
Please note that indicates that this inhalation aerosol does not contain chlorofluorocarbons (CFCs) 
as the propellant.  
1. SHAKE THE INHALER WELL immediately before each use. Then remove the cap from the 
mouthpiece (see Figure 1). Check mouthpiece for foreign objects prior to use. Make sure the 
canister is fully inserted into the actuator. 
 

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2. As with all aerosol medications, it is recommended to prime the inhaler before using for the 
first time and in cases where the inhaler has not been used for more than 2 weeks. Prime by 
releasing four “test sprays” into the air, away from your face.  
3. BREATHE OUT FULLY THROUGH THE MOUTH, expelling as much air from your lungs as 
possible. Place the mouthpiece fully into the mouth, holding the inhaler in its upright position (see 
Figure 2) and closing the lips around it.  
4. WHILE BREATHING IN DEEPLY AND SLOWLY THROUGH THE MOUTH, FULLY 
DEPRESS THE TOP OF THE METAL CANISTER with your index finger (see Figure 2).  
5. HOLD YOUR BREATH AS LONG AS POSSIBLE, up to 10 seconds. Before breathing out, 
remove the inhaler from your mouth and release your finger from the canister.  
6. If your physician has prescribed additional puffs, wait 1 minute, shake the inhaler again, and 
repeat steps 3 through 5. Replace the cap after use.  
7. KEEPING THE PLASTIC MOUTHPIECE CLEAN IS EXTREMELY IMPORTANT TO 
PREVENT MEDICATION BUILDUP AND BLOCKAGE. THE MOUTHPIECE SHOULD BE 
WASHED, SHAKEN TO REMOVE EXCESS WATER, AND AIR DRIED THOROUGHLY AT 
LEAST ONCE A WEEK. INHALER MAY STOP SPRAYING IF NOT PROPERLY 
CLEANED. Routine cleaning instructions: Step 1. To clean, remove the canister and 
mouthpiece cap. Wash the mouthpiece through the top and bottom with warm running water for 
30 seconds at least once a week (see Figure A). Never immerse the metal canister in water.  
 
Figure A 
Wash mouthpiece under warm running water.  

Clinical Study Protocol Appendix C 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
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Figure B  
Allow mouthpiece to air dry, such as overnight.  
Figure C 
When blocked, little or no medicine comes out. Step 2. To dry, shake off excess water and let the 
mouthpiece air dry thoroughly, such as overnight (see Figure B). When the mouthpiece is dry, 
replace the canister and the mouthpiece cap. Blockage from medication buildup is more likely to 
occur if the mouthpiece is not allowed to air dry thoroughly. IF YOUR INHALER HAS 
BECOME BLOCKED (little or no medication coming out of the mouthpiece, see Figure C), 
wash the mouthpiece as described in Step 1 and air dry thoroughly as described in Step 2. IF 
YOU NEED TO USE YOUR INHALER BEFORE IT IS COMPLETELY DRY, SHAKE 
OFF EXCESS WATER, replace the canister, and test spray twice into the air, away from your 
face, to remove most of the water remaining in the mouthpiece. Then take your dose as prescribed. 
After such use, rewash and air dry thoroughly as described in Steps 1 and 2.  
8. The correct amount of medication in each inhalation cannot be assured after 200 actuations, 
even though the canister is not completely empty. The canister should be  
 

Clinical Study Protocol Appendix C 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
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discarded when the labeled number of actuations have been used. Before you reach the specific 
number of actuations, you should consult your physician to determine whether a refill is needed. 
Just as you should not take extra doses without consulting your physician, you also should not 
stop using PROVENTIL HFA Inhalation Aerosol without consulting your physician.  
 
You may notice a slightly different taste or spray force than you are used to with PROVENTIL 
HFA Inhalation Aerosol, compared to other albuterol inhalation aerosol products.  
DOSAGE:  
Use only as directed by your physician.  
WARNINGS:  
The action of PROVENTIL® HFA Inhalation Aerosol should last up to 4 to 6 hours. PROVENTIL 
HFA Inhalation Aerosol should not be used more frequently than recommended. Do not increase 
the number of puffs or frequency of doses of PROVENTIL HFA Inhalation Aerosol without 
consulting your physician. If you find that treatment with PROVENTIL HFA Inhalation Aerosol 
becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to 
use the product more frequently than usual, medical attention should be sought immediately. 
While you are taking PROVENTIL HFA Inhalation Aerosol, other inhaled drugs should be taken 
only as directed by your physician. If you are pregnant or nursing, contact your physician about 
the use of PROVENTIL HFA Inhalation Aerosol.  
Common adverse effects of treatment with PROVENTIL HFA Inhalation Aerosol include 
palpitations, chest pain, rapid heart rate, tremor, or nervousness. Effective and safe use of 
PROVENTIL HFA Inhalation Aerosol includes an understanding of the way that it should be 
administered. Use PROVENTIL HFA Inhalation Aerosol only with the yellow actuator supplied 
with the product. The PROVENTIL HFA Inhalation Aerosol actuator should not be used with 
other aerosol medications.  
For best results, use at room temperature. Avoid exposing product to extreme heat and cold.  
Shake well before use.  
Contents Under Pressure.  
Do not puncture. Do not store near heat or open flame. Exposure to temperatures above 120°F 
may cause bursting. Never throw container into fire or incinerator. Store between 15° - 25°C (59° 
- 77°F). Store the inhaler with the mouthpiece down. Avoid spraying in eyes. Keep out of reach 
of children.  
Further Information: Your PROVENTIL® HFA (albuterol sulfate) Inhalation Aerosol does not 
contain chlorofluorocarbons (CFCs) as the propellant. Instead, the inhaler contains a 
hydrofluoroalkane (HFA-134a) as the propellant.  
Developed and Manufactured by: 3M Health Care Limited  
Loughborough UK or 3M Drug Delivery 
Systems Northridge, CA 91324, USA Rev. 
12/14 Copyright © 1996, 2011, 2012 Merck 
Sharp & Dohme Corp., a subsidiary of 
Merck & Co., Inc.  
All rights reserved.  
653300  
 
 
 

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Study Code D6930C00001 (PT007001) 
Version 2.0 
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Instructions for Use of the VENTOLIN HFA
 

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Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
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Clinical Study Protocol Appendix C 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
92 (97) 
 

Clinical Study Protocol Appendix C 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
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Clinical Study Protocol Appendix C 
Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
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Instructions for Use of PULMICORT FLEXHALER 
 

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Drug Substance PT007  
Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
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Study Code D6930C00001 (PT007001) 
Version 2.0 
Date 12 January 2018 
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Appendix F 
Investigator’s Agreement and Signature Page 
Investigator’s Agreement and Signature Page 
Study Title: 
A Randomized, Double-blind, Single dose, Placebo-controlled, 
5-Period, 5-Treatment, Crossover, Multi-center, Dose-ranging 
Study to Compare PT007 to Placebo MDI and Open-Label 
Proventil® HFA in Adult and Adolescent Subjects With Mild to 
Moderate Asthma 
Study Number: 
D6930C00001 (PT007001) 
Final Date: 
12 January 2018 
 
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: