A Randomized, Open-Label, Two Period Crossover, Chronic Dosing, 1-Week, Pilot Study to Assess the Efficacy and Safety of Budesonide and Formoterol Fumarate Inhalation Aerosol Administered With a Spacer Compared With Symbicort® Turbuhaler® in Subjects With Severe to Very Severe Chronic Obstructive Pulmonary Disease and Low Peak Inspiratory Flow
Phase: PHASE3
Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Sponsor: AstraZeneca

Clinical Study Protocol
AstraZeneca
Drug Substance Budesonide/ Formoterol Fumarate (BFF)
Study Code D5980C00023
Version 4.0
Date 10 August 2020
CONFIDENTIAL AND PROPRIETARY
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Form Doc Number: AZDoc0070547 Parent Doc Number: AZDoc0017426
Clinical Study Protocol 
Drug Substance
Budesonide/ Formoterol Fumarate 
(BFF) MDI
Study Code
D5980C00023
Version
4.0
Date
10 August 2020
A Randomized, Open-Label, Two Period Crossover, Chronic Dosing, 1-Week, 
Pilot Study to Assess the Efficacy and Safety of Budesonide and Formoterol 
Fumarate Inhalation Aerosol Administered with a Spacer Compared with 
Symbicort® Turbuhaler® in Subjects with Severe to Very Severe Chronic 
Obstructive Pulmonary Disease and Low Peak Inspiratory Flow 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s):  IND 118313; EudraCT 2019-001801-26

Clinical Study Protocol
AstraZeneca
Drug Substance Budesonide/ Formoterol Fumarate (BFF)
Study Code D5980C00023
Version 4.0
Date 10 August 2020
CONFIDENTIAL AND PROPRIETARY
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Form Doc Number: AZDoc0070547 Parent Doc Number: AZDoc0017426

Revised wording to clarify that both screening and washout medications Berodual and 
Budesonide (if applicable) should be stopped in the clinic after the evening dose prior to 
study visit the next day.
Section 5.1 Inclusion criteria and Section 5.3 Randomization Criteria:
Rationale for change: To allow the study to enrol an eligible population with PIF of 
<50L/min, recruitment will be limited to patients with severe to very severe COPD. This 
should reduce screen failure rate and support enrolment of the appropriate study population.
The following eligibility criteria are revised in the following sections and throughout the 
protocol as appropriate:

Inclusion criterion 7: revised to require post-bronchodilator FEV1 of <50% instead of 
<80% predicted normal value at Visit 2.

Inclusion criterion 8: revised InCheck device setting from “no resistance” to “Turbuhaler 
S resistance” and lowered PIF limit from “<60 L/min” to “<50 L/min” at Visit 2.

Randomization criterion 1: revised to require FEV1 of <50% instead of <80% predicted 
normal value.

Randomization criterion 2: revised InCheck device setting from “no resistance” to 
“Turbuhaler S resistance” and lowered PIF limit from “<60 L/min” to “<50 L/min”.
Section 5.2 Exclusion Criteria:

Criterion #22 clarified to state randomization instead of enrolment.
Section 5.4.1 Caffeine and Tobacco:

Revised and softened restrictions to refrain from smoking “until after the last spirometry 
assessment” instead of “throughout the duration of each study visit”.
Section 5.5 Screen Failures 

Section revised to align with and allow rescreening based on revised inclusion and 
randomization criteria: “Subjects who did not meet PIF inclusion or randomization 
criterion with InCheck set for no resistance as per previous CSP version 2.0 can be also re-
screened.”
Section 6 Study Treatments

Clarification that InCheck devices are first presented to subjects at Visit 1 for training.
Section 6.2 Preparation/Handling/Storage/Accountability:

Wording of storage requirements for Symbicort Turbuhaler, Budesonide MDI, BFF MDI 
and Berodual revised for consistency with drug labels and appendices at the end of CSP. 

Added storage requirements for Ventolin.
Section 6.3 Measures to Minimise Bias:  Randomization and Blinding:

Clinical Study Protocol
AstraZeneca
Drug Substance Budesonide/ Formoterol Fumarate (BFF)
Study Code D5980C00023
Version 4.0
Date 10 August 2020
CONFIDENTIAL AND PROPRIETARY
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
Estimated date of last subject completed updated

Under Statistical methods section, updates made to the ITT, mITT, and Safety Population
description to include description of data will be handled for patients affected by COVID-
19 related study hold
Section 2.3.1 COVID-19 Impact Assessment 

New sub-section 2.3.1 added to provide an assessment of risk with investigational product 
during COVID-19 pandemic.
Section 4.1 Overall Design

Updated section for additional clarity
Section 4.1.1 Study Conduct Mitigation During Study Disruption Due to Cases of Civil
Crisis, Natural Disaster, or Public Health Crisis

New sub-section 4.1.1 added to provide guidance for study conduct during unforeseen 
events e.g. civil crisis, natural disaster, or public health crisis

Additional sub-section 4.1.1.1 added to provide details on the subject disposition due to 
unforeseen circumstances. 
Section 5.2 Exclusion Criteria

Exclusion criteria 19, and 22 revised to include details for COVID-19 related 
assessment(s)
Section 5.5 Screen Failures and Subjects affected by Study or Site Hold

Section title updated to “Subjects affected by Study or Site Hold”

Updated section 5.5.1 to include all conditions for rescreening of subjects in the study. 

Added Section 5.5.2 titled “Subjects Affected by Study or Site Hold” to include details for 
re-inviting subjects that were screen failed or discontinued due to study being placed on 
hold.
Section 6.1.1 Investigational Products (Table 3)

Asterix added to clarify treatment as Investigational Product.   
Section 6.3 Measure to Minimise Bias: Randomization and Blinding

Updated section to include details on the use of new subject identifiers and 
randomization codes for subjects that were screen failed or discontinued due to 
COVID-19.
Section 6.5.2.1 Prohibited COPD Medications (Table 5)

Footnote a, b, and c updated to clarify and include budesonide (where applicable) and 
berodual and ventolin washout periods

Clinical Study Protocol
AstraZeneca
Drug Substance Budesonide/ Formoterol Fumarate (BFF)
Study Code D5980C00023
Version 4.0
Date 10 August 2020
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Section 7.1 Discontinuation of Treatment and Subject Withdrawal

Added criteria for discontinuation due to exclusion criteria
Section 9.3 Populations for Analyses

Updates made to the ITT, mITT, and Safety Population description to include an 
explanation on how patients who were discontinued due to the study being put on hold 
for COVID-19 related concerns will be handled in the analyses.
Section 9.4.3.2 Analysis of Secondary Efficacy Variable

Statement added under Supportive Analyses regarding additional sensitivity that will 
be carried out to assess the impact of COVID-19.
Appendix M 

Appendix added to provide study instructions for mitigations due to civil crisis, natural 
disaster, or public health crisis.
Appendix N

Abbreviations moved from Appendix M to Appendix N
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

Clinical Study Protocol
AstraZeneca
Drug Substance Budesonide/ Formoterol Fumarate (BFF)
Study Code D5980C00023
Version 4.0
Date 10 August 2020
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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................1
VERSION HISTORY ..........................................................................................2
TABLE OF CONTENTS .....................................................................................8
1.
PROTOCOL SUMMARY .................................................................................12
1.1
Schedule of Activities (SoA)..............................................................................12
1.2
Synopsis.............................................................................................................17
1.3
Schema ..............................................................................................................23
2.
INTRODUCTION .............................................................................................24
2.1
Study Rationale..................................................................................................24
2.2
Background........................................................................................................25
2.3
Benefit/Risk Assessment....................................................................................25
2.3.1
COVID-19 Impact Assessment ..........................................................................26
3.
OBJECTIVES AND ENDPOINTS ....................................................................26
4.
STUDY DESIGN...............................................................................................27
4.1
Overall Design ...................................................................................................27
4.1.1
Study Conduct Mitigation During Study Disruption Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................29
4.1.1.1
Subject Disposition ............................................................................................29
4.2
Scientific Rationale for Study Design.................................................................30
4.3
Justification for Dose .........................................................................................30
4.4
End of Study Definition .....................................................................................31
5.
STUDY POPULATION.....................................................................................31
5.1
Inclusion Criteria................................................................................................31
5.2
Exclusion Criteria ..............................................................................................32
5.3
Randomization Criteria ......................................................................................35
5.4
Lifestyle Restrictions..........................................................................................35
5.4.1
Caffeine and Tobacco.........................................................................................35
5.4.2
Illicit Drugs or Drugs of Abuse ..........................................................................35
5.5
Screen Failures and Subjects affected by Study or Site Hold ..............................35
5.5.1
Rescreening Subjects..........................................................................................36
5.5.2
Subjects Affected By Study or Site Hold............................................................36
6.
STUDY TREATMENTS ...................................................................................36

Clinical Study Protocol
AstraZeneca
Drug Substance Budesonide/ Formoterol Fumarate (BFF)
Study Code D5980C00023
Version 4.0
Date 10 August 2020
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6.1
Treatments Administered ...................................................................................37
6.1.1
Investigational Products .....................................................................................37
6.2
Preparation/Handling/Storage/Accountability.....................................................37
6.3
Measures to Minimise Bias:  Randomization and Blinding.................................39
6.4
Treatment Compliance .......................................................................................40
6.5
Concomitant Therapy.........................................................................................40
6.5.1
Allowed Medications .........................................................................................40
6.5.2
Prohibited Medications.......................................................................................41
6.5.2.1
Prohibited COPD Medications ...........................................................................41
6.5.2.2
Prohibited Non-COPD and Non-Respiratory Medications and Washout 
Periods...............................................................................................................42
6.5.3
Other Concomitant Treatment ............................................................................44
6.6
Dose modification..............................................................................................44
6.7
Treatment After the End of the Study.................................................................44
7.
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL...44
7.1
Discontinuation of Study Treatment ...................................................................44
7.1.1
Procedures for Discontinuation of Study Treatment............................................44
7.2
Lost to Follow-Up..............................................................................................45
7.3
Withdrawal From the Study ...............................................................................45
7.4
Study and Site Closure .......................................................................................45
8.
STUDY ASSESSMENTS AND PROCEDURES...............................................46
8.1
Efficacy Assessments.........................................................................................47
8.1.1
Pulmonary Function Tests..................................................................................47
8.1.2
Peak Inspiratory Flow ........................................................................................48
8.1.3
Inspiratory Capacity...........................................................................................48
8.1.4
Chronic Obstructive Pulmonary Disease Assessment Test (CAT).......................48
8.2
Safety Assessments ............................................................................................49
8.2.1
Clinical Laboratory Assessments........................................................................49
8.2.2
Physical Examinations and Other Screening Assessments ..................................49
8.3
Collection of Adverse Events .............................................................................50
8.3.1
Method of Detecting AEs and SAEs...................................................................50
8.3.2
Time Period and Frequency for Collecting AE and SAE Information .................50
8.3.3
Follow-Up of AEs and SAEs..............................................................................50
8.3.4
Adverse Event Data Collection...........................................................................51
8.3.5
Causality Collection...........................................................................................51
8.3.6
Adverse Events Based on Signs and Symptoms..................................................52
8.4
Safety Reporting and Medical Management .......................................................52

Clinical Study Protocol
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Drug Substance Budesonide/ Formoterol Fumarate (BFF)
Study Code D5980C00023
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Date 10 August 2020
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8.4.1
Reporting of Serious Adverse Events .................................................................52
8.4.2
Pregnancy ..........................................................................................................52
8.4.2.1
Maternal Exposure .............................................................................................53
8.4.3
Overdose............................................................................................................53
8.4.4
Medication Error................................................................................................54
8.5
Pharmacokinetics ...............................................................................................54
8.5.1
Procedure for Blood Sample Collection and Schedule ........................................54
8.5.2
Determination of Drug Concentration.................................................................54
8.5.3
Storage and Destruction of PK Samples .............................................................55
8.6
Pharmacodynamics ............................................................................................55
8.7
Genetics .............................................................................................................55
8.8
Biomarkers.........................................................................................................55
8.9
Medical Resource Utilization and Health Economics .........................................55
9.
STATISTICAL CONSIDERATIONS................................................................55
9.1
Statistical Hypotheses ........................................................................................55
9.2
Sample Size Determination ................................................................................55
9.3
Populations for Analyses....................................................................................56
9.4
Statistical Analyses ............................................................................................57
9.4.1
Baseline for Analyses.........................................................................................58
9.4.2
Visit Windows ...................................................................................................58
9.4.3
Efficacy Analyses ..............................................................................................58
9.4.3.1
Primary Efficacy Analysis..................................................................................58
9.4.3.2
Analysis of Secondary Efficacy Variables ..........................................................58
9.4.3.3
Estimand............................................................................................................60
9.4.1
Safety Analyses..................................................................................................60
9.4.2
Pharmacokinetic Analyses..................................................................................60
9.4.3
Methods for Multiplicity Control........................................................................61
9.5
Interim analyses .................................................................................................61
10.
REFERENCES ..................................................................................................62
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .........................................................................................63
LIST OF TABLES
Table 1
Schedule of Assessments.......................................................................13
Table 2
Study Objectives ...................................................................................26

Clinical Study Protocol
AstraZeneca
Drug Substance Budesonide/ Formoterol Fumarate (BFF)
Study Code D5980C00023
Version 4.0
Date 10 August 2020
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Table 3
Study Treatments ..................................................................................37
Table 4
Allowed COPD and Allergy Medications..............................................41
Table 5
COPD Medications Prohibited Beginning at Visit 1 and Required 
Washout Period Prior to Visit 2.............................................................42
Table 6
Prohibited Non-COPD and Non-Respiratory Medications .....................43
Table 7
Laboratory Safety Variables ..................................................................49
LIST OF FIGURES
Figure 1
Study design..........................................................................................23
LIST OF APPENDICES
Instructions for Use of Berodual Respimat ............................................64
Regulatory, Ethical and Study Oversight Considerations .......................69
Instructions for Use of Ventolin HFA....................................................73
Dose Indicator Display Reading Instructions .........................................81
Subject Instructions for Use of BFF MDI and Budesonide MDI ............82
Instructions for Use of Symbicort Turbuhaler Inhalation Powder 
Device...................................................................................................91
Instructions for Use of AeroChamber PlusFlow Vu...............................93
Spirometry Performance Recommendations ..........................................94
Spirometry Assessment Criteria ..........................................................100
Instruction for Use of InCheck Inspiratory Flow Measurement 
Device.................................................................................................102
COPD Assessment Test.......................................................................109
Adverse Event Definitions and Additional Safety Information.............110
Study Instructions for Mitigation Due to Civil Crisis, Natural 
Disaster, or Public Health Crisis..........................................................114
Abbreviations......................................................................................116

Clinical Study Protocol
AstraZeneca
Drug Substance Budesonide/ Formoterol Fumarate (BFF)
Study Code D5980C00023
Version 4.0
Date 10 August 2020
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1.
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)

Clinical Study Protocol
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Study Code D5980C00023
Version 4.0
Date 10 August 2020
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Table 1
Schedule of Assessments
Screening
Run-in
Treatment Periods and Washout
D/C
Follow-up Call
Details in CSP Section 
and/or Appendix
Treatment 1
Treatment 2
D/C
7 to 14 days 
post-last dose
Visita
1
2
3
4
5
6
Week 
-3 to -1
-1
Rand
1
3
4
Day
-21 to -7
-7 ± 3
1
8 ± 1
22 ± 1
29 ± 1
Informed consent 
X
Section 5.1, Appendix B 4
Inclusion /exclusion criteria
X
X
X
Section 5.1 and Section 5.2
Randomization criteria
X
Section 5.3
Routine clinical procedures
Demography and medicalu/surgical history
X
Section 8.2.2
Physical examination
X
Section 8.2.2
Smoking status
X
Section 8.2.2
CAT score
X
Section 8.1.4 and 
Appendix K
Prior/concomitant medication reviewb
X
X
X
X
X
X
X
X
Section 6.5
Vital signsc
X
Section 8.2.2
12-lead ECGc
X
Section 8.2.2
COPD exacerbation history
X
X
X
Section 8.2.2
Urine pregnancy testingd
X
Section 5.1
Clinical laboratory testingc
X
Section 8.2.1
Discontinue COPD maintenance therapy
X
Section 4.1
Start Berodual/budesonide MDI
Xe
Xf
Section 4.1
Discontinue Berodual/budesonide MDI
Xg
Xg
Section 4.1
Start Randomized treatment
Xh
Xh
Section 4.1
Discontinue Randomized treatment
Xi
Xi
Section 4.1

Clinical Study Protocol
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Study Code D5980C00023
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Screening
Run-in
Treatment Periods and Washout
D/C
Follow-up Call
Details in CSP Section 
and/or Appendix
Treatment 1
Treatment 2
D/C
7 to 14 days 
post-last dose
Visita
1
2
3
4
5
6
Week 
-3 to -1
-1
Rand
1
3
4
Day
-21 to -7
-7 ± 3
1
8 ± 1
22 ± 1
29 ± 1
Routine safety measurements
AE assessmentst
X
X
X
X
X
X
X
X
Section 8.3 and 
Appendix L
Efficacy measurements
Reversibility
Xj
Section 8.1.1
Spirometry (FEV1, FVC)
X
Xk
Xl
Xk
Xl
Xm
Section 8.1.1
Pre-dose peak inspiratory flown (PIF)
X
X
X
X
X
Section 8.1.2
IC
Xo
Xp
Xo
Xp
Section 8.1.3
PK profileq
X
X
Section 8.5
Study treatment administration
Training and demonstration of proper device 
and spacer use including priming
X
X
X
X
X
X
Section 6.2, Appendix A, 
Appendix D, Appendix E, 
Appendix F, and 
Appendix F
PIF training
X
X
X
X
X
X
Section 8.1.2 and 
Appendix J
Study treatment dispensed and collected
X
X
X
X
X
X
X
Section 6.2
Rescue medication dispensed and collected
X
X
X
X
X
X
X
Section 6
Review of paper diaries and dose indicators
X
X
X
X
X
X
Section 6.4
IP administrations
Xr
Xr
Xr
Xr
Section 6.2

Clinical Study Protocol
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Study Code D5980C00023
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Screening
Run-in
Treatment Periods and Washout
D/C
Follow-up Call
Details in CSP Section 
and/or Appendix
Treatment 1
Treatment 2
D/C
7 to 14 days 
post-last dose
Visita
1
2
3
4
5
6
Week 
-3 to -1
-1
Rand
1
3
4
Day
-21 to -7
-7 ± 3
1
8 ± 1
22 ± 1
29 ± 1
Abbreviations:  CAT=COPD Assessment Test; COPD=Chronic Obstructive Pulmonary Disease; CSP=Clinical Study Protocol; D/C=discontinuation; ECG=electrocardiogram; 
eCRF=electronic case report form; FEV1=forced expiratory flow in 1 second; FVC=forced vital capacity; IC=inspiratory capacity; IP=investigational product; PIF=peak inspiratory 
flow; PK=pharmacokinetics; Rand=randomization
a.
Sites should make every effort to maintain subjects within the scheduled visit window.  Subjects who fall outside the visit window will be placed in the appropriate visit window at 
the next scheduled visit.
b.
At all visits, note time of last dose and short-acting bronchodilator and other COPD medications; if less than approximately 6 hours prior to lung function assessments, the visit 
should be rescheduled.
c.
Assessed for screening purposes only.
d.
Pregnancy testing to be performed for women of childbearing potential.
e.
Budesonide (if applicable) and Berodual to be started after the morning visit at Visit 1.
f.
Budesonide (if applicable) and Berodual to be started the evening of Visit 4.
g.
Budesonide (if applicable) and Berodual will be stopped the evening prior to Visits 3 and 5.
h.
Randomized treatment will begin the morning of Visit 3 and Visit 5.
i.
The last dose of randomized treatment will be given the morning of Visit 4 and Visit 6 in the clinic.
j.
Spirometry to be performed approximately 45 minutes pre-bronchodilator and 30 to 60 minutes post-bronchodilator and reversibility calculated to characterize the subject 
population.
k.
At Visits 3 and 5 (Day 1 of each Treatment Period), spirometry will be performed at specific timepoints (approximately 45 minutes pre-dose and 2 hours post-dose).
l.
At Visits 4 and 6 (Day 8 of each Treatment Period), spirometry will be performed at specific timepoints (approximately 45 minutes pre-dose and 30 minutes and 1, 2, and 4 hours 
post-dose).
m.
Spirometry to be performed at the Early Discontinuation/Withdrawal Visit only if subject is still taking IP (last dose of IP on day before or at visit).
n.
PIF to be performed pre-dose using the InCheck Inspiratory Flow Measurement Device set to no resistance and then repeated with resistance equal to Turbuhaler S and then equal 
to ELLIPTA.
o.
At Visits 3 and 5 (Day 1 of each Treatment Period), IC will be conducted approximately 45 minutes pre-dose and 2 hours post-dose.  IC assessments should be performed prior to 
spirometry assessments.
p.
At Visits 4 and 6 (Day 8 of each Treatment Period), IC will be conducted 2 hours post-dose.  IC assessments should be performed prior to spirometry assessments.
q.
PK samples to be collected in the morning of Visit 4 and Visit 6 within 30 minutes prior to dosing and 2, 5, 20, 30, and 40 minutes and 1, 2, 3, and 4 hours post-dose.  If spirometry 
and PK assessments are to be performed at the same timepoint, PK samples should be drawn first followed by spirometry measurements.

Clinical Study Protocol
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Drug Substance Budesonide/ Formoterol Fumarate (BFF)
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Screening
Run-in
Treatment Periods and Washout
D/C
Follow-up Call
Details in CSP Section 
and/or Appendix
Treatment 1
Treatment 2
D/C
7 to 14 days 
post-last dose
Visita
1
2
3
4
5
6
Week 
-3 to -1
-1
Rand
1
3
4
Day
-21 to -7
-7 ± 3
1
8 ± 1
22 ± 1
29 ± 1
r.
Subjects will be admitted to the clinic on the day before Visits 3, 4, 5, and 6.
s.
Starting at Visit 3, IP should be taken at the same times every day. In-clinic dosing time is recorded as time of the second puff/inhalation.  The time of dosing needs to be 
monitored and the time of morning dosing on visit days should be standardized to be no less than 11 hours and no more than 12 hours from the previous evening dose at Visit 4 and 
Visit 6.
t.
Non-serious adverse events will be collected from Randomization throughout the Treatment Period and including the washout and follow-up periods. Serious adverse events will 
be recorded from the time of signing of informed consent form. Risk assessments for the evaluation of any safety events including for COVID-19 should be made prior to and at 
every in-clinic visit during treatment in-line with Protocol Section 4.1.1.1 and COVID-19 guidance (See Study Procedures Manual).
u.
In addition to medical history, a COVID assessment should be made prior to subject coming into clinic and at every in-clinic visit in-line with Protocol section 4.1.1.1 and COVID 
guidance (see Study Procedure manual). Prior to visit 1, site should follow local health guidelines to assess for COVID-19. 

Clinical Study Protocol
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Objectives and Endpoints
Primary Objective:
Endpoint/Variable:
To assess the effects of BFF MDI 
administered with a spacer relative to 
Symbicort Turbuhaler on lung function, 
measured by peak forced expiratory volume 
in 1 second (FEV1) within 4 hours post-dose 
at Week 1, in subjects with COPD and low 
PIF.

Peak change from baseline in FEV1 within 4 
hours post-dose following 1 week of 
treatment
Secondary Objective:
Endpoint/Variable:
To assess the effects of BFF MDI 
administered with a spacer relative to 
Symbicort Turbuhaler on additional measures 
of lung function.

Area under the curve for change from 
baseline in FEV1 from 0 to 4 hours (AUC0-4 h) 
following 1 week of treatment 

Change from baseline in pre-dose FEV1
following 1 week of treatment

Change from baseline in 2-hour post-dose 
inspiratory capacity (IC) following 1 week of 
treatment

Change from baseline in pre-dose PIF 
(InCheck Device set to no resistance, 
resistance set equal to Turbuhaler S, and 
resistance set equal to ELLIPTA) following 1 
week of treatment

Change from baseline in 2-hour post-dose 
FEV1 following the first dose

Change from baseline in 2-hour post-dose IC 
following the first dose
Safety Objective:
Endpoint/Variable:
To assess the safety of BFF MDI administered 
with a spacer and Symbicort Turbuhaler 

AEs

Serious adverse events (SAEs)

Adverse events leading to treatment 
discontinuation

Clinical Study Protocol
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Pharmacokinetic Objective:
Endpoint/Variable:
To characterize the steady state 
pharmacokinetics (PK) of budesonide and 
formoterol from drug administration of BFF 
MDI administered with a spacer and 
Symbicort Turbuhaler
The endpoints following 1 week of treatment are:
1.
Steady state area under the concentration-time 
curve from time 0 to 4-hours post-dose 
(AUC0-4)

Time to maximum observed peak 
concentration (tmax)

Maximum observed plasma concentration 
(Cmax)
Overall design:
This is a Phase IIIb randomized, open-label, 2 period (each 1-week treatment) crossover efficacy 
and safety pilot study comparing BFF MDI 320/9.6 µg administered with a spacer twice daily 
(BID) with Symbicort Turbuhaler 320/9 µg BID in subjects with severe to very severe COPD 
and low PIF.
Following randomization, subjects will undergo 2 treatment periods of 1 week each, with an 
intervening two-week washout period where they will use Berodual and budesonide MDI 320 µg 
BID (budesonide to only be used for subjects receiving ICS therapy at screening).  Subjects will 
be admitted to the clinic on the day before Visits 3, 4, 5, and 6.  The time of dosing needs to be 
monitored and the time of morning dosing on visit days needs to be standardized.
Subject disposition could be adjusted to ensure safety of the subjects during the study due to 
unforeseen circumstances by the study sponsor for e.g. a pandemic, local health advisory, travel 
related restrictions, etc. 
This study will be conducted at approximately 4 sites.  
Study Period:
Estimated date of first subject enrolled Q3 2019
Estimated date of last subject completed Q1 2021
Number of Subjects:
It is planned that approximately 150 prospective subjects will be screened, with approximately 
30 subjects randomized, 15 per sequence, in order to ensure at least 26 subjects completing the 
study.
Randomization will be stratified by the Visit 3 PIF set to Turbuhaler S resistance (<40 L/min 
versus ≥40 L/min).

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Treatments and treatment duration:
All eligible subjects must be taking 2 or more inhaled maintenance therapies including at least 1 
long-acting bronchodilator for the management of their COPD for at least 4 weeks prior to Visit 
1.  At Visit 1, subjects will discontinue their COPD maintenance therapies and will enter a 2- to 
3-week run-in period on Berodual20/50 µg QID and budesonide MDI 320 µg BID (budesonide 
to only be used for subjects receiving ICS therapy at screening).  Albuterol/salbutamol sulfate 
(for the purpose of this protocol referred to as Ventolin HFA) will be provided to use as rescue 
medication throughout the study.
At Visit 2, subjects must demonstrate a post-bronchodilator FEV1/forced vital capacity (FVC) of 
<0.70, a post-bronchodilator FEV1 of <50% predicted normal value, and PIF of <50 L/min using 
the InCheck Inspiratory Flow Measurement Device set to Turbuhaler S resistance.  Additionally, 
subjects will have PIF measured at Visit 2 with the InCheck Device set to no resistance and then 
equal to the ELLIPTA resistance.  Reversibility and COPD Assessment Test (CAT) will also be 
captured at Visit 2 in order to characterize the patient population.
At Visit 3, following the 2- to 3-week run-in period, subjects who demonstrate a pre-dose 
FEV1/FVC of <0.70, an FEV1 of <50% predicted normal value, and a PIF of <50 L/min using 
the InCheck Inspiratory Flow Measurement Device set to Turbuhaler S resistance will 
discontinue treatment with Berodual and budesonide MDI 320 µg BID (budesonide to only be 
used for subjects receiving ICS therapy at screening) and be randomized in a 1:1 scheme to 
either open-label BFF MDI 320/9.6 µg administered with a spacer BID or open-label Symbicort 
Turbuhaler 320/9 µg BID.  At Visit 4, subjects will discontinue their randomized treatment from 
Period 1 and begin treatment with Berodual and budesonide MDI (if applicable) for a 2-week 
wash-out period.  At Visit 5, subjects will discontinue treatment with Berodual and budesonide 
MDI (if applicable) and will begin randomized treatment for Period 2 of the crossover.  Pre- and 
post-dose spirometry assessments will be conducted at Visits 3 through 6.
Statistical methods
A total of approximately 30 subjects, 15 per sequence, (with at least 26 subjects completing the 
study) are planned to be randomized in this study.  The sample size has been selected based on 
practical considerations to obtain reasonable estimates for the primary and secondary objectives 
of this study, which will be used to further inform on the design and sample size needed for 
future studies.

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For purposes of analyses, the following populations are defined:
Population
Description
Enrolled 
All subjects who sign the ICF.
Intent-to-Treat (ITT) 
Population
All subjects who are randomized to treatment and receive at least one 
dose of study treatment.  Subjects will be analyzed according to the 
treatment they were assigned to as randomized, regardless of the 
treatment actually received.
Subjects affected by the study being put on hold for the COVID-
19 pandemic will be handled as follows:

Subjects who were discontinued due to the study being 
put on hold and who restarted the study will only be 
included in the ITT analysis set for the instance of 
enrolment after they restarted. 

Discontinued subjects who do not restart will be included 
in the ITT analysis set. 
This ensures that all randomized subjects are included in the ITT 
set once and once only.
Modified ITT (mITT) 
Population
All subjects in the ITT Population with post-baseline spirometry data 
from both treatment periods at Visits 4 and 6.  Data judged to be 
impacted by major protocol violations will be excluded.  Subjects will 
be analyzed according to the treatment they were assigned to as 
randomized.
Subjects affected by the study being put on hold for the COVID-
19 pandemic will be handled as follows:

Subjects who were discontinued due to the study being 
put on hold and who restarted the study will only be 
included in the mITT analysis set for the instance of 
enrolment after they restarted, if they have post-baseline 
spirometry data for both treatment periods after restart 
and meet the definition described above. 

Discontinued subjects who do not restart will not be 
included in the mITT analysis set as they will not have 
post-baseline spirometry data from both treatment 
periods. 
This ensures that all randomized subjects are included in the 
mITT set at most once, if they meet the relevant definition.
Safety Population
All subjects who are randomized to treatment and receive at least one 
dose of the study treatment.  Subjects will be analyzed according to the 
treatment actually received.
Subjects affected by the study being put on hold for the COVID-19 
pandemic will be handled as follows:

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
Subjects who were discontinued due to the study being 
put on hold and who restarted the study will only be 
included in the Safety analysis set for the instance of 
enrolment after they restarted. 

Discontinued subjects who do not restart will be included 
in the Safety analysis set. 
This ensures that all randomized subjects are included in the 
Safety set once and once only.
PK Population
All subjects in the mITT population with Cmax defined in both 
treatment periods.  Subjects will be analyzed according to the treatment 
actually received.
Demographics and other baseline characteristics will be summarized only using the ITT and 
mITT Populations.  The mITT Population will be used to summarize the primary and secondary 
efficacy variables.  The ITT Population will be used for sensitivity analyses for the primary 
endpoint.  The Safety Population will be used to summarize safety data. Pharmacokinetic 
Population will be used to summarize the PK analyses.
Peak change from baseline in FEV1 within 4 hours post-dose is defined as the maximum of the 
FEV1 assessments within 4 hours post-dosing at each visit minus baseline, provided that there 
are at least 2 non-missing values during the first 4 hours post-dose.
The peak change from baseline in FEV1 will be analyzed using an analysis of covariance model 
with baseline FEV1, PIF at screening and reversibility to Ventolin HFA as continuous covariates 
and treatment, and period as categorical covariates.  The model will include subject as a random 
effect to model correlation within subject across the study.  The model will not include treatment 
sequence unless that term is determined to be important (p<0.10).  95% confidence intervals will 
be produced.  P-values will be produced to aid interpretation although these will not be 
inferential.

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1.3
Schema
The general study design is summarized in Figure 1.
Figure 1
Study design

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2.
INTRODUCTION
The Sponsor is developing a family of orally inhaled drug products containing budesonide, 
glycopyrronium, and/or formoterol fumarate as dual and triple combination products for the 
treatment of COPD.  These drug products are metered dose inhalers (MDIs) formulated as a 
suspension with micronized active pharmaceutical ingredients and Co-Suspension™ Delivery 
Technology.  The Co-Suspension Delivery Technology consists of spray-dried porous particles 
comprised of the phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine and calcium chloride 
suspended in a hydrofluoroalkane (HFA) propellant.  When used in combination MDI products, 
these particles form strong non-specific associations with the active pharmaceutical ingredients, 
preventing the drugs from interacting with each other in the suspension and providing 
reproducible drug delivery and long-term stability.
The test formulation to be evaluated in this study is an MDI containing a combination of 
budesonide, an inhaled corticosteroid (ICS) and formoterol fumarate, a long-acting β2-agonist 
(LABA).
2.1
Study Rationale
Patients who have chronic obstructive pulmonary disease (COPD) with low peak inspiratory 
flow (PIF) may be at risk of suboptimal delivery to the airways of orally inhaled medications, in 
particular, those devices with high inspiratory air flow resistance [Loh, 2017; Mahler, 2017].  
Sharma et al has hypothesized that ineffective inhalation of medications due to low PIF can 
result in poor COPD management and adverse consequences for the patient [Sharma, 2017].  
Inhalation devices differ with respect to airflow resistance with MDIs posing essentially no 
resistance to airflow and dry powder inhalers (DPIs) having resistances which vary by device 
type [Altman, 2018].  The hypothesis of interest for this study is whether lung function outcomes 
in patients with COPD and low PIF (defined as <50 L/min) would be influenced by delivering 
maintenance medication via an MDI versus a DPI.
In order to improve coordination of inhaler actuation and inspiration, a valved holding chamber 
(or spacer) may be used with an MDI.  A spacer may also reduce the amount of drug that is 
deposited in the oropharynx.
The goal of this study is to assess the efficacy and safety of Budesonide and Formoterol 
Fumarate Inhalation Aerosol (hereafter referred to as BFF MDI) administered with a spacer
compared with budesonide/formoterol fumarate DPI (hereafter referred to as Symbicort®
Turbuhaler®) over a 1-week treatment period in a crossover fashion in subjects with COPD and a 
low PIF.  The primary efficacy outcome is lung function following 1 week of treatment.  The 
outcome of this study will further inform on the design and sample size of future studies 
investigating this concept.

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2.2
Background
Chronic obstructive pulmonary disease is a common preventable and treatable disease 
characterized by persistent airflow limitation that is usually progressive and associated with an 
enhanced chronic inflammatory response in the airways and the lung to noxious particles or 
gases.  Exacerbations and co-morbidities contribute to the overall severity in individual patients.  
Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality worldwide 
and results in significant economic and social burden that is both substantial and increasing.  
Pharmacologic therapy in COPD is used to reduce symptoms, reduce the frequency and severity 
of exacerbations, and improve health status and exercise tolerance as described in the Global 
Initiative for Chronic Obstructive Lung Disease (GOLD) [GOLD, 2018].
Bronchodilator medications are central to the management of COPD.  The principal 
bronchodilator treatments are β2-agonists, anticholinergics, and methylxanthines used as 
monotherapy or in combination.  Treatment with long-acting bronchodilators is more convenient 
and more effective at producing maintained symptom relief than treatment with short-acting 
bronchodilators.
Regular treatment with ICS improves symptoms, lung function, and quality of life and reduces 
the frequency of exacerbations in subjects with COPD.  Withdrawal from treatment of ICS may 
lead to exacerbations in some patients.  When combined with a LABA, an ICS is more effective 
than the individual components in improving lung function, quality of life, and reducing 
exacerbations in subjects with moderate to very severe COPD [GOLD, 2018].
A detailed description of the chemistry, pharmacology, efficacy, and safety of BFF MDI is 
provided in the Investigator’s Brochure and of Symbicort Turbuhaler is provided in the package 
insert.
2.3
Benefit/Risk Assessment
In order to evaluate the clinical benefit/risk balance, Phase I and Phase III data with budesonide 
and formoterol fumarate have been considered.  
Budesonide and formoterol fumarate have been well tolerated with a favorable safety profile 
identified in studies to date [Ferguson, 2018].  Potential risks with BFF MDI will be mitigated by 
selected inclusion/exclusion criteria, discontinuation criteria, and continuous monitoring of 
safety data during the study.
The combination of budesonide and formoterol fumarate has a favorable safety profile and is 
available worldwide in different formulations for both asthma and COPD.  The addition of 
Symbicort Turbuhaler to this study allows for the comparison of the differences in the 
effectiveness of drug delivery when the combination of budesonide/formoterol fumarate is 
delivered by an MDI (BFF MDI administered with a spacer) versus a DPI (Symbicort 
Turbuhaler) and how these differences effect lung function improvements in subjects with COPD 
and low PIF.

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During the run-in and washout periods, subjects will be treated with ipratropium bromide and 
fenoterol hydrobromide Respimat® 20/50 µg (hereafter referred to as Berodual®) four times a 
day (QID) and budesonide MDI 320 µg BID (budesonide to only be used for subjects receiving 
ICS therapy at screening).  If additional sites are added to the study and Berodual is not available 
to those sites, Combivent 20/100 µg will be provided.  Instructions for use of Berodual and 
budesonide MDI are provided in Appendix A and Appendix E, respectively.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of BFF MDI may be found in the Investigator’s Brochure.
2.3.1
COVID-19 Impact Assessment 
Neither the mechanisms of action nor available evidence suggest treatments with inhaled 
Budesonide, Glycopyrronium, and Formoterol Fumarate are associated with increased 
susceptibility to viral infections. There is currently no available data regarding the risk of SARS-
CoV-2 infection/COVID-19 in patients treated with either dual ICS-LABA (Budesonide-
Formoterol Fumarate) or triple ICS-LAMA-LABA (Budesonide-Glycopyrronium-Formoterol 
Fumarate) therapies for COPD or on the severity or progression of disease should a patient 
treated with either dual ICS-LABA (Budesonide-Formoterol Fumarate) or triple ICS-LAMA-
LABA (Budesonide-Glycopyrronium-Formoterol Fumarate) therapies become exposed or 
infected with SARS-CoV-2.
3.
OBJECTIVES AND ENDPOINTS
Table 2
Study Objectives
Primary Objective:
Endpoint/Variable:
To assess the effects of BFF MDI 
administered with a spacer relative to 
Symbicort Turbuhaler on lung function, 
measured by peak forced expiratory volume 
in 1 second (FEV1) within 4 hours post-dose 
at Week 1, in subjects with COPD and low 
PIF.

Peak change from baseline in FEV1 within 4 
hours post-dose following 1 week of 
treatment
Secondary Objective:
Endpoint/Variable:
To assess the effects of BFF MDI 
administered with a spacer relative to 
Symbicort Turbuhaler on additional measures 
of lung function.

Area under the curve for change from baseline 
in FEV1 from 0 to 4 hours (AUC0-4 h) 
following 1 week of treatment 

Change from baseline in pre-dose FEV1
following 1 week of treatment

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
Change from baseline in 2-hour post-dose 
inspiratory capacity (IC) following 1 week of 
treatment

Change from baseline in pre-dose PIF 
(InCheck Device set to no resistance, 
resistance set equal to Turbuhaler S, and 
resistance set equal to ELLIPTA) following 1 
week of treatment

Change from baseline in 2-hour post-dose 
FEV1 following the first dose

Change from baseline in 2-hour post-dose IC 
following the first dose
Safety Objective:
Endpoint/Variable:
To assess the safety of BFF MDI administered 
with a spacer and Symbicort Turbuhaler 

AEs

Serious adverse events (SAEs)

Adverse events leading to treatment 
discontinuation
Pharmacokinetic Objective:
Endpoint/Variable:
To characterize the steady state 
pharmacokinetics (PK) of budesonide and 
formoterol from drug administration of BFF 
MDI administered with a spacer and 
Symbicort Turbuhaler
The endpoints following 1 week of treatment are:

Steady state area under the concentration-time 
curve from 0 to 4-hours post-dose (AUC0-4)

Time to maximum observed peak 
concentration (tmax)

Maximum observed plasma concentration 
(Cmax)
4.
STUDY DESIGN
4.1
Overall Design
This is a Phase IIIb randomized, open-label, 2 period (each 1-week treatment) crossover efficacy 
and safety pilot study comparing BFF MDI 320/9.6 µg administered with a spacer twice daily 
(BID) with Symbicort Turbuhaler 320/9 µg BID in subjects with severe to very severe COPD 
and low PIF.  For an overview of the study design see Figure 1. For details on treatments given 
during the study, see Section 6.1 Treatments Administered.

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This study will be conducted at approximately 4 sites.  It is planned that approximately 150 
prospective subjects will be screened, with approximately 30 subjects randomized, 15 per 
sequence, in order to ensure at least 26 subjects completing the study.
At Visit 1, subjects will sign an informed consent form (ICF).  All eligible subjects must be 
taking 2 or more inhaled maintenance therapies including at least 1 long-acting bronchodilator 
for the management of their COPD for at least 4 weeks prior to Visit 1.  At Visit 1, subjects will 
discontinue their COPD maintenance therapies and will enter a 2- to 3-week run-in period on 
Berodual20/50 µg QID and budesonide MDI 320 µg BID (budesonide to only be used for 
subjects receiving ICS therapy at screening).  Albuterol/salbutamol sulfate (for the purpose of 
this protocol referred to as Ventolin HFA) will be provided to use as rescue medication 
throughout the study.
At Visit 2, subjects must demonstrate a post-bronchodilator FEV1/forced vital capacity (FVC) of 
<0.70, a post-bronchodilator FEV1 of <50% predicted normal value, and PIF of <50 L/min using 
the InCheck Inspiratory Flow Measurement Device set to Turbuhaler S resistance. Additionally, 
subjects will have PIF measured at Visit 2 with the InCheck Device set to no resistance and then 
equal to the ELLIPTA resistance.  Reversibility and COPD Assessment Test (CAT) will also be 
captured at Visit 2 in order to characterize the patient population.
At Visit 3, following the 2- to 3-week run-in period, subjects who demonstrate a pre-dose 
FEV1/FVC of <0.70, an FEV1 of <50% predicted normal value, and a PIF of <50 L/min using 
the InCheck Inspiratory Flow Measurement Device set to Turbuhaler S resistance will 
discontinue treatment with Berodual and budesonide MDI 320 µg BID (budesonide to only be 
used for subjects receiving ICS therapy at screening) and be randomized in a 1:1 scheme to 
either open-label BFF MDI 320/9.6 µg administered with a spacer BID or open-label Symbicort 
Turbuhaler 320/9 µg BID.  At Visit 4, subjects will discontinue their randomized treatment from 
Period 1 and begin treatment with Berodual and budesonide MDI (if applicable) for a 2-week 
wash-out period.  At Visit 5, subjects will discontinue treatment with Berodual and budesonide 
MDI (if applicable) and will begin randomized treatment for Period 2 of the crossover.
Randomization will be stratified by the Visit 3 PIF set to Turbuhaler S resistance (<40 L/min 
versus ≥40 L/min).
Following randomization, subjects will undergo 2 treatment periods of 1 week each, with an 
intervening two-week washout period where they will use Berodual and budesonide MDI 320 µg 
BID (budesonide to only be used for subjects receiving ICS therapy at screening).  Subjects will 
be admitted to the clinic prior to evening doses of study treatment on the day before Visits 3, 4, 
5, and 6.  The time of dosing needs to be monitored and the time of morning dosing on visit days 
should be standardized to be no less than 11 hours and no more than 12 hours from the previous 
evening dose at Visit 4 and Visit 6.  In order to minimize diurnal variance, sites should make 
every effort to assess subjects at the same time throughout the study and to discuss the 
importance of dosing in a timely manner every 12 hours.  Dosing for all subjects should be 
completed by 10 AM.  

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Berodual and Budesonide (if used by the subject ) should be withheld in the clinic  after taking 
and recording the evening dose in the diary on the day prior to the study visit.  This will ensure 
that these medications have been withheld for at least 12 hours prior to the time of spirometry on 
the following day at the study visit in the clinic.  Also, rescue medication (Ventolin) can be used 
as needed as long as it is withheld at least 6 hours prior to spirometry on study visit day.
Pre- and post-dose spirometry assessments will be conducted at Visits 3 through 6.
4.1.1
Study Conduct Mitigation During Study Disruption Due to Cases of Civil Crisis, 
Natural Disaster, or Public Health Crisis
This guidance given below supersedes instructions provided elsewhere in this CSP and should be 
implemented only during cases of civil crisis, natural disaster, or public health (e.g. during 
quarantines and resulting site closures, regional travel restrictions, and considerations if site 
personnel or study participants become infected with SARS-CoV-2 or similar pandemic 
infection) which would prevent or place on hold the conduct of study related activities at study 
sites, thereby compromising the study site staff or the participants ability to conduct the study. 
The investigator or designee should contact the study sponsor to discuss whether the mitigation 
plans below should be implemented.
To ensure continuity of the clinical study during crisis, natural disaster, or public health crisis, 
changes may be implemented to ensure the safety of study participants, maintain compliance 
with Good Clinical Practice, and minimize risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(e.g. hospital policies) or local government, these changes may include the following options: 
Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the informed consent form (ICF) should be signed at the participant’s next 
contact with the study site). Prior to informed consent form, local study institution or HA 
guidelines should be followed as appropriate.
4.1.1.1
Subject Disposition
This global study may be re-initiated or conducted during the COVID-19 pandemic, another civil 
crisis, natural disaster, or public health crisis, and the region and/or country level risk to sites and 
participants may vary during the conduct of the study. Guidance will be ratified where possible 
with local regulation, health authority and/or other relevant professional bodies to minimize the 
expected direct risks to site personnel and study participants. Alternative measures and 
procedures may be implemented during the conduct of the study and a few examples of impact 
on subject disposition are presented below.
A subject could be screen failed, also be asked to discontinue IP or be withdrawn from the study 
due to unforeseen circumstances e,g, subject showing signs/symptoms of or positive for COVID 
infection, COVID-19 pandemic related local health advisory restrictions, etc. Due to the global 
pandemic, and keeping in mind the safety of study subjects and study integrity, a decision could

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be taken to put the study or site on hold. During the hold, subject disposition may vary for 
example, e.g. study subjects in run-in could be considered screen failed, or randomized subjects 
could be discontinued from IP etc. To ensure subject safety during the hold all communications 
with study subjects could occur via telephone while assuring adequate follow-up. Both screened 
and randomized subjects who discontinued could be followed up at 7-14 days via telephone to 
assess their status. 
For further details on the study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix M
4.2
Scientific Rationale for Study Design
This study will assess the efficacy and safety of BFF MDI 320/9.6 µg administered with a spacer 
in subjects with COPD who have a low PIF defined as <50 L/min.  The product tested in this 
study, BFF MDI administered with a spacer, is being compared with Symbicort Turbuhaler (an 
approved ICS/LABA).  The study is open-label.
Patients who have COPD with low PIF may be at risk of suboptimal delivery to the airways of 
orally inhaled medications, in particular, those devices with high inspiratory air flow resistance 
[Loh, 2017; Mahler, 2017].  Inhalation devices differ with respect to airflow resistance with 
MDIs posing essentially no resistance to airflow and DPIs having resistances which vary by 
device type [Altman, 2018].  The hypothesis of interest for this study is whether lung function 
outcomes in patients with COPD and low PIF would be influenced by delivering the 
budesonide/formoterol fumarate combination via an MDI with a spacer versus a DPI.
Symbicort Turbuhaler has been selected as the comparator to BFF MDI as it is an approved 
ICS/LABA delivered via a DPI to provide the appropriate comparison between delivery devices.  
The study is open-label in order to simplify study design for a study of two drugs delivered from 
different device types. The lung function endpoints are objective measures not expected to be 
impacted by the open-label nature of the comparison.  The 1-week treatment length in this study 
will be sufficient to reach steady state exposure and to evaluate resulting increases in peak FEV1
within 4 hours post-dose.
Efficacy will be evaluated with the endpoints of peak change from baseline in FEV1 within 4 
hours post-dose, FEV1 AUC0-4 h and change from baseline in pre-dose FEV1, 2-hour post-dose 
IC, and pre-dose PIF.
4.3
Justification for Dose
Data from Phase I and Phase III studies indicate that budesonide at a dose of 320 µg BID and 
formoterol at a dose of 9.6 µg BID are appropriate doses to investigate in this study of subjects 
with COPD.  The dose of Symbicort Turbuhaler (320/9 µg BID) used in this study as an active 
comparator is the approved marketed dose for patients with COPD.

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4.4
End of Study Definition
The end of study is defined as the last expected visit/contact of the last subject undergoing the 
study.  
A subject is considered to have completed the study when he/she has completed his/her last 
scheduled procedure as well as the follow-up telephone call as shown in the SoA (Table 1).
See Appendix B 7 for guidelines for the dissemination of study results.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Each subject should meet all of the inclusion criteria, none of the exclusion criteria, and all of the 
randomization criteria for this study in order to be randomized to a study intervention.  Under no 
circumstances can there be exceptions to this rule.  Subjects who do not meet the entry 
requirements are screen failures, refer to Section 5.5.
In this protocol, “enrolled” subjects are defined as those who sign informed consent.  
“Randomized” subjects are defined as those who undergo randomization and receive a 
randomization number.
For procedures for withdrawal of incorrectly randomized subjects see Section 7.3.
5.1
Inclusion Criteria
Informed consent
1.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol at Visit 1.
The ICF process is described in Appendix B 4.
Age
2.
Subject must be 40 to 80 years of age inclusive, at the time of signing the ICF.
Type of subject and disease characteristics
3.
Individuals who have a physician diagnosis of COPD as defined by the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) [Celli, 2004].
4.
Require COPD maintenance therapy:  all subjects must be receiving 2 or more inhaled 
maintenance therapies, including at least 1 long-acting bronchodilator, for the 
management of their COPD for at least 4 weeks prior to Visit 1.

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Note:  Short-acting β2-agonist (SABA) and/or short-acting muscarinic antagonist 
(SAMA) may be added but will not count towards fulfilling Inclusion criterion #4.
5.
Demonstrate acceptable MDI and DPI administration technique.
6.
Demonstrate the ability to correctly perform the PIF measurement.
7.
A post-bronchodilator FEV1/FVC of <0.70 and post-bronchodilator FEV1 of <50% 
predicted normal value at Visit 2.
8.
A pre-bronchodilator PIF of <50 L/min using the InCheck Inspiratory Flow 
Measurement Device set to Turbuhaler S resistance at Visit 2.
9.
Current or former smokers with a history of at least 10 pack-years of cigarette 
smoking (1 pack year = 20 cigarettes smoked per day for 1 year).
10.
Willing and, in the opinion of the Investigator, able to adjust current COPD therapy, as 
required by the protocol.
11.
Compliance: willing to remain at study center as required per protocol to complete all 
visit assessments.
Sex
12.
Male and/or female
Reproduction
13.
Negative urine pregnancy test for female subjects of childbearing potential.
14.
Female subjects must be 1 year post-menopausal, surgically sterile, or using an 
acceptable method of contraception (an acceptable method of contraception is defined 
as a barrier method in conjunction with a spermicide) for the duration of the study 
(from the time they sign consent) to prevent pregnancy. In addition, oral 
contraceptives, approved contraceptive implant, long-term injectable contraception, 
intrauterine device, or tubal ligation are allowed. Oral contraception alone is not 
acceptable; additional barrier methods in conjunction with spermicide must be used.
5.2
Exclusion Criteria 
Medical conditions
1.
Current diagnosis of asthma, in the opinion of the Investigator.
2.
COPD due to α1-Antitrypsin Deficiency.
3.
Any significant disease or disorder (e.g., gastrointestinal, liver, renal, neurological, 
musculoskeletal, endocrine, metabolic, malignant, psychiatric including any conditions 
such as thyrotoxicosis, phaeochromocytoma, untreated hypokalaemia, and fungal 
infections in the airways) which, in the opinion of the Investigator, may either put the 

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subject at risk because of participation in the study, or influence the results of the 
study.
4.
Sleep apnea that, in the opinion of the Investigator, is uncontrolled.
5.
Other respiratory disorders including known active tuberculosis, lung cancer, cystic 
fibrosis, significant bronchiectasis (high resolution CT evidence of bronchiectasis that 
causes repeated acute exacerbations), immune deficiency disorders, severe 
neurological disorders affecting control of the upper airway, sarcoidosis, idiopathic 
interstitial pulmonary fibrosis, primary pulmonary hypertension, or pulmonary
thromboembolic disease.
Note:  Allergic rhinitis is not exclusionary.
6.
A moderate or severe exacerbation of COPD within 6 weeks prior to randomization 
(Visit 3).
Note:  The end date of an exacerbation is the last day of treatment with systemic 
corticosteroids or antibiotics.
7.
Pulmonary resection or lung volume reduction surgery during the 6 months prior to 
Visit 1 (i.e., lobectomy, bronchoscopic lung volume reduction [endobronchial 
blockers, airway bypass, endobronchial valves, thermal vapor ablation, biological 
sealants, and airway implants]).
8.
Need for mechanical ventilation within 3 months prior to Visit 1. 
9.
Significant or unstable ischemic heart disease, arrhythmia, cardiomyopathy, heart 
failure, uncontrolled hypertension as defined by the Investigator, or any other relevant 
cardiovascular disorder as judged by the Investigator.
10.
Narrow angle glaucoma not adequately treated, as deemed by the Investigator.  All 
medications approved for control of intraocular pressures are allowed including topical 
ophthalmic non-selective beta-blockers (such as betaxolol, carteolol, levobunolol, 
metipranolol, and timolol), and prostaglandin analogues.
11.
Symptomatic prostatic hypertrophy or bladder neck obstruction/urinary retention that, 
in the opinion of the Investigator, is clinically significant.
Note:  Subjects with trans-urethral resection of prostate or full resection of the prostate 
within 6 months prior to Visit 1 are excluded from the study.
12.
Current diagnosis of cancer requiring treatment.
Note:  Squamous cell and basal cell carcinomas of the skin are allowed in the study.
Prior/concomitant therapy
13.
Unable to withhold short-acting bronchodilators for 6 hours prior to lung function 
testing at each study visit.

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14.
Unable to abstain from protocol-defined prohibited medications (see Section 6.5.2) 
within the time period specified in Table 6 prior to and during Screening and 
Randomized Treatment periods.
15.
Using any herbal products either by inhalation or nebulizer within 2 weeks of Visit 1 
and does not agree to stop for the duration of the study.
Prior/concurrent clinical study experience
16.
Treatment with investigational study drug (or device) in another clinical study within 
the last 30 days or 5 half-lives, whichever is longer.
Note:  Observational studies (i.e., studies not requiring change to medication or an 
additional intervention) are allowed.
17.
Known hypersensitivity to β2-agonists, muscarinic antagonists, or corticosteroids, or 
any component of the investigational product (IP).
Diagnostic assessments
18.
Subjects with calculated creatinine clearance ≤30 mL/minute using the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.
Note:  Subjects with overactive bladder syndrome treated with oral anticholinergics 
that have been on treatment for at least one month are allowed in the study.
19.
Any clinically relevant abnormal findings in physical examination, clinical chemistry, 
hematology, urinalysis, COVID-19 test, vital signs, or electrocardiogram (ECG), 
which in the opinion of the Investigator, may put the subject at risk because of his/her 
participation in the study.
Note: E.g., Clinically relevant abnormal findings in ECGs are defined as QT interval 
corrected for heart rate (using Fridericia’s formula; QTcF) ≥500 msec in subjects with 
QRS <120 msec and QTcF ≥530 msec in subjects with QRS ≥120 msec.
Other exclusions
20.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
21.
Judgment by the Investigator that the subject should not participate in the study if the 
subject is unlikely to comply with study procedures, restrictions and requirements.
22.
Previous randomization in the present study except for when the subject had to 
discontinue study due to study and/or site hold. See section 5.5.2 for details. 
23.
Women who are pregnant or lactating, planning to become pregnant during the course 
of the study, or of childbearing potential not using acceptable contraception method.
24.
Significant abuse of alcohol or drugs.

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5.3
Randomization Criteria
At Visit 3, each subject must meet the following randomization criteria:
1.
A pre-dose FEV1/FVC of <0.70 and FEV1 of <50% predicted normal value.
2.
A pre-dose PIF of <50 L/min using the InCheck Inspiratory Flow Measurement 
Device set to Turbuhaler S resistance.
3.
FEV1 baseline stability:  the -45-minute pre-dose FEV1 assessments at Visit 3 must be 
within ±20% or 200 mL of the -45-minute pre-bronchodilator FEV1 assessments 
obtained at Visit 2.
5.4
Lifestyle Restrictions
5.4.1
Caffeine 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 prior to the first lung function 
assessment and for the duration of each in-clinic study visit.  Examples of such products include 
coffee, tea, chocolate, and cola.  Decaffeinated beverages are acceptable.
Changes in subject’s smoking status (i.e., stopping or re-starting smoking) may have an impact 
on the efficacy outcome measures.  Subjects will be required to refrain from smoking (including 
medical marijuana and electronic cigarettes) for at least 4 hours prior to the first lung function 
assessment and until after the last spirometry assessment. Study participants may utilize various 
nicotine replacement treatments such as chewing gum and patches, as needed, in accordance 
with recommendations from the Investigator during the entire study visit.
Note: For this study, the use of electronic cigarettes will be treated in the same manner as 
smoking.
5.4.2
Illicit Drugs or Drugs of Abuse
Illicit drugs or drugs of abuse will not be allowed from Visit 1 to the end of the follow-up 
telephone call or whenever the subject withdraws from the study.  If any illicit drugs or drugs of 
abuse are used by the subject during the study, the dates of use and the amount will be 
documented and the subject will be discontinued from randomized study treatment and will be 
withdrawn from the study at the discretion of the Investigator.
5.5
Screen Failures and Subjects affected by Study or Site Hold
Screen failures are defined as subjects who signed the ICF to participate in the clinical study but 
are not subsequently randomized to study treatment.  A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 

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from regulatory authorities.  Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE.
5.5.1
Rescreening Subjects
Subjects may be rescreened as follows:

Re-screen once if subject(s):
o
Has a moderate or severe exacerbation of COPD and/or COVID-19 or other acute 
airway infection during screening and prior to randomization and it has been at least 
6 weeks following resolution and completion of treatment of these conditions and in 
the opinion of the PI the subject is able to perform study procedures including 
spirometry.
NOTE: Subjects requiring mechanical ventilation or treatment in the ICU (e.g. for 
COPD, trauma, infection, recovery from surgery etc.) are not eligible.
o
Subjects who did not meet PIF inclusion or randomization criterion with InCheck set 
for no resistance as per previous CSP version 2.0  
5.5.2
Subjects Affected By Study or Site Hold
Subjects that may have been in screening/run-in/randomized and considered either screen 
failures and/or discontinued when the study or site could be placed on hold on account of 
COVID-19 pandemic related events for e.g. local health advisory, travel restrictions, etc.; these 
subjects may be re-invited with a new subject identifier, starting with informed consent process
and Visit 1 assessments as appropriate. 
For related documentation please refer to Study Procedures Manual instructions. 
6.
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (IP) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study participant 
according to the study protocol.  Study treatment in this study refers to BFF MDI 320/9.6 µg and 
Symbicort Turbuhaler 320/9 µg (for use during the treatment periods; also referred to as IP) and 
Berodual and budesonide (for use during run-in and washout periods).  All subjects will be 
provided with Ventolin HFA to use as-needed for relief of COPD symptoms.  Instructions for 
use of Ventolin HFA is provided in Appendix C.  Placebo MDIs and DPIs will be provided for 
training purposes.
InCheck Inspiratory Flow Measurement Devices with disposable mouthpieces for measuring PIF 
will be provided only at clinic visits (starting from Visit 1) along with all necessary training (see 
Appendix J).

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6.1
Treatments Administered
6.1.1
Investigational Products
Table 3
Study Treatments
Treatment*
Treatment*
Run-in/Washout
Study 
treatment 
name:
Budesonide and 
formoterol 
fumarate (BFF) 
MDI 320/9.6 µg
Symbicort 
Turbuhaler 320/9 µg
Berodual Respimat 
20/50 µga
Budesonide 
MDI 320 µg
Dosage 
formulation:
160/4.8 µg per 
actuation
160/4.5 µg per 
inhalation
20/50 µg per 
actuation
160 µg per 
actuation
Route of 
administration 
Oral inhalation via 
an AeroChamber 
Plus Flow-Vu 
spacer device
Oral inhalation
Oral inhalation
Oral 
inhalation
Dosing 
instructions:
2 inhalations twice 
daily
2 inhalations twice 
daily
1 inhalation 4 times a 
day
2 inhalations 
twice daily
Total daily dose
640/19.2 µg
640/18 µg
80/200 µg
640 µg
Packaging and 
labelling
Study treatment 
will be provided in 
MDI.  Each MDI 
will be labelled in 
accordance with 
Good 
Manufacturing 
Practice (GMP) 
Annex 13 and per 
country regulatory 
requirement.
Study treatment will 
be provided in DPI.  
Each DPI will be 
labelled in 
accordance with 
GMP Annex 13 and 
per country 
regulatory 
requirement.
Study treatment will 
be provided in MDI.  
Each MDI will be 
labelled in 
accordance with 
GMP Annex 13 and 
per country 
regulatory 
requirement.
Study 
treatment will 
be provided in 
MDI.  Each
MDI will be 
labelled in 
accordance 
with GMP 
Annex 13 and 
per country 
regulatory 
requirement.
a. If additional sites are added to the study and Berodual is not available to those sites, Combivent 20/100 µg 
will be provided.
* Investigational Product
Ventolin HFA will be provided to take 2 inhalations as needed to relieve COPD symptoms 
throughout the study but should be withheld for 6 hours prior to lung function assessments.  
Ventolin HFA should not be used with the study provided AeroChamber spacer device.
6.2
Preparation/Handling/Storage/Accountability
All clinical drug supplies should be kept in a locked cabinet or room with limited access.  The 
temperature of the sites’ storage area for study treatments must be monitored by site staff for 

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temperature ranges consistent with those specified for each product as outlined below.  
Documentation of temperature monitoring should be maintained at the site and available for 
review.

MDIs supplies contain contents under pressure. Do not use or store near heat or open 
flame.  Exposure to temperatures above 49ºC (120ºF) may cause bursting. Never 
throw clinical drug canisters into a fire or incinerator.  Avoid spraying in eyes.

Symbicort Turbuhaler should be stored below 30ºC (86ºF). For best results, the inhaler 
should be at room temperature before use.

Budesonide MDI and BFF MDI should be stored below 25ºC (77ºF) in a dry place; 
excursions permitted up to 30ºC (86ºF). Do not freeze.

Berodual should be stored between 15ºC (59ºF) and 30ºC (86ºF); Do not freeze.

Ventolin should be stored between 20ºC (68ºF) and 25ºC (77ºF); excursions permitted 
from 15ºC to 30ºC (59ºF to 86ºF).
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.
Instructions for priming and use of the BFF MDI and budesonide MDI are provided in 
Appendix D and Appendix E, respectively.  Instructions for the use of Symbicort Turbuhaler is
provided in Appendix F.  The technique for inhalation from an MDI with a spacer (BFF) is 
different from the technique used with a DPI (Symbicort).  It is important to ensure that subjects 
apply correct inhalation technique for both types of inhalers in order to participate in the study.  
Training devices will be available at the study site for instructional purposes, as well as for 
subjects to practice the correct inhalation technique.  Note:  Instruction and practice should 
occur prior to dispensing study medication and review of subjects’ inhalation technique 
should be done at each visit.  Retraining should occur if required.
All MDIs must be primed before the first use.  Priming involves releasing a certain number of 
sprays (4) into the air before the first use of the inhalers.  Shaking and priming the inhaler fills a 
chamber inside the canister with the correct dose and mix of medication so that the inhaler is 
ready to use.
Prior to the first use of Symbicort Turbuhaler, the device must be prepared as follows:

Unscrew the cover and lift it off.  You may hear a rattling sound.

Hold the Turbuhaler upright with the red grip at the bottom.

Turn the red grip as far as it will go in one direction.  Then turn it as far as it will go in 
the other direction (it does not matter which way you turn first).  You should hear a 
click sound.

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
Do this again, turning the red grip on both directions.

The Turbuhaler is now ready for use.
Specific precautions should be taken to prevent any contamination of collected PK samples by 
the particles of IP inhalations.  All devices must be primed in a separate room (i.e., a different 
room than will be used to administer IP to subjects) by study personnel before the first use.  
Administration of IP will take place in a room separate from the room where blood samples are 
drawn.
The AeroChamber Plus Flow-Vu valve holding chamber (VHC) can be used directly out of the 
package.  Before use, the VHC cap is to be removed and the chamber is to be examined for any 
obvious defects.  Refer to Appendix F for instructions for use of the AeroChamber Plus Flow-Vu 
VHC.
Store the VHC at room temperature and keep dry.
Ventolin HFA should not be used with the study provided AeroChamber spacer device.
Only subjects enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment.  All study treatments 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 authorized site staff.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
For each subject, all used study treatment materials will be collected.  Used subject supplies will 
be kept at room temperature in a secure and locked cabinet until returned to Astra Zeneca or 
designee.
Note:  Used study treatment will be stored separately from unused study treatment.
All product complaints (including device malfunctions) must be reported to Astra Zeneca using 
the Product Complains Form provided in each site’s regulatory binder.  Astra Zeneca will 
contact the site to evaluate the nature of the complaint and determine what further action is 
needed.
6.3
Measures to Minimise Bias:  Randomization and Blinding
All subjects will be centrally assigned to randomized study treatment sequence using an 
interactive web response system (IWRS).  Before the study is initiated, the log-in information 
and directions for the IWRS will be provided to each site. 

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If a subject withdraws from the study, then his/her subject identifier cannot be reused. Subjects 
who were discontinued due to COVID-19 and invited back to take part in the study as new 
subjects will be provided a new subject identifier and randomization code.
Clinical supplies will be packaged to support enrolment of the study.  Study personnel will have 
access to an IWRS to allocate subjects and to assign drug to subjects.  Clinical supplies will be 
packaged according to a component schedule generated by the Sponsor.  Each person accessing 
the IWRS must be assigned an individual unique personal identification number (PIN).  They 
must use only their assigned PIN to access the system and they must not share their assigned PIN 
with anyone. 
This is an open-label study for the personnel at study sites; the specific treatment to be taken by a 
subject will be assigned using an IWRS.  The site will contact the IWRS prior to the start of 
study treatment administration for each subject.  The site will record the treatment assignment on 
the applicable electronic case report form (eCRF) page, if required.  Potential bias will be 
reduced through central randomization.
Randomization will be stratified by the Visit 3 PIF set to Turbuhaler S resistance (<40 L/min 
versus ≥40 L/min).
6.4
Treatment Compliance
Administration of study medication (including rescue Ventolin HFA) should be recorded on the 
paper diary provided to the subject.
Study treatment compliance will be checked at all visits.  Treatment compliance will be verified 
through the subject reported IP intake from the paper diary.  The dose indicator reading will 
additionally be checked for consistency, to verify that subjects took IP as reported.  Dose 
indicator readings (to the nearest 10) and total inhalations reported in the paper diary will be 
recorded at the end of each treatment period.  Any issues identified will be documented in the 
appropriate study file and reinstruction will be completed as necessary.  Instructions for reading 
the dose indicator can be found in Appendix D.
6.5
Concomitant Therapy
6.5.1
Allowed Medications
Any current ongoing medications, including over-the-counter medications, herbal supplements, 
and vaccinations, will be allowed provided they are not explicitly prohibited by the protocol (see 
Table 5 and Table 6).  All concomitant medications taken during the study will be recorded on 
the concomitant medications eCRF page with indication, total daily dose, route of administration 
and dates of drug administration.  Any additions, deletions, or changes in the dose of these 
medications while in the study should be entered in the eCRF.  Subjects should also be instructed 
to contact the Investigator if they develop any illnesses, especially those requiring medicinal 
interventions.

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Subjects who are corticosteroid dependent and maintained on an equivalent of up to 5 mg of 
prednisone per day or up to 10 mg every other day for at least 3 months prior to Visit 1 are 
eligible for enrollment.
Ventolin HFA will be provided and is allowed as rescue medication throughout the study; 
however, no dose shall be taken ≤6 hours prior to a clinic visit, including Visit 2.  Ventolin HFA 
should not be used with the study provided AeroChamber spacer device.
Table 4 lists COPD and allergy medications that are allowed as long as the subject has been on a 
stable dose for at least 30 days prior to Visit 1 and remains on a stable dose throughout the study.
Table 4
Allowed COPD and Allergy Medications
Leukotriene antagonists (e.g., zafirlukast, montelukast, zileuton)
Cromoglycate
Nedocromil
Ketotifen (eyedrops and inhalation solution, where available)
Intranasal corticosteroids, intranasal antihistamines, or combination thereof
Note:  Use of cutaneous topical medications, including cutaneous topical corticosteroids, are permitted provided 
they are not applied to more than 20% of the subject’s body service
6.5.2
Prohibited Medications
6.5.2.1
Prohibited COPD Medications
Specific COPD medications that are prohibited beginning at Visit 1 and their required washout 
periods prior to Visit 2are displayed in Table 5.

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Table 5
COPD Medications Prohibited Beginning at Visit 1 and Required 
Washout Period Prior to Visit 2 
Medication
Minimum Washout Period Prior to Visit 2
LAMAs
Tiotropium:  14 days
Aclidinium:  7 days
Glycopyrronium:  7 days
Umeclidinium:  7 days
SAMAs
6 hours
LABAs (inhaled)
7 days (14 days for indacaterol and olodaterol)
Fixed-combinations of LABA/LAMA
7 days (14 days for indacaterol/glycopyrronium and 
olodaterol/tiotropium)
Fixed combinations of LABA/ICSa
7 days
Fixed combinations of SABAs and SAMAsb
6 hours
SABAsc
6 hours
Oral β-agonists
2 days
Theophylline (total daily dose >400 mg/day)d
7 days
a.
With the exception of budesonide MDI (where applicable) provided by the Sponsor at Visit 1 and observe washout of 12 
hours prior to study visits
b.
With the exception of Berodual provided by the Sponsor at Visit 1 (observe washout of 6 hours at Visit 1 and prior to 
study visits)
c.
Discontinue and use only Sponsor provided rescue Ventolin HFA throughout the study (observe washout of 6 hours prior 
to study visit)
d.
Theophylline (≤400 mg/day) is permitted provided the subject has been on a stable dose of therapy for at least 4 weeks 
prior to Randomization
6.5.2.2
Prohibited Non-COPD and Non-Respiratory Medications and Washout Periods
Subjects requiring medications presented in Table 6 are prohibited from participating in this 
study.  Subjects who recently discontinued use of these medications may be considered for study 
enrollment provided they have met the minimum cessation period prior to Visit 1.  These 
medications are prohibited through the course of the study.  If subjects require any of the 
prohibited medications listed in Table 6, the Investigator should discuss with the Medical 
Monitor the suitability of the subject continuing study treatment.

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Table 6
Prohibited Non-COPD and Non-Respiratory Medications
Class of Medicationa
Minimum Cessation Period Prior to 
Visit 1 and Prohibited Throughout the 
Study
Any drug with potential to significantly prolong the QT 
intervalb
14 days or 5 half-lives, whichever is longer
Other investigational drugs
30 days or 5 half-lives, whichever is longer
Non-selective β-blocking agents (except carvedilol)
7 days
Monoamine oxidase inhibitors
14 days
Monoclonal antibodiesc
30 days or 5 half-lives, whichever is longer
Systemic treatment with potent CYP3A4-inhibitors (e.g., 
ketoconazole, itraconazole, and ritonavir) and CYP3A4-
inducers (e.g., rifampin)
30 days
Systemic anticholinergicsd
7 days
Chinese complementary and alternative bronchodilatory 
medicines, i.e., herbal therapies (e.g., Astragalus 
membranaceus [huáng qí], Panax ginseng [ginseng 
products], and Cordyceps sinensis, A. membranaceus 
[ghost moth caterpillar fungus])
10 days
Note:  Benzodiazepines and selective serotonin re-uptake inhibitors are not exclusionary.
a.
Any medications that, in the opinion of the Investigator, would impact the safety of the study or the outcome 
of the study is prohibited.
b.
Subjects who are on medications that have the potential to prolong the QTc interval may be enrolled 
provided the dose has remained stable for at least 3 months prior to Visit 1, the subject meets all of the ECG 
inclusion criteria and none of the ECG exclusion criteria, and if, in the opinion of the Investigator, there are 
no safety concerns for the subject to participate in the study.  Initiation of medications with the potential to 
significantly prolong the QT interval is prohibited throughout the Screening and Randomized Treatment 
Periods.
c.
Investigators should contact the Medical Monitor to determine the appropriateness and safety of continuing 
study drug on a case by case basis (e.g., XOLAIR® [omalizumab] will not be allowed, whereas a monoclonal 
antibody for another indication, such as osteoporosis, may be allowed after consultation with the Medical 
Monitor).
d.
If systemic anticholinergics are used for the treatment of overactive bladder and the treatment has been 
constant for at least 1 month, they are allowed.  

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6.5.3
Other Concomitant Treatment
Medication other than that described above, which is considered necessary for the subject’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF.
6.6
Dose modification
Not applicable for this study.
6.7
Treatment After the End of the Study
At the end of the Randomized Treatment Period, the Investigator should prescribe alternative 
COPD therapy for the subject.  There will be no provisions to supply BFF MDI or Symbicort 
Turbuhaler after the end of the treatment period.
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
7.1
Discontinuation of Study Treatment 
Subjects may be discontinued from IP in the following situations: 

Subject decision.  The subject is at any time free to discontinue treatment, without 
prejudice to further treatment

Adverse event (e.g. paradoxical bronchospasm, severe allergic reaction)

Severe non-compliance with the Clinical Study Protocol 

Development of exclusion criteria or other safety reasons as judged by the Investigator
during the treatment period e.g COVID-19 pandemic related discontinuation (see 
details in section 4.1.1.1) 
See the SoA (Table 1) for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.1.1
Procedures for Discontinuation of Study Treatment
The Investigator should instruct the subject to contact the site before or at the time if study 
treatment is stopped.  A subject that decides to discontinue study treatment will always be asked 
about the reason(s) and the presence of any AEs.  The date of last intake of study treatment 
should be documented in the eCRF.  All study treatment should be returned by the subject at 
their next on-site study visit or unscheduled visit.  Subjects permanently discontinuing study 
treatment should be given locally available standard of care therapy, at the discretion of the 
Investigator.

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7.2
Lost to Follow-Up
A subject will be considered potentially lost to follow-up if he or she fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule.

Before a subject is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the subject by repeat telephone calls.  These contact 
attempts should be documented in the subject’s medical record.

Should the subject be unreachable at the end of the study, the subject should be 
considered to be lost to follow-up.
7.3
Withdrawal From the Study
A subject may withdraw from the study (e.g., withdraw consent), at any time (IP and
assessments) at his/her own request, without prejudice to further treatment.
If the subject withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.
If a subject withdraws from the study, he/she may request destruction of any samples taken, and 
the Investigator must document this in the site study records.  
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs.  The Investigator will follow up subjects as medically indicated.
See SoA (Table 1), for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. All study treatment should be returned
by the subject.
7.4
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate or place the study on 
hold at any time for any reason at the sole discretion of the sponsor. The study may be stopped if, 
in the judgment of AstraZeneca, trial subjects are placed at undue risk because of clinically 
significant findings that:

meet individual stopping criteria or are otherwise considered significant

are assessed as causally related to study drug,

are not considered to be consistent with continuation of the study

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Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests
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 the sponsor or 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, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator 

Discontinuation of further study intervention development
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA (Table 1).
The Investigator will ensure that data are recorded on the eCRF.
The Investigator ensures the accuracy, completeness, legibility and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement.  The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs 
will be archived at the study site.
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue study treatment.
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 subjects 
meet all eligibility criteria.  The Investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.  

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8.1
Efficacy Assessments 
8.1.1
Pulmonary Function Tests
All pulmonary function tests (PFTs) including FEV1 and FEV1/FVC as defined in ATS/ERS 
guidelines will be performed in accordance with ATS criteria (Appendix H, Miller, 2005) and 
will be assessed using a spirometer that meets or exceeds minimum performance
recommendations of the ATS (Appendix I).  Pulmonary function tests will be limited to 3 
attempts.  Every effort should be made to get 3 reproducible and acceptable maneuvers; 
however, if this is not possible, the best of the 3 attempts will be recorded.
To standardize spirometry, all sites will be provided with identical spirometry systems 
(eResearch Technology [ERT], Philadelphia, PA, US) with customized, study-specific software.  
All study staff responsible for performing PFTs will receive standardized training.  As much as 
possible, spirometry assessments should be administered by the same person across the study 
population.
The volume accuracy of the spirometer is to be checked daily using a 3 L syringe across 3 flow 
ranges (i.e., low, medium, and high flows), with temperature and barometric pressure correction.  
The calibration syringe must meet ATS specifications and must not be used beyond the expiry 
date.  Required accuracy is ±3% (i.e., 3.09 L to 2.91 L; ATS/ERS).  The results will be printed 
and maintained in a calibration log, which will be monitored for compliance during the 
monitoring visits.
As spirometry results are primary and secondary efficacy endpoints for this study, it is important 
for the medication withholding conventions and timing of spirometry to be consistently managed 
throughout the study.
Spirometry collection is briefly outlined below.  For exact spirometry collection and 
specifications, please refer to the SoA (Table 1).
At Visit 2, spirometry assessments will be obtained approximately 45 minutes pre-bronchodilator 
and 30 to 60 minutes post-bronchodilator.  Reversibility will be calculated to characterize the 
subject population.  Reversibility is defined as ≥12% and ≥200 mL improvement in baseline 
FEV1 following administration of 4 puffs of Ventolin HFA.  The procedure is as follows:

Perform pre-bronchodilator PFT approximately 45 minutes prior to administration of Ventolin 
HFA

Administer 4 puffs of Ventolin HFA

Perform post-bronchodilator PFT within 30 to 60 minutes after administration of Ventolin
HFA
At Visits 3 and 5 (Day 1 of each Treatment Period), spirometry will be obtained approximately 
45 minutes pre-dose and 2 hours post-dose.  At Visits 4 and 6 (Day 8 of each Treatment Period) 
spirometry will be obtained approximately 45 minutes pre-dose and 30 minutes and 1, 2, and 4 

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hours post-dose.  If spirometry and PK assessments are to be performed at the same timepoint, 
PK samples should be drawn first followed by spirometry measurements.  Spirometry will be 
collected at the Early Discontinuation/Withdrawal Visit only if the subject is still taking IP (last 
dose of IP on day before or day of visit).
FEV1 baseline stability criteria at Visit 3 (as defined in section 5.3) must be met in order for 
subjects to be randomized to treatment.
8.1.2
Peak Inspiratory Flow
Training for the use of the InCheck Inspiratory Flow Measurement Device will be provided to 
the subject at Visit 2.  For instructions on the InCheck Inspiratory Flow Measurement Device see 
Appendix J.
Peak inspiratory flow collection is briefly outlined below.  For exact PIF collection and 
specifications, please refer to the SoA (Table 1).
At Visits 2, 3, 4, 5, and 6 (Screening and Days 1, 8, 22, and 29), PIF will be measured with the 
InCheck Inspiratory Flow Measurement Device set to no resistance and then repeated with the 
resistance equal to Turbuhaler S and then equal to ELLIPTA.  For each resistance level, triplicate 
measurements of pre-dose PIF assessment will be conducted and all 3 measurements will be 
captured in the eCRF.  The average of the 3 measurements with the device set to Turbuhaler S 
resistance will be used to determine eligibility at Visit 2 and Visit 3.
8.1.3
Inspiratory Capacity
On Day 1 of each Treatment Period (Visits 3 and 5), IC assessments will be conducted 
approximately 45 minutes pre-dose and prior to any other spirometry assessments and 2 hours 
post-dose.  On Day 8 of each Treatment Period (Visits 4 and 6), IC assessments will be 
conducted 2 hours post-dose.
All subjects will be instructed on the performance of the IC maneuver.  Subjects must be tested 
in the seated position wearing a nose clip with no air leaks between the mouth and the 
mouthpiece.  Subjects should be relaxed with shoulders down and asked to breathe regularly for 
several breaths until the end-expiratory lung volume is stable (this usually requires at least 5 tidal 
maneuvers).  The subject is then urged to take a deep breath to total lung capacity with no 
hesitation.  
Inspiratory capacity tests will be limited to 3 attempts.  Every effort should be made to get 3 
acceptable trials; however, if this is not possible, the best (highest value) of the 3 attempts will be 
recorded.
8.1.4
Chronic Obstructive Pulmonary Disease Assessment Test (CAT)
The CAT is an 8-item Patient Reported Outcomes developed to measure the overall impact of 
COPD on health status [Jones, 2009, Appendix K].  The instrument uses semantic differential 

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six-point response scales which are defined by contrasting adjectives to capture the impact of 
COPD.  Content includes items related to cough, phlegm, chest tightness, breathlessness going 
up hills/stairs, activity limitation at home, confidence leaving home, sleep and energy.  A CAT 
total score is the sum of item responses.  Scores range from 0-40 with higher scores indicative of 
greater COPD impact on health status.
Subjects will complete the CAT at Visit 2 for screening purposes only.  
8.2
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1).
8.2.1
Clinical Laboratory Assessments
Clinical safety laboratory tests will be analyzed by a local laboratory according to standardized, 
validated assays for screening purposes only.  See Table 7 for the list of clinical safety laboratory 
tests to be performed at Screening (Visit 1).
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at the 
center as source data for laboratory variables.  
Table 7
Laboratory Safety Variables
Hematology (whole blood)
Clinical Chemistry (serum or plasma)
Hemoglobin
Creatinine
White blood cell count with differential
Potassium
Eosinophil count
Sodium
Liver Enzyme/Other Liver Function Tests
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
8.2.2
Physical Examinations and Other Screening Assessments
Medical history including smoking status will be collected at Visit 1.  The number of COPD 
exacerbations requiring oral corticosteroids and/or antibiotics, or hospitalization within 12 
months of Visit 1 will be collected.
A complete physical examination will be performed at Visit 1 and include assessment of the 
following:  general appearance, respiratory, cardiovascular, and abdomen.  Weight assessed in 
ordinary indoor clothing with shoes removed and height will be recorded at Visit 1.

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Vital signs (blood pressure and pulse) and ECGs will be performed for screening purposes only.
8.3
Collection of Adverse Events
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 L.
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative).  
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE.  For information on how to follow-up AEs see 
Section 8.3.3.  
8.3.1
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.3.2
Time Period and Frequency for Collecting AE and SAE Information 
Non-serious adverse events will be collected from Randomization throughout the Treatment 
Period and including the washout and follow-up periods.
Serious adverse events will be recorded from the time of signing of informed consent form.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix L.  The Investigator will submit any updated SAE data to the Sponsor within 24 
hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study subjects; however, if 
the Investigator learns of any SAE, including a death, at any time after a subject’s last visit and 
he/she considers the event to be reasonably related to the study treatment or study participation, 
the Investigator may notify the Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix L.
8.3.3
Follow-Up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts.  All SAEs and non-serious AEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up 

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Any AEs that are unresolved at the subject’s last AE assessment 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 subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
Adverse Event Data Collection
'The following variables will be collected for each AE;

AE (verbatim)

The date when the AE started and stopped

Maximum intensity

Whether the AE is serious or not

Investigator causality rating against the IP(s) (yes or no)

Action taken with regard to IP(s)

AE caused subject’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date Investigator became aware of SAE

AE is serious due to

Date of hospitalization

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
8.3.5
Causality Collection
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the IP?’

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For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix L.
8.3.6
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the subject or reported in response to the open question from 
the study site staff: ‘Have you/the child 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.
8.4
Safety Reporting and Medical Management
8.4.1
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigator or other site personnel 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 works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
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 is undertaken immediately.  Investigators or other site personnel 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.
For further guidance on the definition of a SAE, see Appendix L 2.
AstraZeneca will provide Regulatory Authorities, Ethics Committees, and Principal Investigators 
with safety updates/reports according to local requirements.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca from Visit 1 until 
study completion.

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If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal Exposure
If a subject becomes pregnant during the course of the study, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may 
have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality) should be followed up and documented even if the subject was 
discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no later 
than 24 hours of when 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 1 or 5 calendar 
days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
8.4.3
Overdose
For this study, any dose of BFF MDI greater than 320/9.6 µg twice daily will be considered an 
overdose.
The Sponsor does not recommend specific treatment for an overdose.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives immediately, 
or no later than 24 hours of when he or she becomes aware of it.

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The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 8.4.1.  
For other overdoses, reporting must occur within 30 days.
8.4.4
Medication Error
If a medication error occurs in the course of the study, the Investigator or other site personnel 
informs the appropriate AstraZeneca representative within 1 day i.e., immediately, but no later 
than 24 hours of when he/she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow-up Fatal/Life-
Threatening) or 5 (other serious initial and follow-up) calendar days if there is an SAE associated 
with the medication error (see Section 8.4.1) and within 30 days for all other medication errors.
The definition of Medication Error can be found in Appendix L 8.
8.5
Pharmacokinetics
Pharmacokinetic assessments will be obtained at Visits 4 and 6 (after the morning dose on Day 8 
of each treatment period).  Sample collections will be scheduled for the nominal timepoint and 
actual collection times will be recorded in the source documents.
8.5.1
Procedure for Blood Sample Collection and Schedule
Pre-dose Administration Sample Collection – Visits 4 and 6:  Approximately 10 mL of whole 
blood will be collected within 30 minutes before administration of study drug.
Post-dose Administration Sample Collection – Visits 4 and 6:  Approximately 10 mL of whole 
blood will be collected at 2, 5, 20, 30, and 40 minutes and 1, 2, 3, and 4 hours post-dose.
If spirometry and PK assessments are to be performed at the same timepoint, PK samples should 
be drawn first followed by spirometry measurements.
Collection and storage of PK samples will be detailed in the laboratory manual.
8.5.2
Determination of Drug Concentration
Samples for determination of budesonide and formoterol concentration in plasma will be 
analyzed by Covance on behalf of AstraZeneca using an appropriate bioanalytical method.  Full 
details of the analytical method used will be described in a separate bioanalytical report.

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8.5.3
Storage and Destruction of PK Samples
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 6 
months after issuance of the draft Bioanalytical Report (whichever is earlier), unless requested 
for future analyses. 
Pharmacokinetic samples may be disposed of or destroyed and anonymized by pooling.  
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method.  Any results from such analyses may be reported 
separately from the clinical study report. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of 
the test samples.  The results from the evaluation will not be reported in the clinical study report 
but separately in a bioanalytical report.
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7
Genetics
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data is not evaluated in this study.  
9.
STATISTICAL CONSIDERATIONS 
9.1
Statistical Hypotheses
The purpose of this pilot study is to obtain reasonable estimates of treatment effects related to 
device, as well as variability, for the primary and secondary endpoints. These will be used to 
further inform on the design and sample size needed for future studies. Therefore, the focus will 
be on estimation of individual treatment effects and estimated differences between the 
treatments. Therefore, there will be no formal hypothesis testing for this pilot study, and 
exploratory hypotheses only will be evaluated.
9.2
Sample Size Determination 
A total of approximately 30 subjects, 15 per sequence, (with at least 26 subjects completing the 
study) are planned to be randomized in this study.  The sample size has been selected based on 
practical considerations to obtain reasonable estimates for the primary and secondary objectives 
of this study, which will be used to further inform on the design and sample size needed for 
future studies.

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9.3
Populations for Analyses
For purposes of analyses, the following populations are defined:
Population
Description
Enrolled 
All subjects who sign the ICF.
Intent-to-Treat (ITT) 
Population
All subjects who are randomized to treatment and receive at least one 
dose of study treatment.  Subjects will be analyzed according to the 
treatment they were assigned to as randomized, regardless of the 
treatment actually received.
Subjects affected by the study being put on hold for the COVID-
19 pandemic will be handled as follows:

Subjects who were discontinued due to the study being 
put on hold and who restarted the study will only be 
included in the ITT analysis set for the instance of 
enrolment after they restarted. 

Discontinued subjects who do not restart will be included 
in the ITT analysis set. 
This ensures that all randomized subjects are included in the ITT 
set once and once only.
Modified ITT (mITT) 
Population
All subjects in the ITT Population with post-baseline spirometry data 
from both treatment periods at Visits 4 and 6.  Data judged to be 
impacted by major protocol violations will be excluded.  Subjects will 
be analyzed according to the treatment they were assigned to as 
randomized.
Subjects affected by the study being put on hold for the COVID-
19 pandemic will be handled as follows:

Subjects who were discontinued due to the study being 
put on hold and who restarted the study will only be 
included in the mITT analysis set for the instance of 
enrolment after they restarted, if they have post-baseline 
spirometry data for both treatment periods after restart 
and meet the definition described above. 

Discontinued subjects who do not restart will not be 
included in the mITT analysis set as they will not have 
post-baseline spirometry data from both treatment 
periods. 
This ensures that all randomized subjects are included in the 
mITT set at most once, if they meet the relevant definition.

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Safety Population
All subjects who are randomized to treatment and receive at least one 
dose of the study treatment.  Subjects will be analyzed according to the 
treatment actually received.
Subjects affected by the study being put on hold for the COVID-
19 pandemic will be handled as follows:

Subjects who were discontinued due to the study being 
put on hold and who restarted the study will only be 
included in the Safety analysis set for the instance of
enrolment after they restarted. 

Discontinued subjects who do not restart will be included 
in the Safety analysis set. 
This ensures that all randomized subjects are included in the 
Safety set once and once only.
PK Population
All subjects in the mITT population with Cmax defined in both 
treatment periods.  Subjects will be analyzed according to the treatment 
actually received.
Important protocol deviations and those which lead to exclusion from the mITT population will 
be described in the statistical analysis plan and confirmed prior to unblinding of the study. 
Demographics and other baseline characteristics will be summarized using the ITT and mITT 
Populations.  The mITT Population will be used to summarize the primary and secondary 
efficacy variables.  The ITT Population will be used for sensitivity analyses for the primary 
endpoint.  The Safety Population will be used to summarize safety data. Pharmacokinetic 
Population will be used to summarize the PK analyses.
As there will be some subjects who were discontinued due to COVID-19, who will be invited 
back to the study after study restart, there will be data on these subjects from two instances: 
before and after the study being put on hold. Data on these subjects from both instances will be 
presented in listings. Only subjects having complete data from both treatment periods, entirely 
before or entirely after study restart will be included in the mITT Population and used in primary 
efficacy analyses. If any of these subjects discontinue after restart, they will still be included in 
the ITT and Safety Population. 
Subjects who were randomized and discontinued due to the study being put on hold, but who 
choose not to come back after study restart will have their data included in the ITT and Safety 
Population only. 
9.4
Statistical Analyses
Analyses will be performed by AstraZeneca or its representatives.  A comprehensive statistical 
analysis plan will be developed and finalized before database lock and will describe the subject 

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populations to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data.  This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints.  Any deviations from this plan will be reported in the clinical study
report.
9.4.1
Baseline for Analyses
For all endpoints, baseline is defined as the mean of the pre-dose value from the start of each 
period at Visits 3 and 5.  This will be used for statistical analyses unless otherwise specified.
9.4.2
Visit Windows
No study time windows will be derived by visit and data will be presented according to the 
scheduled study day.  For spirometry endpoints by timepoint pre- and post-dosing, the 
assessments will be allocated to derived nominal collection time windows of minutes from IP 
dosing.  These will be specified in the Statistical Analysis Plan.  Actual time will be used for the 
AUC calculations.
9.4.3
Efficacy Analyses
All primary and secondary efficacy analyses will be conducted using the mITT Population.  In 
addition, a sensitivity analysis will be conducted for the primary endpoint using the ITT 
population.  Subjects will be analyzed according to the treatment randomized.
9.4.3.1
Primary Efficacy Analysis
Peak change from baseline in FEV1 within 4 hours post-dose following 1 week of treatment
Peak change from baseline in FEV1 within 4 hours post-dose is defined as the maximum of the 
FEV1 assessments within 4 hours post-dosing at each visit minus baseline, provided that there 
are at least 2 non-missing values during the first 4 hours post-dose.
The peak change from baseline in FEV1 will be analyzed in the mITT population using an 
analysis of covariance (ANCOVA) model with baseline FEV1, PIF at screening and reversibility 
to Ventolin HFA as continuous covariates and treatment, and period as categorical covariates.  
The model will include subject as a random effect to model correlation within subject across the 
study.  The model will not include treatment sequence unless that term is determined to be 
important (p<0.10).  95% confidence intervals (CIs) will be produced.  P-values will be produced 
to aid interpretation although these will not be inferential.
9.4.3.2
Analysis of Secondary Efficacy Variables
FEV1 AUC0-4 h following 1 week of treatment
FEV1 AUC0-4 h will be calculated using the trapezoidal rule and will be normalized by dividing 
by the time in hours from dosing to the last measurement included (typically 4 hours).  Only one 
non-missing post-dose value is required for the calculation of AUC.  It will be analyzed in a 
similar fashion to the primary efficacy analysis.

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Change from baseline in pre-dose FEV1 following 1 week of treatment 
Change from baseline in pre-dose FEV1 following 1 week of treatment is defined as the 45-
minute pre-dose value following 1 week of treatment minus baseline.  In subjects missing either 
of these pre-dose assessments, the value will be calculated from the single measurement.  It will 
be analyzed in a similar fashion to the primary efficacy analysis.
Change from baseline in 2-hour post-dose IC following 1 week of treatment
Change from baseline in 2-hour post-dose IC following 1 week of treatment will be defined as 
the 2-hour post-dose assessment of IC following 1 week of treatment minus baseline IC and 
analyzed in a similar fashion to the primary efficacy analysis.
Change from baseline in pre-dose PIF following 1 week of treatment
Change from baseline in pre-dose PIF following 1 week of treatment will be defined as the pre-
dose PIF following 1 week of treatment minus baseline PIF and analyzed in a similar fashion to 
the primary efficacy analysis.
At each visit, PIF will be measured with the InCheck Inspiratory Flow Measurement Device set 
to no resistance and then repeated with the resistance equal to Turbuhaler S and then equal to 
ELLIPTA.  Change from baseline in pre-dose PIF with different resistances will be analyzed 
separately in a similar fashion.
Change from baseline in 2-hour post-dose FEV1 following the 1st dose of treatment
Change from baseline in 2-hour post-dose FEV1 following the 1st dose of treatment will be 
defined as the 2-hour post-dose assessment of FEV1 following the 1st dose of treatment (Visit 3 
or 5) minus baseline FEV1 and analyzed in a similar fashion to the primary efficacy analysis.
Change from baseline in 2-hour post-dose IC following the 1st dose of treatment
Change from baseline in 2-hour post-dose IC following the 1st dose of treatment will be defined 
as the 2-hour post-dose assessment of IC following the 1st dose of treatment (Visit 3 or 5) minus 
baseline IC and analyzed in a similar fashion to the primary efficacy analysis.
Supportive analyses
A sensitivity analysis will be conducted for the primary endpoint in the ITT population using a 
similar ANCOVA model.  Sensitivity analyses will be considered in the ITT population for the 
secondary endpoints should the mITT and ITT populations differ substantially.
Subgroup analyses based upon PIF at screening will also be performed for primary and 
secondary endpoints.  The relationship of treatment effects to PIF will be investigated 
graphically.

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An additional sensitivity analysis to assess the impact of COVID-19 related study restart will be 
carried out and details will be outlined in the SAP. 
9.4.3.3
Estimand
The estimand of interest is the per protocol estimand.  This is the effect of the randomized 
treatment in all subjects who are compliant with the protocol (no major protocol violations), 
including the use of randomized medication.  This will enable estimation of the effects that could 
be attributed purely to device, rather than to adherence or other factors.
Analyses for the per protocol estimand will be conducted using the mITT Population where only 
data from subjects completing both treatment periods, without major protocol violations, will be 
utilized.  
9.4.1
Safety Analyses
All safety summaries will be performed on the Safety Population.  Subjects will be analyzed 
according to the actual treatment received.
Adverse events in each Treatment Period will be summarized by the number of subjects 
experiencing an event.  They will be tabulated at the level of the Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term and the MedDRA system organ class.  The 
version of MedDRA current at the time of database lock will be used for the final analysis of 
data.  Tabulations will be broken down by intensity, seriousness, AEs leading to discontinuation 
of study drug, and by relationship to study drug.  No hypothesis tests will be performed.  Tables 
will show the overall incidence of AEs, and the incidence for each treatment.
9.4.2
Pharmacokinetic Analyses
Pharmacokinetic and statistical analysis will be performed using the PK population.  The 
estimation of PK parameters will be performed using non-compartmental methods. 
Pharmacokinetic parameters calculated using pre-defined post-dose serial blood draws over 4 
hours on after the last dose (in the morning on Day 8) of each Treatment Period will include the 
following:

Cmax

AUC0-4

tmax

Ctrough
Other PK parameters may be calculated, as appropriate.
Descriptive statistics for plasma concentrations of budesonide and formoterol by treatment and 
nominal time point will be summarized on the raw and log-normal scales using the PK 

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Population.  Individual plasma concentration at each nominal and actual time point for each 
treatment will be listed by subject using the Safety Population.
All budesonide and formoterol PK parameters will be listed and summarized by treatment using 
appropriate descriptive statistics. 
The log transformed Cmax will be analyzed for PK Population using an ANCOVA model with 
treatment, period as categorical covariates.  The model will include subject as a random effect to 
model correlation within subject across the study.  The model will not include treatment 
sequence unless that term is determined to be important (p<0.10).  Ratios and 90% CIs for Cmax
will be produced by back transformation.  AUC0-4 will be analyzed similarly.
9.4.3
Methods for Multiplicity Control
As this is a pilot study, without formal hypothesis testing, no correction for multiplicity will be 
applied.
9.5
Interim analyses 
Not applicable

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10.
REFERENCES
Altman P, Wehbe L, Juergen D, et al.  Comparison of peak inspiratory flow rate via the 
Breezhaler®, Ellipta® and HandiHaler® dry powder inhalers in patients with moderate to very 
severe COPD: a randomized crossover trial.  BMC Pulmonary Medicine 2018;18:100-107.
Celli B, MaNee W, Agusti A, et al.  Standards for the diagnosis and treatment of subjects with 
COPD:  as summary of the ATS/ERS position paper.  Eur Respir J 2004;23:932-946.
Ferguson GT, Papi A, Anzueto A, et al.  Budesonide/formoterol MDI with co-suspension 
delivery technology in COPD:  the TELOS study.  Eur Respir J 2018;52:1801334.
Global Strategy for the Diagnosis, Management, and Prevention of COPD.  Global Initiative for 
Chronic Obstructive Lung Disease (GOLD) 2018.  Available online at:  
http://www.goldcopd.org.
Jones PW, Harding G, Berry P, et al.  Development and first validation of the COPD Assessment 
Test.  Eur Respir J 2009;34:648-654.
Loh CH, Peters SP, Lovings TM, Ohar JA.  Suboptimal Inspiratory Flow Rates Are Associated 
with Chronic Obstructive Pulmonary Disease and All-Cause Readmission.  AnnalsATS 
2017;14(8):1305-1311.
Mahler DA.  Peak Inspiratory Flow Rate as a Criterion for Dry Powder Inhaler Use in Chronic 
Obstructive Pulmonary disease.  Ann Am Thorac Soc 2017;14(7):1103-1107.
Miller MR, Hankinson J, Brusasco V, et al.  Standardisation of spirometry.  Eur Respir J 
2005;26(2):319-338.
Sharma G, Mahler DA, Mayorga VM, et al.  Prevalence of Low Peak Inspiratory Flow Rate at 
Discharge in Patients Hospitalized for COPD Exacerbation.  JCOPD 2017;4(3):217-224.

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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Instructions for Use of Berodual Respimat

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Regulatory, Ethical and Study Oversight Considerations
B 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 and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable International Conference of Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) by the Investigator and reviewed and approved by the IRB/IEC before 
the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.  
The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulation (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and Human 
Biological Samples.
B 2
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of a 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. 

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The sponsor 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. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. 
For all studies except those utilizing 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 a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then file 
it along with the Investigator’s Brochure or and will notify the IRB/IEC, if appropriate according 
to local requirements.
B 3
Financial disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor 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 course of the study and for 
1 year after completion of the study.
B 4
Informed consent process
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorised representative and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) 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 subject 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.
Subjects must be re-consented 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 subject or the subject’s legally authorised 
representative.  
B 5
Data protection

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Each subject will be assigned a unique identifier by the Sponsor.  Any subject records or data 
sets transferred to the Sponsor will contain only the identifier; subject names or any information 
which would make the subject identifiable will not be transferred.  
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the subject.  
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
B 6
Committees structure
Not applicable
B 7
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available.  
The clinical trial and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.
B 8
Data quality assurance
All subject data relating to the study will be recorded on eCRF unless transmitted to the Sponsor 
or designee electronically (e.g., laboratory data).  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.  
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects 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 15 years after study completion unless local regulations or 

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institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the Sponsor.  No records may be transferred to 
another location or party without written notification to the Sponsor. 
B 9
Source documents
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected.  Source documents are filed at the Investigator’s site.
Data reported on 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.
B 10
Publication policy
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 the Sponsor before submission.  
This allows the Sponsor to protect proprietary information and to provide comments.  
The Sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the Sponsor 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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Instructions for Use of Ventolin HFA

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Clinical Study Protocol
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
Step 9: Rinse your mouth with water after your daily dosing in the morning 
and/or evening and spit it out

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Spirometry Performance Recommendations
Spirometry data of the highest quality must be obtained for proper interpretation of the results of 
this protocol.  To this end, a standard spirometer will be used (provided by ERT), central training 
provided, qualification will be required, and specific operating instruction will be provided.
FEV1 and FVC Maneuvers
Equipment Requirements
The spirometer must be capable of accumulating volume for >15 s (longer times are 
recommended) and measuring volumes of >8 L (body temperature (i.e., 37°C), ambient pressure, 
saturated with water vapor, BTPS) with an accuracy of at least +3% of reading or +0.050 L, 
whichever is greater, with flows between 0 and 14 L-s-1.  The total resistance to airflow at 
14.0 L-s-1 must be <1.5 cmH2O L-1s-1 (0.15 kPa L-1s-1).  The total resistance must be 
measured with any tubing, valves, pre-filter, etc. included that may be inserted between the 
subject and the spirometer.  Some devices may exhibit changes in resistance due to water vapor 
condensation, and accuracy requirements must be met under BTPS conditions for up to 8 
successive FVC maneuvers performed in a 10-minute period without inspiration from the 
instrument.
Display
For optimal quality control, both flow–volume and volume–time displays are useful, and test 
operators should visually inspect the performance of each maneuver for quality assurance before 
proceeding with another maneuver.  This inspection requires tracings to meet the minimum size 
and resolution requirements set forth in this standard.  Displays of flow versus volume provide 
more detail for the initial portion (first 1 s) of the FVC maneuver.  Since this portion of the 
maneuver, particularly the peak expiratory flow (PEF), is correlated with the pleural pressure 
during the maneuver, the flow–volume display is useful to assess the magnitude of effort during 
the initial portions of the maneuver.  The ability to overlay a series of flow–volume curves 
registered at the point of maximal inhalation may be helpful in evaluating repeatability and 
detecting sub-maximal efforts.  However, if the point of maximal inhalation varies between 
blows, then the interpretation of these results is difficult because the flows at identical measured 
volumes are being achieved at different absolute lung volumes.  In contrast, display of the FVC 
maneuver as a volume–time graph provides more detail for the latter part of the maneuver.  A 
volume–time tracing of sufficient size also allows independent measurement and calculation of 
parameters from the FVC maneuvers. In a display of multiple studies, the sequencing of the 
blows should be apparent to the user. For the start of test display, the volume–time display 
should include >0.25 s, and preferably 1 s, before exhalation starts (zero volume).  This time 
period before there is any change in volume is needed to calculate the back extrapolated volume 
(EV) and to evaluate effort during the initial portion of the maneuver.  Time zero, as defined by 
EV, must be presented as the zero point on the graphical output.  The last 2 s of the maneuver 
should be displayed to indicate a satisfactory end of test.

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

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Table A1-2. Summary of Equipment Quality Control
Test
Minimal
Interval
Action
Volume
Daily
Calibration check with a 3 L syringe
Leak
Daily
2 cm H2O (0.3 kPa) constant pressure for 1 minute
Volume
Linearity
Quarterly
1 L increments with a calibrating syringe measured over the
entire volume range
Flow
Linearity
Weekly
Test at least 3 different flow ranges
Time
Quarterly
Mechanical recorder check with stop watch
Software
New versions
Log installation date and perform test using “known” 
subject
Calibration is the procedure for establishing the relationship between sensor-determined values 
of flow or volume and the actual flow or volume.  A calibration check is different from 
calibration and is the procedure used to validate that the device is within calibration limits, e.g., 
+3% of true.  If a device fails its calibration check, then a new calibration procedure or 
equipment maintenance is required.  Calibration checks must be undertaken daily, or more 
frequently, if specified by the manufacturer.  The syringe used to check the volume calibration of 
spirometers must have an accuracy of +15 mL or +0.5% of the full scale (15 mL for a 3-L 
syringe), and the manufacturer must provide recommendations concerning appropriate intervals 
between syringe calibration checks.  Users should be aware that a syringe with an adjustable or 
variable stop may be out of calibration if the stop is reset or accidentally moved.  Calibration 
syringes should be periodically (e.g., monthly) leak tested at more than one volume up to their 
maximum; this can be done by attempting to empty them with the outlet corked.  A dropped or 
damaged syringe should be considered out of calibration until it is checked.
With regard to time, assessing mechanical recorder time scale accuracy with a stopwatch must be
performed at least quarterly.  An accuracy of within 2% must be achieved.
Quality Control for Volume-Measuring Devices
The volume accuracy of the spirometer must be checked at least daily, with a single discharge of 
a 3-L calibrated syringe.  Daily calibration checking is highly recommended so that the onset of 
a problem can be determined within 1 day, and also to help define day-to-day laboratory 
variability.  More frequent checks may be required in special circumstances, such as: 1) during 
industrial surveys or other studies in which a large number of subject maneuvers are carried out, 
the equipment’s calibration should be checked more frequently than daily; and 2) when the 
ambient temperature is changing (e.g., field studies), volume accuracy must be checked more 
frequently than daily and the BTPS correction factor appropriately updated.

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The accuracy of the syringe volume must be considered in determining whether the measured 
volume is within acceptable limits.  For example, if the syringe has an accuracy of 0.5%, a 
reading of +3.5% is appropriate.
The calibration syringe should be stored and used in such a way as to maintain the same 
temperature and humidity of the testing site.  This is best accomplished by keeping the syringe in 
close proximity to the spirometer, but out of direct sunlight and away from heat sources.
Volume-type spirometer systems must be evaluated for leaks every day.  The importance of 
undertaking this daily test cannot be overstressed.  Leaks can be detected by applying a constant 
positive pressure of >3.0 cmH2O (0.3 kPa) with the spirometer outlet occluded (preferably at or 
including the mouthpiece).  Any observed volume loss of 30 mL after 1 minute indicates a leak 
and needs to be corrected.
At least quarterly, volume spirometers must have their calibration checked over their entire 
volume range using a calibrated syringe or an equivalent volume standard.  The measured 
volume should be within +3.5% of the reading or 65 mL, whichever is greater.  This limit 
includes the 0.5% accuracy limit for a 3-L syringe.  The linearity check procedure provided by 
the manufacturer can be used if it is equivalent to one of the following procedures: 1) 
consecutive injections of 1-L volume increments while comparing observed volume with the 
corresponding cumulative measured volume, e.g., 0–1,1–2, 2–3,…6–7 and 7–8 L, for an 8-L 
spirometer; and 2) injection of a 3-L volume starting at a minimal spirometer volume, then 
repeating this with a 1-L increment in the start position, e.g., 0–3, 1–4, 2–5, 3–6, 4–7 and 5-8 L, 
for an 8-L spirometer.  The linearity check is considered acceptable if the spirometer meets the 
volume accuracy requirements for all volumes tested.
Quality Control for Flow-Measuring Devices
With regards to volume accuracy, calibration checks must be undertaken at least daily, using a 
3 L syringe discharged at least 3 times to give a range of flows varying between 0.5 and 12 L-s-1 
(with 3-L injection times of 6 s and 0.5 s).  The volume at each flow should meet the accuracy 
requirement of +3.5%.  For devices using disposable flow sensors, a new sensor from the supply 
used for patient tests should be tested each day.
For linearity, a volume calibration check should be performed weekly with a 3-L syringe to 
deliver 3 relatively constant flows at a low flow, then 3 at a mid-range flow and finally 3 at a 
high flow.  The volumes achieved at each of these flows should each meet the accuracy 
requirement of +3.5%.
VC Maneuvers
Equipment
For measurements of VC, the spirometer or flow meter must comply with the requirements for 
FVC (as described previously) and be capable of accumulating volume for >30 s.  Expiratory 

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maneuvers or, ideally, both inspiratory and expiratory maneuvers should be included in the 
display of VC maneuver.  Regardless of whether the inspiratory or expiratory maneuver is used 
for deriving measurements, a display of the entire recorded VC maneuver must be provided.  The 
maximal expiratory volume must be assessed to determine whether the subject has obtained a 
plateau in the expiratory effort.  For display of the slow VC, the time scale may be reduced to 5 
mm-s-1.
Technical Considerations
Minimal recommendations for spirometry systems
Accurate results require accurate equipment.  Spirometer equipment recommendations apply to 
all spirometers and are minimal requirements.  In some circumstances, it may be appropriate to 
exceed these requirements (i.e., in some research/surveillance applications).  Instrumentation 
recommendations should be followed to provide accurate spirometric data and information that is 
comparable from laboratory to laboratory and from one time period to another.  The accuracy of 
a spirometry system depends on characteristics of the entire system, from the volume or flow 
transducer and the use of an in-line filter, to the recorder, display or processor.  Changes in any 
aspect of the equipment or errors at any step in the process can affect the accuracy of the results.  
For example, if the BTPS correction factor is wrong, an accurately measured FVC will be 
incorrectly reported.  Spirometers are not required to measure all of the indices in Table A1-3 but 
must meet the recommendations for those that are measured.  Accuracy and repeatability 
recommendations apply over the entire volume range of the instrument.
Table A1-3. Range and Accuracy Recommendations Specified for Forced Expiratory 
Maneuvers
Test
Range/Accuracy (BTPS)
Flow
Range
(L-s-1)
Time
(s)
Resistance and
Back Pressure
Test Signal
VC
0.5–8 L, +3% of reading
or +0.050 L, whichever is 
greater
0-14
30
3-L Calibration
syringe
FVC
0.5–8 L, +3% of reading
or +0.050 L, whichever is 
greater
0-14
15
<1.5 cm H2O L-1 s-
1
(0.15 kPa L-1s-
1
24 ATS
waveforms, 3-
L Cal Syringe
FEV1
0.5–8 L, +3% of reading
or +0.050 L, whichever is 
greater
0-14
1
<1.5 cm H2O L-1 s-
1
(0.15 kPa L-1s-
1)
24 ATS
waveforms
Time
Zero
The time point from which
all FEVt measurements are 
taken.
Back extrapolation
FEVt: forced expiratory volume in t seconds

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BTPS correction
All spirometry values should be reported at BTPS by any method (measuring temperature and 
barometric pressure) proven effective by the manufacturer. For volume-type spirometers, the 
temperature inside the spirometer should be measured for each breathing maneuver.  Regardless 
of the BTPS correction technique used, the ambient temperature must always be recorded with 
an accuracy of +1°C.  In situations where the ambient air temperature is changing rapidly (>3°C 
in <30 min), continuous temperature corrections may be necessary.  Spirometer users should be 
aware of potential problems with testing performed at lower ambient temperatures: 17°C is the 
lower limit for ambient temperature, unless a manufacturer states that their spirometer will 
operate accurately at lower ambient temperatures.  If barometric pressure is not used in 
calculating the BTPS correction factor, the range of barometric pressures over which the BTPS 
correction factor is valid must be published.

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Spirometry Assessment Criteria
Acceptable Versus Usable Tests
Acceptable Tests must meet the following 7 Criteria:
1.   Acceptable start of exhalation with brisk upstroke, no hesitation or false start, and back
EV <5% of FVC or 0.150 L, whichever is the greater.  (Refer to example in Figure A2-1)
2.   No cough during the first second.
3.   No Valsalva maneuver.
4.   No leak.
5.   No obstruction of mouthpiece.
6.   No extra breaths.
7.   Plateau achieved, i.e., the volume-time curve shows no change in volume (<0.025 L) for
≥1 second, and the patient has tried to exhale for at least 6 seconds.
An acceptable test meets all 7 criteria listed. This is to be considered the “gold standard”.
Useable spirometry tracings are those that only meet criteria 1 and 2.  If only Usable tests are 
obtained, report results based on the 3 best Usable tests with observed limitations.
Pulmonary function tests will be limited to 3 attempts.  Every effort should be made to get 3 
reproducible and acceptable maneuvers; however, if this is not possible, the best of the 3 
attempts will be recorded.
Figure A2-1. Example of a Usable Spirogram

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The expanded version of the early part of a subject’s volume-time spirogram, illustrating back 
extrapolation through the steepest part of the curve, where flow is PEF, to determine the new 
“time zero”.  Forced vital capacity (FVC)-4.291 L; back extrapolated volume (EV) – 0.123 L 
(2.9% FVC): back extrapolation line through PEF.

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Instruction for Use of InCheck Inspiratory Flow Measurement 
Device

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COPD Assessment Test

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Adverse Event Definitions and Additional Safety Information
L 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a subject or clinical 
study subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended sign 
(e.g.  an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence.  An AE may occur at any time, including run-in or washout 
periods, even if no Study treatment has been administered.
L 2
Definitions of serious adverse event
A serious adverse event 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-subject hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity.  

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent one of the outcomes listed above.
L 3
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the subject’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused death (e.g., hepatitis that resolved without hepatic failure).
L 4
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, 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 subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
L 5
Important medical event or medical treatment

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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 jeopardize the subject 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
L 6
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 L 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 a SAE unless it meets the criteria shown in Appendix L 2.  On 
the other hand, a stroke that results in only a limited degree of disability may be considered a 
mild stroke but would be a SAE when it satisfies the criteria shown in Appendix L 2.
L 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there is 
a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course.  Exposure to suspect drug.  Has the subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 

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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 recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are facts 
(evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough information 
to make an informed judgment.  With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility.
L 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant or 
has the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error.  

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognized that could have led to an error

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Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g.  medication prepared incorrectly, even if it was not actually 
given to the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated e.g.  tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed e.g.  kept in the fridge when it should be at room 
temperature 

Wrong participant received the medication (excluding IWRS errors)

Wrong drug administered to participant (excluding IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) e.g.  forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.

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Study Instructions for Mitigation Due to Civil Crisis, Natural 
Disaster, or Public Health Crisis
To ensure clinical trial continuity in the case of study disruption due to civil crisis, natural 
disaster, or public health crisis, changes may be implemented in order to ensure the safety of trial 
participants, maintain compliance with good clinical practice (GCP), and minimize risks to trial 
integrity. Where allowable by local health authorities, ethics committees and healthcare provider 
guidelines (eg, hospital policies), these changes may include the following but is not limited to:

Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the informed consent form (ICF) should be signed at the participant’s 
next contact with the study site). Prior to informed consent form, local study institution or 
HA guidelines should be followed as appropriate.

Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. The 
investigator should confirm this with the designated study physician. Please refer to Section 
5.5 for additional information.
1.
COMMUNICATION BETWEEN SITES AND PARTICIPANTS
All communication between sites and participants should be in line with local and regional 
guidelines and captured in the study source documents. In the event of a crisis, the study team 
will outline the planned communication strategy in an email to the site. Communication should 
be compliant with all applicable privacy regulations. Methods of written communication may 
include clinic/participant, participant portals, direct email, or secure mail if other methods are not 
available. Staff must ensure that communications adhere to guidelines for the transfer and 
storage of data on digital channels. The guidelines include details about the use of data, 
encryption, servers, authentication, and audit trails. These standards are the responsibility of both 
the vendor and the health provider.
2.
RESCREENING OF PARTICIPANTS TO RECONFIRM STUDY ELIGIBILITY
2.1. Rescreening of Participants Who Were Previously Screen Failures Due to Study 
Disruption
A participant who failed screening due to study disruption may be rescreened in addition to any 
rescreening rules designated in the CSP. The investigator should confirm this with the designated 
study physician.
Screening procedures as designated in the CSP Section 5.5 should be followed.
2.2. Rescreening of Participants Who Were Previously Eligible for Entry into the 
Study but Not Dosed Due to Study Disruption

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During study disruption there may be a delay between confirming eligibility of a participants and 
either randomisation into the study or commencing of dosing with IP. If this delay is outside the 
screening window, the participants will need to be rescreened to reconfirm eligibility before 
commencing study procedures. This will provide another opportunity to re-screen a participant to 
any rescreening rules designated in the CSP. 
Screening procedures as designated in the CSP Section 5.5 should be followed.

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Abbreviations 
Abbreviation or 
special term
Explanation
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATS
American Thoracic Society
AUC0-4
area under the curve 0 to 4 hours
AUC0-4
Area under the concentration-time curve from 0 to 4-hours post-dose
BFF
budesonide and formoterol fumarate
BID
twice daily
CAT
COPD Assessment Test
CFR
Code of Federal Regulation
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum observed plasma concentration
Ctrough
the concentration at the end of the dosing interval
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
CPK-EPI
Chronic Kidney Disease Epidemiology Collaboration
CV%
coefficient of variation
DPI
dry powder inhaler
ECG
Electrocardiogram
eCRF
electronic case report form
ERS
European Respiratory Society
EV
extrapolated volume
FEV1
forced expiratory volume in 1 second
FVC
forced vital capacity
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HFA
Hydrofluoroalkane
HIPAA
Health Insurance Portability and Accountability Act

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Abbreviation or 
special term
Explanation
IC
inspiratory capacity
ICF
informed consent form
ICH
International Conference on Harmonisation
ICS
inhaled corticosteroid
IEC
Independent Ethics Committee
IP
investigational product
IRB
Institutional Review Board
ITT
Intent-to-Treat
IWRS
interactive web response system
LABA
long-acting beta2-agonist
MDI
metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified Intent-to-Treat
PEF
peak expiratory flow
PFT
pulmonary function test
PIF
peak inspiratory flow
PIN
personal identification number
PK
Pharmacokinetics
QID
four times a day
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
serious adverse event 
SABA
short-acting beta2-agonist
SAMA
short-acting muscarinic antagonist
SoA
Schedule of Activities
tmax
time to maximum observed peak concentration
VHC
valve holding chamber

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d5980c00023-csp-v4
Document Title:
D5980C00023 Clinical Study Protocol version 4
Document ID:
Doc ID-003998775
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
14:50 UTC
Content Approval
 14:28 UTC
Management Approval
 13:41 UTC
Content Approval
14:01 UTC
Content Approval
 13:40 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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