Conditions: Asthma, Exercise-Induced
Keywords: Asthma Exercise-Induced Allergies Bronchial Spasm Albuterol Budesonide Bronchodilator Agents Anti-Inflammatory Agents
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 64
Healthy volunteers: no

Brief summary:
The purpose of this Phase III, multicentre, randomized, double-blind, single-dose, 2-period, crossover study is to assess the efficacy and safety of PT027 (budesonide/albuterol sulfate) metered-dose inhaler compared with placebo on exercise-induced bronchoconstriction in adult patients with asthma. Subjects will receive each study treatment on separate visits and undergo a treadmill exercise challenge test so that the effect of study treatment on exercise-induced bronchoconstriction can be evaluated

Detailed description:

Arms:
arm 1: Subjects randomized to receive a single dose of PT027 160/180 μg in treatment Period 1, and a single dose of Placebo in treatment Period 2. arm 2: Subjects randomized to receive a single dose of Placebo in treatment Period 1, and a single dose of PT027 160/180 in treatment Period 2.

Interventions: intervention 1: Budesonide/albuterol metered-dose inhaler 160/180 μg intervention 2: Placebo metered-dose inhaler
Intervention descriptions: intervention 1: Budesonide/albuterol combination aerosol for inhalation, single dose (given as 2 actuations of 80/90 μg) intervention 2: Placebo aerosol for inhalation, single dose (given as 2 actuations)

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol - 1.0
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Budesonide/Albuterol Sulfate - AZ-RU-00004
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Clinical Study Protocol
Study Intervention
Budesonide/Albuterol
Sulfate
Study Code
AZ-RU-00004
Version
1.0
Date
29 August 2023
A Phase III, Multicentre, Randomized, Double-blind, Single-Dose,
2-Arm, 2-Period, Crossover Study to Investigate the Efficacy of 
PT027 Compared with Placebo on Exercise-Induced 
Bronchoconstriction in Adult Patients with Asthma (BREATH)
Sponsor Name: AstraZeneca Pharmaceuticals LLC
Legal Registered Address: Building 1, 21, First Krasnogvardeyskiy lane, floor 30, rooms 13 
and 14, Moscow, Russian Federation
Protocol Number: AZ-RU-00004
This protocol has been subject to a peer review according to AstraZeneca Standard procedures. 
The protocol is publicly registered and the results are disclosed and/or published according to 
the AstraZeneca Global Standard - Bioethics and in compliance with prevailing laws and 
regulations.
Brief Title: A Study to Investigate the Effects of PT027 (Budesonide/Albuterol Sulfate) 
Metered-dose Inhaler Compared with Placebo on Exercise-Induced Bronchoconstriction in 
Adult Patients with Asthma (BREATH)
Study Phase: Phase III
Acronym: BREATH
Study Physician and Contact Information: AstraZeneca Study Physician name and contact 
information will be provided separately
Coordinating Investigator: Name and contact information will be provided separately
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TABLE OF CONTENTS
1
PROTOCOL SUMMARY .................................................................................. 6
1.1
Synopsis ............................................................................................................. 6
1.2
Schema............................................................................................................. 12
1.3
Schedule of Activities ....................................................................................... 13
2
INTRODUCTION............................................................................................ 17
2.1
Study Rationale ................................................................................................ 17
2.2
Background ...................................................................................................... 18
2.2.1
Investigational Intervention............................................................................... 18
2.2.2
Exercise-induced Bronchoconstriction.............................................................. 20
2.3
Benefit/Risk Assessment................................................................................... 21
2.3.1
Risk Assessment ............................................................................................... 21
2.3.2
Benefit Assessment........................................................................................... 22
2.3.3
Overall Benefit/Risk Conclusion....................................................................... 23
3
OBJECTIVES, ENDPOINTS, AND ESTIMANDS .......................................... 24
4
STUDY DESIGN ............................................................................................. 26
4.1
Overall Design.................................................................................................. 26
4.1.1
Screening Period – Visit 1................................................................................. 28
4.1.2
Screening Period – Visit 2................................................................................. 29
4.1.3
Randomized treatment phase – Visits 3 and 4.................................................... 29
4.1.4
Unscheduled visit ............................................................................................. 30
4.1.5
Follow-up period .............................................................................................. 30
4.2
Scientific Rationale for Study Design ............................................................... 30
4.2.1
Justification for Placebo Control....................................................................... 31
4.3
Justification for Dose........................................................................................ 32
4.4
End-of-study Definition.................................................................................... 32
5
STUDY POPULATION.................................................................................... 33
5.1
Inclusion Criteria .............................................................................................. 33
5.2
Exclusion Criteria ............................................................................................. 34
5.3
Lifestyle Considerations ................................................................................... 37
5.3.1
Caffeine, Alcohol, and Tobacco......................................................................... 37
5.3.2
Illicit drugs ....................................................................................................... 37
5.3.3
Activity............................................................................................................. 37
5.4
Screen Failures ................................................................................................. 37
5.5
Criteria for Temporarily Delaying ..................................................................... 37
6
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................. 38
6.1
Study Intervention(s) Administered................................................................... 38
6.2
Preparation, Handling, Storage, and Accountability .......................................... 39
6.2.1
Dose Preparation............................................................................................... 40


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6.2.2
Dose Administration ......................................................................................... 40
6.3
Assignment to Study Intervention ..................................................................... 41
6.4
Blinding............................................................................................................ 41
6.5
Study Intervention Compliance......................................................................... 42
6.6
Dose Modification ............................................................................................ 42
6.7
Continued Access to Study Intervention After the End of the Study .................. 42
6.8
Prior and Concomitant Therapy ........................................................................ 42
6.8.1
Prior and Concomitant Medications .................................................................. 42
6.8.2
Rescue Medicine............................................................................................... 45
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 46
7.1
Discontinuation of Study Intervention............................................................... 46
7.1.1
QTc Stopping Criteria....................................................................................... 46
7.2
Participant Discontinuation/Withdrawal From the Study................................... 46
7.3
Lost to Follow-up ............................................................................................. 47
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 49
8.1
Efficacy Assessments........................................................................................ 49
8.1.1
Lung function measurement by spirometry (FEV1)............................................ 49
8.1.2
Exercise challenge testing ................................................................................. 51
8.2
Safety Assessments........................................................................................... 51
8.2.1
Physical Examinations...................................................................................... 52
8.2.2
Vital Signs ........................................................................................................ 52
8.2.3
Resting 12-lead Electrocardiogram ................................................................... 52
8.2.4
Heart rate monitoring during exercise challenge testing .................................... 52
8.2.5
Clinical Safety Laboratory Tests ....................................................................... 53
8.3
AEs, SAEs, and Other Safety Reporting............................................................ 54
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 55
8.3.2
Follow-up of AEs and SAEs ............................................................................. 55
8.3.3
Causality Collection.......................................................................................... 55
8.3.4
AEs Based on Examinations and Tests.............................................................. 56
8.3.5
AEs Based on Signs and Symptoms.................................................................. 56
8.3.6
Disease Progression.......................................................................................... 56
8.3.7
Disease Under Study......................................................................................... 57
8.3.8
Reporting of SAEs............................................................................................ 57
8.3.9
Pregnancy......................................................................................................... 58
8.3.9.1
Maternal Exposure............................................................................................ 58
8.3.9.2
Paternal Exposure............................................................................................. 58
8.4
Pharmacokinetics.............................................................................................. 59
8.5
Pharmacodynamics........................................................................................... 59
8.6
Optional Genomics Initiative ............................................................................ 59
8.7
Biomarkers ....................................................................................................... 59


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8.8
Immunogenicity Assessments ........................................................................... 59
8.9
Health Economics OR Medical Resource Utilisation and Health Economics..... 59
8.10
Study Participant Feedback Questionnaire ........................................................ 59
9
STATISTICAL CONSIDERATIONS................................................................ 60
9.1
Statistical Hypotheses....................................................................................... 60
9.2
Sample Size Determination............................................................................... 60
9.3
Populations for Analyses................................................................................... 61
9.4
Statistical Analyses ........................................................................................... 61
9.4.1
General Considerations..................................................................................... 61
9.4.2
Efficacy ............................................................................................................ 62
9.4.2.1
Primary Endpoint(s).......................................................................................... 62
9.4.2.2
Secondary Endpoint(s)...................................................................................... 63
9.4.3
Safety ............................................................................................................... 65
9.4.4
Other Analyses.................................................................................................. 65
9.5
Interim Analyses............................................................................................... 65
9.6
Data Monitoring/Other Committee.................................................................... 65
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 66
11
REFERENCES................................................................................................. 80


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LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 12
LIST OF TABLES
Table 1
Treatment Sequences............................................................................... 10
Table 2
Schedule of Activities.............................................................................. 13
Table 3
Spirometry Assessments Relative to the Maximal Exercise Test at Visit 1 15
Table 4
Spirometry Assessments Relative to the Exercise Challenge Test and
Dosing at Visits 2, 3, and 4 ...................................................................... 16
Table 5
Risk Assessment...................................................................................... 21
Table 6
Objectives, Endpoints and Estimands....................................................... 24
Table 7
Study Intervention ................................................................................... 38
Table 8
Restricted and Prohibited Concomitant Medications ................................ 44
Table 9
Laboratory Safety Variables..................................................................... 53
Table 10
Populations for Analysis .......................................................................... 61
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 67
Appendix B
AEs: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting .......................................................................................... 75
Appendix C
Abbreviations .......................................................................................... 78


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase III, Multicentre, Randomized, Double-blind, Single-Dose, 2-Arm, 2-
Period, Crossover Study to Investigate the Efficacy of PT027 Compared with Placebo on 
Exercise-Induced Bronchoconstriction in Adult Patients with Asthma (BREATH).
Brief Title: A Study to Investigate the Effects of PT027 (Budesonide/Albuterol Sulfate) 
Metered-dose Inhaler Compared with Placebo on Exercise-Induced Bronchoconstriction in 
Adult Patients with Asthma (BREATH)
Protocol Number: AZ-RU-00004
Rationale: 
In the Russian Federation, the current clinical guidelines suggest classifying patients with 
asthma by the level of treatment required to maintain good disease control (MoH RF Clinical 
guidelines, 2021), which is also the approach adopted by the Global Initiative for Asthma
guidelines (GINA guidelines, 2023). Patients with mild asthma can be controlled with Step 
1 or 2 treatment and the preferred symptoms reliever option is as-needed low-dose inhaled 
corticosteroid (ICS) with short/rapid-acting β2-adrenoreceptor agonist (SABA). 
AstraZeneca has developed a new fixed-dose combination of low-dose ICS budesonide and
SABA albuterol, coded as «PT027», which has successfully proven its efficacy and safety in 
several international phase III clinical studies in adults, adolescents and children with asthma.
Albuterol sulfate (further referred to as albuterol) is approved in Russia under the generic name 
of salbutamol.
The purpose of this Phase III, multicentre, randomized, double-blind, single-dose, 2-arm, 2-
period, crossover study is to assess the efficacy and safety of PT027 («budesonide/albuterol 
(salbutamol)», metered-dose inhaler 160/180 μg) compared to placebo on exercise-induced 
bronchoconstriction in adult patients with asthma.
Efficacy and safety of PT027 were previously demonstrated during extensive clinical 
development program. But clinical centres from the Russian Federation were not involved in 
these clinical trials and data on Russian population was not obtained. For these reasons there is 
single planned PT027 study in the Russian Federation that will provide clinical data on efficacy 
and safety in the population of Russian patients with asthma and exercise-induced 
bronchoconstriction. The results of this study will provide clinical data on efficacy and safety 
of an innovation drug in the new region (Russian Federation), which will be an important 
additional data source for the PT027 approval process in Russia.


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Objectives, Endpoints and Estimands:
Objectives
Endpoints 
Primary
To 
estimate 
the 
efficacy
of 
PT027 
(budesonide/albuterol) 
metered-dose
inhaler
as 
compared with placebo metered-dose inhaler after a 
single dose on exercise-induced bronchoconstriction in 
adult participants 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
Population for analysis: Full Analysis Set.
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.
Missing results for maximum percentage fall in FEV1 
(i.e., rescue medication prior to the collection of the 5 
minutes measure) will not be imputed.
The measure of interest is the difference between 
treatments in the maximum percentage fall from post-
dose, pre-exercise baseline in FEV1 observed up to 60 
minutes post-exercise challenge.
Secondary
To 
further 
estimate 
the 
efficacy 
of 
PT027 
(budesonide/albuterol) 
metered-dose
inhaler 
as 
compared with placebo metered-dose inhaler after a 
single dose on exercise-induced bronchoconstriction in 
adult participants with asthma

The percentages of subjects with a maximum 
percentage fall in FEV1 post-exercise challenge
of <10% and <20%, respectively
Population for analysis: Full Analysis Set.
The percentage fall will be calculated relative to the 
pre-exercise FEV1 assessment at the respective visit.
The measure of interest is the odds ratio between 
PT027 and Placebo for each threshold separately
(<10% and <20%).

The percentage fall from post-dose, pre-exercise
baseline in FEV1 at each timepoint within 60 
minutes post-exercise challenge
Population for analysis: Full Analysis Set.
The measure of interest is the percentage fall from 
baseline in FEV1 at each timepoint within 60 minutes
post-exercise challenge.
Only FEV1 results prior to administration of rescue
medication (within the study visit) will be included in
the analyses.

Post-exercise FEV1 area under the curve from 0
to 30 minutes (AUC0-30min)
Population for analysis: Full Analysis Set.
The measure of interest is the difference between 
treatments in the post-exercise FEV1 AUC0-30min.


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Objectives
Endpoints 
Only the FEV1 AUC0-30min measurements prior to 
administration of rescue medication will be included 
in the analyses.

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
Population for analysis: Full Analysis Set.
The measure of interest is the median of the time to 
recovery. 
Safety
To assess the safety and tolerability of PT027 
(budesonide/albuterol)
metered-dose
inhaler
as 
compared with placebo metered-dose inhaler after a 
single dose in adult participants with asthma.
Safety and tolerability will be evaluated in terms of 

adverse events (AEs), 

serious adverse events (SAEs), 

AEs lead to discontinuation,
Vital signs, physical examination, electrocardiograms 
(ECGs) will be analysed in terms of adverse event 
data.
Population for analysis: Safety Analysis Set.
The measure of interest is frequencies and percentages
of participants with reported AEs.
Overall Design Synopsis:
Brief summary: The purpose of this Phase III, multicentre, randomized, double-blind, single-
dose, 2-period, crossover study is to assess the efficacy and safety of PT027 
(budesonide/albuterol sulfate) metered-dose inhaler compared with placebo on exercise-
induced bronchoconstriction in adult patients with asthma.
Subjects will receive each study treatment on separate visits and undergo a treadmill exercise 
challenge test so that the effect of study treatment on exercise-induced bronchoconstriction can 
be evaluated.
Disclosure Statement: This is a Phase III, multicentre, randomized, double-blind, single-dose, 
2-arm, 2-period, crossover study assessing the efficacy and safety of PT027 
(budesonide/albuterol) compared with placebo.
Participant Population:
The target population of interest in this study is male and female participants aged 18-70 years 


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with asthma and exercise-induced bronchoconstriction. The study will include patients with two 
types of current therapy: 1) subjects currently   treated only with short/rapid-acting β2-
adrenoreceptor agonist (SABA) on an as-needed regimen, and 2) subjects on low-to-medium-
dose inhaled corticosteroid (ICS) maintenance therapy (according to the Clinical guidelines 
"Bronchial asthma" of the Ministry of Health of the Russian Federation, 2021) and SABA as
needed.
Number of Participants:
Approximately 107 participants will be screened to achieve 64 randomized/assigned to study 
intervention and 56 evaluable participants (refer to FAS population, Section 9.3) at 6 to 12 
investigational centers in the Russian Federation. 
Enrolled/screened*
Estimated 107 participants
Randomized/assigned
Estimated 64 participants
Evaluable participants
Estimated 56 participants
Note: * - “Enrolled/Screened” means a participant’s, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, but are 
not randomized/assigned in the study, are considered “screen failures”, unless otherwise specified by the 
protocol. 
Study Arms and Duration:
Investigational Medical Product will be PT027 (budesonide/albuterol) metered-dose inhaler and 
a matching placebo metered-dose inhaler, which will be used as the comparator. The IMP will 
be administered as a single dose as follows:

A: PT027 (budesonide/albuterol) metered-dose inhaler 160/180 μg (given as 2 
inhalations of metered-dose inhaler 80/90 μg per puff)

B: Placebo metered-dose inhaler (given as 2 inhalations)
This is a single-dose, 2-arm, 2-period, crossover study. Approximately 64 subjects will be 
randomized 1:1 to one of two treatment sequences – A/B or B/A, as specified in Table 1.


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Table 1
Treatment Sequences
Treatment
sequence
Period 1 
(Visit 3)
Period 2 
(Visit 4)
A/B
PT027 (BUDESONIDE/ALBUTEROL)
metered-dose inhaler 160/180 μg 
(given as 2 actuations of 80/90 μg)
PLACEBO
metered-dose inhaler
(given as 2 actuations)
B/A
PLACEBO
metered-dose inhaler
(given as 2 actuations)
PT027 (BUDESONIDE/ALBUTEROL)
metered-dose inhaler 160/180 μg 
(given as 2 actuations of 80/90 μg)
At Visit 3/Period 1 and Visit 4/Period 2, IMP will be administered 30 (±5) minutes prior to the
PFT before exercise challenge. During the study, subjects will not be allowed to use any asthma
medication other than the SABA in an as-needed regimen or ICS maintenance therapy plus 
SABA in an as-needed regimen 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.
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 IMP at Visits 3 and 4, which will 
be approximately 1 week apart. A final follow-up visit will be conducted via a telephone call
(TC) 3 to 5 days after the final in-clinic visit. The overall study duration will take approximately
3 to 4 weeks.
Data Monitoring / Other Committee: 
Not applicable for this study.
Statistical Methods
The main objective of this study is to estimate the efficacy of PT027 (budesonide/albuterol) as 
compared with placebo based on the evaluation of the primary endpoint «maximum percentage 
fall from post-dose, pre-exercise baseline in FEV1 observed up to 60 minutes post-exercise 
challenge». The corresponding hypotheses for the primary analysis are as follows:

H0: Difference between treatments «∆A – ∆B» = 0,

H1: Difference between treatments «∆A – ∆B» ≠0.
there: ∆- maximum percentage fall of FEV1, A - PT027 (budesonide/albuterol), B - placebo.
The primary efficacy endpoint will be analyzed with a mixed effect model including categorical 
fixed effects for treatment, treatment period and treatment sequence. Continuous covariates 


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include period-specific pre-dose baseline FEV1 and average pre-dose baseline FEV1. Also, a
random subject within treatment sequence effect will be specified. Post-dose, pre-exercise 
baseline FEV1 will be defined as the 30 minutes post-dose value, i.e., 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 2-sided 95% 
confidence intervals (CIs) will be provided.
Applied significance level (alpha): 0.05 (using a 2-sided test).
No interim efficacy analysis is planned in this study.
The secondary efficacy endpoints will be analysed using the methodology specified in Section 
9.4.2.2.
Safety data will be summarized descriptively and will not be formally analyzed unless otherwise 
specified. Data will be presented using the safety analysis set.
Analysis sets:
Population/Analysis set
Description
Enrolled/Screened
All participants who sign the ICF.
Full analysis set (FAS)
All participants who are randomized to treatment and have at least one
post-dose, pre-exercise baseline and at least one corresponding post-dose
post-exercise FEV1 measure at Visit 3 and/or Visit 4.
Safety analysis set
All participants who have received any amount of the study intervention.
Sample size justification:
Sample size determination based on a previous clinical study NCT04234464, Phase III 
«TYREE» (LaForce C et al 2022) with a similar design and patient population. Using the 
obtained difference for maximum percentage fall from post-dose, pre-exercise baseline in FEV1
observed up to 60 minutes post-exercise challenge equals to
 
 and corresponding SD=
% (the calculated SD of 
treatment difference based on previous study results), a sample size of 28 subjects in each 
treatment sequence will provide a 95% probability to detect a difference between PT027 
(budesonide/albuterol) and placebo based on 2 sided 95% CI.
Considering, a drop-out rate of ~10% (8 subjects), the sample size in this study will be 64 
randomized subjects (32 randomized subjects per study sequence arm). Due to the possible 
withdrawal during the screening up to 40%, it is planned to screen up to 107 subjects.
CCI
CCI


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1.2
Schema
Figure 1
Study Design
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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1.3
Schedule of Activities
Table 2
Schedule of Activities
Screening a
(up to 14 days 
before Day 1)
Double-blind
Treatment Phase a
Unscheduled
Visit or PDV b
(if applicable)
Follow-up
TC (3 to 5 days
after V4 or PDV)
Details in protocol 
section or appendix
Period 1
Period 2
Visit number
1
2
3
4
Procedure                                                         Day of study
-14 to -8
-7 to -2
1
8±6
Informed consentl
X
Inclusion and exclusion criteria c
X
X
Sections 5.1 and 5.2
Randomization criteria verification d
X
Section 4.1.3
Demography
X
Medical history (includes medical/surgical history, alcohol 
consumption and smoking) and current medical conditions
X
Physical examination 
X
X
X
Section 8.2.1
Weight measurement
X
X
X
Height measurement and BMI calculation
X
Pregnancy test (WOCBP only) e
X
X
X
X
Section 5.1
Clinical laboratory tests f
X
Section 8.2.5
Alcohol detection in exhaled air
X
X
X
X
Section 8.2.5
Drugs of abuse and cotinine urine testing
X
X
X
X
Section 8.2.5
Seated vital signs (blood pressure and heart rate) g
X
X
X
X
X
Section 8.2.2
12-lead ECG g, h
X
X
X
X
Sections 8.2.3 and 8.2.4
Spirometry (FEV1) g
X
X
X
X
Section 8.1.1
Maximal exercise test h
X i
Section 8.1.2
ECT with Treadmill h
X i, j
X i, j
X i, j
Section 8.1.2
Confirm FEV1 stabilityk
X
X
X
Section 4.1.3
Randomization d
X
Administration of IMP (PT027/placebo)
placebo
X
X
AE assessment
X
X
X
X
X
X
Section 8.3


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Screening a
(up to 14 days 
before Day 1)
Double-blind
Treatment Phase a
Unscheduled
Visit or PDV b
(if applicable)
Follow-up
TC (3 to 5 days
after V4 or PDV)
Details in protocol 
section or appendix
Period 1
Period 2
Visit number
1
2
3
4
Procedure                                                         Day of study
-14 to -8
-7 to -2
1
8±6
Concomitant medication review
X
X
X
X
X
X
Section 6.8
Notes for Table 2:
a The «run-in period» length at screening can be shortened at the discretion of the investigator, but the screening and double-blind (randomized) treatment phase 
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 Those subjects not meeting criteria will be considered screen failed. See Sections 4.1.1, 4.1.2, 5.1 and 5.2 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 4.1.3 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 8.2.5.
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 35 minutes after IMP 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.
l Upon signing the informed consent form, the subject will also be given a study participant card with emergency contact details of the Investigator and study 
sponsor.
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; IMP=Investigational Medical Product; PDV=Premature discontinuation visit; 
TC=Telephone call; V=Visit; WOCBP= women of childbearing potential.


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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
Assessments                                       Time, minutes
-50
(±10)
-35
(±5)
-5
(±3)
0
5
(±3a)
10
(±3a)
15
(±3a)
20
(±5a)
30
(±5 a)
40
(±5a)
45
(±5a)
60
(±5)
Seated vital signs (blood pressure and heart rate)
X b
X b
X b
X c
12-lead ECG
X d
X
Spirometry e
X
X
X
X
X
X
X
Exercise challenge f
X
Heart rate monitoring g
<------------------------------------------------------------------------------------------------------->
AE assessment
<--------------------------------------------------------------------------------------------------------------------------------------->
Concomitant medication review
<--------------------------------------------------------------------------------------------------------------------------------------->
Notes for Table 3:
a Procedures of previous time point should be finished before the start of procedures of the next time point.
b Vital signs should be recorded with the subject in the seated position and after 5 minutes of rest.
c Seated vital signs at the 60-minutes post-exercise challenge time point should be recorded 5-10 minutes AFTER the last PFT (i.e., 65 minutes [±5 minutes]).
d 12-lead ECG recording at the pre-exercise challenge time point should be conducted after 10 minutes of rest.
e 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
Visit 1 through Visit 4 (i.e., ±1 hour of the timing of the initial assessment at Visit 1).
f 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.
g 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 (i.e., intermittently during PFTs).
Abbreviations: AE=adverse event; ECG=electrocardiogram; ECT=exercise challenge test; PFT=pulmonary function test.


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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
Assessments                                  Time, minutes
-50
(±15)
-5
(±3)
0
30
(±5)
ECT
35
5
(±3a
)
10
(±3a
)
15
(±3a
)
20
(±5a
)
30
(±5a
)
40
(±5a
)
45
(±5a
)
60
(±5)
Seated vital signs (blood pressure and heart rate)
X b
X b
X b
X c
12-lead ECG
X d
X
Spirometry e, f
X e, f
X
X
X
X
X
X
Administration of IMP (PT027/placebo) g
X
Exercise challenge h
X
Heart rate monitoring i
<------------------------------------------------------------------------------->
AE assessment
<--------------------------------------------------------------------------------------------------------------------------------------->
Concomitant medication review
<--------------------------------------------------------------------------------------------------------------------------------------->
Notes for Table 4:
a Procedures of previous time point should be finished before the start of procedures of the next time point
b Vital signs should be recorded with the subject in the seated position and after 5 minutes of rest.
c Seated vital signs at the 60-minutes post-exercise challenge time point should be recorded 5-10 minutes AFTER the last PFT (i.e., 65 minutes [±5 minutes]).
d 12-lead ECG recording at pre-dose time point should be conducted after 10 minutes of rest.
e At Visits 2 through 4, if the FEV1 criteria are not met in the first spirometry measurement (i.e., 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 fulfil all criteria, then the subject can proceed to dosing.
f Every attempt should be made to perform the first pre-exercise spirometry measurement prior to 11:00 AM consistently across Visit 1 through Visit 4 (i.e., 
±1 hour of the timing of the initial spirometry performed at Visit 1).
g At Visit 2, subjects will receive placebo; while at Visit 3 and Visit 4 they will receive IMP (PT027 MDI or placebo MDI) depending on their randomization 
assignment.
h 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.
i Heart rate will be monitored continuously during the ECT and intermittently after ECT until 60 minutes after completion of the exercise challenge (i.e., 
intermittently during PFTs).
Abbreviations: AE=adverse event; ECG=electrocardiogram; ECT=exercise challenge test; FEV1=forced
expiratory
volume
in 1 second; 
IMP=Investigational Medical Product; MDI=metered dose inhaler; PFT=pulmonary function test.


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2
INTRODUCTION
2.1
Study Rationale
Asthma is a common respiratory disease with a substantial burden for patients and healthcare systems. 
Patients with mild asthma represent the largest proportion of the asthma population, with estimates 
ranging from 50 to 75%. Several studies have found that up to half of exacerbations requiring 
emergency care occur in patients who report asthma symptoms less than once a week; thus, 
exacerbations are an important contributor to disease burden in mild asthma. One of the common 
triggers of an asthma symptoms is exercise-induced bronchoconstriction, which often leads 
to exercise avoidance as a means to control symptoms in this category of patients. Indeed, patients 
with reported mild asthma use considerable healthcare resources and commonly have an impaired 
quality of life (Golam SM et al 2022, Akhmerova YN et al 2023, Côté A et al 2018).
In the Russian Federation, the current clinical guidelines suggest classifying patients by the level of 
treatment required to maintain good asthma control (MoH RF Clinical guidelines, 2021), which is also 
the approach adopted by the Global Initiative for Asthma guidelines (GINA guidelines, 2023). Patients
with mild asthma can be controlled with Step 1 or 2 treatment and the preferred symptoms reliever 
option is as-needed low-dose inhaled corticosteroid (ICS) with short/rapid-acting β2-adrenoreceptor 
agonist (SABA). The fixed-dosed combinations for symptom relief available on the Russian market 
are limited – «beclomethasone (ICS) + salbutamol (SABA)», «beclomethasone (ICS) + formoterol 
(rapid-acting LABA)» and «budesonide (ICS) + formoterol (rapid-acting LABA)», and expanding the 
available therapeutic arsenal is a very important task.
AstraZeneca has developed a new fixed-dose combination «budesonide + albuterol sulfate (further 
referred to as albuterol, also known in Russia under the generic name of salbutamol)» (PT027), which 
has successfully proven its efficacy and safety in several international phase III clinical studies in 
adults, adolescents and children with asthma (see Section 2.2.1). And was approved for commercial 
use by the US FDA on 10 January 2023 under the trade name «AIRSUPRA™».
Currently, there is no gold standard for the treatment and prevention of exercise-induced 
bronchoconstriction in patients with asthma in the Russian Federation. More up-to-date data are 
available on the features of the incidence and course of asthma in Russia, including those associated 
with a genetic factor (Akhmerova YN et al 2023). The effective drug combinations available on the 
market are limited, and newly developed combinations may have a different degree of effect in the 
local population.
The purpose of this Phase III, multicentre, randomized, double-blind, single-dose, 2-arm, 2-period, 
crossover study is to assess the efficacy and safety of PT027 («budesonide/albuterol (salbutamol)»,
metered-dose inhaler 160/180 μg) compared to placebo on exercise-induced bronchoconstriction in 
adult patients with asthma.


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Efficacy and safety of PT027 were previously demonstrated during extensive clinical development 
program. But clinical centres from the Russian Federation were not involved in these clinical trials and 
data on Russian population was not obtained. For these reasons there is single planned PT027 study in 
the Russian Federation that will provide clinical data on efficacy and safety in the target population of 
Russian participants. The results of this study will provide clinical data on efficacy and safety of an 
innovation drug in the new region (Russian Federation), which will be an important additional data 
source for the PT027 approval process in Russia.
2.2
Background
2.2.1
Investigational Intervention
AstraZeneca (Sponsor) is developing budesonide/albuterol (PT027, a fixed-dose combination product; 
also referred to as budesonide and albuterol metered-dose inhaler [BDA MDI]) pressurized inhalation 
suspension product in adults, adolescents 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 in Russia is also known 
under the generic name of salbutamol. In clinical practice, albuterol is used as reliever therapy on an 
as-needed basis (GINA guidelines, 2023).
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), (i.e., formoterol).
In vitro studies have demonstrated that inhaled corticosteroid (ICS) agents potentiate the effects of 
SABAs in reducing airway smooth muscle tone (Mendes ES et al 2008) and can reverse adrenergic 
receptor tolerance and desensitization (Cooper PR et al 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 ES 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 guidelines, 2023), 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 PM et al 2005, Rabe KF et al 2006). In addition, budesonide/formoterol as 


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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 paediatric patients (O'Byrne PM 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 also on an 
as-needed basis 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 on an as-needed basis 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 (MoH RF Clinical guidelines, 2021; GINA 
guidelines, 2023) recommend addition of low-dose ICS to SABA used as reliever medication as early 
as in GINA step 1 asthma (previously treated with SABA on an as-needed basis 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 on an as-needed basis in a fixed-dose combination 
are expected to result in overall better asthma control and decreased risk of experiencing asthma 
symptoms than bronchodilation alone.
In MANDALA (NCT03769090) Phase III randomized, double-blind, active-comparator, multicenter 
study the efficacy and safety of PT027 was evaluated in patients with moderate to severe asthma (Papi 
A et al 2022). 
 
 
 
 
 
 
 
 
 
 
 
 
 
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In DENALI (NCT03847896) Phase III randomized, double-blind, active-comparator and placebo-
controlled multicenter study the efficacy of PT027 on lung function was evaluated in patients with 
mild to moderate asthma previously treated with as-needed SABA alone or with low-dose ICS 
maintenance therapy plus as-needed SABA (Chipps BE et al 2023). 
 
 
 
 
 
 
In TYREE (NCT04234464) Phase III randomized, double-blind, single-dose, placebo-controlled, 2-
period, crossover multicenter study the efficacy and safety of PT027 was evaluated in adult and 
adolescent patients with asthma and exercise-induced bronchoconstriction (LaForce C et al 2022). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2.2
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 
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for a daily ICS, a daily leukotriene receptor antagonist, or a mast cell stabilizing agent before exercise 
(Parsons JP et al 2013). Inhaled disodium cromoglycate and β2-agonists administered immediately
before an exercise challenge test (ECT) also provide good protection (Molema J et al 1989, Richter K 
et al 2002).
2.3
Benefit/Risk Assessment
Potential risks of budesonide and albuterol combination are based on the safety data from the previous 
studies and also on identified and potential risks of the mono-components budesonide and albuterol.
More detailed information about the known and expected benefits and risks and reasonably expected 
AEs of PT027 (budesonide/albuterol) may be found in the Investigator Brochure.
In the conditions of a single dosage of the investigational product, the risks for the study participants 
are minimal. In a previous study (NCT04234464, Phase III «TYREE») with the similar design and 
patient population 60 subjects received single-dose of PT027 (budesonide/albuterol) and placebo in 
two sequential study periods (LaForce C et al 2022). There were no deaths, SAEs, or discontinuations 
due to an AE. And there were only 2 treatment related AEs reported in the study, both of which occurred 
following administration of placebo.
2.3.1
Risk Assessment
Table 5
Risk Assessment
Potential risk of 
clinical significance
Summary of data/rationale for risk
Mitigation strategy
Study intervention – PT027 (Budesonide/Albuterol)
Hypersensitivity 
Reactions, Including 
Anaphylaxis
Hypersensitivity reactions can occur after administration of 
albuterol and budesonide, components of PT027, as 
demonstrated by cases of anaphylaxis, angioedema, 
bronchospasm, oropharyngeal edema, rash, and urticaria.
After administration of the 
drug, the patient will be under 
the 
supervision 
of 
the 
investigator. 
The study will include patients 
who have previously already 
received ICS and/or SABA
(see Section 5).
Paradoxical 
bronchospasm or 
deterioration of 
asthma
PT027 can produce paradoxical bronchospasm, which may be 
life threatening. If paradoxical bronchospasm occurs 
following dosing with PT027, it should be discontinued 
immediately, and alternative therapy should be instituted. It 
should be recognized that paradoxical bronchospasm, when 
associated with inhaled formulations, frequently occurs with 
the first use of a new canister. 
Asthma may deteriorate acutely over a period of hours or 
chronically over several days or longer. If the patient 
continues to experience symptoms after using of PT027, this 
After administration of the 
drug, the patient will be under 
the 
supervision 
of 
the 
investigator. 
Subjects 
will 
only 
be 
discharged from the clinic 
after satisfactory lung function
based on the investigator’s 
clinical judgment.


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Table 5
Risk Assessment
Potential risk of 
clinical significance
Summary of data/rationale for risk
Mitigation strategy
may be a marker of destabilization of asthma and requires 
evaluation of the patient and their treatment regimen. 
Cardiovascular 
Effects
PT027, like other drugs containing β2-adrenergic agonists, 
can produce clinically significant cardiovascular effects in 
some patients as measured by increases in pulse rate, blood 
pressure, and/or other symptoms. In addition, beta-agonists 
have been reported to produce ECG changes, such as 
flattening of the T wave, prolongation of the QTc interval, 
and ST-segment depression. The clinical significance of these 
findings is unknown. 
Patients 
with 
clinically 
significant 
cardiovascular 
disorders (especially coronary 
insufficiency, 
cardiac 
arrhythmias, and hypertension 
heart 
disease) 
and 
ECG 
abnormalities 
will 
not 
participate in the study (see 
Section 5).
Study intervention – Placebo
Lack of efficacy/
exercise-induced 
bronchoconstriction
Exercise challenge testing is a mandatory procedure in this
study and will be performed repeatedly.
During and after
exercise
challenge testing the patient 
will be under the supervision 
of the investigator. To mitigate 
any potential risks, all subjects 
will be closely monitored to 
ensure subject safety. Rescue 
medication will be provided if 
needed (see Section 6.8.2).
At study visits, subjects will 
only be discharged from the 
clinic after satisfactory lung 
function 
based
on 
the
investigator’s 
clinical 
judgment.
Study procedures
There are no 
identified risks of 
clinical significance
All procedures correspond to the routine methodology of their 
implementation in patients with asthma.
For a detailed description of 
the individual procedures (see 
Section 8).
2.3.2 Benefit 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. This study 
will be conducted in a similar design as previously published studies.


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2.3.3 Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimise risk to participants participating in this study, 
the potential risks identified in association with PT027 (budesonide/albuterol) are justified by the 
anticipated benefits that may be afforded to participants with asthma.


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3
OBJECTIVES, ENDPOINTS, AND ESTIMANDS
Table 6
Objectives, Endpoints and Estimands
Objectives
Endpoints and Estimands Description
Primary
To 
estimate 
the 
efficacy
of 
PT027 
(budesonide/albuterol) 
metered-dose
inhaler
as 
compared with placebo metered-dose inhaler after a 
single dose on exercise-induced bronchoconstriction in 
adult participants 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
Population for analysis: Full Analysis Set.
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.
Missing results for maximum percentage fall in FEV1 
(i.e., rescue medication prior to the collection of the 5 
minutes measure) will not be imputed.
The measure of interest is the difference between 
treatments in the maximum percentage fall from post-
dose, pre-exercise baseline in FEV1 observed up to 60 
minutes post-exercise challenge.
Secondary
To 
further 
estimate 
the 
efficacy 
of 
PT027 
(budesonide/albuterol) 
metered-dose
inhaler
as 
compared with placebo metered-dose inhaler after a 
single dose on exercise-induced bronchoconstriction in 
adult participants with asthma

The percentages of subjects with a maximum 
percentage fall in FEV1 post-exercise challenge
of <10% and <20%, respectively
Population for analysis: Full Analysis Set.
The percentage fall will be calculated relative to the 
pre-exercise FEV1 assessment at the respective visit.
The measure of interest is the odds ratio between 
PT027 and Placebo for each threshold separately
(<10% and <20%).

The percentage fall from post-dose, pre-exercise
baseline in FEV1 at each timepoint within 60 
minutes post-exercise challenge
Population for analysis: Full Analysis Set.
The measure of interest is the percentage fall from 
baseline in FEV1 at each timepoint within 60 minutes
post-exercise challenge.
Only FEV1 results prior to administration of rescue
medication (within the study visit) will be included in
the analyses.


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Objectives
Endpoints and Estimands Description

Post-exercise FEV1 area under the curve from 0
to 30 minutes (AUC0-30min)
Population for analysis: Full Analysis Set.
The measure of interest is the difference between 
treatments in the post-exercise FEV1 AUC0-30min.
Only the FEV1 AUC0-30min measurements prior to 
administration of rescue medication will be included 
in the analyses.

Time to recovery, defined as the time from 
completionof the exercise challenge to the first 
measured post-exercise challenge FEV1 value 
within 10% of the post- dose, pre-exercise
challenge baseline FEV1
Population for analysis: Full Analysis Set.
The measure of interest is the median of the time to 
recovery. 
Safety
To assess the safety and tolerability of PT027 
(budesonide/albuterol)
metered-dose
inhaler
as 
compared with placebo metered-dose inhaler after a 
single dose in adult participants with asthma.
Safety and tolerability will be evaluated in terms of 

adverse events (AEs), 

serious adverse events (SAEs), 

AEs lead to discontinuation.
Vital signs, physical examination, electrocardiograms 
(ECGs) will be analysed in terms of adverse event 
data.
Population for analysis: Safety Analysis Set.
The measure of interest is frequencies and percentages 
of participants with reported AEs.


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4
STUDY DESIGN
4.1
Overall Design
This will be a multicenter, double-blind, randomized, placebo-controlled, 2-arm, 2-period, single-dose, 
crossover study. 
Approximately 64 subjects will be randomized 1:1 to one of two treatment sequences – A/B or B/A, 
as specified in Table 1. The IMP will be administered as a single dose as follows:

А: PT027 (budesonide/albuterol) metered-dose inhaler 160/180 μg (given as 2 inhalations of
metered-dose inhaler 80/90 μg per puff)

B: Placebo metered-dose inhaler (given as 2 inhalations)
The study will consist of a 1 to 2-week screening (Visit 1 and Visit 2) and randomized treatment phase 
– 2 treatment visits (Visit 3 and Visit 4) with an interval of about 1 week. The double-blind treatment 
will occur with single dosing of IMP at Visits 3 and 4. A final follow-up visit will be conducted via a 
telephone call (TC) 3 to 5 days after the final in-clinic visit. The overall study duration will take
approximately 3 to 4 weeks.
Screening 
Visit 1 will include general screening procedures, spirometry, and demonstration of exercise-induced 
bronchoconstriction 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,
undergo spirometry testing and confirmation of exercise-induced bronchoconstriction («run-in 
period»). The «run-in period» length at screening can be shortened at the discretion of the investigator, 
but the screening and randomized treatment phase must include at least 1 non-exercise test day between
visit days.
Randomized treatment phase
At Visit 3, eligible subjects will be randomized to 1 of 2 treatment sequences (i.e., A/B or B/A), in 
which single doses of PT027 and placebo will be administered in separate treatment periods (i.e., 
Period 1 and Period 2). At Visit 4, subjects who received PT027 at Visit 3 will receive placebo, while
those who received placebo at Visit 3 will receive PT027. At Visit 3/Period 1 and Visit 4/Period 2, 
IMP will be administered 30 (±5) minutes prior to the PFT before exercise challenge.
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.


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During the study, standardized ECTs will be conducted according to American Thoracic Society 
(ATS)/European Respiratory Society (ERS) guidelines (see Section 8.1.2). 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 (see 
Section 8.1.1).
To be eligible for the treatment phase of the study, subjects with asthma will be required to meet
spirometry criteria and demonstrate exercise-induced bronchoconstriction 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.
During the study, subjects will not be allowed to use any asthma medication other than the SABA in
an as-needed regimen or ICS maintenance therapy plus SABA in an as-needed regimen 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 (see Section 6.8.1). 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.
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 8.
Additional 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 must comply with the life style restrictions described in the Section 5.3.

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:


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o
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.
o
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.
o
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.
4.1.1
Screening Period – Visit 1
At Visit 1, consenting subjects are assessed to ensure that they meet eligibility criteria. Subjects who 
do not meet the criteria must not continue screening period and be randomized. Subjects meeting all
eligibility criteria will enter a screening period.
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; A standard medical, disease, and 
surgical history, alcohol consumption, and smoking 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 Section 8.2 for details.
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 (i.e., 
acceptability) and/or pre-exercise FEV1 ≥70% predicted, prior to randomization. The 1 retest will 
also be permitted for a lack of FEV1 drop (i.e., 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
Screening Period – 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 assessmentat Visit 1 (±1 hour) and
before 11:00 AM. Subjects will be administered placebo, with an ECT conducted 35 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
(e.g., 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 (i.e., 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 (i.e., negative EIB outcome). Those subjects not meeting
criteria will be considered screen failed.
4.1.3
Randomized treatment phase – Visits 3 and 4
The treatment phase consists of 2 visits (Visit 3 and Visit 4). At Visit 3, eligible subjects will be 
randomized (1:1) to receive 1 of 2 treatment sequences (A/B or B/A). 
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

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.


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Investigational product will be administered to eligible subjects at Visit 3 and Visit 4. To allow for 
proper preparation of IMP, 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 IMP followed:

After IMP is primed (see the separate manual for instructions on MDI handling and cleaning)
and ready for use, provide assigned IMP to the subject

IMP 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)
4.1.4
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.
4.1.5
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.
4.2
Scientific Rationale for Study Design
This is a multicenter, double-blind, randomized, placebo-controlled, 2-arm, 2-period, single-dose, 
crossover study of the effects on exercise-induced bronchoconstriction in adult patients with asthma . 
Currently, there is no gold standard for the treatment and prevention of exercise-induced 
bronchoconstriction in patients with asthma in the Russian Federation. More up-to-date data are 
available on the features of the incidence and course of asthma in Russia, including those associated 
with a genetic factor (Akhmerova YN et al 2023). The effective drug combinations available on the 
market are limited, and newly developed combinations may have a different degree of effect in the 
local population.
The purpose of this study is to assess the efficacy and safety of PT027 («budesonide/albuterol 
(salbutamol)», metered-dose inhaler 160/180 μg) compared to placebo on exercise-induced 
bronchoconstriction in adult patients with asthma in Russian population.
This local Phase III study is conducted in addition to the three main international Phase III studies:
MANDALA (NCT03769090) – exacerbation risk study, DENALI (NCT03847896) – lung function 
study and TYREE (NCT04234464) – exercise-induced bronchoconstriction study (see Section 2.2.1).
Asthma patients with exercise-induced bronchoconstriction, who use their SABA reliever therapy 
prophylactically before exercise to prevent exercise-induced bronchoconstriction, may benefit from a 


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fixed-dosed combination (budesonide/albuterol MDI), taken prior to exercise, to prevent asthma
symptoms. This study will assess the efficacy and safety of single-dose PT027 (budesonide/albuterol) 
MDI as compared with placebo MDI in subjects with asthma and
exercise-induced 
bronchoconstriction. It is important to evaluate whether PT027 MDI would prevent or reduce
bronchoconstriction when used prophylactically.
Spirometry is one of the fundamental outcome measures used in asthma studies. It provides an 
objective and highly reproducible measure of airflow limitation caused by smooth muscle contraction 
or structural changes. Forced expiratory volume in 1 s (FEV1) is recommended as the primary endpoint 
for studies of bronchodilator therapy by the American Thoracic Society (ATS) and the European 
Respiratory Society (ERS) in their official statement on asthma control and exacerbations (Halpin 
DMG et al 2019). FEV1 recorded after withholding bronchodilators for their duration of action, is a 
strong, independent predictor of future exacerbation risk, and has been used in the majority of asthma 
clinical trials as the primary lung function endpoint in recent decades (Reddel HK et al 2009). This is 
in line with regulatory recommendations for clinical trials in asthma that also consider FEV1 as the 
most suitable variable with the clarification that in a case of exercise-induced bronchoconstriction 
/asthma the relevant endpoint should be the prevention of a fall in FEV1 following exercise using a 
standardised (treadmill) exercise test (EMA Guideline on the clinical investigation of medicinal 
products for the treatment of asthma 2015).
Accordingly, the primary endpoint in this study will be based on an assessment of the FEV1 change:
«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». A similar primary endpoint was 
used in a previous TYREE (NCT04234464) study (LaForce C et al 2022).
4.2.1
Justification for Placebo Control
Evaluation of efficacy and safety compared to placebo is a highly sensitive and generally accepted 
approach in phase II and III studies of combined drugs (Recommendation of the Board of the Eurasian 
Economic Commission of September 2, 2019 №25 «Guidelines for preclinical and clinical 
development of combined drugs»). This approach provides optimal comparative data for subsequent 
interpretation, is ethically justified and does not carry any additional risks in the conditions of lung 
function study with single dose administration. Placebo-controlled clinical trials in patients with mild 
asthma are in line with international guidelines (EMA Guideline, 2015).
In a previous placebo-controlled study (NCT04234464, Phase III «TYREE») with the similar design 
and patient population there were no deaths, SAEs, or discontinuations due to an AE (LaForce C et al 
2022). There were only 2 TEAEs which occurred following administration of Placebo MDI and only 
one patient was demanded an additional use of bronchodilators after ECT.
Also, there are several other placebo-controlled clinical trials of exercise-induced asthma published


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(Ostrom NK et al 2015, Hawksworth RJ et al 2002, Dockhorn RJ et al 1997). There is no evidence of
significant adverse events and additional risks associated with the use of placebo in these clinical trials.
During and after exercise challenge testing the patient will be under the supervision of the investigator. 
Rescue medication will be provided (see Section 6.8.2).
4.3
Justification for Dose
The studied PT027 (budesonide/albuterol) MDI dosing regimen – «160/180 μg, given as 2 
inhalations/actuations of MDI 80/90 μg per puff», corresponds to that in previous studies and in line 
with approved by the US FDA recommended dosage for commercial product «AIRSUPRA™».
To maintain a double-blind design, a placebo will be applied in a similar way (2 inhalations/actuations).
4.4
End-of-study Definition
For the purpose of Clinical Trial Transparency (CTT) the definition of the end of the study differs 
under FDA and EU regulatory requirements:
European Union requirements define study completion as the last visit of the last subject for any 
protocol related activity.
Food and Drug Administration requirements defines two completion dates:
Primary Completion Date – the date that the final participant is examined or receives an intervention 
for the purposes of final collection of data for the primary outcome measure, whether the clinical study 
concluded according to the pre-specified protocol or was terminated. In the case of clinical studies 
with more than one primary outcome measure with different completion dates, this term refers to the 
date on which data collection is completed for all of the primary outcomes.
Study Completion Date – the date the final participant is examined or receives an intervention for 
purposes of final collection of data for the primary and secondary outcome measures and AEs (for 
example, last participant’s last visit), whether the clinical study concludes according to the pre-
specified protocol or is terminated.
A participant is considered to have completed the study if they have completed all phases of the study 
including the last scheduled procedure shown in the SoA.


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5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and gender
1 
Female or male participant must be 18 to 70 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2 
Documented history of asthma (as defined by GINA criteria) for at least 6 months prior to Visit 
1.
3 
Receiving one of the following asthma therapies with stable dosing for at least 4 weeks before 
Visit 1 (no other asthma therapies are permitted during the study):
SABA in an as-needed regimen, or
Low-to-medium dose maintenance therapy with ICS and SABA in an as-needed regimen.
4 
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. At Visit 2 pre-
dose FEV1 best value not exceeding ±20% of the best value measured at Visit 1 pre-exercise. See 
Sections 4.1.1, 4.1.2, 4.1.3 for procedural details.
5 
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 (one retest will be allowed for a lack 
of FEV1 drop (i.e., negative EIB outcome) at Visit 1 only if the FEV1 drop is between 15% and 
<20%.). See Sections 4.1.1, 4.1.2 for procedural details.
6 
Demonstrate acceptable spirometry performance (i.e., meet ATS/ERSacceptability/repeatability
criteria).
7 
Demonstrate acceptable MDI administration technique.
Note: Use of a spacer device during the randomized treatment phase is not permitted.
Weight
8 
Body mass index (BMI) within the range <40 kg/m2 (inclusive).
Sex and Contraceptive/Barrier Requirements
9 
Contraceptive use by males or females should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Male participants:


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Male subjects who are sexually active must be surgically sterile or agree to use a double-
barrier method of contraception (condom with spermicide) from the first dose of randomized 
study drug until 2 weeks after their last dose, and must not donate sperm during their study 
participation period.
Female participants:
Women of childbearing potential* must agree to 1 of the following to prevent pregnancy: 

Practice abstinence 

If a female of childbearing potential and sexually active, agrees to prevent pregnancy 
by using 1 of the following methods of birth control from the date the ICF is signed 
until 2 weeks after the final dose of study drug is taken: 
o
Hormonal contraception (e.g., oral contraceptive, contraceptive implant, or 
injectable hormonal contraceptive) 
o
Double-barrier birth control (e.g., condom plus intrauterine device, diaphragm 
plus spermicide, or condom plus spermicide) 
o
Maintenance of a monogamous sexual relationship with a male partner who 
has been surgically sterilized by vasectomy 
* Note: Women are considered to be of non-childbearing potential if they are 
physiologically incapable of becoming pregnant, including any female who is 2 years post-
menopausal, or surgically sterile, defined as having a bilateral oophorectomy, 
hysterectomy, or tubal ligation). For purposes of this protocol, menopausal women are 
defined as women ≥50 years old who are amenorrhoeic for 12 consecutive months or more 
following cessation of all exogenous hormonal treatment. 
Informed Consent
10 Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
As judged by the investigator, any historical or current evidence of a clinically significant disease 
including, but not limited to: cardiovascular (e.g., congestive heart failure, known aortic aneurysm, 
clinically significant cardiac arrhythmia, coronary heart disease), hepatic, renal, hematological,
infectious, neuropsychological, endocrine (e.g., uncontrolled diabetes mellitus, uncontrolled 
thyroid disorder, Addison’s disease, Cushing’s syndrome), or gastrointestinal (e.g., poorly
controlled peptic ulcer, gastroesophageal reflux disease) disorders. Significant is defined as any
disease which in the investigator’s opinion makes it undesirable for the participant to participate 


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in the study, or which could affect the efficacy or safety analysis if the disease/condition
exacerbated during the study.
2
Chronic obstructive pulmonary disease or other significant lung disease (e.g., chronic bronchitis, 
emphysema, bronchiectasis with the need of treatment, cystic fibrosis, bronchopulmonary
dysplasia), including regular or occasional use of oxygen.
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 unable to tolerate the lung function testing performed after ECT at Visit 1 or 2 without
use of rescue medication.
5
Current smokers, former smokers with >10 pack-years history, or former smokers whostopped 
smoking <6 months (including all forms of tobacco, e-cigarettes [vaping], andmarijuana).
6
Subjects with contraindications to ECT according to ATS/ERS guidelines.
7
Completed treatment for lower respiratory infection within 6 weeks prior to Visit 1, regardless if
resulting in accompanying asthma symptoms aggravation or not.
8
Upper respiratory infection involving antibiotic treatment not resolved within 7 days prior to Visit 
1.
9
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.
10 Hospitalization for psychiatric disorder or attempted suicide within 1 year of Visit 1.
11 History of psychiatric disease, intellectual deficiency, poor motivation, or other conditions if their
magnitude is limiting informed consent validity.
Prior/Concomitant Therapy
12 Systemic corticosteroids use (any dose and any indication) within 3 months before Visit1.
13 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 6.8.1 for details.
14 Subjects with a known or suspected hypersensitivity to budesonide, albuterol (salbutamol) or any 


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of the excipients of the product.
15 Having received any marketed (e.g., omalizumab, mepolizumab, reslizumab, benralizumab, 
dupilumab) or investigational biologic within 3 months or 5 half-livesbefore Visit 1, whichever is 
longer, or any other medication specifically prohibited by the protocol within the indicated 
exclusionary time periods.
16 Treatment with any IMP within the last 30 days (or 5 half-lives, whichever is longer) of Visit 1.
17 Inability (and/or unwillingness) to abstain from protocol-defined prohibited medications during
the study.
18 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.
19 Received a live attenuated vaccination within 7 days of Visit 1.
20 Significant abuse of alcohol or drugs, in the opinion of the investigator.
Prior/Concurrent Clinical Study Experience
21 Current participation in any interventional study.
22 Previous enrolment or randomization in the present study. 
Diagnostic Assessments
23 Clinically significant laboratory abnormalities in the opinion of the Investigator, or having any of 
the following results at screening:
(a) a serum creatinine value >1.5 times the upper limit of the reference range
(b) a serum total bilirubin value >1.5 times the upper limit of the reference range
(c) a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >2.5 
times the upper limit of the reference range
Note: if laboratory tests have to be repeated, the results should be available for review before 
randomization. 
24 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
Other Exclusions
25 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or 
staff at the study site).
26 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.


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27 For females only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
28 Having a scheduled/planned hospitalization during the study.
5.3 Lifestyle Considerations
5.3.1
Caffeine, Alcohol, and Tobacco
Subjects must not ingest xanthine and/or xanthine analogue (caffeine)-containing foods or beverages 
or caffeine-containing medications for at least 6 hours before each study visit and throughout the 
duration of each study visit. Examples of such products include coffee, tea, chocolate, and cola. 
Decaffeinated beverages are acceptable. 
Subjects should avoid having a large meal at least 2 hours prior to a study visit.
Use of tobacco products will not be allowed from screening until after the final follow-up visit.
Alcohol-containing beverages are not recommended throughout the study. It is forbidden to drink 
alcohol the day before any visit to the center.
5.3.2
Illicit drugs
Illicit drugs or drugs of abuse will not be allowed. If any illicit drugs or drugs of abuse are used by the 
subject during the study, the dates of use and the amount will be documented and the subject will be 
discontinued from study drug and withdrawn from the study at the discretion of the Investigator.  
5.3.3
Activity
Subjects should avoid intensive physical exercise during the 24 hours prior to the visits.
5.4
Screen Failures
A screen failure occurs when a participant who has consented to participate in the clinical study is not 
subsequently assigned to study intervention. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, and 
any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.
5.5
Criteria for Temporarily Delaying
Not applicable for this study.


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6
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all pre-specified, IMPs and NIMPs, medical devices and other interventions 
(e.g., surgical and behavioral) intended to be administered to the study participants during the study 
conduct.
6.1
Study Intervention(s) Administered
AstraZeneca will centrally supply IMPs (PT027 (budesonide/albuterol) and placebo) for further 
packaging and labelling in Russian Federation. 
IMPs will be supplied “IN-BULK” form or as Finished Product (released for circulation in foreign 
Markets). Packaging/Repackaging and Labelling/Relabelling, QC and QP release will be performed 
by Russian Manufacturing site in fully compliance with local and AZ GMP requirements. Additional 
labelling (is required) can be performed by the site.
Placebo will be supplied “IN-BULK” with further Packaging, Labelling, QC and QP release will be 
performed by Russian Manufacturing site in fully compliance with local and AZ GMP requirements. 
Both IMPs will be provided as metered-dose inhalers.
 
 
 
 
Details of all study interventions are presented in Table 7. Subjects will be randomized to receive both 
IMPs in one of two treatment sequences – A/B or B/A, as specified in Table 1.
A description of the use of rescue medication (NIMP) is provided in Section 6.8.2.
Table 7
Study Intervention
Arm name
PT027 (A)
Placebo (B)
Rescue medication
Intervention 
name
Budesonide/Albuterol 
(salbutamol)
Placebo
Type 
drug
Placebo
drug
Dose 
formulation
inhalation 
suspension 
in 
metered-dose inhaler
inhalation
suspension
in
metered-dose inhaler
inhalation 
suspension
in
metered-dose inhaler
Unit dose 
strength(s)
80 μg budesonide and 90 μg
albuterol* per puff.
0 μg of active product**
** - each puff contains 183 μg 
of porous particles and 63 μg of 
100 μg salbutamol
per puff
CCI
CCI
CCI


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Arm name
PT027 (A)
Placebo (B)
Rescue medication
* - each puff contains 108 μg 
albuterol sulfate corresponding
to 90 μg albuterol base per
actuation
hydrofluoroalkane-134a 
propellant made to be identical 
inappearance to PT027
Dosage level(s)
2 actuations
2 actuations
1-2 actuations
Route of 
administration
inhalation 
Inhalation
inhalation
Regimen
single use
single use
as-needed
Use
experimental
Placebo
rescue medication
IMP or NIMP
IMP 
IMP 
NIMP
Sourcing
provided 
centrally 
by 
the 
Sponsor
provided 
centrally 
by 
the 
Sponsor
provided centrally by 
the Sponsor
Packaging and 
labelling
IMP (“IN-BULK” or Finished 
Product for Foreign Country)
will be provided in metered-
dose
inhalers.
Packaging/Repackaging, 
Labelling/Relabelling, 
QC, 
Batch 
release 
of 
Finished 
Product will be performed in 
accordance with global AZ and 
local 
GMP 
regulatory 
guidelines. The labels will fulfil 
GMP Annex 13 requirements 
for labelling.
IMP
(“IN-BULK")
will be 
provided 
in 
metered-dose
inhalers. Packaging, Labelling, 
QC, Batch release of Finished 
Product will be performed in 
accordance with global AZ and
local
GMP
regulatory 
guidelines. The labels will 
fulfil 
GMP 
Annex 
13 
requirements for labelling.
Commercial Product. 
Each canister will be 
labelled as required 
per 
country 
requirement.
6.2
Preparation, Handling, Storage, and Accountability
!
IMP metered-dose inhalers should be stored below 25°C (77°F) in a dry place. Excursions 
permitted up to 30°C (86°F).
!
The investigator or designee (e.g., unblinded pharmacist) must confirm appropriate 
conditions (e.g., temperature) have been maintained during transit for all study 
intervention received at the site and throughout the entire study until authorisation is 
provided for on-site destruction or removal of the IMP, reflecting completion of the study. 
In the event of a temperature excursion detected at any time during the study, sites will 
follow the reporting procedures for notifying AstraZeneca (or designated party); release of 
IMP for clinical use can only occur once the event has been reviewed and approval is 
provided by AstraZeneca (or designated party).
!
Inhalers for both IMPs (PT027 and placebo) look identical except for the labels.
 
 
 
 
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!
Only participants enrolled in the study may receive study intervention, and only authorised
site staff may supply, prepare, or administer study intervention. All study intervention must 
be stored in a secure, environmentally-controlled, and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the 
investigator and authorised site staff.
!
The investigator, institution, or the head of the medical institution (where applicable), is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study interventions are 
provided in the Investigational Product Handling Manual.
6.2.1
Dose Preparation
The IMPs will be delivered in a ready-to-use form. 
6.2.2
Dose Administration
The IMP will be administered as a single dose as follows:
!
А: PT027 (budesonide/albuterol) metered-dose inhaler 160/180 μg (given as 2 inhalations of
metered-dose inhaler 80/90 μg per puff)
!
B: Placebo metered-dose inhaler (given as 2 inhalations)
At Visit 2, subjects will be administered placebo.
At Visits 3 and 4 subjects will receive both IMPs in one of two treatment sequences – A/B or B/A, as 
specified in Table 1.
IMP will be administered 30 (±5) minutes prior to the PFT before exercise challenge.
Handling instructions for the MDI device will be available for each site in the form of a “Site Manual”
document throughout the study. 
The importance of the device priming requirements should be emphasized. Priming of the IMP MDI 
must occur. Device priming should not be conducted in the same room as spirometry assessments are
being conducted.
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6.3
Assignment to Study Intervention
Participants will be randomized 1:1 to one of two treatment sequences – A/B or B/A, as specified in
Table 1. Randomization will be stratified by background ICS therapy (ICS or no ICS).
All participants will be centrally assigned to randomized study intervention using an IWRS. Before 
the study is initiated, IWRS access and instruction will be provided to each site. 
Returned study intervention should not be re-dispensed to the participants.
6.4
Blinding
This is a double-blind study: neither the participant nor any of the Investigators or Sponsor staff who 
are involved in the treatment or clinical evaluation and monitoring of the participants will be aware of 
the study intervention received. 
The IWRS will provide to the Investigator(s) or pharmacists the kit identification number to be 
allocated to the participant at the dispensing visit. Study intervention will be dispensed at the study 
visits summarised in SoA. Routines for this will be described in the IWRS user manual that will be 
provided to each center.
In this study the following personnel will have access to the randomization list during the study, prior 
to database lock:
!
Those carrying out the packaging and labelling of IMP
!
Those generating the randomization list and IRT/RTSM system
!
The AstraZeneca supply chain department
!
Unblinded AstraZeneca designees (if applicable)
 
The randomisation code should not be broken except in medical emergencies when the appropriate 
management of the participant requires knowledge of the treatment randomisation. The investigator 
documents and reports the action to AstraZeneca, without revealing the treatment given to participant 
to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are suspected to be 
causally related to a study intervention and that potentially require expedited reporting to regulatory 
authorities. Randomisation codes will not be broken for the planned analyses of data until all decisions 
on the evaluability of the data from each individual participant have been made and documented.The 
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IWRS will be programmed with blind-breaking function. Unblinding should only occur within the 
IWRS system. In case of an emergency, in which the knowledge of the specific blinded study 
intervention will affect the immediate management of the participant’s condition (e.g., antidote 
available), the therapy can be unblinded by authorized representatives of the study site. Participant 
safety must always be the first consideration in making such a determination. If a participant’s 
intervention assignment is unblinded, the Sponsor must be notified within 24 hours after breaking the 
blind. The Investigator documents and reports the event to AstraZeneca, without revealing the 
treatment given to participant to the AstraZeneca staff.
6.5
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF. The 
dose of study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention. 
6.6
Dose Modification
Not applicable for this study.
6.7
Continued Access to Study Intervention After the End of the Study
Not applicable for this study, there will be no intervention following the end of the study.
6.8
Prior and Concomitant Therapy
6.8.1
Prior and Concomitant Medications
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 in eCRF along 
with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose, frequency and route
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 as needed alone or ICS with SABA as 
needed, as applicable) that were started before screening and continued as part of maintenance 
treatment. See the inclusion criteria for details.
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as presented at screening. Dose changes to maintenance therapy are discouraged unless clinically 
indicated in accordance with current guidelines. Investigators should notify the Study Physician 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.
If, following the ECT, the investigator considers that the subject is experiencing asthma symptoms 
which are not tolerable, then rescue SABA can be administered.
Table 8 lists the restricted and prohibited medications during the study. The Study Physician should be 
contacted if there are any questions regarding concomitant or prior therapy.


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Table 8
Restricted and Prohibited Concomitant Medications
Use Category
Type of 
medication/
treatment
Timeline/instructions
Restricted
Medications that 
may affect 
reversibility and 
FEV1 testing
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.
Prohibited
Systemic 
corticosteroids
(prohibited at least 
3 months before 
Visit 1 and during 
the study)
Systemic corticosteroids (e.g., oral, parenteral, intraocular, 
intraarticular, rectal) is prohibited for the duration of the study, 
including both the Screening and randomized Treatment Periods, 
and within 3 months before Visit 1
Other Medications 
(prohibited at least 
1 month before Visit 
1 and during the 
study (unless 
otherwise
specified))

Any asthma medication (except Sponsor-provided IP during 
Visits 3 and 4 and the permitted SABA as needed alone or 
ICS with SABA as needed 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) 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-
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6.8.2 Rescue Medicine
AstraZeneca will supply rescue medication –
(salbutamol, SABA), 100 μg metered dose 
inhaler, to the study site.
If, following the ECT, the investigator considers that the subject is experiencing asthma symptoms
which are not tolerable, then rescue medication (
) can be administered according to local 
routine practice. The date and time of rescue medication administration as well as the name and dosage 
regimen of the rescue medication must be recorded.
Use of rescue medication following the exercise challenge test may impact the interpretation of the 
IMP treatment effect. Subjects who have any rescue medication administered during the post-dose
assessments will be censored at the time of receiving rescue medication.
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7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
7.1
Discontinuation of Study Intervention
Note that discontinuation from study intervention is not the same thing as a discontinuation or 
withdrawal from the study (see Section 7.2).
If study intervention is permanently discontinued, the participant should, if at all possible, remain in 
the study. See the SoA for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed.
7.1.1
QTc Stopping Criteria
If a clinically significant finding is identified (including, but not limited to, changes from baseline in 
QT interval corrected using Bazett’s formula [QTcB] or Fridericia’s formula [QTcF]) after enrolment, 
the investigator or qualified designee will determine if the participant can continue on the study 
intervention and if any change in participant management is needed. This review of the ECG printed 
at the time of collection must be documented. Any new clinically relevant finding should be reported 
as an AE.
7.2
Participant Discontinuation/Withdrawal From the Study
Discontinuation of the participant from the study by the investigator
A participant may be discontinued from the study at any time at the discretion of the investigator for 
safety, behavioral, compliance, or administrative reasons. 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 (e.g., post-enrollment eligibility violation).

Lost to Follow-up: please see section 7.3.

Intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that
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e.g., 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.
Voluntary withdrawal from the study by the participant

A participant may withdraw from the study at any time at the participant’s own request for any 
reason (or without providing any reason).

A participant who wishes to withdraw from the study must be informed by the investigator about 
modified follow-up options (e.g., telephone contact, a contact with a relative or treating physician, 
or information from medical records).

If the participant withdraws from the study, AstraZeneca may retain and continue to use any 
samples collected before such a withdrawal of consent for the purposes the participant originally 
consented unless the participant withdraws consent for use of samples already collected. If the 
participant specifically withdraws consent for any use of samples, it must be documented in the 
site study records by the investigator and the investigator must inform the Study Team. 
Destruction of any samples taken and not yet tested should be carried out in line with documented 
sample withdrawal wishes in conjunction with what was stated in the informed consent and local 
regulation.
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 follow-up TC (except ICF withdrawal). 
The safety follow-up TC contact will occur 3 to 5 days after the last study visitor PDV, as indicated in
the Schedule of Assessments (Table 2).
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.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if the participant repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the study site for a required study 
visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as possible. 
The participant should be counselled on the importance of maintaining the assigned visit schedule.
At this time ascertain whether the participant should or wishes to or continue in the study.


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
Before a participant is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls, texts, emails, and
if necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record.

Should the participant continue to be unreachable, the participant will be considered to have 
withdrawn from the study.


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8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the Section 1.3 SoA. Protocol waivers or 
exemptions are not allowed.
Urgent safety concerns should be discussed with AstraZeneca immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential and 
required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential participants meet 
all eligibility criteria. The investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure, as applicable.
In the event of a significant study-continuity issue (e.g., caused by a pandemic), alternate strategies for 
participant visits, assessments, medication distribution and monitoring may be implemented by 
AstraZeneca or the investigator, as per local health authority/ethics requirements.  
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 15 mL. Repeat or unscheduled 
samples may be taken for safety reasons or for technical issues with the samples.
8.1
Efficacy Assessments
Planned timepoints for all efficacy assessments are provided in the Section 1.3 SoA.
Efficacy assessments include ECTs with spirometry (FEV1) measurements.
8.1.1
Lung function measurement by spirometry (FEV1)
The procedure should be carried out in compliance with the ATS/ERS guidelines and the 
recommendations on spirometry of the Ministry of Health of the Russian Federation (Graham BL et al 
2019, MoH RF Spirometry (methodological guide) ).
The spirometry/exercise challenge test procedure will be carried out on the equipment of the clinical 
center by qualified, properly certified personnel with the skills of spirometric measurements. All 
measurements during the study in a particular patient should be performed on the same equipment.


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Calibration of the spirometer should be carried out daily before starting operation of the device or more 
often if it is provided by the manufacturer's instructions. If the calibration results are unsatisfactory, 
the calibration should be performed again.
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 repeatable spirometry maneuvers 
will be used. For the pre-dose PFTs, FEV1 and forced vital capacity repeatability will be required. For 
each post-exercise challenge spirometry, the highest value of 2 acceptable spirograms will be used.
Pre- and post-exercise FEV1 will be performed at Visit 1 and pre-dose, post-dose, and post-exercise at 
Visit 2 through Visit 4. The 5-minute pre-exercise post-dose spirometry assessment at Visit 2 through 
Visit 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.
During the procedure, the patient should be closely monitored in order to avoid undesirable phenomena 
associated with sharp and deep exhalation (for example, syncopal state). If dizziness appears or the 
patient's well-being worsens, a pause may be made and the study continued when the undesirable 
symptoms have passed.
When performing breathing maneuvers, it is necessary to control the absence of air leakage (for this 
purpose, additional fixation of the lips around the mouthpiece with fingers is possible), obstruction of 
the mouthpiece with the tongue. If the patient has removable dentures, it is recommended not to remove 
them during spirometry, however, in a situation where they prevent the patient from tightly grasping 
the mouthpiece and cause air leakage, the study should be continued without them.
Demonstration of exercise-induced bronchoconstriction
Subjects will be required to meet the following criteria at Visit 1 (see Section 4.1.1) and Visit 2 (see 
Section 4.1.2):

EIB as demonstrated by a ≥20% decrease from the 5-minute pre-exercise challenge absolute
FEV1


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8.1.2
Exercise challenge testing
During the study, standardized ECTs will be conducted according to American Thoracic Society 
(ATS)/European Respiratory Society (ERS) guidelines (Crapo RO et al 2000).
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 atreadmill as specified 
in Table 2, Table 3 and Table 4. 
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 prior to the visits they must comply with the life style restrictions 
described in the Section 5.3.
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 subjects 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 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 7.2
for details. The visit can be rescheduled once within 7 to 10 days for an upper respiratory tract infection 
(e.g., 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 (i.e., 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.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the Section 1.3 SoA.


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8.2.1
Physical Examinations
A complete physical examination will be performed and include assessments of the following; general 
appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose, and 
throat), lymph nodes, thyroid, musculoskeletal (including spine and extremities), and neurological
systems. 
Physical examination will be performed at timepoints as specified in the Section 1.3 SoA. 
8.2.2
Vital Signs
Vital signs will be performed at timelines as specified in the Section 1.3 SoA.
Blood pressure and pulse measurements will be assessed with the subject in the seated position with a 
completely automated device. Manual techniques will be used only if an automated device is not 
available. Duration of rest before these measurements are specified in Table 3, Table 4.
Vital signs will consist of 1 pulse and 3 blood pressure measurements (3 consecutive blood pressure 
readings will be recorded at intervals of at least 1 minute). The average of the 3 blood pressure readings 
will be recorded on the eCRF.
8.2.3
Resting 12-lead Electrocardiogram
12-lead ECG will be performed at timepoints as specified in the Section 1.3 SoA.
The 12-lead ECG will be after the subject has been resting supine for at least 10 minutes. The subject 
should be examined using the same ECG 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 inthe 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.
8.2.4
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 Visit 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.


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8.2.5
Clinical Safety Laboratory Tests
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis will be 
taken only at Screening (Visit 1). 
A serum pregnancy test (β-human chorionic gonadotropin [β-hCG]) will be performed at Visit1, 4 and 
PDV; urine β-hCG test will be performed at Visit 3 (for women of childbearing potential only).
Urine samples will be taken during Visits 1-4 for drugs of abuse and cotinine testing. The analysis will 
be carried out using test strips. The list of psychoactive agents for testing includes marijuana, 
benzodiazepines, barbiturates, opiates, methadone, phencyclidine, cocaine, amphetamines.
Also, during Visits 1-4 alcohol detection test will be performed using breathalyser.
Additional safety samples may be collected if clinically indicated at the discretion of the investigator. 
The date, time of collection and results (values, units, and reference ranges) will be recorded on the 
appropriate eCRF.
The clinical chemistry, hematology, and urinalysis will be performed at a local laboratory at site or 
laboratory contracted by Sponsor if site is not feasible to perform any of the required tests. Sample 
tubes and sample sizes may vary depending on laboratory method used and routine practice at the site.
The following laboratory variables will be measured (see Table 9).
Table 9
Laboratory Safety 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


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Table 9
Laboratory Safety Variables
White blood cells (leukocytes)
Potassium
Platelet count
Protein, total
Lymphocytes Abs
Sodium
Lymphocytes (%)
Triglycerides
Urea
Urine
Serum β-hCG pregnancy (Visit 1, 4 and PDV) a
Urine β-hCG pregnancy (at Visit 3) 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
8.3
AEs, SAEs, and Other Safety Reporting
The Principal Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
Participants (or, when appropriate, a caregiver, surrogate, or the participant’s legally authorised 
representative) will notify the investigator or designees of symptoms. These must then be assessed by 
the investigator and if considered an AE it will be reported by the investigator.
The investigator and any designees are responsible for detecting, documenting, and recording events 
that meet the definition of an AE.
AE variables
The following variables will be collected for each AE:

AE (verbatim)

The date and time when the AE started and stopped

Maximum intensity (Appendix B)

Changes in intensity (report only the maximum intensity)

Whether the AE is serious or not (Appendix B)

Investigator causality rating against the IMP(s) (yes or no)


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
Action taken with regard to IMP(s)

AE caused participant’s withdrawal from the study (yes or no)

Administration of treatment for the AE

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

AE description

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse Events will be collected from the time of signing of the ICF and throughout the treatment 
period and including the follow-up period (Visit 4 or PDV).
Serious Adverse Events will be recorded in eCRF from the time of signing of the ICF.
If the investigator becomes aware of an SAE with a suspected causal relationship to the IMPthat occurs 
after the end of the clinical study in a treated participant, the investigator shall, without undue delay, 
report the SAE to AstraZeneca.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically indicated, but 
without further recording in the eCRF. AstraZeneca retains the right to request additional information 
for any participant with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.3 Causality Collection
The investigator should assess causal relationship between IMP 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 


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caused by the IMP?’
For SAEs, causal relationship should 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 B.
8.3.4 AEs Based on Examinations and Tests
Deterioration as compared to baseline in protocol-mandated vital signs, laboratory tests and 
instrumental examination results should only be reported as AEs if they meet any of the following:

fulfil any of the SAE criteria

are the reason for discontinuation of the IMP

are clinically relevant as judged by the investigator (which may include but is not limited to 
consideration as to whether intervention or non-planned visits were required or other action was 
taken with the IMP, e.g., dose adjustment or drug interruption).
If deterioration in a vital sign, laboratory or instrumental examination result is associated with clinical 
signs and symptoms, the sign or symptom will be reported as an AE and the associated vital sign, 
instrumental examination result will be considered as additional information. Wherever possible the 
reporting investigator uses the clinical term. 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 unless unequivocally related to the 
disease under study (DUS).
The results from the protocol mandated examinations and vital signs will be summarised in the CSR. 
8.3.5 AEs Based on Signs and Symptoms
All signs or symptoms spontaneously reported by the participant or reported in response to the open 
question from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms that are 
not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately.
8.3.6
Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable to the 


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disease for which the IMP is being studied. It may be an increase in the severity of the DUS and/or 
increases in the symptoms of the disease. The development of wheeze, breathlessness and cough on 
days when the IMP was not used should be considered as disease progression and not an AE. Events, 
which are unequivocally due to disease progression, should not be reported as AEs during the study.
8.3.7
Disease Under Study
Symptoms of the disease under study are those which might be expected to occur as a direct result of 
the subject’s asthmatic condition (e.g., wheeze, breathlessness, cough). Events that are unequivocally 
due to the disease under study should not be reported as an AE during the study unless they meet SAE 
criteria or lead to discontinuation of study the IMP.
8.3.8
Reporting of SAEs
All SAEs must be reported, whether or not considered causally related to the IMP. All SAEs will be 
recorded in the eCRF.
If any SAE occurs during the study, investigators or other site personnel will inform the appropriate 
AstraZeneca representatives within one day, i.e., immediately but no later than 24 hours of when he 
or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days 
of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active follow-up 
will be undertaken immediately. Investigators or other site personnel will inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within one calendar day, 
i.e., immediately but no later than 24 hours of when he or she becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the Electronic Data Capture 
(EDC) system, an automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the investigator or other study site staff reports the SAE via 
secure method to the appropriate AstraZeneca representative. Relevant contact information will be 
provided on the SAE reporting form.
When the EDC is temporarily not accessible, the AstraZeneca Study Representative should confirm 
that the investigator/site staff enters the SAE in the AstraZeneca EDC when access resumes.
For further guidance on the definition of an SAE, see Appendix B.


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The reference document for definition of expectedness/listedness is the IB for the AstraZeneca IMP.
8.3.9
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following the first date of study 
intervention, including pregnancy in the partner of male participants, should be reported to 
AstraZeneca.
8.3.9.1
Maternal Exposure
If a participant becomes pregnant during the study intervention should be discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention may 
have interfered with the effectiveness of a contraceptive medication. Congenital anomalies/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 anomaly/birth defect) 
should be followed up and documented even if the participant was discontinued from the study.
If any pregnancy occurs during the study, then the investigator or other site personnel informs the 
appropriate AstraZeneca representatives immediately but no later than 24 hours after he or she 
becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within one or 5 calendar 
days for pregnancies associated with SAEs (see Section 8.3.8) and within 30 days for all other 
pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper based PREGOUT 
module is used to report the outcome of the pregnancy.
8.3.9.2
Paternal Exposure 
Male subjects who are sexually active (with females) must agree to use a double barrier method of 
contraception (condom with spermicide) from the first dose of randomized treatment until 2 weeks 
after their last dose, and must not donate sperm during their study participation period. Male subject's 
partner pregnancy itself is not regarded as an AE. Information about pregnancy and pregnancy 
outcomes (spontaneous miscarriages, planned pregnancy termination, ectopic pregnancy, congenital 
anomalies/birth defects and normal delivery) must be reported to the Sponsor within 24 hours of the 
Investigator learning of its occurrence. This information must be documented in medical records and 
passed to the data entry center of AstraZeneca's Patient Safety Department. Before information can 


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be collected and shared with AstraZeneca, consent must be obtained from the participant's partner. 
Once pregnancy report has been received, Investigator must obtain consent from the participant's 
partner before collecting any pregnancy information. The local study team should adapt the general 
consent form for the pregnant partner in accordance with local procedures/requirements and submit 
it to the relevant regulatory authorities / IRB / IEC prior to its implementation.
8.4
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.5
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.6
Optional Genomics Initiative
Optional Genomics Initiative research is not applicable in this study.
8.7
Biomarkers
Not applicable for this study.
8.8
Immunogenicity Assessments
Immunogenicity is not evaluated in this study.
8.9
Health Economics OR Medical Resource Utilisation and Health Economics
Health economics/Medical resource utilisation and health economics parameters are not evaluated in 
this study.
8.10
Study Participant Feedback Questionnaire
Not applicable for this study.


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9
STATISTICAL CONSIDERATIONS
The Statistical Analysis Plan will be finalised prior to clinical data lock and it will include a more 
technical and detailed description of the planned statistical analyses. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary and key secondary 
endpoints.
9.1
Statistical Hypotheses
The main objective of this study is to estimate the efficacy of PT027 (budesonide/albuterol) as 
compared with placebo based on the evaluation of the primary endpoint «maximum percentage fall 
from post-dose, pre-exercise baseline in FEV1 observed up to 60 minutes post-exercise challenge».
The corresponding hypotheses for the primary analysis are as follows:
!
H0: Difference between treatments «∆A – ∆B» = 0,
!
H1: Difference between treatments «∆A – ∆B» ≠0.
there: ∆- maximum percentage fall of FEV1, A - PT027 (budesonide/albuterol), B - placebo.
9.2
Sample Size Determination
Approximately 107 participants will be screened to achieve 64 randomized/assigned to study 
intervention and 56 evaluable participants (refer to FAS population, Section 9.3) at 6 to 12 
investigational centers in the Russian Federation. 
Enrolled/screened*
Estimated 107 participants
Randomized/assigned
Estimated 64 participants
Evaluable participants
Estimated 56 participants
Note: * - “Enrolled/Screened” means a participant’s, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process. Potential participants who 
are screened for the purpose of determining eligibility for the study, but are not randomized/assigned in the 
study, are considered “screen failures”, unless otherwise specified by the protocol. 
Sample size justification:
Sample size determination based on a previous clinical study NCT04234464, Phase III «TYREE» 
(LaForce C et al 2022) with a similar design and patient population. Using the obtained difference for 
maximum percentage fall from post-dose, pre-exercise baseline in FEV1 observed up to 60 minutes 
post-exercise challenge equals to 
 
and corresponding SD=
(the calculated SD of treatment difference based on 
previous study results), a sample size of 28 subjects in each treatment sequence will provide a 95% 
probability to detect a difference between PT027 (budesonide + albuterol) and placebo based on 2 
sided 95% CI.
CCI
CCI


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Considering, a drop-out rate of ~10% (8 subjects), the sample size in this study will be 64 randomized 
subjects (32 randomized subjects per study sequence arm). Due to the possible withdrawal during the 
screening up to 40%, it is planned to screen up to 107 subjects.
Sample size calculations were performed as described in the book Chow, S., Shao, J. and Wang, H. 
(2008) Sample Size Calculations in Clinical Research. 2nd Edition, Chapman and Hall/CRC (Section 
3.3.2). The assumptions used results are summarized in the table below:
Description
Value
Group ratio
1:1
Mean Difference
%
Standard deviation
%
Z for alpha=0.05
1.96
Z for beta=0.95
1.64
Superiority Margin
0
Result (number pairs, ie number of subjects in both groups)
56
Result adjusted for 10% dropout rate (number of subjects 
which should be randomized)
64
Calculations were performed using SAS v9.4 (proc POWER) by study statistician and validated by 
independent statistician.
9.3
Populations for Analyses
The following populations are defined:
Table 10
Populations for Analysis
Population/analysis set
Description
Enrolled/Screened
All participants who sign the ICF.
Full analysis set (FAS)
All participants who are randomized to treatment and have at least one post-
dose, pre-exercise baseline and at least one corresponding post-dose post-
exercise FEV1 measure at Visit 3 and/or Visit 4.
Safety analysis set
All participants who have received any amount of the study intervention.
9.4
Statistical Analyses
9.4.1
General Considerations
Categorical variables will be presented as frequencies and proportions in percent.  Continuous 
variables will be presented as means, geometric means (where applicable), standard deviations, 
CCI
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geometric standard deviations (where applicable), medians, minimum and maximum, and quartiles 
(where applicable), with number of observations. When necessary, means and geometric means will 
be provided with two-sided 95% confidence intervals (CI). 
The data and results of the analyses will be presented in the form of tables as well as listings, sorted 
by treatment arms and participant numbers. Methods of analysis will be outlined in detail in the 
Statistical Analysis Plan.
Validated SAS software version 9.4 or R statistical package version 4.2 or higher will be used for 
statistical analysis and reporting of the study data. The results of the analysis presented in the clinical 
study report will be validated according to the company's standard operating procedures.
9.4.2
Efficacy 
9.4.2.1
Primary Endpoint(s)
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 IMP 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.
The primary analysis will include all data obtained before subjects withdraw from the study and will
use the Full analysis set (FAS).
The primary efficacy endpoint will be analyzed with a mixed effect model including categorical fixed 
effects for treatment, treatment period and treatment sequence. Continuous covariates include period-
specific pre-dose baseline FEV1 and average pre-dose baseline FEV1. Also, a random subject within
treatment sequence effect will be specified. 
Post-dose, pre-exercise baseline FEV1 will be defined as the 30 minutes post-dose value, i.e., 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.
Applied significance level (alpha): 0.05 (using a 2-sided test).
Sensitivity analysis


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Missing results for maximum percentage fall in FEV1 are unlikely (i.e., 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. Further details will be given in the SAP.
Subgroup Analysis
Subgroup analyses will be conducted for the primary endpoint in the following subgroups of the FAS:

by background ICS therapy (ICS or no ICS)
Additional subgroups of interest and analysis methods will be outlined in the SAP.
9.4.2.2
Secondary Endpoint(s)
Fall in post-exercise FEV1 at individual time points
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 in Section 9.4.2.1.
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.
Responder analysis in post-exercise FEV1
A binary response variable will be assigned to identify subjects with a maximum percentage fall in 
FEV1 post-exercise for the two thresholds (<10% and <20%) 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% and <20%

Not Protected: Maximum percentage fall from post-dose, pre-exercise baseline in FEV1 up to 
60 minutes post-exercise challenge ≥10% and ≥20%
As with the primary efficacy endpoint specified in Section 9.4.2.1, the maximum percentage fall will 
be calculated based on post-dose FEV1 measures prior to use of rescue medication. Subjects who have 


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no post-exercise FEV1 measure prior to rescue medication will have a missing responder status at the
given visit.
The odds of being protected against EIB (i.e., having a maximum percentage fall in FEV1 post-exercise 
challenge under the corresponding threshold (<10% and <20%)) 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, period specific pre-dose baseline 
FEV1 and average pre-dose baseline FEV1 as continuous covariates, 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.
Time to recovery
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 IMP 
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 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 S 1993).
Further details will be clarified in the SAP.
Post-exercise FEV1 AUC0-30min
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.
The post-exercise FEV1 AUC0-30min will be analyzed with a similar mixed effects model as described 
in Section 9.4.2.1 for the change from post-dose, pre-exercise baseline in the maximum percentage fall 


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in FEV1
without exercise pre-treatment. Only the FEV1
AUC0-30min measurements prior to 
administration of rescue SABA therapy will be included in the analyses.
9.4.3
Safety
Safety data will be summarized descriptively and will not be formally analyzed unless otherwise 
specified. These data will be presented using the safety analysis set.
Adverse events will be coded using the most current version of MedDRA, where possible. They will 
be summarised by system-organ class, preferred term, severity and relationship to the study 
intervention as assessed by the Investigator.
Adverse events will be presented as frequencies and percentages of participants with reported AEs for 
each system-organ class (SOC) and preferred term (PT) in the tables by treatment groups:
- Overall table for AEs;
- AEs leading to discontinuation of study intervention;
- AEs by SOC and PT, with additional breakdown by relationship to the study intervention;
- AEs by SOC and PT, with additional breakdown by intensity;
- SAEs by SOC and PT, with additional breakdown by relationship to the study intervention;
- Additional tables can be planned and detailed in the Statistical Analysis Plan.
Screening laboratory values will be presented in the listings. Vital signs as well as electrocardiogram 
(ECG) results will be presented in tables with descriptive statistics by treatment arm for each visit for 
the measured values and for each visit after study intervention administration for changes relative to 
the initial values.
9.4.4
Other Analyses 
Not applicable for this study.
9.5
Interim Analyses 
No interim efficacy analysis is planned in this study.
9.6
Data Monitoring/Other Committee
Not applicable for this study.


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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki as amended at 64th WMA General Assembly, Fortaleza, Brazil, October 2013 
and Council for International Organizations of Medical Sciences (CIOMS) International 
Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulations

The protocol, revised protocol, ICF, IB, and other relevant documents (eg, advertisements) must 
be submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC before 
the study is initiated.

Any revised protocol will require IRB/IEC and applicable Regulatory Authority approval before 
implementation of changes made to the study design, except for changes necessary to eliminate 
an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the study 
from the concerned Regulatory Authority. This responsibility may be delegated to a CRO, but the 
accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at the site 
and adherence to requirements of ICH guidelines, the IRB/IEC and all other applicable local 
regulations.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to AstraZeneca of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met.

AstraZeneca has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. 
AstraZeneca will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilising medical devices, investigator safety reports must be prepared 
for suspected unexpected serious adverse reactions (SUSAR) according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from AstraZeneca will review and then file 
it along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.


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Regulatory Reporting Requirements for Serious Breaches of Protocol or GCP
Prompt notification by the Investigator to AstraZeneca of any (potential) serious breach of the protocol 
or regulations is essential so that legal obligations and ethical obligations are met.

A “serious breach” means a breach likely to affect to a significant degree the safety and rights of 
a participant or the reliability and robustness of the data generated in the clinical trial.
AstraZeneca will comply with country-specific regulatory requirements relating to serious breach 
reporting to the regulatory authority, IRB/IEC, and Investigators.
If any (potential) serious breach occurs in the course of the study, Investigators or other site personnel 
will inform the appropriate AstraZeneca representatives immediately.
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about such breaches.
The investigator should have a process in place to ensure that:

The site staff or service providers delegated by the investigator/institution are able to identify the 
occurrence of a (potential) serious breach

A (potential) serious breach is promptly reported to AstraZeneca or delegated party, through the 
contacts (email address or telephone number) provided by AstraZeneca.
A 2
Financial Disclosure
Investigators and sub-investigators will provide AstraZeneca with sufficient, accurate financial 
information as requested to allow AstraZeneca to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the study and for one year after completion of the 
study.
A 3
Informed Consent Process

The investigator or their representative will explain the nature of the study to the participant or 
their legally authorised representative and answer all questions regarding the study.

Participants must be informed that their participation is voluntary, and they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the study. 
Participants or their legally authorised representative will be required to sign a statement of 
informed consent that meets the requirements of local regulations, ICH guidelines, privacy and 
data protection requirements, where applicable, and the IRB/IEC or study centre.

The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF.


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
If new information requires changes to the ICF, consider if participants must be re-consented and 
if so, this must be to the most current version of the ICF(s) during their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally authorised 
representative.
A 4
Data Protection

Participants will be assigned a unique identifier by AstraZeneca. Any participant records or 
datasets that are transferred to AstraZeneca will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred.

The participant must be informed that their personal study-related data will be used by 
AstraZeneca in accordance with local data protection law. The level of disclosure and use of their 
data must also be explained to the participant in the informed consent.

The participant must be informed that their medical records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by AstraZeneca, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.

The participant must be informed that data will be collected only for the business needs. We will 
only collect and use the minimum amount of personal data to support our business activities and 
will not make personal data available to anyone (including internal staff) who is not authorised or
does not have a business need to know the information. 

The participant must be informed that in some cases their data may be pseudonymised. The 
General data Protection Regulation (GDPR) defines pseudonymisation as the processing of 
personal data in such a way that the personal data can no longer be attributed to a specific 
individual without the use of additional information, provided that such additional information is 
kept separately and protected by technical and organisational measures to ensure that the personal 
data are not attributed to an identified or identifiable natural person.
Personal Data Breaches
A ‘personal data breach’ means a breach of security leading to the accidental or unlawful destruction, 
loss, alteration, unauthorized disclosure of, or access to, personal data transmitted, stored or otherwise 
processed.


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
In compliance with applicable laws, the Data Controller1 for the processing activity where the 
personal data breach occurred (AstraZeneca or respectively the site), will notify the data protection 
authorities without undue delay within the legal terms provided for such notification and within 
the prescribed form and content.

Whilst AstraZeneca has processes in place to deal with personal data breaches it is important that 
investigators that work with AstraZeneca have controls in place to protect patient data privacy.
The Investigator should have a process in place to ensure that:

allow site staff or service providers delegated by the investigator/institution to identify the 
occurrence of a (potential) personal data breaches.

Any (potential) personal data breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (e-mail address or telephone number) provided by AstraZeneca.
AstraZeneca and the site must demonstrate that they:

have taken all necessary steps to avoid personal data breaches and 

have undertaken measures to prevent such breaches from occurring in the first place and to 
mitigate the impact of occurred data breaches (e.g., applying encryption, maintaining and keeping 
systems and IT security measures up-to-date, regular reviews and testing, regular training of 
employees, and developed security policies and standards).

where possible, have developed an internal data breach reporting and investigation process and 
internal protocols with guidance on how to respond swiftly and diligently to the occurrence of a 
personal data breach.

where it has not been possible to develop an internal data breach reporting and investigation 
process, the site follows AstraZeneca’s instructions.
Notification of personal Data Breach to participants:

notification to participants is done by the site for the data breaches that occurred within the 
processing activities for which the site is the Data Controller and for data breaches occurred within 
the processing activities of AstraZeneca as the Data Controller, the notification is done in 
                                               
1 The data controller determines the purposes for which and the means by which personal data is 
processed, as defined by the European Commission


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collaboration with the site and is performed by the site and/or Principal Investigator, acting on 
behalf of AstraZeneca, so that AstraZeneca has no access to the identifying personal information 
of the participants. The site and/or Principal Investigator shall conduct the notification by 
contacting the participants using the information that they gave for communication purposes in 
clinical research.

If a personal data breach occurs in a processor’s systems, engaged by AstraZeneca, the processor 
under contractual obligations with AstraZeneca promptly and in due course after discovering the 
breach notifies AstraZeneca and provides full cooperation with the investigation. In these cases, 
to the extent AstraZeneca is the Data Controller for the processing activity where the breach 
occurred, it will be responsible for the notification to data protection authorities and, if applicable, 
to participants. If the personal data breach needs to be notified to the participants, the notification 
to participants is done in collaboration with the site and is performed by the site and/or Principal 
Investigator, acting on behalf of the Sponsor, so that AstraZeneca has no access to the identifying 
personal information of the participants.

If a personal data breach involving an AstraZeneca's representative device (i.e. Study Monitor 
laptop), AstraZeneca representative will provide will provide AstraZeneca with all of the 
information needed for notification of the breach, without disclosing data that allows AstraZeneca 
directly or indirectly to identify the participants. The notification will be done by AstraZeneca 
solely with the information provided by the Study Monitor and in no event with access to 
information that could entail a risk of re-identification of the participants. If the data breach must 
be notified to the data subjects, the notification will be done directly by the Study Monitor in 
collaboration with the site and/or Principal Investigator, acting on behalf of the Sponsor, so that 
AstraZeneca has no access to the identifying personal information of the participants. The contract 
between AstraZeneca and the Study Monitor shall expressly specify these conditions.

The contract between the site and AstraZeneca for performing the clinical research includes the 
provisions and rules regarding who is responsible for coordinating and directing the actions in 
relation to the breaches and performing the mandatory notifications to authorities and participants, 
where applicable.
A 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by AstraZeneca 
representatives in consultation with Patient Safety. Issues identified will be addressed; for instance, 
this could involve amendments to the CSP and letters to investigators.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the summary of 
the main study results when they are available. The clinical study and/or summary of main study results 


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may also be available on other websites according to the regulations of the countries in which the main 
study is conducted.
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF. The investigator is responsible 
for verifying that data entries are accurate and correct by electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the information 
entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.

Monitoring details describing strategy, including definition of study-critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as Risk Management and 
Mitigation Strategies and Analytical Risk-based Monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are included in the Monitoring Plan.

AstraZeneca or designee is responsible for medical oversight throughout the conduct of the study 
which includes clinical reviews of study data in accordance with the currently approved protocol. 
Monitoring details describing clinical reviews of study data from a medical perspective are 
included in more detail in the Monitoring Plan.

AstraZeneca or designee is responsible for the data management of this study including quality 
checking of the data.

AstraZeneca assumes accountability for actions delegated to other individuals (eg, CROs).

Study monitors will perform ongoing source data verification as per the Monitoring Plan to 
confirm that data entered into the eCRF by authorised site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for a minimum of 25 years after study archiving or as required by local 
regulations, according to the AstraZeneca Global retention and Disposal (GRAD) Schedule. No 
records may be destroyed during the retention period without the written approval of AstraZeneca. 
No records may be transferred to another location or party without written notification to 
AstraZeneca.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.


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
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, depending on the study. Also, current medical 
records must be available.

All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and evaluation 
of the study are defined as source documents. Source data are contained in source documents 
(original records or certified copies).
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of participants.
The first act of recruitment is the first site open and will be the study start date.
AstraZeneca designee reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of AstraZeneca. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by AstraZeneca or the investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, AstraZeneca’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, AstraZeneca shall promptly inform the 
investigators, the IRBs/IECs, the regulatory authorities, and any CRO(s) used in the study of the reason 
for termination or suspension, as specified by the applicable regulatory requirements. The investigator
shall promptly inform the participant and should assure appropriate participant therapy and/or follow-
up.
Participants from terminated sites will have the opportunity to be transferred to another site to continue 
the study.
A 10
Publication Policy


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
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to AstraZeneca before submission. 
This allows AstraZeneca to protect proprietary information and to provide comments.

AstraZeneca will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, AstraZeneca will generally support publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a coordinating 
investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.


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Appendix B
AEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting
B 1
Definition of AEs
An AE is the development of any untoward medical occurrence in a patient or clinical study participant
administered a medicinal product, and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (eg, an abnormal laboratory 
finding), symptom (for example nausea, chest pain), or disease temporally associated with the use of 
a medicinal product, whether it’s considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and a deterioration of a pre-existing 
medical occurrence. An AE may occur at any time, including run-in or washout periods, even if no 
study intervention has been administered.
B 2
Definition of SAEs
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow-up), that 
fulfils one or more of the following criteria:

Results in death.

Is immediately life-threatening.

Requires in-patient hospitalisation or prolongation of existing hospitalisation.

Results in persistent or significant disability or incapacity. 

Is a congenital anomaly or birth defect.

May require medical treatment to prevent one of the outcomes listed above.
Adverse Events for malignant tumours reported during a study should generally be assessed as SAEs. 
If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be used. In certain 
situations, however, medical judgement on an individual event basis should be applied to clarify that 
the malignant tumour event should be assessed and reported as a non-SAE. For example, if the tumour 
is included as medical history and progression occurs during the study, but the progression does not 
change treatment and/or prognosis of the malignant tumour, the AE may not fulfil the attributes for 
being assessed as serious, although reporting of the progression of the malignant tumour as an AE is 
valid and should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalisation, may be assessed as non-serious; examples in 
adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
Life-threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it occurred,


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or it is suspected that use or continued use of the medicinal product would result in the participant’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might have 
caused death (e.g., hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it may be 
(e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations planned 
before or during a study are not considered AEs if the illness or disease existed before the participant
was enrolled in the study, provided that it did not deteriorate in an unexpected way during the study.
Important Medical Event or Medical Treatment
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, 
hospitalisation, disability or incapacity but may jeopardise the participant or may require medical 
treatment to prevent one or more outcomes listed in the definition of serious. These should usually be 
considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring IV 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 (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or convulsions 
that do not result in hospitalisation.

Development of drug dependency or drug abuse.
Intensity Rating Scale:

Mild (awareness of sign or symptom, but easily tolerated)

Moderate (discomfort sufficient to cause interference with normal activities)

Severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Appendix B 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 Appendix B 2. On the 
other hand, a stroke that results in only a limited degree of disability may be considered a mild stroke 


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but would be an SAE when it satisfies the criteria shown in Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When assessing causality consider the following factors when deciding if there is a ‘reasonable 
possibility’ that an AE may have been caused by the medicinal product.

Time Course. Exposure to suspect drug. Has the participant 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 aetiology such as the 
underlying disease, other drugs, other host, or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after having 
been stopped? AstraZeneca 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 recognised 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 based on the available data including enough information to 
make an informed judgment. With no available facts or arguments to suggest a causal relationship, the 
event(s) will be assessed as ‘not related’. Causal relationship in cases where the disease under study
has deteriorated due to lack of effect should be classified as ‘no reasonable possibility’.


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Appendix C
Abbreviations
Abbreviation or 
special term
Explanation
ACQ
asthma control questionnaire
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
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
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
CTT
Clinical Trial Transparency
DUS
disease under study
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
EDC
Electronic Data Capture
EIB
exercise-induced bronchoconstriction
EMA
European Medicines Agency
ERS
European Respiratory Society
ERT
eResearch Technology
FAS
full analysis set
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FVC
forced vital capacity
GCP
Good Clinical Practice
GDPR
General data Protection Regulation
GINA
Global Initiative for Asthma
GMP
Good Manufacturing Practice
GRAD
Global retention and Disposal


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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 / IMP
investigational product / investigational medicinal product
IWRS
Interactive Web Response System
LABA
long-acting β2-agonist
LAMA
long-acting muscarinic antagonists
MDI
metered-dose inhaler
MoH
Ministry of Health
NIMP
non-investigational medicinal product
PDV
premature discontinuation visit
PEF
peak expiratory flow
PT
preferred term
RF
Russian Federation
PFT
pulmonary function test
QTcF
QT interval corrected by Fridericia
SABA
short/rapid-acting β2-adrenoreceptor agonist
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SMART
Symbicort Maintenance And Reliever Therapy
SoA
schedule of activities
SoC
system-organ class
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment emergent adverse event
TC
telephone call
US
United States
WBDC
web based data capture
WOCBP
women of childbearing potential


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11
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guide), 
2023. 
Available 
at 
https://spulmo.ru/upload/kr/Spirometria_2023.pdf?t=1
Molema J et al 1989
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.
O'Byrne PM et al 2005
O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, et al.
Budesonide/formoterol combination therapy as both maintenance and reliever medicationin
asthma. Am J Respir Crit Care Med. 2005;171(2):129-136.
O'Byrne PM 2007
O'Byrne PM. Acute asthma intervention: insights from the STAY study. J Allergy Clin
Immunol. 2007;119(6):1332-1336.
Ostrom NK et al 2015
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.
Papi A et al 2022
Papi A, Chipps BE, Beasley R, Panettieri RA Jr, Israel E, Cooper M, Dunsire L, Jeynes-Ellis 
A, Johnsson E, Rees R, Cappelletti C, Albers FC. Albuterol-Budesonide Fixed-Dose 


Clinical Study Protocol - 1.0
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Combination Rescue Inhaler for Asthma. N Engl J Med. 2022 Jun 2;386(22):2071-2083. doi: 
10.1056/NEJMoa2203163. Epub 2022 May 15. PMID: 35569035.
Parsons JP et al 2013
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.
Papi A et al 2022
Papi A, Chipps BE, Beasley R, Panettieri RA Jr, Israel E, Cooper M, Dunsire L, Jeynes-Ellis 
A, Johnsson E, Rees R, Cappelletti C, Albers FC. Albuterol-Budesonide Fixed-Dose 
Combination Rescue Inhaler for Asthma. N Engl J Med. 2022 Jun 2;386(22):2071-2083. doi: 
10.1056/NEJMoa2203163. Epub 2022 May 15. PMID: 35569035.
Reddel HK et al 2009
Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official 
American Thoracic Society/European Respiratory Society statement: asthma control and 
exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J 
Respir Crit Care Med. 2009;180(1):59–99.
Rabe KF et al 2006
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.
Richter K et al 2002
Richter K, Janicki S, Jörres RA, Magnussen H. Acute protection against exercise-induced
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SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN
Study Code
AZ-RU-00004
Edition Number
3.0
Date
6-Aug-2024
A Phase III, Multicentre, Randomized, Double-blind, Single-
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Efficacy of PT027 Compared with Placebo on Exercise-Induced
Bronchoconstriction in Adult Patients with Asthma (BREATH)
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TABLE OF CONTENTS 
1 
INTRODUCTION ......................................................................................... 8 
2 
CHANGES TO PROTOCOL PLANNED ANALYSES .............................. 8 
3 
DATA ANALYSIS CONSIDERATIONS .................................................... 8 
3.1 
Timing of Analyses........................................................................................ 8 
3.2 
Analysis Populations ..................................................................................... 8 
3.3 
General Considerations .................................................................................. 9 
3.3.1 
General Study Level Definitions ................................................................... 9 
3.3.1.1 
Period specific post-dose pre-exercise baseline .......................................... 10 
3.3.1.2 
Period specific pre-dose baseline................................................................. 10 
3.3.1.3 
Average pre-dose baseline ........................................................................... 10 
3.3.1.4 
Absolute and percent change from baseline ................................................ 10 
3.3.1.5 
Percentage fall from post-dose pre-exercise baseline FEV1 ........................ 10 
3.3.1.6 
Crossover difference in maximum percentage fall of FEV1 ........................ 11 
3.3.2 
Visit Window ............................................................................................... 11 
3.3.3 
Handling of Unscheduled Visits .................................................................. 11 
3.3.4 
Multiplicity/Multiple Comparisons ............................................................. 11 
3.3.5 
Handling of Protocol Deviations in Study Analysis .................................... 11 
3.3.6 
Missing Data ................................................................................................ 12 
4 
STATISTICAL ANALYSIS ....................................................................... 13 
4.1 
Study Population .......................................................................................... 13 
4.1.1 
Subject Disposition and Completion Status ................................................ 13 
4.1.1.1 
Definitions and Derivations ......................................................................... 13 
4.1.1.2 
Presentation.................................................................................................. 14 
4.1.2 
Analysis Sets ................................................................................................ 14 
4.1.2.1 
Definitions and Derivations ......................................................................... 14 
4.1.2.2 
Presentation.................................................................................................. 14 
4.1.3 
Protocol Deviations ..................................................................................... 14 
4.1.3.1 
Definitions and Derivations ......................................................................... 14 
4.1.3.2 
Presentation.................................................................................................. 15 
4.1.4 
Demographics .............................................................................................. 15 
4.1.4.1 
Presentation.................................................................................................. 15 
4.1.5 
Baseline Characteristics ............................................................................... 15 
4.1.5.1 
Presentation.................................................................................................. 15 
4.1.6 
Disease Characteristics ................................................................................ 15 
4.1.6.1 
Definitions and Derivations ......................................................................... 15 
4.1.6.2 
Presentation.................................................................................................. 16 
4.1.7 
Medical History and Concomitant Disease ................................................. 16 
4.1.7.1 
Definitions and Derivations ......................................................................... 16 
4.1.7.2 
Presentation.................................................................................................. 16 
4.1.8 
Prior and Concomitant Medications ............................................................ 16 
4.1.8.1 
Definitions and Derivations ......................................................................... 16 
4.1.8.2 
Presentation.................................................................................................. 17 


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4.1.9 
Study Drug Compliance .............................................................................. 18 
4.2 
Endpoint Analyses ....................................................................................... 18 
4.2.1 
Primary Endpoint ......................................................................................... 20 
4.2.1.1 
Definition ..................................................................................................... 20 
4.2.1.2 
Derivations ................................................................................................... 20 
4.2.1.3 
Handling of Dropouts and Missing Data ..................................................... 20 
4.2.1.4 
Primary Analysis of Primary Endpoint........................................................ 20 
4.2.1.5 
Sensitivity Analyses of the Primary Endpoint ............................................. 21 
4.2.2 
Secondary Endpoint: the percentages of subjects with a maximum 
percentage fall in FEV1 of <10% and <20% ............................................... 22 
4.2.2.1 
Definition ..................................................................................................... 22 
4.2.2.2 
Derivations ................................................................................................... 22 
4.2.2.3 
Handling of Dropouts and Missing Data ..................................................... 22 
4.2.2.4 
Primary Analysis of Secondary Endpoint.................................................... 22 
4.2.2.5 
Supplementary Analysis of Secondary Endpoint ........................................ 22 
4.2.3 
Secondary Endpoint: the percentage fall in FEV1 from post-dose, pre-
exercise at each timepoint within 60 minutes post-exercise ........................ 22 
4.2.3.1 
Derivations ................................................................................................... 22 
4.2.3.2 
Handling of Dropouts and Missing Data ..................................................... 23 
4.2.3.3 
Primary Analysis of Secondary Endpoint.................................................... 23 
4.2.4 
Secondary Endpoint: post-exercise FEV1 area under the curve from 0 to 30 
minutes ......................................................................................................... 23 
4.2.4.1 
Definition ..................................................................................................... 23 
4.2.4.2 
Derivations ................................................................................................... 23 
4.2.4.3 
Handling of Dropouts and Missing Data ..................................................... 24 
4.2.4.4 
Primary Analysis of Secondary Endpoint.................................................... 24 
4.2.5 
Secondary Endpoint: time to recovery ........................................................ 24 
4.2.5.1 
Definition ..................................................................................................... 24 
4.2.5.2 
Derivations ................................................................................................... 24 
4.2.5.3 
Handling of Dropouts and Missing Data ..................................................... 24 
4.2.5.4 
Primary Analysis of Secondary Endpoint.................................................... 24 
4.2.6 
Other Endpoints ........................................................................................... 25 
4.2.7 
Subgroup Analyses ...................................................................................... 25 
4.3 
Pharmacodynamic Endpoint(s) .................................................................... 25 
4.4 
Pharmacokinetics ......................................................................................... 25 
4.5 
Immunogenicity ........................................................................................... 26 
4.6 
Safety Analyses (if not already covered as endpoint variables) .................. 26 
4.6.1 
Exposure ...................................................................................................... 26 
4.6.1.1 
Definitions and Derivations ......................................................................... 26 
4.6.1.2 
Presentation.................................................................................................. 26 
4.6.2 
Adverse Events ............................................................................................ 26 
4.6.2.1 
Definitions and Derivations ......................................................................... 26 
4.6.2.2 
Presentation.................................................................................................. 26 
4.6.3 
Clinical Laboratory, Blood Sample ............................................................. 27 
4.6.3.1 
Definitions and Derivations ......................................................................... 27 


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4.6.3.2 
Presentations ................................................................................................ 27 
4.6.4 
Clinical Laboratory, Urinalysis ................................................................... 27 
4.6.4.1 
Definitions and Derivations ......................................................................... 27 
4.6.4.2 
Presentations ................................................................................................ 27 
4.6.5 
Other Laboratory Evaluations...................................................................... 28 
4.6.5.1 
Definitions and Derivations ......................................................................... 28 
4.6.5.2 
Presentations ................................................................................................ 28 
4.6.6 
Vital Signs ................................................................................................... 28 
4.6.6.1 
Definitions and Derivations ......................................................................... 28 
4.6.6.2 
Presentations ................................................................................................ 28 
4.6.7 
Electrocardiogram........................................................................................ 28 
4.6.7.1 
Definitions and Derivations ......................................................................... 28 
4.6.7.2 
Presentations ................................................................................................ 28 
4.6.8 
Other Safety Assessments............................................................................ 29 
5 
INTERIM ANALYSIS ................................................................................ 29 
6 
REFERENCES ............................................................................................ 29 
7 
APPENDIX ................................................................................................. 29 
 
 
 


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LIST OF ABBREVIATIONS  
List abbreviations and definitions of specialized or unusual terms, measurements, or units. 
Examples are provided below. These can be modified at study level. 
Abbreviation or 
Specialized Term 
Definition 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AR(1) 
Autoregressive order 1 covariance matrix 
AUC 
Area Under Curve 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRF 
Case Report Form 
CS 
Clinically Significant or Compound Symmetric 
covariance matrix 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
ECT 
Exercise Challenge Test 
FAS 
Full Analysis Set 
FEV1 
Forced Expiratory Volume in 1 second 
FU 
Follow Up 
GAM 
Generalized Additive Model 
GCP 
Good Clinical Practice 
HR 
Heart Rate 
ICE 
Intercurrent Event 
ICH 
International Council for Harmonisation 
ICS 
Inhaled Corticosteroid 
IP 
Investigational Product 
IPD 
Important Protocol Deviation 
KM 
Kaplan-Meier 
LSMD 
Least Squares Mean Difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model with Repeated Measures 
NCS  
Not Clinically Significant 
PD 
Protocol Deviation 
PE 
Physical Examination 
PK 
Pharmacokinetics 
PT 
Preferred Term 
SAE 
Serious Adverse Event 


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Abbreviation or 
Specialized Term 
Definition 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SOC 
System Organ Class 
TC 
Telephone Call 
TOEP 
Toeplitz covariance matrix 
UN 
Unstructured covariance matrix 
VS 
Vital Signs 
WHO Drug 
World Health Organization Drug dictionary 
 
 


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AMENDMENT HISTORY  
CATEGORY 
Change refers to: 
Date 
Description of change 
In line with CSP? 
Rationale 
N/A 
11/2/2023 
Initial approved SAP 
N/A 
N/A 
Analysis sets 
31/07/2024 
Name of 
enrolled/screened 
participants set is 
clarified 
Yes 
Clarification 
Baseline 
characteristics 
31/07/2024 
Desription of analysis 
of smoking history is 
added 
Yes 
Clarification 
Prohibited 
medications 
31/07/2024 
Method of 
classification is added 
Yes 
Clarification after 
meeting with 
Study Clinical 
Lead 
Subgroup analysis 
31/07/2024 
Wording is updated. 
GAM models are 
excluded  
Yes 
In order to be in 
line with the 
global study 
Adverse events 
31/07/2024 
Some clarifications in 
analysis. 
Yes 
Clarification after 
meeting with 
Study Clinical 
Lead 
Other laboratory 
data 
31/07/2024 
Weight, height and 
BMI will be presented 
only in listings 
Yes 
Clarification after 
meeting with 
Study Clinical 
Lead 
Prior and 
concomitant 
medications 
31/07/2024 
Definitions and 
presentation of prior 
and concomitant 
medications was 
clarified  
Yes 
Clarification after 
meeting with 
Lead Statistician 
Intercurrent event  
06/08/2024 
Intercurrent event 
strategy was clarified 
Yes 
Clarification after 
meeting with 
Lead Statistician 
 


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1 
INTRODUCTION 
The purpose of the current statistical analysis plan (SAP) is a detailed description of basic 
principles of statistical analysis, description of methods used to analyse the primary and 
secondary endpoints, and other data obtained during the study. 
This plan provides for compliance of the planned and conducted statistical analysis with 
the clinical study protocol (CSP), including the definition of datasets for analysis, 
transformations and calculations for endpoints, the required number of observations, etc. 
All discrepancies with the CSP should be clarified. 
The current statistical analysis plan is prepared in compliance with: 
•
ICH harmonised tripartite guideline. Statistical principles for clinical trials (E9).
Step 5 finalized guideline February 1998
•
ICH harmonised tripartite guideline. Structure and Content of Clinical Study
Reports (E3). Step 5 finalized guideline dated November 1995
•
Good Clinical Practice of the Eurasian Economic Union, adapted by the decision
of the Council of Eurasian Economic Commission on 3 November 2016, N 79
•
Recommendation of the Board of the Eurasian Economic Commission No. 19 "On
Guidelines for the Application of Biostatistics principles in Clinical trials of
Medicinal Products", dated 3 November 2020
This SAP is based on version 1.0 of the CSP dated 29 August 2023. In case of future 
amendments to the protocol, the SAP may be modified to account for changes relevant to 
the statistical analysis. 
2 
CHANGES TO PROTOCOL PLANNED ANALYSES 
This SAP is written in line with the current version of the CSP. All planned analyses 
correspond to the statistical section of the CSP. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
Timing of Analyses  
It is planned to conduct only final analysis. It will be performed when all participants 
completed the study. 
3.2 
Analysis Populations  
The following populations are defined: 
Table 1. Populations for Analysis 


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Population/analysis set 
Description 
Enrolled/screened 
participants set 
All participants who sign the ICF. 
Full analysis set (FAS) 
All participants who are randomized to treatment and 
have at least one postdose, pre-exercise baseline and at 
least one corresponding post-dose postexercise FEV1 
measure at Visit 3 and/or Visit 4. 
Safety analysis set 
All participants who have received any amount of the 
study intervention. 
 
3.3 
General Considerations  
The data analyses will be conducted using SAS® System (SAS Institute Inc., Cary, NC), 
version 9.4 or higher. 
In general, all data will be listed, sorted by treatment sequence (i.e. PT027/Placebo and 
Placebo/PT027) and participant, and when appropriate by visit number within participant.  
Unless otherwise noted, data will be presented in tables by treatment sequence using 
descriptive statistics. 
3.3.1 
General Study Level Definitions  
The below-mentioned general principles will be followed throughout the study: 
• 
Descriptive statistics will be used for all variables, as appropriate.  
− 
Continuous variables will be summarised by the number of observations, mean, 
standard deviation, median, upper, and lower quartiles where indicated, 
minimum, and maximum by timepoint as appropriate.  
− 
Categorical variables will be summarised by frequency counts and percentages 
for each category. Unless otherwise stated, percentages will be calculated 
based on the analysis set population total by timepoint as appropriate. 
• 
For continuous data, the mean, standard deviation and median are rounded to one 
additional decimal place compared to the original data. Minimum and maximum 
are displayed with the same accuracy as the original data. 
• 
Time-to-event variables will be presented using the Kaplan-Meier (KM) 
methodology, including median time calculated from the KM curves. 
• 
For categorical data, percentages are rounded to one decimal place with the 
exception of 100% which is presented as a whole number. 
Only acceptable or usable spirometry values will be recorded in eCRF and included in 
the analyses and presented in tables, listings and figures. Values marked as usable will 
be utilizied only in case if acceptable values are unavailable. 


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3.3.1.1 
Period specific post-dose pre-exercise baseline  
Post-dose pre-exercise baseline is defined as the FEV1 result taken post-dose of 
randomized treatment and prior to the exercise challenge test conducted at Visit 3 and 
Visit 4 (approximately occurring 30 minutes post dose of IP, see CSP, Table 4).  
The post-dose pre-exercise baseline is period specific and therefore will be calculated at 
each Visit 3 and Visit 4.  
The post-dose pre-exercise baseline will be used to calculate the primary and secondary 
endpoints of changes from baseline. 
3.3.1.2 
Period specific pre-dose baseline  
The period specific pre-dose baseline is defined as the spirometry measurement taken 
prior to dosing of randomized treatment, which should occur at 5 minutes pre-dose of IP 
(Table 4). The period specific pre-dose baseline will be calculated separately at Visit 3 
and Visit 4. 
The period specific pre-dose baseline will be included as a covariate in parametric 
analyses of the primary and secondary endpoints. 
The period specific pre-dose baseline will additionally be used to calculate changes from 
baseline in safety endpoints of vital sign parameters and ECG parameters. 
3.3.1.3 
Average pre-dose baseline  
The average pre-dose baseline will be calculated as the average of the non-missing period 
specific pre-dose baseline result for each subject. The average pre-dose baseline will be 
included as a covariate in parametric analyses of the primary and secondary endpoints. 
3.3.1.4 
Absolute and percent change from baseline  
Absolute change from baseline outcome variables is computed as: 
Absolute change from baseline = (post-baseline value – baseline value). 
Percent change from baseline is computed as: 
Percentage change from baseline = [(post-baseline value – baseline value) / baseline 
value] * 100%. 
If either the post-baseline value or the baseline value is missing, then the absolute/percent 
change from baseline value will also be set to missing.  
3.3.1.5 
Percentage fall from post-dose pre-exercise baseline FEV1  
Percentage fall from post-dose pre-exercise baseline FEV1 will be used to calculate 
primary and secondary lung function endpoints and is defined as: 


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Percentage fall from post-dose pre-exercise baseline = [(post-dose pre-exercise baseline 
value – post-exercise value) / post-dose pre-exercise baseline value] × 100%. 
The percentage fall from post-dose pre-exercise FEV1 will be calculated at each post-
exercise timepoint at Visits 2, 3 and 4. 
If either the post-baseline value or the baseline value is missing, then the percentage fall 
from baseline value will also be set to missing.  
3.3.1.6 
Crossover difference in maximum percentage fall of FEV1  
Crossover difference in maximum percentage fall of FEV1 will be calculated for each 
participant as difference of maximum percentage fall of FEV1 registered in period of 
PT027 administration and maximum percentage fall of FEV1 registered in period of 
Placebo administration. 
3.3.2 
Visit Window  
Due to the design of this trial, there will be no visit windowing applied other than the 
identification of baseline. 
3.3.3 
Handling of Unscheduled Visits  
Retest and reassessment of spirometry will be registered as unscheduled visits. If some 
retests will be registered after Visit 3 and before Visit 4 then the latest result will be 
included in the analysis as result of Visit 3. If some retests will be registered after Visit 
4 then the latest result will be included in the analysis as result of Visit 4. All other 
results will be presented only in listings. Other unscheduled and early discontinuation 
measurements will not be included in by-visit summaries. 
3.3.4 
Multiplicity/Multiple Comparisons  
For purposes to demonstrate statistically significant superiority of the IMP, the 
following comparison sequence will be conducted: 
1. Primary endpoint: 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 
2. Secondary endpoint: the percentages of subjects with a maximum percentage fall in 
FEV1 post-exercise challenge of <10% 
If 1st comparison is significant ie obtained 2-sided p-value < 0.05, then 2nd comparison 
will be reported as significant if corresponding obtained 2-sided p-value < 0.05. 
3.3.5 
Handling of Protocol Deviations in Study Analysis  
Protocol deviations will be collected, reviewed, and reconciled throughout the study. 
Important protocol deviations (IPDs) will be identified from the complete set of 
protocol deviations. IPDs are those which may significantly impact the completeness, 


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accuracy, or reliability of the study data or that may significantly affect a participant’s 
rights, safety, or wellbeing. 
All decisions on importance will be made throughout the study and finalised before 
clinical data base lock. 
3.3.6 
Missing Data  
Safety assessments of the form of “<x” (ie, below the lower limit of quantification) or 
“>x” (ie, above the upper limit of quantification) are imputed as “x” in the calculation 
of summary statistics but are displayed as “<x” or “>x” in the listings. 
For missing start dates for adverse events (AEs) and medications/procedures, the 
following rules are applied: 
• 
Missing day: Impute the first of the month unless the month is the same as month 
of the first dose of study drug and the end date is on or after the first dose of study 
drug or ongoing then impute first dose date 
• 
Missing day and month: Impute 01 January unless year is the same as first dose 
date and the end date is on or after the first dose of study drug or ongoing then 
impute first dose date. 
• 
Completely missing date:  
o For AEs and treatment identified as prior to study start in the eCRF (i.e. end date 
before day of first dose): Impute the day before first dose date unless the end 
date is prior to this in which case impute the date the patient was enrolled. 
o For treatment not identified as prior to study start in the eCRF, no imputation 
will be performed. For an AE not identified as prior to study start, the date of 
first dose will be imputed. 
An imputed start date of an AE must be prior to the end date of the AE. 
For missing stop dates of AEs or medications/procedures, the following rules are 
applied: 
• 
Missing day: Impute the last day of the month unless month is the same as month 
of study discontinuation, then impute as study discontinuation date. For prior 
medications impute date of informed consent if month is the same as month 
informed consent was provided. 
• 
Missing day and month: Impute 31 December unless year is the same as year of 
study discontinuation then impute study discontinuation date. For prior medications 
impute date of informed consent if year is the same as month informed consent was 
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• 
Completely missing: If an AE/medication has a completely missing end date then it 
is treated as ongoing unless the outcome is stated in the eCRF as 
recovered/resolved for AEs or treatment continues stated as “No” for medications.  
o If the AE/medication is not ongoing (as identified in the eCRF), then the stop 
date will be imputed by the date of study discontinuation.  
o For stopped medication, if the medication is marked as prior and start date is 
prior to first dose date, then impute the date of the day before first dose.  
o If the medication started on or after first dose date, then impute the date of study 
discontinuation. 
The imputation of dates for AEs and medications are used to determine if an AE is 
treatment emergent and whether a medication is concomitant. Flags are retained in the 
database indicating where any programmatic imputation has been applied, and in such 
cases, any durations are not calculated. 
For time to event endpoints, dropouts and missing data are handled according to the 
censoring rules detailed within the relevant sections for the endpoint. 
Other rules for handling missing data are described under the derivation rules for that 
particular variable. 
4 
STATISTICAL ANALYSIS  
This section provides information on definitions, derivation and analysis/data 
presentation per domain. 
4.1 
Study Population  
The domain study population covers subject disposition, analysis sets, protocol 
deviations, demographics, baseline characteristics medical history, prior and 
concomitant medication and study drug compliance.  
4.1.1 
Subject Disposition and Completion Status  
4.1.1.1 
Definitions and Derivations  
Participants disposition and completion status will be comprised of the following: 
• Enrolled participants; 
• Non-randomized participants (screen failures); 
• Randomized participants; 
• Participants who were randomized but no dosed with reasons; 
• Participants who were randomized and treated on 1st period; 
• Participants who were randomized and treated on 2nd period; 


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• Participants who were randomized and treated with PT027 
• Participants who were randomized and treated with placebo 
• Randomized participants who completed FU visit. 
• Randomized participants who withdrew from the study with reasons 
4.1.1.2 
Presentation  
Number and percentage of participants in each category will be reported by treatment 
sequence for Enrolled/Screened Participants Set. 
4.1.2 
Analysis Sets  
4.1.2.1 
Definitions and Derivations  
Refer to Section 3.2 for definition of analysis sets: 
• Enrolled/Screened Participants Set 
• Full Analysis Set 
• Safety Analysis Set 
4.1.2.2 
Presentation  
The number of participants included in each analysis set will be reported by treatment 
sequence for Enrolled/Screened Participants Set. In addition, for each analysis set, the 
number of participants excluded, including the reasons, will be reported, if applicable. 
4.1.3 
Protocol Deviations  
4.1.3.1 
Definitions and Derivations  
A detailed list of possible important protocol deviations (IPDs) and the process for 
reviewing them by the clinical study team will be outlined in the Protocol Deviation 
plan (PD plan). 
The medical and statistical team members will review the protocol deviation categories 
in a blinded fashion before the clinical database lock and be classified as important per 
the PD plan. 
At a minimum, the following deviations categories will be included for review and 
classified as important for the evaluation and implementation of the study: 
• Inclusion Criteria Deviations 
• Exclusion Criteria Deviations 
• Discontinuation Criteria for study product met but participant not withdrawn from 
study treatment 
• Discontinuation Criteria for overall study withdrawal met but participant not 
withdrawn from study 
• Investigational Product Deviation 
• Excluded Medications taken 


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• Deviations to study procedure 
• Other Important Protocol Deviations 
4.1.3.2 
Presentation  
The number and percentage of participants with IPDs will be provided per protocol 
deviation category. The summary will be based on the Safety Analysis Set. 
All important protocol deviations will be presented in a listing. 
4.1.4 
Demographics  
4.1.4.1 
Presentation  
Following demographic characteristics will be summarized for all participants in the 
Safety Analysis Set: 
• Age 
• Age group 
o <65 years 
o ≥65 years 
• Sex 
• Race 
• Ethnic group 
4.1.5 
Baseline Characteristics  
4.1.5.1 
Presentation  
Following baseline characteristics will be summarized for all participants in the Safety 
Analysis Set: 
• Weight (kg) 
• Height (cm) 
• Body mass index (BMI, kg/m2) 
• Maximal HR results during Exercise Test for visits 1 and 2 
• Smoking history 
• Results of spirometry on Visits 1 and 2 
• Results of spirometry on Visit 3 prior randomization 
4.1.6 
Disease Characteristics  
Disease characteristics will be presented for the Safety Analysis Set. 
4.1.6.1 
Definitions and Derivations  
The following characteristics will be collected: 


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• Allergen asthma trigger 
• Aspirin asthma trigger 
• Exercise asthma trigger 
• Other asthma trigger 
The time since diagnosis of asthma (years) will be calculated as: 
(Date of first dose of randomized treatment (Visit 3) - Date of diagnosis of 
asthma)/365.25. 
Partial dates for the above calculations will be handled as per Section 3.3.6. 
4.1.6.2 
Presentation  
Disease characteristics will be presented in a table with descriptive statistics and in a 
listing. 
4.1.7 
Medical History and Concomitant Disease  
4.1.7.1 
Definitions and Derivations  
Medical history and relevant surgical history will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 26.1 or later. The version used 
will be indicated in the tables and listings. 
Any medical history which is ongoing at time of informed consent will be considered as 
current medical history, otherwise it is considered as past medical history. 
Clinically significant abnormal physical examination findings at screening will be 
recorded as adverse events 
4.1.7.2 
Presentation  
Past and current medical history will be grouped by MedDRA System Organ Class (SOC) 
and Preferred Term (PT) and summarized in the Safety Analysis Set as number and 
percentage of participants in each treatment sequence. 
Also past and current medical history will be presented in listings. 
4.1.8 
Prior and Concomitant Medications  
4.1.8.1 
Definitions and Derivations  
Prior medication: all prescripted drugs, herbal products, vitamins, minerals, and over-
the-counter medications with end date within 3 months before date of randomization.  
Concomitant medications: all medications with start date on or after date of 
randomization, or with end date after date of randomization or ongoing at the time of  
the follow-up telephone call (TC). 


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If a medication has start date before date of randomization and end date after date of 
randomization or ongoing the follow-up telephone call (TC), so this medication will be 
considered as prior and as concomitant, therefore it will be presented in both 
corresponding tables. 
Restricted Medications 
As described in Table 8 of the CSP. 
Prohibited Medications 
As described in Table 8 of the CSP. Medications will be classified as prohibited or not on 
the medical review. 
Rescue Medications 
AstraZeneca will supply rescue medication – Ventolin® (salbutamol, SABA), 100 μg 
metered dose inhaler, to the study site. 
For the purpose of inclusion in prior or concomitant mediation, incomplete medication 
start and stop dates will be imputed as detailed in Section 3.3.6. 
4.1.8.2 
Presentation  
All medications will coded using World Health Organization Drug dictionary (WHO 
Drug) version Sep 2023 B3 or later. The version used will be indicated in the data 
summaries and listings. Medications will be presented in the Safety Analysis Set. 
Prior and concomitant medications will be presented in separate outputs. 
The number and percentage of participants receiving prior or concomitant medication 
(by ATC classification system codes and generic name) will be presented by treatment 
sequence. 
Additionally, prior and concomitant medications will be listed. The listing of concomitant 
medications will include reason for use, start and end dates of administration, dosage 
information including dose, frequency and route. 
Restricted medications also will be listed. The listing will include date and time of SABA 
administration and date and time of consequent planned FEV1 testing procedures. 
Events of prohibited medication administration will be registered and presented as 
protocol deviations (Section 4.1.3). 
Data on rescue medication administrations will be listed. The listing will include date, 
time of administration, name and dosage regimen. 


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4.1.9 
Study Drug Compliance  
Not applicable for this study. 
4.2 
Endpoint Analyses  
This section covers details related to the endpoint analyses such as primary, secondary, 
other endpoints including sensitivity and supportive analyses. 
Descriptive statistics and analysis results (if applicable) will be presented by treatment, 
unless otherwise specified. 
Examples of SAS code implemented efficacy analysis models presented in 
corresponding sections. These codes can be updated, for example, in order to obtain 
necessary statistics of a model. 
Statistical 
category 
Endpoint 
Analysis 
Set 
Intercurrent event strategy 
Population 
level summary 
(analysis) 
Details 
in 
section 
Objective 1: To estimate the efficacy of PT027 (budesonide/albuterol) metered-dose inhaler as compared 
with placebo metered-dose inhaler after a single dose on exercise-induced bronchoconstriction in adult 
participants with asthma  
Primary 
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 
Full 
Analysis 
Set 
Intercurrent event defined as 
rescue medication 
administration prior to the 
first spirometry reading. 
Only FEV1 results prior to 
rescue therapy (within the 
study visit) will be included 
in the analyses. 
A while on treatment 
strategy will be used such 
that missing values will be 
assumed missing at random 
(MAR) and handled by the 
direct likelihood methods of 
the mixed effects model. 
Missing data not preceded by 
an intercurrent event, such as 
subjects who withdraw from 
study will be assumed to be 
MAR. 
Difference of 
means between 
treatments 
4.2.1 
Objective 2: To further estimate the efficacy of PT027 (budesonide/albuterol) metered-dose inhaler as 
compared with placebo metered-dose inhaler after a single dose on exercise-induced bronchoconstriction in 
adult participants with asthma 
Secondary 
The percentages of 
subjects with a 
maximum 
percentage fall in 
FEV1 post-exercise 
challenge of <10% 
and <20%, 
respectively 
Full 
Analysis 
Set 
While on treatment strategy 
will be applied as a primary 
strategy: only FEV1 results 
prior to administration of 
rescue medication (within 
The percentage 
fall will be 
calculated 
relative to the 
pre-exercise 
FEV1 
assessment at 
4.2.2 


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Statistical 
category 
Endpoint 
Analysis 
Set 
Intercurrent event strategy 
Population 
level summary 
(analysis) 
Details 
in 
section 
the study visit) will be 
analysed. 
Composite strategy will be 
used for purposes of a 
supplementary analysis: 
articipants who used rescue 
medication administration 
prior to the first spirometry 
reading will be analysed as 
non-responders  
the respective 
visit. 
The measure of 
interest is the 
odds ratio 
between PT027 
and Placebo for 
each threshold 
separately 
(<10% and 
<20%). 
Secondary 
The percentage fall 
from post-dose, pre-
exercise baseline in 
FEV1 at each 
timepoint within 60 
minutes post-
exercise challenge 
Full 
Analysis 
Set 
Hypothetical strategy will be 
used for analysis of this 
endpoint: only FEV1 results 
prior to administration of 
rescue medication (within 
the study visit) will be 
included in the analyses, 
missing values will be 
utilized in the analysis by 
using the mixed model with 
repeated measures 
(MMRM). 
The measure of 
interest is the 
percentage fall 
from baseline in 
FEV1 at each 
timepoint within 
60 minutes post-
exercise 
challenge. 
4.2.3 
Secondary 
Post-exercise FEV1 
area under the curve 
from 0 to 30 minutes 
(AUC0-30min) 
Full 
Analysis 
Set 
While on treatment strategy 
will be applied: only the 
FEV1 AUC0-30min 
measurements prior to 
administration of rescue 
medication will be included 
in the analyses. 
The measure of 
interest is the 
difference 
between 
treatments in the 
post-exercise 
FEV1 AUC0-
30min. 
 
4.2.4 
Secondary 
Time to recovery, 
defined as the time 
from completionof 
the exercise 
challenge to the first 
measured post-
exercise challenge 
FEV1 value within 
10% of the post- 
dose, pre-exercise 
challenge baseline 
FEV1 
Full 
Analysis 
Set 
While on treatment strategy 
will be applied: only FEV1 
results prior to 
administration of rescue 
medication (within the study 
visit) will be included in the 
analyses 
The measure of 
interest is the 
median of the 
time to 
recovery. 
4.2.5 
Objective 3: To assess the safety and tolerability of PT027 (budesonide/albuterol) metered-dose inhaler 
as compared with placebo metered-dose inhaler after a single dose in adult participants with asthma. 
Safety 
Safety and 
tolerability will be 
evaluated in terms 
of: 
• AEs 
• SAEs 
• AEs lead to 
discontinuation. 
Safety 
Analysis 
Set 
All data will be analysed 
The measure of 
interest is 
frequencies and 
percentages of 
participants with 
reported AEs 
4.6.2 


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Statistical 
category 
Endpoint 
Analysis 
Set 
Intercurrent event strategy 
Population 
level summary 
(analysis) 
Details 
in 
section 
VS, PE, ECGs will 
be analysed in terms 
of AE data. 
 
4.2.1 
Primary Endpoint  
4.2.1.1 
Definition  
The primary variable is the maximum percentage fall of FEV1 available in the post-
exercise 60-minute assessment period prior to the use of rescue medication, from FEV1 
value measured after study treatment and prior to the exercise. It will be calculated at 
Visit 3 and Visit 4.  
4.2.1.2 
Derivations  
The fall from post-dose, pre-exercise baseline in FEV1 will be calculated at each post-
exercise FEV1 assessment time point within Visits 3 and 4 as described in Section 3.3.1.  
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 within Visits 3 
and 4.  
The percentage fall in FEV1 will be calculated as difference from to the post-exercise 
value to the pre-exercise value at each measurement during the 60-minute assessment 
period divided by the pre-exercise value and presented in percents within Visits 3 and 4.  
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. 
4.2.1.3 
Handling of Dropouts and Missing Data  
Values of FEV1 obtained after rescue medication and missing values will not be 
imputed.  
4.2.1.4 
Primary Analysis of Primary Endpoint  
The primary analysis will be performed in the FAS. Only data prior to the occurrence of 
an intercurrent event (ICE) will be included in the analysis in accordance with the WoT 
strategy. 
The primary efficacy endpoint will be analyzed with a mixed effect model including 
categorical fixed effects for treatment, treatment period and treatment sequence. 
Continuous covariates include period-specific pre-dose baseline FEV1 and average pre-
dose baseline FEV1 (as defined in Section 3.3.1.3) in order to eliminate cross-level bias 
whilst using pre-treatment baselines. Also, a random subject within treatment sequence 
effect will be specified. 


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Post-dose, pre-exercise baseline FEV1 will be defined as the 30-minute post-dose value, 
i.e., 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. 
Applied significance level (alpha): 0.05 (using a 2-sided test). 
Additionally, least squares mean estimates, 95% confidence intervals and associated p-
values of the treatment difference will be calculated for the subgroups of clinical 
interest by additionally adjusting for background therapy (ICS or no ICS) and 
background therapy*treatment group interaction in the mixed model. 
A forest plot will be created showing the difference in least squares mean estimates and 
associated 95% confidence intervals for the Overall, ICS and non-ICS subgroups.   
Model results as well as descriptive statistics will be presented in tables. Figure for 
adjusted means and 95% CIs will be presented. 
All data will be listed. 
4.2.1.5 
Sensitivity Analyses of the Primary Endpoint  
Missing results for maximum percentage fall in FEV1 are unlikely (i.e., rescue 
medication prior to the collection of the 5 minutes measure) and will be assumed to be 
missing at random. Sensitivity analysis will be conducted to explore the robustness of 
the primary analysis with respect to this missing data assumption. This analysis will be 
conducted in supportive purposes. 
Data that are missing will be imputed using reference-based imputation. Participants 
with a missing maximum percentage fall in the 60-minute assessment period, for any 
visit, will be imputed using the least squares mean estimate of the maximum percentage 
fall in the Placebo treatment from a mixed model as specified in Section 4.2.1.4, using 
the observed data. After imputation the dataset of complete data, will be analyzed using 
the same model as descripted in Section 4.2.1.4. 
Model results as well as descriptive statistics will be presented in tables. Figure for 
adjusted means and 95% CIs will be presented. 
All data will be listed. 


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4.2.2 
Secondary Endpoint: the percentages of subjects with a maximum 
percentage fall in FEV1 of <10% and <20%  
4.2.2.1 
Definition  
Protection against EIB will be defined having a maximum percentage fall in FEV1 post-
exercise change under the corresponding threshold values (<10% and <20%) 
4.2.2.2 
Derivations  
Derivation will be completely based on comparing primary efficacy variable (described 
in Section 4.2.1.1) and threshold values of 10% and 20%. 
For each threshold value a participant will be considered as protected patient 
(responder) if their maximum percentage fall in FEV1 post-exercise change was less 
than the threshold value. Therefore two different types of responders will be analysed. 
4.2.2.3 
Handling of Dropouts and Missing Data  
 Participants with missing maximum percentage fall will not be included in the primary 
analysis. 
4.2.2.4 
Primary Analysis of Secondary Endpoint  
The odds of being protected against EIB will be analyzed using a generalized linear 
mixed model with logit link function to compare the treatments. Two separate models 
will be presented for each two types of responders (participants protected against EIB) 
as described in Section 4.2.2.2.  
The models will be adjusted with fixed effects for treatment, treatment period and 
treatment sequence, period specific pre-dose baseline FEV1 and average pre-dose 
baseline FEV1 as continuous covariates, and a random subject within treatment 
sequence effect. The odds ratio and 95% CI will be reported for pairwise treatment 
comparisons.  
Model results as well as descriptive statistics will be presented in tables and figures. All 
data will be listed. 
4.2.2.5 
Supplementary Analysis of Secondary Endpoint  
The suplementary analysis of this endpoint will be performed using the same models as 
in the primary analysis but participants who didn’t withdraw the study prematurely and 
had missing maximum percentage fall will be analysed as non-responders. 
Model results as well as descriptive statistics will be presented in tables and figures.All 
data will be listed. 
4.2.3 
Secondary Endpoint: the percentage fall in FEV1 from post-dose, 
pre-exercise at each timepoint within 60 minutes post-exercise  
4.2.3.1 
Derivations  
Described in Section 4.2.1.2. 


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4.2.3.2 
Handling of Dropouts and Missing Data  
Described in Section 4.2.1.2. 
4.2.3.3 
Primary Analysis of Secondary Endpoint  
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 (UN) over the time points. In case of impossible to build the model due to 
divergence, the following variants of the covariance matrix will be sequentially tested: 
Compound Symmetric (CS), Autoregressive, order 1 (AR(1)), Toeplitz (TOEP). 
Only FEV1 results prior to administration of rescue therapy (within the study visit) will 
be included in the analyses. 
Model results as well as descriptive statistics will be presented in tables. Figures for 
adjusted means and 95% CIs as well as unadjusted means and 95% CIs will be 
presented. 
All data will be listed. 
4.2.4 
Secondary Endpoint: post-exercise FEV1 area under the curve 
from 0 to 30 minutes  
4.2.4.1 
Definition  
Post-exercise FEV1 area under the curve (AUC) from 0 to 30 minutes will be defined on 
the base of changes from baseline in FEV1 as defined in Section 4.2.1.2 for time points 
planned up to 30 minutes after the test. 
4.2.4.2 
Derivations  
Post-exercise FEV1 area under the curve from 0 to 30 minutes (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 
the exercise challenge test 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. 
𝐴𝑈𝐶0−30 𝑚𝑖𝑛𝑢𝑡𝑒𝑠= 
1
𝑡𝑁−𝑡0
× ∑(𝑦𝑖−1 + 𝑦𝑖) × (𝑡𝑖−𝑡𝑖−1)
2
𝑁
𝑖=1
 
For FEV1 change from baseline results 𝑦𝑖 recorded 𝑡𝑖 minutes after the exercise 
challenge test (actual clock time) at 𝑖= 0, 1, 2, … , 𝑁 actual timepoints. If all post-
exercise timepoints are available, then 𝑁= 4, t0 corresponds to the end time of the 
exercise challenge test and y0 = 0. Only FEV1 results of ‘acceptable’ or ‘borderline 
acceptable’ (investigator assigned) quality will be used in the derivation of FEV1 
AUC0−30min. If a FEV1 result is missing or recorded in the database, but assigned an 


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‘unacceptable’ quality grade at the scheduled assessment, then the assessment will be 
excluded from the calculation of FEV1 AUC0-30min. To calculate FEV1 AUC0-30 min, there 
must be at least 1 non-missing post-dose FEV1 within 0 to 30 minutes post-dose. 
Missing FEV1 post-dose measures will not be imputed. 
4.2.4.3 
Handling of Dropouts and Missing Data  
Values of FEV1 obtained after rescue medication and missing values will not be 
imputed. Missing actual times for non-missing change from baseline values will be 
replaced with planned times. 
4.2.4.4 
Primary Analysis of Secondary Endpoint  
The endpoint will be analyzed using the same approach as described in Section 4.2.1.4. 
4.2.5 
Secondary Endpoint: time to recovery  
4.2.5.1 
Definition  
Recovery will be defined as return of post-exercise changes of the FEV1 within 10% 
interval of the value recorded at the post-dose, pre-exercise baseline. 
4.2.5.2 
Derivations  
Time to recovery at each of Visits 3 and 4 will be derived as the time (in minutes) post-
exercise challenge in which the FEV1 result returns to within 10% of the value recorded 
at the post-dose, pre-exercise baseline.  
The post-dose, pre-exercise baseline FEV1 assessment and percentage fall in FEV1 will 
be calculated as described in Section 4.2.1.2, at Visit 3 and Visit 4 separately.  
4.2.5.3 
Handling of Dropouts and Missing Data  
Missing values of FEV1 and times of measurements will not be imputed. 
4.2.5.4 
Primary Analysis of Secondary Endpoint  
The median time to recovery will be reported descriptively by treatment. P-values will 
be calculated using a Prescott's period-adjusted sign test, based on categorizing subjects 
into period preferences (Senn S 1993). 
Censoring rules: 
• If a participant has not observed a fall greater than 10% of the post-dose pre-
exercise baseline in their post-exercise challenge test by 60 minutes, they will be 
left censored at 0 minutes. 
• Participants who have any rescue medication administered during the post-dose 
assessments will be censored at the time of receiving rescue medication.  
• Participants who do not recover to within 10% of the post-dose, pre-exercise 
baseline will be censored at their last assessment.  


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4.2.6 
Other Endpoints  
Not applicable. 
4.2.7 
Subgroup Analyses  
The assessment of treatment effect will also be investigated for primary endpoint 
(described in Section 4.2.1) and first secondary endpoint (described in Section 4.2.2) in 
the other clinically important subgroups described in Table: 
 
Table 3. Subgroup Analyses 
Group 
Subgroup 
Sex 
Male 
 
Female 
Age group (years) 
Adults: ≥ 18 - < 65 
 
Elderly: >= 65 
BMI (kg/m2)  
Median value cut-off [1] 
Baseline FEV1 % 
Median value cut-off [1] 
[1] Subgroup will be categorized into 2 groups defined by the median value observed at 
baseline. Baseline FEV1 % for grouping purposes here will be pre-dose baseline FEV1 
% predicted normal at Visit 3. 
For all subgroup analyses, if there are less than 10 subjects/events available within a 
subgroup and at least 5 subjects with data available per treatment group under 
comparison, or the model does not converge, then only descriptive (summary) statistics 
will be presented. Subgroup analyses will be further broken down into the overall 
population, and ICS and non-ICS populations. Subjects with insufficient data to be 
allocated to a subgroup category will be excluded from the subgroup analyses.  
Model results as well as descriptive statistics will be presented in tables. Figures for 
adjusted means and 95% CIs will be presented.  
Forest plots will be produced showing the least squares mean difference and associated 
95% confidence intervals within each subgroup for the primary endpoint of maximum 
percentage fall from post-dose, pre-exercise baseline in FEV1. 
All data will be listed. 
4.3 
Pharmacodynamic Endpoint(s)  
Not applicable 
4.4 
Pharmacokinetics  
Not applicable 


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4.5 
Immunogenicity  
Not applicable 
4.6 
Safety Analyses (if not already covered as endpoint variables)  
The domain safety covers exposure, adverse events, clinical laboratory, vital signs, and 
ECG.  
Tables and listings will be provided for the Safety Analysis Set. 
4.6.1 
Exposure  
4.6.1.1 
Definitions and Derivations  
Participants will have single administration of placebo at the screening period and 
single administrations of placebo or PT027 (depending of randomization) on each of 
both study periods. 
4.6.1.2 
Presentation  
Number and percentage of participants who received both treatments and who didn’t 
receive the second treatment (Visit 4) with reasons will be presented by treatment 
sequence. Placebo administration on Visit 2 will not be accounted. 
All data on exposure will be listed. 
4.6.2 
Adverse Events  
4.6.2.1 
Definitions and Derivations  
AEs will be coded by System Organ Class (SOC) and Preferred Term (PT) using the 
latest version of the MedDRA dictionary. 
4.6.2.2 
Presentation  
AEs started before time of study treatment on Visit 3 will be considered as pre-
treatment AEs and will be presented in a separate listing.  
AEs of participants from A/B treatment sequence registered in period from time of 
study treatment on Visit 3 to time of study treatment on Visit 4 and AEs of participants 
from B/A treatment sequence registered after time of study treatment on Visit 4 will be 
considered as AEs of PT027. If participant from A/B treatment sequence didn’t receive 
study treatment on Visit 4, then all AEs occurred after time of study treatment on Visit 3 
will be considered as AEs of PT027. 
AEs of participants from B/A treatment sequence registered in period from time of 
study treatment on Visit 3 to time of study treatment on Visit 4 and AEs of participants 
from A/B treatment sequence registered after time of study treatment on Visit 4 will be 
considered as AEs of Placebo. If participant from B/A treatment sequence didn’t receive 
study treatment on Visit 4, then all AEs occurred after time of study treatment on Visit 3 
will be considered as AEs of placebo. 


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The following tables by IP will be presented: 
• Overall table for AEs 
• AEs by SOC and PT 
• SAEs by SOC and PT 
• AEs related to study intervention by SOC and PT 
• SAEs related to study intervention by SOC and PT 
• AEs by SOC and PT, by severity 
• AEs by SOC and PT, by outcome 
• SAEs by SOC and PT, by outcome 
• AEs by SOC and PT, by action taken with IMP 
• SAEs by SOC and PT, by action taken with IMP 
• AEs leading to discontinuation of study intervention, by SOC and PT 
• AEs by SOC and PT caused participant to withdraw from the study 
The following lisitngs will be provided: 
• Pre-treatment AEs 
• AEs (excluding the pre-treatment AEs) 
• SAEs (excluding the pre-treatment AEs) 
• AEs with fatal outcome 
4.6.3 
Clinical Laboratory, Blood Sample  
4.6.3.1 
Definitions and Derivations  
Blood samples for determination of clinical chemistry and hematology will be taken only 
at Screening (Visit 1). Additional safety samples may be collected if clinically indicated 
at the discretion of the investigator. Detailed list of parameters is presented in the CSP, 
Section 8.2.5. 
4.6.3.2 
Presentations  
Measured values at Screening will be presented with descriptive statistics as planned in 
Section 3.3.1 by treatment sequence in tables. 
All data on blood samples will be presented in listings. 
4.6.4 
Clinical Laboratory, Urinalysis  
4.6.4.1 
Definitions and Derivations  
Urine samples for urinalysis will be taken only at Screening (Visit 1). Detailed list of 
parameters is presented in the CSP, Section 8.2.5. 
4.6.4.2 
Presentations  
Results of urinalysis will be presented in a listing. 


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4.6.5 
Other Laboratory Evaluations  
4.6.5.1 
Definitions and Derivations  
A serum pregnancy test (β-human chorionic gonadotropin [β-hCG]) will be performed at 
Visit1, 4 and PDV; urine β-hCG test will be performed at Visit 3 (for women of 
childbearing potential only). 
Urine samples will be taken during Visits 1-4 for drugs of abuse and cotinine testing. The 
analysis will be carried out using test strips. The list of psychoactive agents for testing 
includes marijuana, benzodiazepines, barbiturates, opiates, methadone, phencyclidine, 
cocaine, amphetamines. 
Also, during Visits 1-4 alcohol detection test will be performed using breathalyser. 
4.6.5.2 
Presentations  
All data of these additional laboratory tests will be presented in listings. 
4.6.6 
Vital Signs  
4.6.6.1 
Definitions and Derivations  
Vital sings will be collected according to the Schedule of Activities: CSP, Section 1.3.  
4.6.6.2 
Presentations  
SBP, DBP and HR will be presented with descriptive statistics in tables using the 
following approach: 
For Visit 1: measured values and changes for values on 20, 40 and 60 minutes after the 
test from values on 50 minutes before the test. Grouping by treatment sequence. 
For Visit 2: measured values and changes for values on 20, 40 and 60 minutes after the 
dosing from values on 50 minutes before the dosing. Grouping by treatment sequence. 
For visits 3 and 4: measured values and changes for values on 20, 40 and 60 minutes 
after the dosing from values on 50 minutes before the dosing. Grouping by treatment.  
For visits 3 and 4: maximal HR during ECT. Grouping by treatment.  
Treatments will be summarized using the same algorithm as described for AEs in 
Section 4.6.2.2. 
Also all data on vital signs, including weight, height and BMI, will be presented in a 
listing. 
4.6.7 
Electrocardiogram  
4.6.7.1 
Definitions and Derivations  
Electrocardiogram will be performed according to the Schedule of Activities: CSP, 
Section 1.3.  
4.6.7.2 
Presentations  
Continuous parameters of ECG will be presented using the following approach: 


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For each visit: measured values and changes for values on 45 minutes after the test from 
values on 50 minutes before the test.  
Interpretation of ECG as nominal parameter will be presented in shift tables for values 
on 50 minutes before the test and for values on 45 minutes after the test. Number and 
percentages of participants with values: Normal, Borderline, Abnormal NCS and 
Abnormal CS will be presented. 
For visits 1 and 2, for continuous parameters and interpretation grouping will be 
performed by treatment sequence. 
For visits 3 and 4, for continuous parameters and interpretation grouping will be 
performed by treatment. Treatments will be summarized using the same algorithm as 
described for AEs in Section 4.6.2.2. 
Also all data on vital signs will be presented in a listing. 
4.6.8 
Other Safety Assessments  
Not Applicable 
5 
INTERIM ANALYSIS  
Not Applicable 
6 
REFERENCES  
• ICH harmonised tripartite guideline. Statistical principles for clinical trials (E9). 
Step 5 finalized guideline February 1998; 
• ICH harmonised tripartite guideline. Structure and Content of Clinical Study 
Reports (E3). Step 5 finalized guideline dated November 1995; 
• Good Clinical Practice of the Eurasian Economic Union, adapted by the decision 
of the Council of Eurasian Economic Commission on 3 November 2016, N 79.  
• Senn S, Cross-over Trials in Clinical Research. Wiley, Chichester.1993. 
7 
APPENDIX  
Not Applicable 


Signature Page for 
 System v1.0
BREATH_SAP_3.0
Signature Page for 
 System v1.0
BREATH_SAP_3.0
Approve: Document Level Task
Verdict: Approved
val
06-Aug-2024 08:06:20 GMT+0000
Approve: Document Level Task
Verdict: Approved
Approval
06-Aug-2024 08:12:54 GMT+0000
CCI
CCI
PPD
PPD