A Randomized, Double-blind, Single-dose, 2-Period, Crossover Study to Assess the Efficacy of PT027 Compared With Placebo on Exercise-Induced Bronchoconstriction in Adult and Adolescent Subjects With Asthma
Phase: PHASE3
Conditions: Exercise Induced Bronchospasm
Sponsor: Bond Avillion 2 Development LP

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Clinical Study Protocol  
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Budesonide/Albuterol Sulfate (BDA), AV005 
Version 1.0, 25 Oct 2019 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
 
A Randomized, Double-blind, Single-Dose, 2-Period, Crossover 
Study to Assess the Efficacy of PT027 Compared with Placebo on 
Exercise-Induced Bronchoconstriction in Adult and Adolescent 
Subjects with Asthma (TYREE) 
 
 
Coordinating Investigator  
Craig LaForce, MD 
 
 
Study site(s) and number of subjects planned 
Approximately 6 study sites in the United States are anticipated to be included. A total of 60 
adult and adolescent subjects (12 to 70 years of age) will be randomized. Due to an anticipated 
screen failure rate of 50%, approximately 120 subjects will be screened. 
Phase of development 
Phase III 
Study design 
This will be a multicenter, randomized, double-blind, single-dose, placebo-controlled, 2-
period, crossover study to evaluate the efficacy and safety of budesonide/albuterol metered-
dose inhaler (PT027; hereafter referred to as BDA MDI), as compared with placebo MDI on 
exercise-induced bronchoconstriction (EIB) in adult and adolescent subjects (12 to 70 years of 
age) with asthma.  
Approximately 60 subjects will be randomized 1:1 to 1 of 2 treatment sequences (ie, A/B or 
B/A) as specified in Table 1: 
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Table 1 
Treatment sequences 
Treatment 
sequence 
Visit 3/Period 1 
Visit 4/Period 2 
A/B 
BDA MDI 160/180 μg (given as 2 
actuations of BDA MDI 80/90 μg) 
Placebo MDI (given as 2 actuations) 
B/A 
Placebo MDI (given as 2 actuations) 
BDA MDI 160/180 μg (given as 2 actuations of BDA MDI 
80/90 μg)  
Abbreviations:  BDA=budesonide/albuterol; MDI metered-dose inhaler. 
Objectives 
Primary Objective: 
Outcome Measure: 
To assess the efficacy of a single dose of BDA MDI 
(160/180 µg) compared with placebo MDI on EIB 
in adult and adolescent subjects with asthma 
The maximum percentage fall from post-dose, pre-exercise 
baseline in forced expiratory volume in 1 second (FEV1) 
observed up to 60 minutes post-exercise challenge  
 
Secondary Objective: 
Outcome Measure: 
To further assess the efficacy of a single dose of 
BDA MDI compared with placebo MDI on EIB in 
adult and adolescent subjects with asthma 
Percentage of subjects with a maximum percentage fall in 
FEV1 post-exercise challenge of <10% 
 
 
Safety Objective: 
Outcome Measure: 
To evaluate the safety and tolerability of BDA MDI 
relative to placebo MDI on EIB in adult and 
adolescent subjects with asthma 
Incidence of adverse events (AEs)/serious AEs (SAEs) 
 
Exploratory Objectives: 
Outcome Measures: 
To characterize the effect of BDA MDI 160/180 μg 
administered as a single-dose on 
bronchoconstriction compared with placebo 
1. Percentage of subjects with a maximum percentage fall 
in FEV1 post-exercise challenge of <20% 
2. Time to recovery, defined as the time from completion 
of the exercise challenge to the first measured post-
exercise challenge FEV1 value within 10% of the post-
dose, pre-exercise challenge baseline FEV1 
3. The percentage fall from baseline in FEV1 at each time 
point within 60 minutes post-exercise challenge 
4. Post-exercise FEV1 area under the curve from 0 to 30 
minutes (AUC0-30min) 
 
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Target subject population 
The target population will be outpatient subjects 12 to 70 years of age with asthma and EIB.  
Two subgroups of equal size will be included in the study, 1 subgroup of subjects currently 
treated with short/rapid-acting β2-adrenoreceptor agonist (SABA) prn alone, and a second 
subgroup on low-to-medium-dose inhaled corticosteroid (ICS) maintenance therapy 
(according to Global Initiative for Asthma [GINA] guidelines) and SABA prn.  
Duration of treatment 
The randomized treatment phase will start after a 1 to 2-week screening period (Visits 1 and 
2). The double-blind treatment will occur with single dosing of investigational product (IP) at 
Visits 3 and 4, which will be approximately 1 week apart. The overall study duration will take 
approximately 3 to 4 weeks. 
Investigational product, dosage and mode of administration 
Investigational Product will be BDA MDI and a matching placebo MDI, which will be used as 
the comparator. The IP will be administered as a single dose as follows: 
• 
BDA MDI 160/180 μg (given as 2 inhalations of BDA MDI 80/90 μg per puff) 
• 
Placebo MDI (given as 2 inhalations) 
At Visit 3/Period 1 and Visit 4/Period 2, IP will be administered 30 (±5) minutes prior to the 
exercise challenge. During the study, subjects will not be allowed to use any asthma 
medication other than the SABA prn or ICS plus SABA prn that they were using before study 
entry. Subjects will be restricted from SABA within 6 hours before any lung function testing 
and/or exercise testing. Non-asthma medications which are necessary for the subject’s safety 
and wellbeing, and which do not affect the participation in or results of the study, are allowed 
at the discretion of the investigator. 
 
Statistical methods 
Sample Size 
Prior studies of a similar design have randomized subjects who experience exercise-induced 
symptoms without other generalized asthma symptoms. Other studies have permitted 
enrollment of those subjects experiencing exercise symptoms who may or may not be subjects 
with asthma (Bonini et al 2013). This study will only randomize subjects with asthma who are 
receiving background therapy for asthma (SABA prn alone; low-to-medium dose ICS plus 
SABA prn). Sub-analyses will be conducted on the primary endpoint for each of these 
subgroups of equal size. 
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Power calculations are based on the properties of the primary endpoint, the maximum 
percentage fall from post-dose, pre-exercise baseline in FEV1 observed up to 60 minutes post-
exercise challenge. A sample size of 30 subjects in each subgroup will provide a 92% 
probability to detect a difference of -9% between BDA MDI versus placebo MDI, within each 
of the 2 subgroups of interest (SABA prn alone; low-to-medium dose ICS plus SABA prn), 
assuming 2-sided, 5% level tests and a within-subject standard deviation of 10%. 
Randomization of 60 subjects in total will provide >99% overall probability to detect a 
difference of -9% between BDA MDI versus placebo MDI assuming a 2-sided, 5% level test 
and an estimated within-subject standard deviation of 10%. Since all subjects randomized in 
the study will be receiving background therapy for asthma, a more conservative estimate of 
variability and treatment effect has been assumed compared to studies of similar design 
(Ostrom et al 2015). 
Primary Efficacy Analyses 
The maximum percentage fall from post-dose, pre-exercise baseline in FEV1 observed up to 
60 minutes post-exercise challenge will be analyzed with a mixed effect model including 
categorical fixed effects for treatment, treatment period, treatment sequence, period-specific 
pre-dose baseline FEV1 and average pre-dose baseline FEV1, and a random subject within 
treatment sequence effect. Post-dose, pre-exercise baseline FEV1 will be defined as the 30 
minutes post-dose value, ie, 5 minutes before exercise challenge, at each visit for the 
respective treatment. The period-specific pre-dose baseline FEV1 will be calculated separately 
at Visit 3 and Visit 4 as the pre-dose result, approximately 5 minutes prior to dosing. The 
average pre-dose baseline FEV1 will be calculated as the mean of the period-specific pre-dose 
FEV1 baselines. Estimated treatment differences and 95% confidence intervals (CIs) will be 
provided. 
The primary analysis will be repeated on the subgroups on clinical interest (SABA prn alone; 
low-to-medium dose ICS plus SABA prn). To control the overall type-I error, a hierarchical 
testing strategy will be adopted. The treatment comparisons of BDA MDI 160/180 versus 
placebo MDI will be conducted on the subject populations in the sequence given below: 
1. Overall population (SABA prn only OR low-to-medium dose ICS plus SABA prn 
background therapy) 
2. Subjects taking SABA prn only for background therapy 
3. Subjects taking low-to-medium dose ICS plus SABA prn for background therapy 
If a comparison is significant (alpha=0.05, 2-sided), testing will proceed to the next 
comparison. Comparisons will stop if a non-statistically significant result occurs. All 
comparisons are of superiority. 
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Secondary/ Other Efficacy Analyses 
The percentage of subjects with a maximum percentage fall in FEV1 post-exercise challenge 
of <10% will be tabulated by treatment.  
The odds of having a maximum percentage fall in FEV1 post-exercise challenge of <10% will 
be analyzed using a generalized linear mixed model with logit link function to compare the 
treatments. The model will be adjusted for treatment, treatment period, treatment sequence, 
and a random subject within treatment sequence effect. The odds ratio and 95% CI will be 
reported for pairwise treatment comparisons. The odds of having a maximum percentage fall 
in FEV1 post-exercise challenge of <20% will be separately analyzed in a similar manner. 
Time to recovery at each of Visits 3 and 4 will be derived as the time (minutes) post-exercise 
challenge in which the FEV1 result returns to within 10% of the value recorded at the post-
dose, pre-exercise baseline. Only subjects who achieve a percentage fall in FEV1 post-exercise 
challenge of >10% will have an event time derived; otherwise their value will be left 
censored. Subjects who have any rescue medication administered during the post-dose 
assessments will be censored at the time of receiving rescue medication. Subjects who do not 
recover to within 10% of the post-dose, pre-exercise baseline will be censored at 60 minutes. 
P-values will be calculated using a period-adjusted sign test, based on categorizing subjects 
into period preferences (Senn 1993).  
The percentage fall in FEV1 post-exercise challenge will be summarized descriptively by 
treatment group and planned time point within 60 minutes of the serial spirometry assessments 
conducted post-exercise challenge. An analysis of percentage fall in FEV1 post-exercise 
challenge will be conducted using methods as per the primary analysis, with an additional 
adjustment for planned time point in the repeated measures model. The covariance within 
subject-periods will be unstructured over the time points. 
The post-exercise FEV1 AUC0-30 min will be analyzed with a similar mixed effects model as 
described above using methods as per the primary analysis.  
Analysis Sets 
The following analysis sets are defined in this study: 
The full analysis set is defined as all subjects who are randomized to treatment and have at 
least 1 post-dose, pre-exercise baseline and corresponding post-dose FEV1 measure at Visits 3 
and/or 4. Subjects will be analyzed according to the treatment they were assigned to as per the 
randomization scheme. 
The safety analysis set is defined as all subjects receiving any amount of the IP. Subjects will 
be classified on the basis of treatment they actually received. Occurrences of safety events (ie, 
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AEs and use of concomitant medication) will be summarized under the actual treatment 
corresponding to the treatment period of which the event occurred. All safety summaries will 
be based on the safety analysis set. 
The all subjects enrolled population will be defined as all subjects who provide informed 
consent. This subject population will be used for descriptive summaries of disposition. 
There are no interim analyses planned for this study. 
Estimands 
The estimand of interest is the Efficacy Estimand, defined as the effect of the randomized 
treatments in all subjects in the absence of intercurrent events which may impact the 
interpretation of the treatment effect, such as use of rescue medication following the exercise 
challenge test. This estimand could be considered a while-on-treatment strategy or a 
hypothetical strategy as defined in the draft International Conference on Harmonisation (ICH) 
E9 Addendum. 
 
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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
VERSION HISTORY................................................................................................................ 1 
CLINICAL STUDY PROTOCOL SYNOPSIS ........................................................................ 2 
TABLE OF CONTENTS .......................................................................................................... 8 
List of Tables ........................................................................................................................... 11 
List of Figures .......................................................................................................................... 11 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 12 
1 
INTRODUCTION ................................................................................................ 14 
1.1 
Background ........................................................................................................... 14 
1.2 
Exercise-induced bronchoconstriction .................................................................. 15 
1.3 
Rationale for study design, doses and control groups .......................................... 15 
1.4 
Benefit/risk and ethical assessment ...................................................................... 16 
1.5 
Study design.......................................................................................................... 16 
2 
STUDY OBJECTIVES ........................................................................................ 18 
2.1 
Primary objective .................................................................................................. 18 
2.2 
Secondary objectives ............................................................................................ 18 
2.3 
Safety objective .................................................................................................... 18 
2.4 
Exploratory objectives .......................................................................................... 18 
3 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 19 
3.1 
Inclusion criteria ................................................................................................... 19 
3.2 
Exclusion criteria .................................................................................................. 20 
3.3 
Subject enrollment and randomization ................................................................. 22 
3.4 
Procedures for handling incorrectly enrolled or randomized subjects ................. 23 
3.5 
Methods for assigning treatment groups............................................................... 24 
3.6 
Methods for ensuring blinding.............................................................................. 24 
3.7 
Methods for unblinding ........................................................................................ 24 
3.8 
Restrictions ........................................................................................................... 25 
3.9 
Criteria for study withdrawal ................................................................................ 25 
3.9.1 
Screen failures ...................................................................................................... 26 
3.10 
Discontinuation of the study ................................................................................. 26 
4 
STUDY PLAN AND TIMING OF PROCEDURES ........................................... 26 
4.1 
Screening period ................................................................................................... 32 
4.1.1 
Visit 1.................................................................................................................... 32 
4.1.2 
Visit 2.................................................................................................................... 33 
4.2 
Randomization/Treatment phase .......................................................................... 33 
4.2.1 
Visit 3 and 4 .......................................................................................................... 33 
4.3 
Study withdrawal .................................................................................................. 34 
4.4 
Unscheduled visit .................................................................................................. 34 
4.5 
Follow-up period .................................................................................................. 34 
5 
STUDY ASSESSMENTS .................................................................................... 35 
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5.1 
Efficacy assessments ............................................................................................ 35 
5.1.1 
Lung function measurement by spirometry (FEV1) ............................................. 35 
5.1.1.1 
Demonstration of exercise-induced bronchoconstriction ..................................... 36 
5.1.2 
Exercise challenge testing ..................................................................................... 36 
5.2 
Safety assessments ................................................................................................ 37 
5.2.1 
Laboratory assessments ........................................................................................ 37 
5.2.2 
Physical examination ............................................................................................ 38 
5.2.3 
ECG ...................................................................................................................... 39 
5.2.3.1 
Resting 12-lead ECG ............................................................................................ 39 
5.2.4 
Heart rate monitoring during exercise challenge testing ...................................... 39 
5.2.5 
Vital signs ............................................................................................................. 39 
5.2.6 
Adverse event assessments ................................................................................... 39 
5.3 
Other assessments ................................................................................................. 40 
5.3.1 
Concomitant medications ..................................................................................... 40 
6 
SAFETY REPORTING AND MEDICAL MANAGEMENT ............................. 40 
6.1 
Definition of adverse events ................................................................................. 40 
6.2 
Definitions of serious adverse event ..................................................................... 40 
6.3 
Recording of adverse events ................................................................................. 41 
6.3.1 
Period for collection of adverse events ................................................................. 41 
6.3.2 
Follow-up of unresolved adverse events .............................................................. 41 
6.3.3 
Variables ............................................................................................................... 41 
6.3.4 
Causality collection .............................................................................................. 42 
6.3.5 
Adverse events based on signs and symptoms ..................................................... 42 
6.3.6 
Adverse events based on examinations and tests ................................................. 43 
6.4 
Reporting of serious adverse events ..................................................................... 43 
6.5 
Overdose ............................................................................................................... 44 
6.6 
Pregnancy ............................................................................................................. 45 
6.6.1 
Maternal exposure ................................................................................................ 45 
6.6.2 
Paternal exposure .................................................................................................. 45 
6.7 
Medication error ................................................................................................... 45 
6.8 
Management of investigational product-related toxicities ................................... 47 
7 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 47 
7.1 
Identity of investigational product(s) .................................................................... 47 
7.2 
Dose and treatment regimens ................................................................................ 47 
7.3 
Labelling ............................................................................................................... 48 
7.4 
Storage .................................................................................................................. 48 
7.5 
Compliance ........................................................................................................... 49 
7.6 
Accountability ....................................................................................................... 49 
7.7 
Metered-dose inhaler handling ............................................................................. 49 
7.8 
Concomitant and other treatments ........................................................................ 49 
7.8.1 
Investigational product ......................................................................................... 49 
7.8.2 
Permitted asthma therapies ................................................................................... 49 
7.8.3 
Medication that may affect FEV1 testing .............................................................. 50 
7.8.4 
Prohibited medications ......................................................................................... 50 
7.8.5 
Food and beverage restrictions ............................................................................. 51 
7.8.6 
Other concomitant treatment ................................................................................ 51 
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8 
STATISTICAL ANALYSES ............................................................................... 51 
8.1 
Statistical considerations ...................................................................................... 51 
8.1.1 
Estimands .............................................................................................................. 51 
8.2 
Sample size estimate ............................................................................................. 51 
8.3 
Definitions of analysis sets ................................................................................... 52 
8.3.1 
Full analysis set ..................................................................................................... 52 
8.3.2 
Safety analysis set ................................................................................................. 52 
8.3.3 
All subjects enrolled ............................................................................................. 52 
8.4 
Violations and deviations ..................................................................................... 52 
8.5 
Outcome measures for analyses ............................................................................ 52 
8.5.1 
Primary efficacy analysis ...................................................................................... 52 
8.5.1.1 
Derivation of primary efficacy endpoint .............................................................. 53 
8.5.2 
Secondary efficacy analysis .................................................................................. 53 
8.5.2.1 
Derivation of secondary efficacy endpoints ......................................................... 53 
8.5.3 
Exploratory efficacy analysis ............................................................................... 53 
8.5.3.1 
Derivation of exploratory efficacy endpoints ....................................................... 53 
8.6 
Methods for statistical analyses ............................................................................ 54 
8.6.1 
Analysis of the primary variable(s) ...................................................................... 54 
8.6.2 
Analysis of the secondary variable(s) ................................................................... 55 
8.6.2.1 
Responder analysis in post-exercise FEV1 ........................................................... 55 
8.6.3 
Analysis of the exploratory variables ................................................................... 56 
8.6.3.1 
Responder analysis in post-exercise FEV1 (20% threshold) ................................. 56 
8.6.3.2 
Time to recovery ................................................................................................... 56 
8.6.3.3 
Fall in post-exercise FEV1 at individual time points ............................................ 56 
8.6.3.4 
Post-exercise FEV1 AUC0-30min ............................................................................. 56 
8.6.4 
Subgroup analysis ................................................................................................. 56 
8.6.5 
Interim analysis ..................................................................................................... 57 
8.6.6 
Sensitivity analysis ............................................................................................... 57 
9 
STUDY AND DATA MANAGEMENT ............................................................. 57 
9.1 
Training of study site staff .................................................................................... 57 
9.2 
Monitoring of the study ........................................................................................ 57 
9.2.1 
Source data ............................................................................................................ 58 
9.2.2 
Study agreements .................................................................................................. 58 
9.2.3 
Archiving of study documents .............................................................................. 58 
9.3 
Study timetable and end of study .......................................................................... 58 
9.4 
Data management ................................................................................................. 58 
10 
ETHICAL AND REGULATORY REQUIREMENTS........................................ 59 
10.1 
Ethical conduct of the study ................................................................................. 59 
10.2 
Subject data protection ......................................................................................... 60 
10.3 
Ethics and regulatory review ................................................................................ 60 
10.4 
Informed consent/assent ....................................................................................... 61 
10.5 
Changes to the clinical study protocol and informed consent form/assent .......... 61 
10.6 
Audits and inspections .......................................................................................... 61 
11 
LIST OF REFERENCES ...................................................................................... 63 
APPENDIX A AVILLION PROTOCOL SIGNATURE PAGE ............................................ 65 
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APPENDIX B PRIMARY INVESTIGATOR SIGNATURE PAGE ..................................... 66 
APPENDIX C ADDITIONAL SAFETY INFORMATION ................................................... 67 
APPENDIX D SPIROMETRY ASSESSMENT CRITERIA ................................................. 69 
 
List of Tables 
Table 1 
Treatment sequences ..................................................................................... 3 
Table 2 
Schedule of assessments.............................................................................. 28 
Table 3 
Spirometry assessments relative to the maximal exercise test at Visit 1 .... 30 
Table 4 
Spirometry assessments relative to the exercise challenge test and dosing 
at Visits 2, 3, and 4 ...................................................................................... 31 
Table 5 
Laboratory variables .................................................................................... 38 
Table 6 
Investigational product strength and dosage form ...................................... 47 
Table 7 
Treatment sequences ................................................................................... 47 
 
List of Figures 
Figure 1 
Study schema............................................................................................... 17 
 
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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 
ATS 
American Thoracic Society 
AUC0-30min 
area under the curve from 0 to 30 minutes 
BDA MDI (PT027) 
budesonide/albuterol metered-dose inhaler 
β-hCG 
β-human chorionic gonadotropin 
BMI 
body mass index 
CI 
confidence interval 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECT 
exercise challenge test 
EIB 
exercise-induced bronchoconstriction 
ERS 
European Respiratory Society 
 
 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
GMP 
Good Manufacturing Practice 
HFA 
hydrofluoroalkane 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICS 
inhaled corticosteroid 
Coordinating Investigator 
The Coordinating Investigator is the investigator coordinating the investigators 
and/or activities in several study sites nationally.  
IP 
investigational product  
 
IWRS 
Interactive Web Response System 
LABA 
long-acting β2-agonist 
PDV 
premature discontinuation visit 
PEF 
peak expiratory flow 
prn 
as needed  
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Abbreviation or special 
term 
Explanation 
QTcF 
QT interval corrected by Fridericia 
SABA 
short/rapid-acting β2-adrenoreceptor agonist 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SMART 
Symbicort Maintenance And Reliever Therapy 
TC 
telephone call 
WBDC 
web based data capture 
 
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1 
INTRODUCTION 
1.1 
Background  
Bond Avillion 2 Development LP (Sponsor) is developing budesonide/albuterol sulfate 
(PT027, a fixed-dose combination product; hereafter referred to as budesonide and albuterol 
metered-dose inhaler [BDA MDI]) pressurized inhalation suspension product in adults and 
children (≥4 years of age) with asthma. Please refer to the current Investigator Brochure for 
additional information. 
Albuterol is a short/rapid-acting β2-adrenoreceptor agonist (SABA), inducing airway smooth 
muscle relaxation and reducing or preventing bronchoconstriction. Albuterol is approved in 
many countries in multiple formulations for treatment or prevention of bronchoconstriction, 
and is also known under the generic name of salbutamol. In clinical practice, albuterol is used 
as reliever therapy on an as-needed (prn) basis (Global Initiative for Asthma [GINA] 
guidelines).  
Budesonide is a well-established anti-inflammatory corticosteroid that exhibits potent 
glucocorticoid and weak mineralocorticoid activity and is approved worldwide in inhaled 
formulations for the treatment of asthma and chronic obstructive pulmonary disease both as a 
mono-product and in combination with a long-acting β2-agonist (LABA), (ie, formoterol).  
In vitro studies have demonstrated that inhaled corticosteroid (ICS) agents potentiate the 
effects of SABAs in reducing airway smooth muscle tone (Mendes et al 2008) and can reverse 
adrenergic receptor tolerance and desensitization (Cooper and Panettieri 2008). Clinically, 
similar functional potentiation with combined ICSs and albuterol has been observed in 
patients with asthma for functional measures of airway smooth muscle and airway blood flow 
(Mendes et al 2015).  
Combining albuterol with budesonide in the proposed BDA MDI combination product should 
not only provide rapid bronchodilation, but also treat worsening airway inflammation by the 
addition of the budesonide component. Per current treatment guidelines (GINA 2019), 
ICS/formoterol maintenance and reliever can be used in patients with asthma. Studies of 
budesonide and a rapid-acting LABA (formoterol) as reliever therapy have demonstrated 
enhanced protection from severe exacerbations in patients already receiving combination 
therapy for maintenance without an increase in adverse effects (O'Byrne et al 2005, Rabe et al 
2006). In addition, budesonide/formoterol as maintenance and reliever therapy or “Symbicort 
Maintenance And Reliever Therapy (SMART)” (available commercially as the Symbicort 
Turbuhaler [Symbicort] in the European Union and other markets) significantly reduced 
severe exacerbation risk in pediatric patients (O'Byrne 2007).  
In some markets, Symbicort is approved for maintenance and reliever therapy. With SMART 
application, patients with asthma use Symbicort as maintenance inhalation medication and 
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also prn in response to symptoms. The simultaneous administration of budesonide with 
formoterol when symptoms occur ensures that patients with asthma receive both a 
rapid-acting bronchodilator for symptom relief and anti-inflammatory medication to treat their 
persistent airway inflammation.  
The BDA MDI is proposed to be available prn to use in response to symptoms to all patients 
with asthma, regardless of maintenance therapy. BDA MDI would have added effect on 
improvement of lung function and achieving asthma improvement beyond what is seen with 
albuterol and budesonide alone. Current treatment guidelines (GINA 2019) recommend 
addition of low-dose ICS to SABA used as reliever medication as early as in GINA step 1 
asthma (previously treated with SABA prn alone), broadening the range of asthma severity 
grades that would be treated by both ICS and β2-adrenoreceptor agonist. Anti-inflammatory 
and bronchodilation components used prn in a fixed-dose combination are expected to result 
in overall better asthma control and decreased risk of experiencing asthma symptoms than 
bronchodilation alone. 
1.2 
Exercise-induced bronchoconstriction 
Exercise-induced bronchoconstriction (EIB) describes acute airway narrowing that occurs as a 
result of exercise. EIB occurs in a substantial proportion of patients with asthma, but may also 
occur in individuals without an asthma diagnosis. The quality of evidence supporting the 
recommendations for the treatment of EIB is variable. Recommendations include using an 
inhaled SABA at least 15 minutes before exercise in all patients with EIB. While for patients 
who continue to have symptoms of EIB despite the administration of an inhaled SABA before 
exercise, strong recommendations were made for a daily ICS, a daily leukotriene receptor 
antagonist, or a mast cell stabilizing agent before exercise (Parsons et al 2013). Inhaled 
disodium cromoglycate and β2-agonists administered immediately before an exercise 
challenge test (ECT) also provide good protection (Molema et al 1989, Richter et al 2002). 
1.3 
Rationale for study design, doses and control groups 
TYREE is a multicenter, randomized, double-blind, placebo-controlled, 2-period, single-dose, 
crossover study in adults and adolescents (12 to 70 years of age) with asthma and EIB. This 
Phase III study is conducted in addition to the AV003-MANDALA exacerbation and AV004-
DENALI lung function studies.  
Asthma patients with EIB, who use their SABA reliever therapy prophylactically before 
exercise to prevent EIB, may benefit from a fixed-dosed combination (BDA MDI), taken prior 
to exercise, to prevent asthma symptoms. The TYREE study will assess the efficacy and 
safety of single-dose BDA MDI as compared with placebo MDI in subjects with asthma and 
EIB. It is important to evaluate whether BDA MDI would prevent or reduce 
bronchoconstriction when used prophylactically.  
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Efficacy measures have been selected to demonstrate the therapeutic benefit of BDA MDI 
compared with placebo MDI: 
1) The maximum percentage fall from post-dose, pre-exercise baseline in forced expiratory 
volume in 1 second (FEV1) up to 60 minutes post-exercise challenge  
2) The percentage of subjects with a maximum percentage fall in FEV1 post-exercise 
challenge of <10% 
1.4 
Benefit/risk and ethical assessment 
The study will be conducted in accordance with International Conference on Harmonisation 
(ICH) guidelines. Permission from the research ethics committee (EC) will be sought and the 
study will start only after authorization. In the study, single-dose treatment and a comparison 
with placebo is necessary, to show that the presumed protection against EIB is an effect of 
active treatment.  
To mitigate any potential risks, all subjects will be closely monitored to ensure subject safety. 
At study visits, subjects will only be discharged from the clinic after satisfactory lung function 
based on the investigator’s clinical judgment.  
The study will be conducted in a similar design as previously published studies (eg, Ostrom et 
al 2015). When considering and assessing all non-clinical and clinical data available for study 
treatments, the Sponsor considers the risk and benefit profile of Study TYREE to be 
acceptable. 
1.5 
Study design  
This will be a multicenter, double-blind, randomized, placebo-controlled, 2-period, single-
dose, crossover study. The study will consist of a screening period (Visit 1 and Visit 2) and 2 
treatment visits (Visit 3 and Visit 4). A final follow-up visit will be conducted via a telephone 
call (TC) 3 to 5 days after the final in-clinic visit.  
During the study, standardized ECTs will be conducted according to American Thoracic 
Society (ATS)/European Respiratory Society (ERS) guidelines (Crapo et al 2000). At each 
visit, standard FEV1 spirometry assessments will be performed relative to ECT and dosing, 
(before and after) as applicable. All spirometry and testing procedures will be in accordance 
with current guidelines. A centralized spirometry data collection system incorporating a 
quality control program will be used to reduce FEV1 variability between and within subjects, 
and between study sites. 
To be eligible for the treatment phase of the study, subjects with asthma will be required to 
meet spirometry criteria and demonstrate EIB through standardized ECT. If any of the 
spirometry criteria are not met at Visit 1 (or Visit 2), subjects can be retested. See 
Sections 4.1.1 and 4.1.2 for specific details on retesting.  
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Visit 1 will include general screening procedures, spirometry, and demonstration of EIB 
through standardized ECT. Those subjects continuing to meet eligibility criteria will enter a 1 
to 2-week screening period to Visit 2, at which they will be administered placebo MDI, 
undergo spirometry testing and confirmation of EIB. At Visit 3, eligible subjects will be 
randomized to 1 of 2 treatment sequences (ie, A/B or B/A), in which single doses of BDA 
MDI and placebo MDI will be administered in separate treatment periods (ie, Period 1 and 
Period 2). At Visit 4, subjects who received BDA MDI at Visit 3 will receive placebo, while 
those who received placebo at Visit 3 will receive BDA MDI. 
Safety will be monitored by spontaneously reported adverse events (AEs)/serious AEs (SAEs) 
and physical examination findings. Further, heart rate will be monitored continuously during 
the ECTs and intermittently after ECT until 60 minutes after completion of the exercise 
challenge. 
Figure 1 
Study schema 
   
Abbreviations: AE=adverse event; BDA=budesonide/albuterol; Conmeds=concomitant medication; 
EIB=exercise-induced bronchoconstriction; MDI=metered-dose inhaler; IP=investigational product; 
PDV=premature discontinuation visit. 
 
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2 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary Objective: 
Outcome Measure: 
To assess the efficacy of a single dose of BDA MDI 
(160/180 µg) compared with placebo MDI on EIB 
in adult and adolescent subjects with asthma 
The maximum percentage fall from post-dose, pre-exercise 
baseline in FEV1 observed up to 60 minutes post-exercise 
challenge  
2.2 
Secondary objectives 
Secondary Objectives: 
Outcome Measures: 
To further assess the efficacy of a single dose of 
BDA MDI compared with placebo MDI on EIB in 
adult and adolescent subjects with asthma 
Percentage of subjects with a maximum percentage fall in 
FEV1 post-exercise challenge of <10% 
 
2.3 
Safety objective 
Safety Objective: 
Outcome Measures: 
To evaluate the safety and tolerability of BDA MDI 
relative to placebo MDI on EIB in adult and 
adolescent subjects with asthma 
Incidence of AEs/SAEs 
 
2.4 
Exploratory objectives   
Exploratory Objective: 
Outcome Measures: 
To characterize the effect of BDA MDI 160/180 μg 
administered as a single-dose on 
bronchoconstriction compared with placebo 
 
1. Percentage of subjects with a maximum percentage fall 
in FEV1 post-exercise challenge of <20% 
2. Time to recovery, defined as the time from completion 
of the exercise challenge to the first measured post-
exercise challenge FEV1 value within 10% of the post-
dose, pre-exercise challenge baseline FEV1 
3. The percentage fall from baseline in FEV1 at each time 
point within 60 minutes post-exercise challenge 
4. Post-exercise FEV1 area under the curve from 0 to 30 
minutes(AUC0-30min) 
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3 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL  
Each subject must meet all inclusion criteria and none of the exclusion criteria for this study. 
Under no circumstances can there be exceptions to this rule. 
3.1 
Inclusion criteria 
For inclusion in the study subjects should fulfill the following criteria: 
1 
Willing and able to provide/sign written informed consent or age-appropriate assent prior 
to any study-specific procedures; subjects below the legal age of consent must have 
parent(s) or guardian sign the informed consent form (ICF) before participation.  
2 
Female or male aged 12 to 70 years at the time of informed consent. 
3 
Documented history of asthma (as defined by GINA criteria) for at least 6 months prior to 
Visit 1.  
4 
Receiving 1 of the following asthma therapies with stable dosing for at least the 4 weeks 
before Visit 1; no other asthma therapies are permitted during the study: 
(a) SABA prn, or 
(b) Low-to-medium dose maintenance therapy with ICS and SABA prn.  
5 
Each pre-exercise challenge (and pre-dose at Visits 2 and 3) best FEV1 determination 
from the beginning of screening and before randomization ≥70% of predicted normal 
value.  
6 
EIB as defined by a ≥20% decrease from pre-exercise challenge best FEV1 observed 
within 60 minutes after an exercise challenge at Visit 1 and at Visit 2. 
7 
Demonstrate acceptable spirometry performance (ie, meet ATS/ERS 
acceptability/repeatability criteria). See Appendix D. 
8 
Demonstrate acceptable MDI administration technique. 
(a) Note: Use of a spacer device during the randomized treatment phase is not permitted. 
9 
Body mass index (BMI) <40 kg/m2. 
10 Females of childbearing potential must have a negative serum pregnancy test. 
11 Females of childbearing potential who are sexually active and in heterosexual 
relationships, must agree to 1 of the following options to prevent pregnancy: 
(a) Practice complete abstinence defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatments. Periodic 
abstinence is not acceptable. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. Therefore, complete abstinence is an acceptable method of 
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contraception only if it is consistent with the preferred and usual lifestyle of the 
subject. 
(b) Use of 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: 
(i) Hormonal contraception (eg, oral contraceptive, contraceptive implant, or 
injectable hormonal contraceptive); 
(ii) Double-barrier birth control (ie, a combination of male condom with either cap, 
diaphragm, or sponge with spermicide); or 
(iii) Maintenance of a monogamous sexual relationship with a male partner who has 
been surgically sterilized by vasectomy provided that the male partner is the sole 
sexual partner of the female (of childbearing potential) participant and that the 
vasectomized partner has received medical assessment of the surgical success 
(ie, documented history of medical confirmation of success of vasectomy). 
Note: Female subjects 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 (a postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause), or surgically sterile, defined as having a bilateral 
salpingectomy, bilateral oophorectomy, or hysterectomy. Tubal ligation will be 
considered an acceptable permanent birth control measure for this protocol. For purposes 
of this protocol, menopausal women are defined as women ≥50 years old who are 
amenorrheic for 12 consecutive months or more after cessation of all exogenous 
hormonal treatment.  
Adolescent-specific recommendations: If the subject is female and has reached menarche, 
or has reached Tanner stage 3 breast development (even if not having reached menarche), 
the subject will be considered a female of childbearing potential. Contraceptive methods 
may be recommended for adolescent females only if they are already sexually active. Use 
of hormonal contraceptives in adolescent females must always be in consultation with a 
gynecologist. 
12 Male subjects who are sexually active in heterosexual relationships must be surgically 
sterile or agree to use a double-barrier method of contraception (ie, a combination of male 
condom with either cap, diaphragm, or sponge with spermicide) from the first dose of 
randomized study drug until 2 weeks after their last dose. Male subjects must not donate 
sperm during their study participation period. 
13 Willingness and ability to comply with all required study procedures including 
completion of all study visit assessments. 
3.2 
Exclusion criteria  
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
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1 
Chronic obstructive pulmonary disease or other significant lung disease (eg, chronic 
bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, 
bronchopulmonary dysplasia), including regular or occasional use of oxygen. 
2 
Systemic corticosteroids use (any dose and any indication) within 3 months before Visit 
1. 
3 
Subject has a history of life-threatening asthma, defined by past intubations for asthma, or 
intensive care unit admission for asthma within the prior 24 months. 
4 
Subjects receiving regular maintenance treatment with prohibited anti-inflammatory or 
long-acting bronchodilator asthma medication (inhaled, nebulized, oral, or systemic) 
within 1 month prior to Visit 1. Note: During the treatment phase, subjects are not 
allowed to use any asthma treatments/medications (of any class) other than the IP and the 
permitted SABA or ICS treatment that was started before screening. No subject can be on 
other asthma maintenance therapies. See Section 7.8.2 for details. 
5 
Subjects unable to tolerate the lung function testing performed after ECT at Visit 1 or 2 
without use of rescue medication. 
6 
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). 
7 
Subjects with contraindications to ECT according to ATS/ERS guidelines. 
8 
Completed treatment for lower respiratory infection within 6 weeks prior to Visit 1, 
regardless if resulting in accompanying asthma symptoms aggravation or not. 
9 
Upper respiratory infection involving antibiotic treatment not resolved within 7 days prior 
to Visit 1. 
10 Subjects with a known or suspected hypersensitivity to albuterol/salbutamol, or 
budesonide and/or their excipients. 
11 Having received any marketed (eg, omalizumab, mepolizumab, reslizumab, 
benralizumab, dupilumab) or investigational biologic within 3 months or 5 half-lives 
before Visit 1, whichever is longer, or any other prohibited medication.  
12 Treatment with any IP within the last 30 days (or 5 half-lives, whichever is longer) of 
Visit 1. 
13 Any of the following results at Visit 1:  
(a) an abnormal electrocardiogram (ECG) that is, in the investigator’s opinion, clinically 
significant 
(b) a QT interval corrected by Fridericia (QTcF) interval >480 ms  
14 Historical or current evidence of a clinically significant disease including, but not limited 
to: cardiovascular (eg, congestive heart failure, known aortic aneurysm, clinically 
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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) disorders. 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. 
15 Cancer not in complete remission for at least 5 years before Visit 1. 
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 clinically controlled and the subject’s 
participation in the study would not represent a safety concern. 
16 Hospitalization for psychiatric disorder or attempted suicide within 1 year of Visit 1. 
17 History of psychiatric disease, intellectual deficiency, poor motivation, or other 
conditions if their magnitude is limiting informed consent validity. 
18 Having a scheduled/planned hospitalization during the study. 
19 Inability (and/or unwillingness) to abstain from protocol-defined prohibited medications 
during the study. 
20 Use of any herbal products by inhalation or nebulizer within 2 weeks of Visit 1 and/or the 
unwillingness to stop during the study duration. 
21 Significant abuse of alcohol or drugs, in the opinion of the investigator. 
22 For females only: currently pregnant (confirmed with positive serum pregnancy test), 
planning a pregnancy during the study, or breastfeeding.  
23 Current participation in any interventional study. 
24 Previous enrollment in the present study or randomization in any other BDA MDI 
(budesonide/albuterol) clinical study. 
25 Involvement in the planning and/or conduct of the study (applies to both Sponsor’s staff 
and/or staff at the study site, including investigators and immediate family members). 
For procedures for withdrawal of incorrectly enrolled subjects, see Section 3.4. 
3.3 
Subject enrollment and randomization 
Approximately 6 study sites in the United States are anticipated to be included. 
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Approximately 120 adult and adolescent subjects (12 to 70 years of age) will need to be 
screened for asthma and EIB, assuming an estimated screen failure rate of 50% prior to 
randomization.  
Approximately 60 adult and adolescent subjects (12 to 70 years of age) will be randomized 
1:1 to 1 of 2 treatment sequences (ie, A/B or B/A) as described in Table 1.  
Randomization will be centralized and stratified by age (adults: 18 to 70; adolescents: 12 to 
17) and background ICS therapy (ICS or no ICS). 
Investigator(s) should keep a record, ie, the subject screening log, of subjects who entered pre-
study screening. 
The investigator(s) will: 
1 
Obtain signed informed consent/assent (as applicable) from the potential subject and/or 
their guardian/legal representative before any study-specific procedures are performed. 
2 
Enter the subject data into the enrollment module in Rave Web Based Data Capture 
(WBDC) electronic case report form (eCRF) to enable the allocation of subject 
identification code (Ecode). 
3 
Determine subject eligibility. See Sections 3.1 and 3.2. 
4 
Enter the information required to enable the Interactive Web Response System (IWRS) to 
initiate randomization and generate the randomization code. 
Randomization codes will be assigned through IWRS strictly sequentially to subjects eligible 
for randomization. If a subject withdraws from participation in the study, then his/her 
enrollment/randomization code cannot be reused. 
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, randomized, or receive IP. There can be no exceptions to this rule. There can be no 
waivers granted from the Sponsor for any subject not meeting inclusion or exclusion criteria. 
Where a subject does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the investigator should inform the medical monitor 
immediately, and a discussion should occur between the medical monitor and the investigator 
regarding whether to continue or withdraw the subject in the study. The medical monitor must 
ensure all decisions are appropriately documented. 
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3.5 
Methods for assigning treatment groups 
A randomization schedule will be generated by a designated statistical representative 
performing statistical support for the study. This schedule will be prepared before the start of 
the treatment phase. The designated statistical representative will follow their established 
standard operating procedures regarding generation, security, and distribution of the 
randomization schedule.  
Upon enrollment, subjects will be assigned a unique subject identification code (Ecode) which 
is automatically generated by the electronic data capture system (Rave WBDC) based on the 
order of entry. Once it has been determined that a subject meets all eligibility criteria, the 
subject information will be integrated into the IWRS (Randomization and Trial Supply 
Management) for randomization. 
3.6 
Methods for ensuring blinding 
The study blind is to be maintained until all subjects have completed the treatment phase and 
until after the database has been locked. The study site receives documentation of subject 
study identification and kit allocation through the IWRS. The randomization code will not be 
available, with the exception of unblinding procedures described in Section 3.7, to the study 
team, study center personnel, Sponsor monitors, Sponsor project statisticians, or any other 
personnel employed or affiliated with the Sponsor, as well as investigators and subjects until 
after the database has been locked.  
The 2 different kit types of study IP and placebo are visually identical, protecting the blind 
through their similarity in appearance.  
3.7 
Methods for unblinding  
The treatment blind should not be broken except in medical emergencies and based on the 
investigator’s clinical judgment, when the appropriate management and welfare of the subject 
requires knowledge of the treatment allocation. Individual treatment details, for each subject, 
will be available to the investigator(s) or pharmacists from the IWRS, if needed. If unblinding 
occurs, the investigator must notify the Sponsor as soon as possible, but without revealing the 
treatment assignment of the unblinded subject. Routines for this will be described in the IWRS 
user manual that will be provided to each center. The IWRS provides unblinding procedures, 
if needed.  
The designated representative retains the right to break the code for SAEs that are unexpected 
and are suspected to be causally related to an IP 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. 
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With the exception of emergency unblinding as described above, all members of the study 
team, investigators, and site staff will be blinded.  
3.8 
Restrictions 
During the study, subjects are not allowed to use any asthma medication other than the IP and 
their background treatment (ie, SABA prn alone or ICS with SABA) that was started before 
screening and continued as part of their asthma treatment (see inclusion criteria). Non-asthma 
medications which are necessary for the subject’s wellbeing and which do not affect the 
participation or results of the study are allowed at the investigator’s discretion. All such 
medication should be recorded in the subject’s eCRF. 
3.9 
Criteria for study withdrawal  
At any time, subjects may withdraw from the study (ie, study procedures/visits) at their own 
request (or their parent/legal representative’s request, as applicable) for any reason, without 
prejudice. Subjects may also be withdrawn from the study upon request of the investigator, or 
by the Sponsor at any time or for any reason. Some reasons for study withdrawal include:  
• 
An AE or other unacceptable toxicity considered to jeopardize the safety of a subject 
participating in the study. 
• 
Subjects who suffer 1 severe exacerbation or worsening of asthma that in the 
investigator’s opinion could affect short-term disease course or stability of lung function 
will be discontinued if the Sponsor and the investigator decide that it is in the best interest 
of the subject to withdraw from the study.  
• 
General or specific change(s) in the subject's condition that render(s) him/her ineligible 
for further participation according to the inclusion/exclusion criteria. 
• 
Non-compliance: in the opinion of the investigator, the subject is non-compliant with the 
requirements of the Clinical Study Protocol (eg, post-enrollment eligibility violation).  
• 
Lost to Follow-up: the subject is lost to follow-up and no alternative contact information 
is available (this implies that at least 2 documented attempts have been made to contact 
the subject). 
• 
Intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that 
became apparent during treatment and necessitated the subject’s termination from the 
study, eg, a symptomatic lower respiratory tract infection that puts the subjects at 
potential risk and interferes with the subject’s ability to carry out the required procedures. 
• 
Pregnancy; if a female subject becomes pregnant, she will be immediately withdrawn 
from the study. 
If a subject is withdrawn from the study for any reason, the study site must immediately notify 
the medical monitor. The date and the reason for study withdrawal must be recorded on the 
eCRF. The subject will be asked to complete a premature discontinuation visit (PDV) and the 
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follow-up TC. The safety follow-up TC contact will occur 3 to 5 days after the last study visit 
or PDV, as indicated in the Schedule of Assessments (Table 2).  
In the event that a subject withdraws prematurely from the study because of an AE or SAE, 
the AE/SAE will be followed up until it resolves (returns to normal or baseline values) or 
stabilizes, or until it is judged by the investigator to no longer be clinically significant. 
Once a subject is withdrawn from the study, the subject may not re-enter the study. If a subject 
withdraws from participation in the study, then his/her enrollment/randomization code cannot 
be reused. Withdrawn subjects will not be replaced.  
3.9.1 
Screen failures  
Screening failures are subjects who do not fulfill the eligibility criteria for the study, and 
therefore must not be randomized. These subjects should have the reason for study withdrawal 
recorded as “Screen failure” (the potential subject who does not meet 1 or more criteria 
required for participation in a trial, this reason for study withdrawal is only valid for non-
randomized subjects). Subjects who are screen failures will not be rescreened. 
Subjects who fail to meet Visit 1/Visit 2 criteria will be considered for retesting. See 
Section 4.1.2 for specific details on all retesting.  
3.10 
Discontinuation of the study 
The study may be stopped if, in the judgment of the Sponsor, trial subjects are placed at undue 
risk because of clinically significant findings that: 
• 
meet individual stopping criteria or are otherwise considered significant  
• 
are assessed as causally related to study drug  
• 
are not considered to be consistent with continuation of the study 
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented. 
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  
Table 2 presents study assessments and procedures; Table 3 and Table 4 presents timed 
spirometry assessments relative to the ECT (and dosing, as applicable) at Visit 1 through 
Visit 4. Repeat assessments, if needed, will be captured in unscheduled visits. Details on study 
assessments are presented in Section 5. 
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General Considerations 
To ensure standardization, it is recommended that sites review and remind/discuss the 
following with the subject on at least the day before a scheduled visit, as applicable: 
• 
Site personnel will remind/instruct subjects not to take any prohibited asthma medications 
during the study. Non-asthma medications which are necessary for the subject’s 
wellbeing and which do not affect the participation in or results of the study, are allowed. 
All such medication should be recorded in the subject’s eCRF.  
− 
At every visit during which lung function testing will be performed, subjects must 
withhold SABA for at least 6 hours prior to start of test day procedures. If subjects 
have taken SABA within 6 hours before the planned lung function test, the test 
should not be carried out and the visit should be rescheduled.    
• 
Subjects are not allowed to perform physical exercise during the 24 hours prior to the 
visits.  
• 
Subjects must not ingest/consume xanthine and/or xanthine analogue (caffeine)-
containing foods and beverages for at least 6 hours prior to each study visit and for the 
duration of each study visit. Examples of such products include coffee, tea, chocolate, and 
cola. Decaffeinated beverages are acceptable. 
• 
Subjects should avoid having a large meal at least 2 hours prior to a study visit. 
• 
Subjects will be required to return to the clinic at approximately the same time beginning 
at Visit 2 for all visits (±2 hours of timing of Visit 1). Therefore, all subjects 
appointments must be scheduled with careful attention to the following criteria:  
− 
The first spirometry assessment each at Visits 2, 3, and 4 should be completed prior 
to 11:00 AM and within ±1 hour of the timing of the first spirometry measurement 
done at Visit 1.  
− 
After Visit 1, every attempt should be made to have subsequent ECTs done ±2 hours 
of the timing of the exercise challenge done at Visit 1. 
− 
Subjects will be required to remain at clinic until completion of all protocol-defined 
assessments. To minimize diurnal variance, sites should make every effort to assess 
subjects at the same time throughout the study. 
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Table 2 
Schedule of assessments 
 
Screening a 
Double-blind Treatment Phase 
Unscheduled 
Visit or PDV 
b (if 
applicable) 
Follow up 
Visit 
1 
2 
3 
4 
TC (3 to 5 days 
after V4 or 
PDV) 
Period 1 
Period 2 
Day 
-14 to -8 a 
-7 to -2 a 
1 
8(±6) 
Informed consent/assent 
X 
 
 
 
 
 
Eligibility criteria 
X c 
X c 
 
 
 
 
Verify randomization criteria 
 
 
X d 
 
 
 
Routine clinical procedures 
Medical/surgical history 
X 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
Alcohol consumption and smoking 
history 
X 
 
 
 
 
 
Physical examination 
X 
 
 
X 
X 
 
Height and BMI 
X 
 
 
 
 
 
Weight 
X 
 
 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Routine safety measurements 
Pregnancy test e 
X 
 
X 
X 
X 
 
Laboratory assessments f 
X 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
Seated vital signs (blood pressure 
and heart rate) g 
X 
X 
X 
X 
 
 
12-lead ECG g, h 
X 
X 
X 
X 
 
 
Efficacy measurements 
Spirometry (FEV1) g 
X  
X  
X  
X  
 
 
Maximal exercise test  h 
X i 
 
 
 
 
 
ECT with Treadmill  h 
 
X i, j  
X i, j  
X i, j  
 
 
Confirm FEV1 stability k 
 
X k  
X k  
X k  
 
 
Study treatment  
Randomization 
 
 
X d 
 
 
 
IP 
 
 (placebo MDI) 
X 
X 
 
 
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Abbreviations: β-hCG=beta-human chorionic gonadotropin; BMI=body mass index; ECG=Electrocardiogram; ECT=Exercise Challenge Test; EIB=exercise-
induced bronchoconstriction; FEV1=Forced expiratory volume in 1 second; IP=Investigational Product; PDV=Premature discontinuation visit; TC=Telephone 
call; V=Visit. 
Notes: 
a The run-in periods at Screening are suggestions which can be shortened; the Screening and Double-blind Treatment Phase period must include at least 1 non-
exercise test day between visit days. 
b Subjects who prematurely withdraw from the study will undergo a PDV.  
c Eligibility criteria: At V2 pre-dose FEV1 best value not exceeding ±20% of the best value measured at V1 pre-exercise; pre-exercise FEV1 ≥70% of predicted at 
V1 and V2; demonstration of EIB (at both V1 and V2). One retest will also be allowed for a lack of FEV1 drop (ie, negative EIB outcome) at V1 only if the FEV1 
drop is between 15% and <20%. Those subjects not meeting criteria will be considered screen failed. See Sections 4.1.1 and 4.1.2 for specific details.  
d Subjects will be randomized at V3 to treatment if they demonstrate (at V3) a pre-exercise challenge FEV1 ≥70% of predicted and a best pre-dose, pre-exercise 
challenge FEV1 that does not exceed ±20% of the best pre-exercise challenge FEV1 at V1. See Section 4.2.1 for details. 
e A serum pregnancy test (β-hCG) will be performed at V1, V4 and PDV; and a urine β-hCG test will be performed at V3 (for women of childbearing potential 
only). 
f Laboratory assessments (clinical chemistry, hematology and urinalysis) to be performed according to Section 5.2.1.  
g The spirometry (and related safety) assessments to be performed in association with the exercise challenge at V1 to V4 are described in detail in Table 3 and 
Table 4. 
h Heart rate to be monitored continuously during the exercise challenge and until 60 minutes after completion.  
i After V1, every attempt should be made to have subsequent ECTs started ±2 hours of the timing of the maximal exercise test done at V1. 
j At V2, V3, and V4, an ECT will be conducted 30 (±5) minutes after IP administration. 
 k The pre-dose, pre-exercise challenge best FEV1 value measured at each denoted visit (performed before exercise challenge) should not exceed ±20% of the 
pre-dose, pre-exercise challenge best FEV1 value measured at V1. 
 
 
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Table 3 
Spirometry assessments relative to the maximal exercise test at Visit 1 
 
Pre-exercise challenge 
Maximal exercise 
test 
Post-exercise challenge 
Time (minutes) 
Assessments 
-50 
(±15) 
-35 
(±5) 
-5 
(±3) 
0 
5 
(±3) 
10 
(±3) 
15 
(±3) 
20 
(±5) 
30 
(±5) 
40 
(±5) 
45 
(±5) 
60 
(±5) 
Seated vital signs (BP and HR) 
X a 
 
 
 
 
 
 
X 
 
X 
 
X b 
12-lead ECG 
X c 
 
 
 
 
 
 
 
 
 
X 
 
Spirometry d 
 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
Exercise challenge e 
 
 
 
X 
 
 
 
 
 
 
 
 
HR monitoring f 
 
 
 
X -----------------------------------------------------------------------------------X 
Concomitant medication 
monitoring 
X ------------------------------------------------------------------------------------------------------------------X 
AE monitoring 
X ------------------------------------------------------------------------------------------------------------------X 
Abbreviations: AE=adverse event; BP=blood pressure; ECG=electrocardiogram; ECT=exercise challenge test; HR=heart rate; PFT=pulmonary function test. 
Notes:  
a Vital signs should be recorded with the subject in the seated position and after 10 minutes of rest.  
b Seated vital signs at the 60-minutes post-exercise challenge time point should be recorded 5-10 minutes AFTER the last PFT (ie, 65 minutes [±5 minutes]). 
c 12-lead ECG recording at the pre-exercise challenge time point should be conducted after 10 minutes of rest. 
d Every attempt should be made to perform the first pre-exercise (and pre-dose at Visits 2 to 4) spirometry measurement prior to 11:00 AM consistently across 
Visits 1 through 4 visit (ie, ±1 hour of the timing of the initial assessment at Visit 1). 
e After Visit 1, every attempt should be made to have the subsequent ECTs done ±2 hours of the timing of the maximal exercise test done at Visit 1. 
f Heart rate will be monitored continuously during the maximal exercise test and intermittently after maximal exercise test until 60 minutes after completion of 
the exercise challenge (ie, intermittently during PFTs). 
 
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Table 4 
Spirometry assessments relative to the exercise challenge test and dosing at Visits 2, 3, and 4  
 
Pre-dose 
Dose 
Post-dose 
Post-exercise challenge 
Time (minutes) 
Assessments 
-50  
(±15) 
-5 
(±3) 
0 
30 
(±5) 
ECT 
5 
(±3) 
10 
(±3) 
15 
(±3) 
20 
(±5) 
30 
(±5) 
40 
(±5) 
45 
(±5) 
60 
(±5) 
Seated vital signs (BP and HR) 
X a 
 
 
 
 
 
 
 
X 
 
X 
 
X b 
12-lead ECG 
X c 
 
 
 
 
 
 
 
 
 
 
X 
 
Spirometry d, e 
 
X d, e  
 
X 
 
X 
X 
X 
 
X 
 
 
X 
Administer study drug f 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Exercise challenge g 
 
 
 
 
X 
 
 
 
 
 
 
 
 
HR monitoring h 
 
 
 
 
X --------------------------------------------------------------------X 
Concomitant medication 
monitoring 
X ------------------------------------------------------------------------------------------------------------X 
AE monitoring 
X ------------------------------------------------------------------------------------------------------------X 
Abbreviations: AE=adverse event; BDA=budesonide/albuterol; BP=blood pressure; ECG=electrocardiogram; ECT=exercise challenge test; HR=heart rate; 
FEV1=forced expiratory volume in 1 second; IP=investigational product; MDI=metered dose inhaler; PFT=pulmonary function test. 
Notes:  
a Vital signs should be recorded with the subject in the seated position and after 10 minutes of rest.  
b Seated vital signs at the 60-minutes post-exercise challenge time point should be recorded 5-10 minutes AFTER the last PFT (ie, 65 minutes [±5 minutes]). 
c 12-lead ECG recording at pre-dose time point should be conducted after 10 minutes of rest. 
d At Visits 2 through 4, if the FEV1 criteria are not met in the first spirometry measurement (ie, 5 minutes pre-dose), 1 optional pre-dose spirometry measurement 
can be repeated after 30 minutes of the initial attempt. If first pre-dose FEV1 fulfill all criteria, then the subject can proceed to dosing. 
e Every attempt should be made to perform the first pre-exercise spirometry measurement prior to 11:00 AM consistently across Visits 1 through 4 visit (ie, ±1 
hour of the timing of the initial spirometry performed at Visit 1). 
f At Visit 2, subjects will receive placebo; while at Visit 3 and Visit 4 they will receive IP (BDA MDI or placebo MDI) depending on their randomization 
assignment. 
g After Visit 1, every attempt should be made to have the subsequent ECTs done ±2 hours of the timing of the maximal exercise test done at Visit 1. 
h Heart rate will be monitored continuously during the ECT and intermittently after ECT until 60 minutes after completion of the exercise challenge (ie, 
intermittently during PFTs). 
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4.1 
Screening period 
Procedures will be performed according to study assessments and procedures presented in 
Table 2, Table 3, and Table 4. At Visit 1, consenting subjects are assessed to ensure that they 
meet eligibility criteria. Subjects who do not meet the criteria must not be enrolled in the 
study. Subjects meeting all eligibility criteria will enter a screening period.  
4.1.1 
Visit 1 
Standard demographic data and other characteristics will be recorded and will include age and 
year of birth; gender, race, and/or ethnicity according to local regulations; alcohol 
consumption, and smoking history. 
A standard medical, disease, and surgical history will be obtained with review of the inclusion 
and exclusion criteria with the subject. Other study procedures carried out during this period 
will include physical examination (with weight, height, and BMI), concomitant medications 
review, seated vital signs (blood pressure and heart rate), 12-lead ECG, AEs 
assessment/review, serum pregnancy test for women of childbearing potential, blood samples 
for hematology and clinical chemistry, and urine samples for urinalysis. See Sections 5.2 and 
5.3 for details on assessments. 
Visit 1 will also include spirometry (lung function testing and baseline FEV1 determination) 
and subjects suitable for the study will perform a maximal exercise test on a treadmill in 
which maximal aerobic capacity is defined. Heart rate will be monitored continuously during 
the maximal exercise test and heart rate will be noted when the test is stopped and at specific 
time points as per Table 3. 
Spirometry FEV1 determinations will be made as per Table 3. To be eligible for the treatment 
phase of the study, subjects will be required to meet the following criteria at Visit 1: 
• Pre-exercise challenge best FEV1 ≥70% of predicted value 
• EIB as demonstrated by a ≥20% decrease from the 5-minute pre-exercise challenge 
absolute FEV1 
If any of the spirometry criteria are not met at Visit 1, subjects can be retested within 2 to 10 
days of the initial visit. Only 1 retest will be permitted for reasons related to technical issues 
(ie, acceptability) and/or pre-exercise FEV1 ≥70% predicted, prior to randomization. The 1 
retest will also be permitted for a lack of FEV1 drop (ie, negative EIB outcome) at Visit 1 only 
if the FEV1 drop is between 15% and <20%. Those subjects not meeting criteria will be 
considered screen failed. 
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4.1.2 
Visit 2 
At Visit 2, a standardized ECT with spirometry FEV1 determinations will be performed 
according to Table 4 for continuing eligibility determination. The first spirometry assessment 
will be performed beginning at approximately the same time as the subject’s initial assessment 
at Visit 1 (±1 hour) and before 11:00 AM. Subjects will be administered placebo MDI, with 
an ECT conducted 30 (±5) minutes after placebo administration. 
Subjects will be required to meet the following criteria: 
• The pre-dose, pre-exercise challenge best FEV1 ≥70% of predicted value 
• The pre-dose, pre-exercise challenge best FEV1 value measured not exceeding ±20% 
of the pre-exercise challenge best FEV1 value measured at Visit 1 
• The post-dose, pre-exercise challenge best FEV1 ≥70% of predicted value 
• EIB as demonstrated by a ≥20% decrease from the post-dose, pre-exercise challenge 
FEV1 
• No development of a respiratory tract infection or asthma exacerbation between Visit 1 
and 2. The visit can be rescheduled once within 7 to 10 days for an upper respiratory 
tract infection (eg, common cold) that resolves and does not interfere with the 
subject’s ability to perform the study procedures. 
If any of the spirometry criteria are not met at Visit 2, subjects can be retested within 2 to 10 
days of the initial visit. Only 1 retest will be permitted for reasons related to technical issues 
(ie, acceptability) and/or pre-exercise FEV1 ≥70% predicted and/or exceeding ±20%, prior to 
randomization. No retest will be allowed for a lack of FEV1 drop (ie, negative EIB outcome). 
Those subjects not meeting criteria will be considered screen failed. 
4.2 
Randomization/Treatment phase 
Procedures will be performed according to study visit assessments presented in Table 2, and 
Table 4. The treatment phase consists of 2 visits (Visit 3 and Visit 4). Subjects meeting 
eligibility criteria will be randomized at Visit 3. 
4.2.1 
Visit 3 and 4 
At Visit 3, eligible subjects will be randomized (1:1) to receive 1 of 2 treatment sequences 
(A/B or B/A). Randomization will be centralized and stratified by age (adults: 18 to 70; 
adolescents: 12 to 17) and background ICS therapy (ICS or no ICS). 
At Visits 3 and 4, subjects will also be required to continue to meet the following criteria: 
• The pre-dose, pre-exercise challenge best FEV1 ≥70% of predicted value  
• The pre-dose, pre-exercise challenge best FEV1 value measured did not exceed ±20% 
of the pre-exercise challenge best FEV1 value measured at Visit 1 
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• The post-dose, pre-exercise challenge best FEV1 ≥70% of predicted value. (This is for 
safety reasons; however, if this criterion is not met, it is at the investigator’s discretion 
to proceed if it is considered that there is no safety risk for the subject to proceed to the 
ECT.) 
If any of the spirometry criteria are not met at Visit 3 or 4, subjects can be retested. Those 
subjects not meeting criteria will be withdrawn. See Sections 4.1.1 and 4.1.2 for specific 
details on retesting. 
Investigational product will be administered to eligible subjects at Visit 3 and Visit 4. To 
allow for proper preparation of IP, it is recommended that the seal around the study day 
treatment box is opened with sufficient time prior to dosing and the instructions for 
administration of IP followed: 
• After IP is primed (see the separate manual for instructions on MDI handling and 
cleaning) and ready for use, provide assigned IP to the subject 
• IP will be administered in the clinic 
• Complete post-dose assessments presented in Table 2 and Table 4 (in particular, 
standardized ECT with spirometry FEV1 determinations will be made according to 
Table 4) 
4.3 
Study withdrawal 
Planned end of study will occur on completion of Visit 4. Subjects who prematurely withdraw 
from the study (ie, withdrawal prior to Visit 4) will be asked to undergo a PDV. The 
assessments for Visit 4 and PDV will be performed according to the study visits and 
procedures presented in Table 2.   
See Sections 3.9 and 3.10 for details on study withdrawal procedures. 
4.4 
Unscheduled visit 
Repeat assessments/visits, if needed, will be captured in unscheduled visits and the procedures 
carried out during an unscheduled visit will be determined by the investigator. 
4.5 
Follow-up period 
Procedures will be performed according to study visits and procedures presented in Table 2. 
The safety follow-up TC contact will occur 3 to 5 days after Visit 4 or PDV. 
The study procedures carried out during the follow-up period will include recording of 
concomitant medications and AEs. 
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5 
STUDY ASSESSMENTS 
The Rave WBDC system will be used for data collection and query handling. The investigator 
will ensure that data are recorded on the eCRFs 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 Trial Agreement. The 
investigator will sign the completed eCRF. A copy of the completed eCRF will be archived at 
the study site. 
The laboratory assessments will be sent for analysis to a central laboratory.  
The spirometry and ECG assessments will be performed at each site using MasterScope 
equipment provided by 
  
5.1 
Efficacy assessments 
Efficacy assessments include ECTs with spirometry (FEV1) measurements.  
5.1.1 
Lung function measurement by spirometry (FEV1) 
Lung function will be measured by spirometry at the study site using equipment provided by 
. Spirometry will be performed according to ATS/ERS guidelines (Miller et al 2005). 
Spirometry calibration will be detailed in a separate spirometry procedures manual. 
The vendor providing central spirometry services will be responsible for assuring that the 
spirometer used by each site meets ATS/ERS recommendations, and that the study site 
personnel who will be performing the testing are properly certified. Preferably, the same study 
personnel should oversee the ECT procedure throughout the study to reach optimal 
performance and to enhance reproducibility. A centralized spirometry data collection system 
incorporating a quality control program will be used to reduce FEV1 variability between and 
within subjects and between study sites.  
Spirometry should be performed as specified in Table 3 and Table 4. The measurements are to 
be made with the subject seated in an upright position (preferably), or if not comfortable, a 
standing position is also acceptable. The same position should be used for all spirometry 
measures during the entire study. The head must not be tilted during measurements. During 
the breathing maneuvers, the thorax should be able to move freely; hence tight clothing should 
be loosened.   
The subject should rest for at least 15 minutes prior to the initial test. Multiple maneuvers are 
necessary. For each pre-dose and/or pre-exercise challenge spirometry, a maximum of 8 
maneuvers can be performed, and the highest value obtained from 3 acceptable and 2 
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repeatable spirometry maneuvers will be used. (For the pre-dose PFTs, FEV1 and forced vital 
capacity repeatability will be required [Appendix D].) For each post-exercise challenge 
spirometry, the highest value of 2 acceptable spirograms will be used (Appendix D). 
Pre- and post-exercise FEV1 will be performed at Visit 1 and pre-dose, post-dose, and post-
exercise at Visits 2 through Visit 4. The 5-minute pre-exercise post-dose spirometry 
assessment at Visits 2 through 4 is crucial to accurately measure baseline FEV1 prior to 
exercise testing. The subject and site personnel should be adequately prepared for this 
assessment prior to the exercise test.  
5.1.1.1 
Demonstration of exercise-induced bronchoconstriction 
Subjects will be required to meet the following criteria at Visit 1 (Section 4.1.1) and Visit 2 
(Section 4.1.2): 
• EIB as demonstrated by a ≥20% decrease from the 5-minute pre-exercise challenge 
absolute FEV1 
5.1.2 
Exercise challenge testing 
A standardized maximal exercise test on a treadmill in which maximal aerobic capacity is 
defined will be completed at Visit 1. At Visits 2 through 4, an ECT, with duration of 6 to 8 
minutes, at approximately 80% to 95% of maximal aerobic capacity will be performed on a 
treadmill as specified in Table 2, Table 3, and Table 4. The subjects will have a face mask 
during exercise and will breathe dry air.  
Details on exercise testing will be provided in a separate manual. (Measurement procedures 
should be performed in accordance with the manual.) 
Subjects will also be reminded that they are not allowed to perform physical exercise during 
the 24 hours prior to the visits. 
Subjects will be reminded to avoid having a large meal at least 2 hours prior to a study visit, 
and that they must not ingest/consume xanthine and/or xanthine analogue (caffeine)-
containing foods and beverages for at least 6 hours prior to each study visit and for the 
duration of each study visit. Examples of such products include coffee, tea, chocolate, and 
cola. Decaffeinated beverages are acceptable.  
The ECT should be done at approximately the same time (±2 hours of the timing of exercise 
challenge done at Visit 1) at each subsequent visit. Before any procedure is done the subject 
should rest for at least 15 minutes. The subject needs to be stable before the test.  
During the maximal exercise challenge, the subject’s heart rate will be monitored 
continuously. Maximal heart rate should be noted when the test is stopped at Visit 1. After the 
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establishment of exercise challenge criteria at Visit 1, subjects will undergo standardized 
ECTs at Visit 2 for eligibility determination and at Visit 3 and Visit 4 (30 [±5] minutes after 
IP administration). Heart rate will be monitored continuously during the ECTs until 60 
minutes after ECT completion. See Section 4.1.2 for details on spirometry assessments and 
timing relative to ECTs (and dosing).  
If the subject has been diagnosed with an intercurrent illness or suffers a severe asthma 
exacerbation before a visit, the subject will be withdrawn from the study, depending on the 
reason. See Section 3.9 for details. The visit can be rescheduled once within 7 to 10 days for 
an upper respiratory tract infection (eg, common cold) that resolves and does not interfere 
with the subject’s ability to perform the study procedures. 
If at any visit an exercise test and/or the post-exercise lung function tests need to be stopped 
prematurely (ie, the FEV1 drops > 40% [which requires treatment with SABA]), or the subject 
has asthma symptoms that require treatment with SABA as judged by the investigator, the 
subject’s visit will be stopped. After an appropriate observation period, if the subject’s 
condition has stabilized as judged by the investigator, the subject’s visit will end. 
5.2 
Safety assessments 
Safety assessments include 12-lead ECG readings and the collection of AEs. 
5.2.1 
Laboratory assessments 
Samples for determination of clinical chemistry, hematology, and urinalysis will be taken at 
the times indicated in Table 2.  
A serum pregnancy test (β-human chorionic gonadotropin [β-hCG]) will be performed at Visit 
1, 4 and PDV; urine β-hCG test will be performed at Visit 3 (for women of childbearing 
potential only). 
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator.  
The clinical chemistry, hematology, and urinalysis assessments will be performed using a 
centralized laboratory. Sample tubes and sample sizes may vary depending on laboratory 
method used and routine practice at each site. 
The following laboratory variables in Table 5 will be measured: 
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Table 5 
Laboratory variables 
Hematology/Hemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
Basophils (%) 
Albumin 
Basophils Abs 
Alanine transaminase  
Eosinophils (%) 
Alkaline phosphatase  
Eosinophils Abs 
Aspartate transaminase  
Hemoglobin  
Bilirubin, total 
Hematocrit 
Calcium, total 
Mean Corpuscular Hemoglobin 
Chloride 
Mean Corpuscular Hemoglobin Concentration 
Cholesterol, total 
Mean Corpuscular Volume 
Creatinine 
Monocytes (%) 
Creatine kinase 
Monocytes Abs 
Gamma-glutamyl transpeptidase  
Neutrophils (%) 
Glucose (random) 
Neutrophils Abs 
Magnesium 
Red blood cells (erythrocytes) 
Phosphate  
White blood cells (leukocytes)  
Potassium  
Platelet count 
Protein, total 
Lymphocytes Abs 
Sodium 
Lymphocytes (%) 
Triglycerides 
Urine 
Urea 
Urine β-hCG pregnancy (at Visit 3) a 
Serum β-hCG pregnancy (Visit 1, 4 and PDV) a 
Urine hemoglobin 
 
Urine erythrocytes 
 
Urine protein 
 
Urine albumin 
 
Urine glucose 
 
Abbreviations: Abs=absolute; β-hCG=β-human chorionic gonadotropin; PDV=premature discontinuation visit 
a β-hCG pregnancy testing for women of childbearing potential only 
5.2.2 
Physical examination 
A complete physical examination will be performed at Visit 1, Visit 4, and PDV (if 
applicable) as detailed in Table 2. This will include an assessment of the following items: 
height in centimeters and BMI (both at Visit 1 only), weight, general appearance, respiratory 
system, cardiovascular system, abdomen, skin, head and neck (including ears, eyes, nose, and 
throat), lymph nodes, thyroid, musculoskeletal system (including spine and extremities), and 
neurological system.  
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5.2.3 
ECG 
Twelve-lead ECGs will be obtained using a centralized laboratory. A standardized ECG 
machine should be used and the subject should be examined using the same machine 
throughout the study. 
5.2.3.1 
Resting 12-lead ECG 
A resting 12-lead ECG will be performed at Visit 1 (Table 2). The 12-lead ECG will be 
obtained using a centralized laboratory after the subject has been resting semi-supine for at 
least 10 minutes.  
The ECG should be recorded with the subject in the same physical position, using a 
standardized ECG machine. The subject should be examined using the same machine 
throughout the study, where feasible. 
After ECGs have been recorded, the investigator or designated physician will review each of 
the ECGs and may refer to a local cardiologist, if appropriate. A paper copy should be filed in 
the subject’s medical records. If an abnormal ECG finding at screening/baseline is considered 
to be clinically significant by the investigator, it should be reported as an AE. For all ECGs, 
details of rhythm, PR, RR, QRS, and QT intervals, as well as an overall evaluation will be 
recorded. 
5.2.4 
Heart rate monitoring during exercise challenge testing 
During the exercise challenge at Visit 1, the subject’s heart rate will be monitored 
continuously for 60 minutes as detailed in Table 3. At Visit 1, Maximal heart rate should be 
noted when the maximal exercise test is stopped at Visit 1. 
At Visits 2 through Visit 4 standardized ECTs will be conducted and the subject’s heart rate 
will be monitored continuously for 60 minutes as detailed in Table 4.  
5.2.5 
Vital signs 
Vital signs will include measurements of blood pressure and heart rate, while the subject is 
seated, as detailed in Table 2, Table 3, and Table 4.  
Blood pressure measurements should be taken in the sitting position after at least 10 minutes 
of rest. 
Any clinically significant values in vital signs should be recorded as an AE if applicable. 
5.2.6 
Adverse event assessments 
Adverse events will be collected from time of signature of informed consent/assent through to 
the follow-up time point, as described in Section 6. 
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5.3 
Other assessments 
5.3.1 
Concomitant medications  
The collection and recording of all concomitant medications, including all pre-enrollment 
asthma therapies will be performed as detailed in Table 2. Permitted and restricted 
concomitant medications are further described in Sections 7.8.2, 7.8.3, and 7.8.4. 
All prescription drugs, herbal products, vitamins, minerals, and over-the-counter medications 
taken within 3 months before screening will be recorded as previous medications. All 
medications taken after screening and through the follow-up TC will be recorded as 
concomitant therapy.   
For restrictions relating to concomitant medications, see Sections 3.1 and 3.2.   
6 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section. 
Serious AEs will be reported as per standard reporting guidance. Associated symptoms of 
asthma are considered as symptoms of disease under study and will not be recorded as AEs 
unless considered an SAE. 
6.1 
Definition of adverse events 
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
the screening period, even if no IP has been administered. 
6.2 
Definitions of serious adverse event 
An SAE is an AE occurring during any study phase (ie, after the signing of the informed 
consent/assent through to the safety follow-up TC), that fulfills 1 or more of the following 
criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
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• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity  
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent 1 of the outcomes listed above 
For further guidance on the definition of an SAE, see Appendix C. 
6.3 
Recording of adverse events 
6.3.1 
Period for collection of adverse events 
Adverse events (including SAEs) will be collected from the time of signature of informed 
consent/assent through the safety follow-up TC. 
6.3.2 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last assessment visit in the study are followed up 
by the investigator for as long as medically indicated, but without further recording in the 
eCRF. The Sponsor or a 
 Safety and Pharmacovigilance Department 
representative retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study (after the subject’s follow-up telephone call) and capture 
that information in the eCRF, if judged necessary. 
6.3.3 
Variables  
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
Dates when the AE started and stopped 
• 
Maximum severity 
• 
Seriousness 
• 
Investigator causality rating against the IP (yes or no) 
• 
Action taken with regard to the IP 
• 
Outcome 
In addition, the following variables will be collected for SAEs, when applicable: 
• 
Date AE met criteria for SAE 
• 
Date the investigator became aware of SAE 
• 
Reason why the AE is considered serious 
• 
Treatment given for the SAE 
• 
Date of hospitalization 
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• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Whether an autopsy is performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
• 
Description of AE 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Section 6.2. 
The severity of the event should be assessed as mild, moderate, or severe. 
6.3.4 
Causality collection 
The investigator and the Sponsor will assess causal relationship between IP 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 investigational product?” 
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as “yes”. 
A guide to the interpretation of the causality question is found in Appendix C. 
6.3.5 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the subject or care provider or reported in response to the 
open question from the study site staff: “Have you/your child had any health problems since 
the previous visit/you (or your child) were last asked?”, or revealed by observation will be 
collected and recorded in the eCRF. When collecting AEs, recording a diagnosis is preferred 
(when possible) to the recording of 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. 
Asthma symptoms or signs, such as wheeze, cough, chest tightness, dyspnea, breathlessness, 
and phlegm, will be recorded as AEs only when: 
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• The sign or symptom is serious 
• The subject discontinues the study because of the sign or symptom 
• The sign or symptom is new to the subject or not consistent with the subject’s pre-existing 
asthma history (defined as within 1 year of Visit 1) as judged by the investigator 
6.3.6 
Adverse events based on examinations and tests 
The results from the Clinical Study Protocol mandated laboratory tests, ECGs, vital signs (ie, 
blood pressure and heart rate) and other assessments will be summarized in the Clinical Study 
Report. Deterioration from baseline in these parameters should therefore only be reported as 
AEs if they fulfill any of the AE criteria or are the reason for discontinuation from the study or 
are considered “clinically significant.” 
The criteria for determining whether the mandated laboratory tests, ECGs, vital signs, and 
other assessments are clinically significant and should be reported as AEs are generally:  
• 
Test result is associated with accompanying symptoms or signs, and/or  
• 
Test result requires additional diagnostic testing or medical/surgical intervention, and/or  
• 
Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy, and/or  
• 
Test result is considered to be an AE by the investigator or Sponsor. 
If deterioration in a laboratory value, ECG, vital sign, or other assessment is associated with 
clinical signs and symptoms, the sign or symptom will be reported as an AE and the 
associated parameter 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). 
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. 
6.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs during the course of the study, then investigators or other site personnel 
should inform the 
 Safety and Pharmacovigilance Department within 1 day ie, 
immediately but no later than 24 hours of when he/she becomes aware of it. 
Should the eCRF system become non-operational, SAEs shall be sent in paper form to: 
 Safety and Pharmacovigilance Department 
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 Safety and Pharmacovigilance Department will work with the investigator to 
ensure that all the necessary information is provided.  
For fatal or life-threatening SAEs where important or relevant information is missing, active 
follow-up is undertaken immediately.   
Investigators or other site personnel should inform the 
Safety and 
Pharmacovigilance Department of any follow-up information on a previously reported SAE 
within 1 calendar day ie, immediately but no later than 24 hours of when he or she becomes 
aware of it. 
The Sponsor will also report to all applicable health authorities within 7 days of awareness 
for a fatal or life-threatening reaction or within 15 days for a reaction neither fatal nor life-
threatening of any serious unexpected adverse drug reaction related to the drug which 
occurred during the study. 
6.5 
Overdose 
For the purpose of this study, an accidental or deliberate intake of blinded treatment of more 
than 2 actuations during Visits 3 and 4 is defined as an overdose and must be reported as such 
as described below. 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose/Medication Error eCRF module. An overdose 
without associated symptoms is only reported on the Overdose/Medication Error eCRF 
module. 
The maximum daily dosage of IP should not exceed 2 actuations per visit. If an overdose of IP 
occurs in the course of the study which has an associated SAE, then the investigator or other 
site personnel will inform the 
 Safety and Pharmacovigilance Department 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The 
 Safety and Pharmacovigilance Department works with the investigator to 
ensure that all relevant information is provided to the 
 Safety and 
Pharmacovigilance Department representative. 
For overdoses associated with an SAE, the standard SAE reporting timelines apply, see 
Section 6.4.   
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6.6 
Pregnancy 
All pregnancies and outcomes of a pregnancy should be reported to the 
 Safety 
and Pharmacovigilance Department representative except if the pregnancy is discovered 
before the study subject has received any IP. 
6.6.1 
Maternal exposure 
If a subject becomes pregnant during the course of the study, IP should be discontinued 
immediately and “Pregnancy” recorded as the reason for discontinuation on the eCRF. The 
subject will be withdrawn from the study. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP 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 discontinued from the study. 
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
will inform the 
 Safety and Pharmacovigilance Department within 1 day; ie, 
immediately but no later than 24 hours of when he/she becomes aware of it. Any conception 
occurring from the date of dosing through the safety follow-up TC should be reported. 
The 
 Safety and Pharmacovigilance Department will work with the investigator 
to ensure that all relevant information is provided. 
The same timelines apply when outcome information is available. 
6.6.2 
Paternal exposure  
Pregnancy of a subject’s partner is not considered to be an AE. However, any conception 
occurring from the date of dosing through the safety follow-up TC should be reported to the 
 Safety and Pharmacovigilance Department representative and followed up for 
its outcome. 
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 the Sponsor’s IP 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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A medication error includes situations where an error:  
• 
occurred 
• 
was identified and intercepted before the subject received the drug 
• 
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: 
• 
Drug name confusion 
• 
Preparation error, eg, medication prepared incorrectly, even if it was not actually given to 
the subject 
• 
Drug not administered as indicated, eg, wrong route or wrong site of administration 
• 
Drug not taken as indicated  
• 
Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature  
• 
Wrong subject received the medication (excluding IWRS errors) 
• 
Wrong drug administered to subject (excluding IWRS errors) 
• 
Subject received the medication in the wrong order (excluding IWRS errors) 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IWRS - including those which lead to 1 of the above 
listed events that would otherwise have been a medication error  
• 
Accidental overdose (will be captured as an overdose) 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.   
All medication errors must be recorded in the Overdose/Medication Error eCRF. Any 
associated AEs should also be recorded as the AE diagnosis/symptoms on the relevant 
AE/SAE modules in the eCRF. 
If a medication error occurs during the course of the study which has an associated SAE, then 
the investigator or other site personnel will inform the 
 Safety and 
Pharmacovigilance Department immediately, or no later than 24 hours of when he or she 
becomes aware of the medication error. 
The 
 Safety and Pharmacovigilance Department will work with the investigator 
to ensure that all relevant information is provided to 
 Safety and 
Pharmacovigilance Department representative. For medication errors associated with an SAE, 
the standard SAE reporting timelines apply, (see Section 6.4). 
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6.8 
Management of investigational product-related toxicities  
In the absence of a specific antidote, management of toxicities can be dealt with on the basis 
of the symptoms. 
7 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product(s) 
BDA MDI is formulated (Table 6) as both micronized budesonide and micronized albuterol 
co-suspended with spray-dried porous particles in an HFA propellant. The co-suspension 
formulation ensures that subjects receive a consistent delivery of the drug from each actuation 
of the MDI.  
Table 6 
Investigational product strength and dosage form 
Investigational product 
name and dose 
Product strength 
Dosage form/  
Fill count 
Administration 
Manufacturer 
BDA MDI 160/180 μg 
BDA MDI  
80 μg budesonide and 
90 μg albuterola per puff 
MDI/120 
actuations 
Taken as 2 
actuations 
AstraZeneca 
Placebo MDI 
0 μg of active productb 
MDI/120 
actuations 
Taken as 2 
actuations 
AstraZeneca 
Abbreviations:  BDA MDI=budesonide/albuterol metered-dose inhaler; HFA=hydrofluoroalkane.  
a Each puff contains 108 μg albuterol sulfate corresponding to 90 µg albuterol base per actuation. 
b Each puff contains 183 μg of porous particles and 63 μg of HFA-134a propellant made to be identical in 
appearance to BDA MDI. 
7.2 
Dose and treatment regimens 
At Visit 2, subjects will be administered placebo MDI.  
At Visit 3, eligible subjects will be randomized (1:1) to 1 of the following 2 sequences of 
double-blind single-dose treatment phase (Table 7):  
Table 7 
Treatment sequences 
Treatment 
sequences 
Visit 3/Period 1 
Visit 4/Period 2 
A/B 
BDA MDI 160/180 μg (given as 2 actuations of 
BDA MDI 80/90 μg) 
Placebo MDI (given as 2 actuations) 
B/A 
Placebo MDI (given as 2 actuations) 
BDA MDI 160/180 μg (given as 2 actuations of 
BDA MDI 80/90 μg)  
 Abbreviations:  BDA=budesonide/albuterol; MDI metered-dose inhaler. 
Handling instructions for the MDI device will be available for each site throughout the study 
(Section 7.7). 
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7.3 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfill GMP Annex 13 requirements for labelling. Label 
text will be translated into local language. 
Each kit will contain an MDI device, wrapped in a foil bag held within a carton. The MDI 
devices provided in this study and the packaging and labelling of the kits are visually identical 
to maintain the blind.  
Each kit will contain the following blinded labels: 
• 
Single panel canister label (English only) 
• 
Single panel actuator label or multilanguage actuator booklet label 
• 
MDI device shield label (single panel, English only) 
• 
Foil bag label (single panel, English only) or multilanguage booklet label 
• 
Single panel carton label or multilanguage carton booklet label 
The labels will include the following information: 
• 
Name of Sponsor (Bond Avillion 2 Development LP – Clinical Development Company: 
Avillion LLP) 
• 
IP dosage form, route of administration, and quantity of dosage units (blinded across all 
treatment groups) 
• 
Storage conditions 
• 
Study Trial Reference 
• 
Medication ID number 
• 
Directions for use 
• 
The name of the investigator, where applicable (this will be added on the label manually 
when the IP is administered) 
• 
The period of use, eg, expiry date 
The label will include the following standard statements: 
• 
“Caution: New Drug –Limited by Federal law to investigational use.” 
• 
 “Keep out of reach of children” 
7.4 
Storage 
All IP should be kept in a secure place under appropriate storage conditions. The IP label 
specifies the appropriate storage. 
Blinded supplies: BDA MDI 80/90 μg per puff and placebo should be stored below 25°C 
(77°F) in a dry place. Excursions permitted up to 30°C (86°F). 
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7.5 
Compliance 
The administration of all IP will be captured and recorded in the appropriate sections of the 
eCRF, as applicable, with the exception of the details of any interruptions for which the dates 
and reason for interruption will be recorded. The IP accountability will be recorded in the 
eCRF.  
7.6 
Accountability 
The IP provided for this study will be used only as directed in the Clinical Study Protocol. 
All IP will be returned to the approved study returns vendor for destruction after 
accountability and reconciliation is complete.  
7.7 
Metered-dose inhaler handling  
Detailed handling instructions will be provided to the site in the form of a “Site Manual” 
document, which will cover all aspects of the study with regards to IP.  
The importance of the device priming requirements should be emphasized. Priming of the IP 
MDI must occur. Device priming should not be conducted in the same room as spirometry 
assessments are being conducted.  
7.8 
Concomitant and other treatments  
7.8.1 
Investigational product 
In addition to the Sponsor-provided IP, the only other asthma treatments/medications (of any 
class) allowed during the study are the asthma medications (ie, SABA prn alone or ICS with 
SABA, as applicable) that were started before screening and continued as part of maintenance 
treatment. See the inclusion criteria for details. 
7.8.2 
Permitted asthma therapies 
SABA prn or low-to-medium dose ICS plus SABA prn are the only permitted therapies to be 
used as asthma therapy on-study as specified in the inclusion criteria. No subject can be on 
any other asthma maintenance therapies. 
During the study, subjects should maintain stable dosing of their maintenance and/or prn 
therapy as presented at screening. Dose changes to maintenance therapy are discouraged 
unless clinically indicated in accordance with GINA guidelines. Investigators should notify 
the study medical monitors of any change to maintenance therapy for study subjects; 
considerations should be made to subject drug compliance and other factors in advance of 
making changes to maintenance therapy.   
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If, following the ECT, the investigator considers that the subject is experiencing asthma 
symptoms which are not tolerable, then rescue SABA can be administered. 
7.8.3 
Medication that may affect FEV1 testing 
Investigators should notify the study medical monitors of any change to maintenance therapy 
for study subjects. At the start of each treatment visit, subjects must withhold SABA for at 
least 6 hours prior to start of test day procedures. If a subject has taken SABA within 6 hours 
before the planned FEV1 test, the test should not be carried out and the subject’s visit should 
be rescheduled.  
7.8.4 
Prohibited medications 
Prohibited concomitant medications during and at least 1 month prior to the study include the 
following, with specified timeframes where needed: 
• 
Oral, parenteral, or rectal corticosteroids (except if required to treat severe asthma 
exacerbation) during and at least 3 months prior to Visit 1 
• 
Any other asthma medication except Sponsor-provided IP during Visits 3 and 4 and the 
permitted SABA prn alone or ICS with SABA treatment that was started before screening 
and continued as part of maintenance treatment (see inclusion criteria), regular SABA use 
(eg, four times a day [QID]) is not permitted) 
• 
Inhaled disodium cromoglycate or inhaled nedocromil sodium 
• 
5-lipoxygenase inhibitors (ie, zileuton) 
• 
Inhaled short-acting anticholinergics (or short-acting muscarinic antagonists [SAMA], ie, 
ipratropium) 
• 
Inhaled long-acting muscarinic antagonists (LAMA) 
• 
Phosphodiesterase-4 inhibitors (ie, roflumilast) 
• 
Leukotriene receptor antagonists (ie, montelukast, zafirlukast), also for the treatment of 
other allergic conditions  
• 
Xanthine and theophylline 
• 
Omalizumab, benralizumab, mepolizumab, reslizumab, dupilumab, or any other 
monoclonal or polyclonal therapy for any reason during the study or within 3 months or 5 
half-lives before Visit 1, whichever is longer; (locally administered biologics, eg, intra-
ocular, are allowed) 
• 
Beta-2-adrenergic blockers, including eye-drops; (For the purpose of this study, 
metoprolol is considered to have beta-2-adrenergic receptor blocking ability.) 
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7.8.5 
Food and beverage restrictions 
Subjects must not ingest/consume xanthine and/or xanthine analogue (caffeine)-containing 
foods and beverages for at least 6 hours prior to each study visit and for the duration of each 
study visit. Examples of such products include coffee, tea, chocolate, and cola.  
Decaffeinated beverages are acceptable. 
Subjects should avoid having a large meal at least 2 hours prior to a study visit. 
7.8.6 
Other concomitant treatment 
Non-asthma medication other than those described above, which is/are 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. 
8 
STATISTICAL ANALYSES  
8.1 
Statistical considerations 
All personnel involved with the analysis of the study will remain blinded until database lock 
and identification of Clinical Study Protocol violators are identified.   
Analyses will be performed by the Sponsor or its representatives. 
A comprehensive statistical analysis plan (SAP) will be prepared and any subsequent 
amendments will be documented, with final amendments completed before the unblinding of 
the data. 
8.1.1 
Estimands 
The estimand of interest is the Efficacy Estimand, defined as the effect of the randomized 
treatments in all subjects and in the absence of intercurrent events which may impact the 
interpretation of the treatment effect, such as use of SABA medication following the exercise 
challenge test. This estimand could be considered a while-on-treatment strategy or a 
hypothetical strategy as defined in the draft ICH E9 Addendum. 
8.2 
Sample size estimate 
Power calculations are based on the properties of the primary endpoint, the maximum 
percentage fall from post-dose, pre-exercise baseline in FEV1 observed up to 60 minutes post-
exercise challenge. A sample size of 30 subjects in each subgroup will provide a 92% 
probability to detect a difference of -9% between BDA MDI versus placebo MDI, within each 
of the 2 subgroups of interest (SABA prn alone; low-to-medium dose ICS plus SABA prn), 
assuming 2-sided, 5% level tests and a within-subject standard deviation of 10%. 
Randomization of 60 subjects in total will provide >99% overall probability to detect a 
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difference of -9% between BDA MDI versus placebo MDI assuming a 2-sided, 5% level test 
and an estimated within-subject standard deviation of 10%. Since all subjects randomized in 
the study will be receiving background therapy for asthma, a more conservative estimate of 
variability and treatment effect has been assumed compared to studies of similar design 
(Ostrom et al 2015). 
8.3 
Definitions of analysis sets 
8.3.1 
Full analysis set 
The full analysis set is defined as all subjects who are randomized to treatment and have at 
least 1 baseline and corresponding post-dose FEV1 measure. Subjects will be analyzed 
according to the treatment they were assigned as per the randomization scheme.   
All efficacy analyses will be conducted on the full analysis set. 
8.3.2 
Safety analysis set 
The safety analysis set is defined as all subjects receiving any amount of the IP. Subjects will 
be classified on the basis of treatment they actually received within each treatment period. 
Occurrences of safety events (ie, AEs and use of concomitant medication) will be summarized 
under the actual treatment corresponding to the treatment period of which the event occurred. 
All safety summaries will be based on the safety analysis set. 
8.3.3 
All subjects enrolled 
The all subjects enrolled analysis set will be defined as all subjects who provide informed 
consent. This analysis set will be used for descriptive summaries of disposition. 
8.4 
Violations and deviations 
Important protocol deviations will be listed and summarized by randomized treatment group. 
A per protocol analysis excluding subjects with significant protocol deviations is not planned. 
All subjects who failed any inclusion/exclusion criteria will be listed along with details of the 
failed criteria. This information will also be summarized in terms of the number and 
percentage of subjects failing any of the inclusion/exclusion criteria and will be based on the 
full analysis set. 
8.5 
Outcome measures for analyses 
8.5.1 
Primary efficacy analysis 
The primary analysis will include all data obtained before subjects withdraw from the study 
and will use the full analysis set, in accordance with the Efficacy Estimand (Section 8.1.1). 
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8.5.1.1 
Derivation of primary efficacy endpoint 
The fall from post-dose, pre-exercise baseline in FEV1 will be calculated at each post-exercise 
FEV1 assessment time point at Visit 3 and Visit 4. The post-dose, pre-exercise baseline FEV1 
assessment is expected to occur 30 minutes after administration of IP and 5 minutes prior to 
the exercise challenge. The percentage fall in FEV1 will be calculated proportional to the post-
dose, pre-exercise FEV1 value at each visit. The maximum percentage fall available in the 60-
minute assessment period, prior to the use of rescue medication, will be calculated at Visit 3 
and Visit 4.  
8.5.2 
Secondary efficacy analysis 
The secondary analysis will include all data obtained before subjects withdraw from the study 
and will use the full analysis set, in accordance with the Efficacy Estimand (Section 8.1.1). 
8.5.2.1 
Derivation of secondary efficacy endpoints 
The fall in FEV1 will be calculated at Visit 3 and Visit 4 as the difference in the baseline post-
dose, pre-exercise FEV1 assessment and each post-exercise assessment at the respective visit, 
as per the serial spirometry timings detailed in Table 3 and Table 4. The percentage fall will 
be calculated relative to the pre-exercise FEV1 assessment at the respective visit. The post-
dose, pre-exercise baseline FEV1 is defined as per Section 8.5.1.1. 
A binary response variable will be assigned to identify subjects with a maximum percentage 
fall in FEV1 post-exercise of <10% separately at Visit 3 and Visit 4: 
• Protected: Maximum percentage fall from post-dose, pre-exercise baseline in FEV1 up 
to 60 minutes post-exercise challenge <10%  
• Not Protected: Maximum percentage fall from post-dose, pre-exercise baseline in 
FEV1 up to 60 minutes post-exercise challenge ≥10% 
As with the primary efficacy endpoint specified in Section 8.5.1.1, the maximum percentage 
fall will be calculated based on post-dose FEV1 measures prior to use of rescue medication. 
Subjects who have no post-exercise FEV1 measure prior to rescue medication will have a 
missing responder status at the given visit. 
8.5.3 
Exploratory efficacy analysis 
The exploratory analysis will include all data obtained before subjects discontinue the study 
and will use the full analysis set, in accordance with the Efficacy Estimand (Section 8.1.1). 
8.5.3.1 
Derivation of exploratory efficacy endpoints 
The binary response variable specified in Section 8.5.2.1 will be replicated to identify subjects 
with a maximum percentage fall in FEV1 post-exercise of <20% at each of Visits 3 and 4. 
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Time to recovery at each of Visits 3 and 4 will be derived as the time (minutes) post-exercise 
challenge in which the FEV1 result returns to within 10% of the value recorded at the post-
dose, pre-exercise baseline. Only subjects who achieve a percentage fall in FEV1 post-exercise 
challenge of >10% will have an event time derived; otherwise their value will be left 
censored. Subjects who have any rescue medication administered during the post-dose 
assessments will be censored at the time of receiving rescue medication. Subjects who do not 
recover to within 10% of the post-dose, pre-exercise baseline will be censored at 60 minutes. 
The fall from post-dose, pre-exercise baseline in FEV1 will be calculated at each of the post-
exercise assessment time points at Visit 3 and Visit 4. The post-dose, pre-exercise baseline 
FEV1 assessment is expected to occur 30 minutes after administration of IP and 5 minutes 
prior to the exercise challenge. The percentage fall in FEV1 will be calculated proportional to 
the post-dose, pre-exercise FEV1 value at each visit. 
FEV1 AUC0-30min will be derived for the changes from the post-dose, pre-exercise baseline 
using the trapezoidal rule and will be normalized by dividing by the actual time (in minutes) 
from dosing to the last included measurement, scheduled at 30 minutes post-exercise 
challenge at each of Visits 3 and 4. Only FEV1 results prior to the use of rescue medication 
will be considered when calculating FEV1 AUC0-30min. 
8.6 
Methods for statistical analyses 
All tests will be 2-sided and at 5% level of significance unless otherwise stated.  
In addition to the analyses described below, all variables will be summarized descriptively 
where appropriate. All descriptive and formal analyses will be described in accordance with 
the Efficacy Estimand. 
8.6.1 
Analysis of the primary variable(s) 
The maximum percentage fall from post-dose, pre-exercise baseline in FEV1 observed up to 
60 minutes post-exercise challenge will be analyzed with a mixed effect model including 
categorical fixed effects for treatment, treatment period, treatment sequence, period-specific 
pre-dose baseline FEV1 and average pre-dose baseline FEV1, and a random subject within 
treatment sequence effect. Post-dose, pre-exercise baseline FEV1 will be defined as the post-
dose value measured 5 minutes before exercise challenge, at each visit for the respective 
treatment. The period-specific pre-dose baseline FEV1 will be at the respective Visit 3 or Visit 
4 pre-dose result, approximately 5 minutes prior to dosing. The average pre-dose baseline 
FEV1 will be calculated as the mean of the period-specific baselines. Estimated treatment 
differences and 95% confidence intervals (CIs) will be provided. 
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The corresponding hypotheses for the primary analysis are as follows: 
H01: Difference between treatments =0, 
HA1: Difference between treatments ≠0. 
The primary treatment comparison of BDA MDI 160/180 versus placebo MDI for the 
maximum percentage fall from post-dose, pre-exercise baseline in FEV1 observed up to 60 
minutes post-exercise challenge will be conducted on the full analysis set and include all data 
up to study withdrawal as per the Efficacy Estimand (Section 8.1.1). Missing results for 
maximum percentage fall in FEV1 is unlikely (ie, rescue medication prior to the collection of 
the 5 minutes measure) and will be assumed to be missing at random. Sensitivity analyses will 
be conducted to explore the robustness of the primary analysis with respect to this missing 
data assumption (Section 8.6.6). 
The primary analysis will be repeated on the subgroups on clinical interest (SABA prn alone; 
low-to-medium dose ICS plus SABA prn). To control the overall type-I error, a hierarchical 
testing strategy will be adopted. The treatment comparisons of BDA MDI 160/180 versus 
placebo MDI will be conducted on the subject populations in the sequence given below: 
1. Overall population (SABA prn only OR low-to-medium dose ICS plus SABA prn 
background therapy) 
2. Subjects taking SABA prn only for background therapy 
3. Subjects taking low-to-medium dose ICS plus SABA prn for background therapy 
If a comparison is significant (alpha=0.05, 2-sided), testing will proceed to the next 
comparison. Comparisons will stop if a non-statistically significant result occurs. All 
comparisons are of superiority. 
8.6.2 
Analysis of the secondary variable(s) 
In addition to the analyses described below, all variables will be summarized descriptively 
where appropriate. All descriptive and formal analyses will be described in accordance with 
the Efficacy Estimand. 
8.6.2.1 
Responder analysis in post-exercise FEV1 
The odds of being protected against EIB (ie, having a maximum percentage fall in FEV1 post-
exercise challenge of <10%) will be analyzed using a generalized linear mixed model with 
logit link function to compare the treatments. The model will be adjusted with fixed effects for 
treatment, treatment period and treatment sequence, and a random subject within treatment 
sequence effect. The odds ratio and 95% CI will be reported for pairwise treatment 
comparisons. The analysis will only include maximum percentage falls in FEV1 prior to study 
discontinuation. The data considered missing under the primary Efficacy Estimand will be 
assumed to be missing at random in the analysis. 
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8.6.3 
Analysis of the exploratory variables 
In addition to the analyses described below, all variables will be summarized descriptively 
where appropriate. All descriptive and formal analyses will be described in accordance with 
the Efficacy Estimand. 
8.6.3.1 
Responder analysis in post-exercise FEV1 (20% threshold) 
The odds of having a maximum percentage fall in FEV1 post-exercise challenge of <20% will 
be separately analyzed using a generalized linear mixed model to compare treatments as 
specified in Section 8.6.2.1.  
8.6.3.2 
Time to recovery 
The median time to recovery will be reported descriptively by treatment. P-values will be 
calculated using a period-adjusted sign test, based on categorizing subjects into period 
preferences (Senn 1993). Further details will be clarified in the SAP. 
8.6.3.3 
Fall in post-exercise FEV1 at individual time points 
The percentage fall in FEV1 post-exercise challenge will be summarized descriptively by 
treatment group and planned time point within 60 minutes of the serial spirometry assessments 
conducted post-exercise challenge. An analysis of percentage fall in FEV1 post-exercise 
challenge will be conducted using methods as per the primary analysis, with an additional 
adjustment for planned time point in the repeated measures model. The covariance within 
subject-periods will be unstructured over the time points. Only FEV1 results prior to 
administration of rescue therapy (within the study visit) will be included in the analyses, as 
per the Efficacy Estimand. 
8.6.3.4 
Post-exercise FEV1 AUC0-30min 
The post-exercise FEV1 AUC0-30 min will be analyzed with a similar mixed effects model as 
described in Section 8.6.1 for the change from post-dose, pre-exercise baseline in the 
maximum percentage fall in FEV1 without exercise pre-treatment. Only the FEV1 AUC0-30 min 
measurements prior to administration of rescue SABA therapy will be included in the 
analyses. 
8.6.4 
Subgroup analysis 
Two subgroups of equal size will be included in the study, 1 subgroup of subjects on SABA 
prn only and the other subgroup on low-dose ICS maintenance therapy according to GINA 
guidelines. All primary, secondary and exploratory analyses will be repeated on each of these 
subgroups of interest. Please refer to the testing strategy in Section 8.6.1 for analyzing the 
primary endpoint in these subgroups of interest. 
The assessment of treatment effect will be investigated in other clinically important subgroups 
and will be defined in more detail in the SAP.  
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8.6.5 
Interim analysis 
There are no interim analyses planned for this study. 
8.6.6 
Sensitivity analysis 
If there are missing data, sensitivity analyses on the impact of such data will be conducted on 
the primary endpoint of maximum percentage fall from post-dose, pre-exercise baseline FEV1 
observed up to 60 minutes post-exercise challenge. Under the Efficacy Estimand, missing data 
are assumed missing at random. The sensitivity analysis will explore the robustness of 
conclusions when data are considered missing not at random. Further details will be given in 
the SAP. 
9 
STUDY AND DATA MANAGEMENT  
9.1 
Training of study site staff 
Before the first subject is entered into the study, a designated representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the Rave WBDC 
system(s) utilized. 
The investigator(s) 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 investigator(s) will maintain a record of all individuals involved in the study (medical, 
nursing, and other staff). 
9.2 
Monitoring of the study 
During the study, the Sponsor or a designated representative will have regular contacts with 
the study site, including visits to: 
• 
Provide information and support to the investigator(s) 
• 
Confirm that facilities remain acceptable 
• 
Confirm that the investigational 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 IP accountability checks are 
being performed 
• 
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/assent of participating subjects. This will 
require direct access to all original records for each subject (eg, clinic charts) 
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• 
Ensure all SAEs and AEs have been captured and reported correctly, providing oversight 
of subject safety while on-study 
• 
Verify the correct storage, handling, administration, and return of all IP  
The designated representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct. 
9.2.1 
Source data 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records. Also, current medical records must be 
available. 
Definition of what constitutes source data can be found in the Source Data Agreement, agreed 
with each investigator before site initiation. 
9.2.2 
Study agreements 
The investigator(s)/the participating center(s) should comply with all the terms, conditions, 
and obligations of the Clinical Study Protocol, or equivalent, for this study.   
Clinical Trial Agreements with the investigator(s)/the participating center(s) 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 follows the principles outlined in the Clinical Trial Agreement. 
9.3 
Study timetable and end of study 
The end of the study is defined as “the last visit of the last subject undergoing the study”. 
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow. The Sponsor 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with the IP. 
9.4 
Data management  
Data management will be performed by the Data Management Team at 
 
according to the Data Management Plan. 
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The data collected through third party sources will be obtained and reconciled against study 
data. Data from third parties will be transferred in accordance with data transfer specifications 
and reconciled in accordance with the Data Management Plan. 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of the Medical Dictionary for Regulatory Activities at the time of database 
lock.  
Medications will be classified according to the World Health Organization Drug Dictionary. 
All coding will be performed by the Medical Coding Team at 
 
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process. 
Serious adverse event (SAE) reconciliation 
SAE reconciliation reports are produced and reconciled with the applicable 
 
Safety and Pharmacovigilance Department safety database and/or the investigational site.  
Management of external data 
 Data Management will set up import agreements with third party data sources, 
to ensure external data is integrated in line with applicable data standards. 
Final database lock 
Database lock will occur once “the last visit of the last subject participating in the study has 
been completed” and all data have been coded, validated, signed, and locked, and clean file 
has been declared. 
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, and applicable regulatory 
requirements. 
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10.2 
Subject data protection 
The ICF/assent will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets 
that are transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred. Subjects must 
be informed that his/her personal study-related data will be used by the Sponsor in accordance 
with local data protection law(s). The level of disclosure must also be explained to the subject. 
Subjects must also be informed that his/her medical records may be examined by study 
monitors, clinical quality assurance auditors, or other authorized personnel appointed by the 
Sponsor, by appropriate EC members, and by inspectors from regulatory authorities. 
10.3 
Ethics and regulatory review 
An EC should approve the final Clinical Study Protocol, including the final version of the 
ICF/assent and any other written information and/or materials to be provided to the subjects. 
The investigator will ensure the distribution of these documents to the applicable EC, and to 
the study site staff. 
The opinion of the EC should be given in writing. The investigator should submit the written 
approval to the Sponsor or designated representative before enrollment of any subject into the 
study.  
The EC should approve all advertising used to recruit subjects for the study. 
The Sponsor or designated representative should approve any modifications to the ICF/assent 
that are needed to meet local requirements. 
If required by local regulations, the Clinical Study Protocol should be re-approved by the EC 
annually. 
Before enrollment of any subject into the study, the final Clinical Study Protocol, including 
the final version of the ICF/assent, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
The Sponsor or designated representative will handle the distribution of any of these 
documents to the national regulatory authorities. 
The Sponsor or designated representative will provide regulatory authorities, ECs and 
investigator(s) with safety updates/reports according to local requirements. 
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10.4 
Informed consent/assent 
The investigator(s) at each center will: 
• 
Ensure each subject (and/or parent/legal representative, as applicable) is given full and 
adequate oral and written information about the nature, purpose, possible risk(s) and 
benefit(s) of the study. 
• 
Ensure each subject (and/or parent/legal representative, as applicable) is notified that they 
are free to discontinue from the study at any time. 
• 
Ensure that each subject (and/or parent/legal representative, as applicable) is given the 
opportunity to ask questions and allowed time to consider the information provided. 
• 
Ensure each subject (and/or parent/legal representative, as applicable) provides signed 
and dated informed consent/assent before conducting any procedure specifically for the 
study. 
• 
Ensure the original, signed ICF/assent(s) is/are stored in the Investigator’s Study File. 
• 
Ensure a copy of the signed ICF/assent is given to the subject (and/or parent/legal 
representative, as applicable). 
• 
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/assent that is approved by an EC. 
10.5 
Changes to the clinical study protocol and informed consent 
form/assent 
Study procedures will not be changed without the mutual agreement of the international 
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. 
The new version of the Clinical Study Protocol is to be approved by the relevant EC and if 
applicable, also the national regulatory authority, 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 
investigator for distribution to EC, see Section 10.3. 
If a change to a Clinical Study Protocol requires a change to a center’s ICF/assent, the 
Sponsor and the center’s EC are to approve (or submit a notification to the national regulatory 
authority, where applicable for) the revised ICF/assent before the revised form is used.  
10.6 
Audits and inspections 
Authorized representatives of the Sponsor, a regulatory authority, or an EC may perform 
audits or inspections at the center, including source data verification. The purpose of an audit 
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or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, data were recorded, 
analyzed, 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 center. 
 
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11 
LIST OF REFERENCES 
1. Bonini  M, Di Mambro  C, Calderon  MA, Compalati  E, Schünemann  H, Durham  S, et al. 
Beta2‐agonists for exercise‐induced asthma. Cochrane Database of Systematic Reviews 
2013, Issue 10. Art. No.: CD003564. DOI: 10.1002/14651858.CD003564.pub3.  
2. Cooper PR, Panettieri RA. Steroids completely reverse albuterol-induced β2-adrenergic 
receptor tolerance in human small airways. J Allergy Clin Immunol. 2008;122(4):734-740. 
3. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, et al. Guidelines 
for methacholine and exercise challenge testing—1999. This official statement of the 
American Thoracic Society was adopted by the ATS Board of Directors, July 1999. 
Am J Respir Crit Care Med. 2000;161(1):309-329. 
4. Global Initiative for Asthma. Global strategy for asthma management and prevention. 
2019. Available from: https://ginasthma.org/gina-reports/. 
5. Investigator Brochure Edition 2.0. Budesonide/Albuterol Sulfate Pressurized Inhalation 
Suspension (BDA MDI, PT027); Budesonide Pressurized Inhalation Suspension (BD MDI, 
PT008); Albuterol Sulfate Pressurized Inhalation Suspension (AS MDI, PT007), 
20 September 2019. 
6. Mendes ES, Horvath G, Campos M, Wanner A. Rapid corticosteroid effect on β(2)-
adrenergic airway and airway vascular reactivity in patients with mild asthma. J Allergy 
Clin Immunol. 2008;121(3):700-704. 
7. Mendes ES, Cadet L, Arana J, Wanner A. Acute effect of an inhaled glucocorticosteroid 
on albuterol-induced bronchodilation in patients with moderately severe asthma. Chest. 
2015;147(4):1037-1042.  
8. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338.  
9. Molema J, van Herwaarden CL, Folgering HT. Effects of long-term treatment with inhaled 
cromoglycate and budesonide on bronchial hyperresponsiveness in patients with allergic 
asthma. Eur Respir J. 1989;2(4):308-316. 
10. O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, et al. 
Budesonide/formoterol combination therapy as both maintenance and reliever medication 
in asthma. Am J Respir Crit Care Med. 2005;171(2):129-136. 
11. O'Byrne PM. Acute asthma intervention: insights from the STAY study. J Allergy Clin 
Immunol. 2007;119(6):1332-1336. 
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12. Ostrom NK, Taveras H, Iverson H, Pearlman DS. Novel albuterol multidose dry powder 
inhaler in patients with exercise-induced bronchoconstriction: a single-dose, double-blind, 
randomized, 2-way crossover study. Respir Med. 2015;109(11):1410-1415. 
13. Parsons JP, Hallstrand TS, Mastronarde JG, Kaminsky DA, Rundell KW, Hull JH, et al. 
An official American Thoracic Society clinical practice guideline: exercise-induced 
bronchoconstriction. Am J Respir Crit Care Med. 2013;187(9):1016-1027. 
14. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in 
combination with formoterol for reliever therapy in asthma exacerbations: a randomized 
controlled, double-blind study. Lancet. 2006;368(9537):744-753. 
15. Richter K, Janicki S, Jörres RA, Magnussen H. Acute protection against exercise-induced 
bronchoconstriction by formoterol, salmeterol and terbutaline. Eur Respir J. 
2002;19(5):865-871.  
16. Senn S, Cross-over Trials in Clinical Research. Wiley, Chichester.1993. 
 
 
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APPENDIX B PRIMARY INVESTIGATOR SIGNATURE PAGE 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
Please keep the signed original form in your study files, and return a copy to your local study 
monitor. 
 
 
 
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APPENDIX C 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 
Out-patient treatment in an emergency room is not in itself an SAE, 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 1 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. Examples of important medical events include but are not limited to: 
• 
Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
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 
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. 
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• 
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? 
• 
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? 
• 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another cause/etiology 
such as, the underlying disease, other drugs, and other host or environmental factors. 
• 
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. 
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognized feature of overdose of the drug? 
• 
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 on the basis of the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is highly encouraged for the reporting investigator to express his/her clinical opinion. 
If (despite all efforts) the causality assessment cannot be made, these SAEs will be considered 
to be “related.” 
Causal relationship in cases where the disease under study has deteriorated because of lack of 
effect should be classified as “no reasonable possibility.” 
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Version 1.0, 25 Oct 2019 
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APPENDIX D 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 back 
extrapolation volume <5% of forced vital capacity (FVC) or 0.150 L, whichever is the 
greater (see example in Figure 1) 
2. No cough during the first second 
3. No Valsalva maneuver 
4. No leak 
5. No obstruction of mouthpiece 
6. No extra breaths 
7. Plateau achieved: ie, the volume-time curve shows no change in volume (<0.025 L) for 
≥ 1 second, and the subject has tried to exhale for at least 6 seconds 
 
An acceptable test meets all 7 criteria listed. This is to be considered the “gold standard.” 
Usable spirometry tracings are those that only meet criteria 1 and 2. When this occurs, repeat 
testing up to 8 attempts for pre-dose and 5 attempts for post-dose assessments, in an effort to 
obtain 3 acceptable spirograms. If only usable tests are obtained, report results based on the 3 
best usable trials with observed limitations. 
Figure 1 
Example of a Usable Spirogram 
 
EV=back extrapolation volume 
 
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The expanded version of the early part of a subject’s volume-time spirogram, illustrating back 
extrapolation through the steepest part of the curve, where flow is peak expiratory flow (PEF) 
rate, to determine the new “time zero”. Forced vital capacity -4.291 L; extrapolated volume 
(EV) – 0.123 L (2.9% FVC): back extrapolation line through PEF. 
Between-Manoeuver Reproducibility Criteria 
Pre-dose assessments 
After 3 acceptable spirograms have been obtained, apply the following tests: 
• The 2 largest values of FVC must be within 0.150 L of each other 
• The 2 largest values of FEV1 must be within 0.150 L of each other 
If these criteria are met, the spirometry testing for that time point may conclude, however, if 
possible, please continue collecting additional spirograms to a maximum of 8 pre-dose and 5 
post-dose attempts. The highest FEV1 and the highest FVC obtained at each testing time point 
(even if from different reproducible tracings), will be collected. 
If acceptability criteria are not met, continue testing until they are met or the subject cannot/ 
should not continue (maximum of 8 attempts). 
Post-dose assessments 
After 2 acceptable spirograms have been obtained, apply the following tests: 
• 
The 2 largest values of FVC are within 0.150 L of each other and/or 
• 
The 2 largest values of FEV1 are within 0.150 L of each other 
If these criteria are met, the spirometry testing for that time point may conclude. The highest 
FEV1 and the highest FVC obtained at each testing time point (even if from different 
reproducible tracings), will be collected. 
If acceptability/reproducibility criteria are not met, continue testing until they are met or the 
subject cannot/ should not continue (maximum of 5 attempts). 
 
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