Clinical trial NCT05569421
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: Bioequivalence Propellant Corticosteroid Long acting muscarine agonist (LAMA) Long acting beta agonist Lung exposure Healthy subjects Inhaled corticosteroid (ICS) Long-acting β2 agonist (LABA) Next generation propellant (NGP)
Sponsor: AstraZeneca
Start date: 2022-10-11; Completion date: 2023-04-14
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study will evaluate bioequivalence, pharmacokinetics, safety, and tolerability of Budesonide, Glycopyrronium and Formoterol (BGF) metered dose inhaler (MDI) formulated with hydrofluoroolefin (HFO) \[Test\] and hydrofluoroalkane (HFA) \[Reference\] in healthy participants (male or female).

Detailed description:
This is a Phase I, randomized, double-blind, single-dose, single-center, partial-replicate, 3 way cross-over study to assess pharmacokinetic and safety of BGF MDI when administered with different propellants, HFO (HFO-1234ze) - test and HFA (HFA-134a) - reference.

The study will comprise of:

* A screening period up to 28 days prior to first dosing;
* Three Treatment Periods: Participants will be resident at the Clinical Unit from the morning on the day before dosing with BGF MDI on Day -1 of Treatment Period 1, until 24 hours following the final dose on Day 2 of Treatment Period 3, with a washout period of 3 to 7 days between each dose; and
* Follow-up: final safety Follow-up Phone Call within 3 to 7 days after the last administration of BGF MDI in Treatment Period 3.

Each participant will receive 3 single dose treatments of BGF MDI (Treatment A: BGF MDI HFO \[Test\]; Treatment B: BGF MDI HFA \[Reference\]) following an overnight fast of at least 8 hours on Day 1 of each treatment period.

The reference formulation will be administered during 2 of the 3 treatment periods.

There will be a minimum of a 3 to 7 day washout between administration of each treatment.

Each participant will be involved in the study for approximately 55 days.

Arms: arm 1: Participants will receive Test formulation in 1 of 3 possible treatment sequences: ABB, BAB, or BBA. The reference formulation will be administered during 2 of the 3 treatment periods in order to estimate intra-subject variability. arm 2: Participants will receive Reference formulation in 1 of 3 possible treatment sequences: ABB, BAB, or BBA. The reference formulation will be administered during 2 of the 3 treatment periods in order to estimate intra-subject variability.
Interventions: intervention 1: Treatment A: BGF MDI HFO intervention 2: Treatment B: BGF MDI HFA
Intervention descriptions: intervention 1: Participants will receive 4 oral inhalations as a single dose - test formulation; administered during 1 treatment period. intervention 2: Participants will receive 4 oral inhalations as a single dose - reference formulation; administered during 2 treatment periods.

Protocol documents:
Prot_SAP_000.pdf: 
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Clinical Study Protocol
A Phase I, Randomized, Double-blind, Single-dose, 
Partial-replicate, 3-way Cross-over Study to Assess the Total 
Systemic Exposure Bioequivalence of Budesonide, 
Glycopyrronium, and Formoterol Delivered by BGF MDI HFO 
Compared with BGF MDI HFA
Parexel Study No.:
PXL274083
Sponsor Study Code:
D5985C00004
IND No./Eudra CT No:
118313
Study Type:
Pharmacokinetics (PK)/Bioequivalence
Study Intervention (Test Product):
Budesonide/glycopyrronium/formoterol (BGF) metered dose 
inhaler (MDI) formulated with hydrofluoroolefin (HFO) 
propellant
Study Intervention (Reference Product):
BGF MDI formulated with hydrofluoroalkane (HFA) propellant
Therapeutic Indication:
Chronic Obstructive Pulmonary Disease
Pharmacological Class:
Corticosteroid/long-acting muscarinic antagonist/Long-acting
beta agonist
Development Phase:
Phase I
Sponsor:
AstraZeneca AB
151 85 Södertälje
Sweden
Manufacturer:
AstraZeneca AB
151 85 Södertälje
Sweden
Study Center:
Parexel Early Phase Clinical Unit Los Angeles
1560 Chevy Chase Drive, Suite 140
Glendale, CA 91206
United States of America
Date of Protocol:
Final 1.0, 12 July 2022
This clinical study will be conducted according to the protocol and in compliance with Good Clinical 
Practice, with the Declaration of Helsinki, and with other applicable regulatory requirements.
Confidentiality Statement
This confidential document is the property of AstraZeneca. No unpublished information contained 
herein may be disclosed without prior written approval from AstraZeneca. Access to this document 
must be restricted to relevant parties.


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PROTOCOL SYNOPSIS
Title of the Study
A Phase 1, randomized, double-blind, single-dose, partial-replicate, 3-way cross-over study to 
assess the total systemic exposure bioequivalence of budesonide, glycopyrronium, and 
formoterol delivered by BGF MDI HFO compared with BGF MDI HFA
Principal Investigator (PI)
Study Center
This study will be conducted at a single study center.
Parexel Early Phase Clinical Unit Los Angeles
1560 Chevy Chase Drive, Suite 140
Glendale, CA 91206
United States of America
Study Rationale
This study will be conducted to demonstrate that budesonide/glycopyrronium/formoterol 
metered dose inhaler with hydrofluoroolefin (BGF MDI HFO) provides equivalent total 
systemic exposure for budesonide, glycopyrronium, and formoterol compared with the 
currently approved BGF MDI with hydrofluoroalkane (HFA).
A randomized, double-blind, single-dose, cross-over, partial-replicate study design has been 
chosen to prevent bias in allocation of treatments in each treatment period, to minimize any 
bias from the subjects, investigator, or sponsor that may affect the study results and to allow 
determination of within-subject variability and possible expansion of the bioequivalence 
criteria limits.
Number of Subjects Planned
A total of 108 subjects will be randomized to ensure at least 96 evaluable subjects.
Study Period
Estimated date of first subject enrolled:
October 2022 (signing of informed consent)
Estimated date of last subject completed: April 2023
Study Objectives
The objectives of the study are:
Primary Objective:
!
To assess the bioequivalence of the total systemic exposure of budesonide, 
glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF 
MDI HFA.
PPD


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Secondary Objectives:

To characterize the pharmacokinetic (PK) profiles of budesonide, glycopyrronium, and 
formoterol administered as BGF MDI HFO and BGF MDI HFA.

To assess the safety and tolerability of single doses of BGF MDI HFO and BGF MDI 
HFA in healthy subjects.
Exploratory Objective:
Not applicable.
Study Design
This is a Phase I, randomized, double-blind, single-dose, single-center, cross-over study to 
assess the PK and safety of BGF MDI in healthy subjects (male or female). Pharmacokinetic 
profiles of each active ingredient (budesonide, glycopyrronium, and formoterol) will be 
determined after administration of BGF MDI HFO (test) and BGF MDI HFA (reference) 
following an overnight fast of at least 8 hours. Each subject will receive 3 single dose 
treatments of BGF MDI:

Treatment A: BGF MDI HFO 160/7.2/4.8 µg ex-actuator; 4 inhalations as a single dose -
test formulation; administered during 1 treatment period.

Treatment B: BGF MDI HFA 160/7.2/4.8 µg ex-actuator; 4 inhalations as a single dose -
reference formulation; administered during 2 treatment periods.
Subjects will receive treatments in 1 of 3 possible treatment sequences: ABB, BAB, BBA. 
The reference formulation will be administered during 2 of the 3 treatment periods in order to 
estimate intra-subject variability.
The study will comprise:

A screening period up to 28 days prior to first dosing;

Three Treatment Periods: subjects will be resident at the Clinical Unit from the morning 
on the day before dosing with BGF MDI on Day -1 of Treatment Period 1, until 24 hours 
following the final dose on Day 2 of Treatment Period 3 with a washout period of 
3 to 7 days between each dose; and

Follow-up: final safety Follow-up Phone Call within 3 to 7 days after the last 
administration of BGF MDI in Treatment Period 3.
Expected Duration of the Study
Each subject will be involved in the study for approximately 55 days.
Targeted Study Population
This study will be conducted in healthy male and female subjects, 18 to 60 years of age.


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Study Intervention
Arm Name
BGF MDI HFO
BGF MDI HFA
Intervention name
Budesonide/Glycopyronium/ 
Formoterol fumarate pressurized 
inhalation suspension, HFO
Budesonide/Glycopyronium/ 
Formoterol fumarate pressurized 
inhalation suspension, HFA 
Type 
Combination product
Combination product
Dose formulation
MDI
MDI
Unit dose strength(s) 
(delivered dose)
160/7.2/4.8 μg per actuation
160/7.2/4.8 μg per actuation
Dosage level
4 inhalations
4 inhalations
Route of administration
Oral inhalation
Oral inhalation
Use
Experimental
Comparator
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the sponsor
Provided centrally by the sponsor
Packaging and labeling
Study intervention will be provided in 
an MDI. Each MDI will be labeled as 
required per country requirements.
Study intervention will be provided in 
an MDI. Each MDI will be labeled as 
required per country requirements.
BGF = budesonide, glycopyrronium, formoterol; HFA = hydrofluoroalkane; HFO = hydrofluoroolefin; 
IMP = investigational medicinal product; MDI = metered dose inhaler; NIMP = non-investigational medicinal 
product.
Dosing instructions and dispensing details will be provided by AstraZeneca.
Budesonide, glycopyrronium, and formoterol MDI is a combination product (drug + device).
Outcome Endpoints
Safety and Tolerability Endpoints:
Safety and tolerability variables will include

Adverse events (AEs)/serious adverse events (SAEs)

Vital signs (systolic and diastolic blood pressure [BP], pulse rate, body temperature, and 
respiratory rate)

12-lead electrocardiograms (ECGs)

Physical examination

Laboratory assessments (hematology, clinical chemistry, and urinalysis)


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Viral serology and drugs of abuse, alcohol and cotinine will be assessed for eligibility. 
Follicle-stimulating hormone (FSH) (females only), pregnancy testing (females only) and use 
of concomitant medication will also be assessed and reported.
Pharmacokinetic Endpoints:
Where possible, PK parameters will be assessed for budesonide, glycopyrronium, and 
formoterol.

Primary PK parameters: AUCinf, AUClast, and Cmax

Secondary PK parameters: tmax, λz, t½λz, MRTinf, CL/F, and Vz/F
Additional PK parameters may be determined where appropriate.
Exploratory Endpoints:
Not applicable.
Statistical Methods
Presentation and Analysis of Pharmacokinetic Data:
Plasma concentrations for each analyte (budesonide, glycopyrronium, and formoterol) will be 
listed by treatment occasion, subject and time point. Plasma concentrations will also be 
summarized by treatment occasion and for each analyte using protocol scheduled times and 
appropriate descriptive statistics.
The statistical analysis will be performed for the PK analysis set. Pharmacokinetic parameters 
will be calculated using non-compartmental analysis.
For each analyte, individual plasma concentrations versus actual time will be plotted in linear 
and semi-logarithmic scale with all treatment occasions overlaid on the same plot and separate 
plots for each subject. Combined individual plasma concentration versus actual times will be 
plotted in linear and semi-logarithmic scale for each treatment occasion and analyte. 
Geometric mean plasma concentration (± geometric standard deviation [gSD]) versus nominal 
sampling time will be plotted in linear and semi-logarithmic (no standard deviation [SD]
presented) scale with all treatment occasions overlaid on the same figure.
Plasma PK parameters will be listed and summarized using descriptive statistics for each 
treatment occasion and analyte. Where possible, the following descriptive statistics will be 
presented: n, geometric mean, geometric co-efficient of variation, arithmetic mean, arithmetic 
SD, median, minimum, and maximum. For tmax, only the number of subjects (n), median, 
minimum, and maximum will be presented.
Bioequivalence will be assessed between test treatment BGF MDI HFO and reference 
treatment BGF MDI HFA, based on the PK analysis set.
Presentation and Analysis of Safety and Eligibility Data:
All safety data (scheduled and unscheduled) will be presented in the data listings. Continuous 
variables will be summarized using descriptive statistics (n, mean, SD, minimum, median, 
maximum) by treatment group. Categorical variables will be summarized in frequency tables 
(frequency and proportion) by treatment /dose group. The analysis of the safety variables will 
be based on the safety analysis set.


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Adverse events will be summarized by preferred term and System Organ Class using Medical 
Dictionary for Regulatory Activities vocabulary. Furthermore, listings of SAEs and AEs that 
led to the discontinuation (DAE) of investigational medicinal product (IMP) will be made. 
Adverse events that occur before dosing will be reported separately.
Tabulations and listings of data for vital signs, clinical laboratory tests, ECGs, will be 
presented. Any new or aggravated clinically relevant abnormal medical physical examination 
finding compared to the baseline assessment will be reported as an AE. Data will be 
summarized for the observed values at each scheduled assessment, together with the 
corresponding changes (and/or percentage change) from the baseline when baseline is defined. 
Clinical laboratory data will be reported in the units provided by the clinical laboratory for the 
Safety Review Committee meeting, and in Système International units in the Clinical Study 
Report.
Out-of-range values for safety laboratory will be flagged in individual listings as well as 
summarized descriptively using agreed reference ranges (eg, laboratory ranges).
Determination of Sample Size:
The sample size for this study was based on 
 
 
 
 
 
 
 
The number of subject identifiers generated for the study will account for the number of 
randomized subjects per the sample size calculation (N = 108). For this study, a total of 
108 subject identifiers will be randomly assigned to 1 of 3 possible treatment sequences: 
ABB, BAB, BBA.
CCI
CCI


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS...................................................................................................... 2
TABLE OF CONTENTS...................................................................................................... 7
List of Tables...................................................................................................................... 10
List of Figures..................................................................................................................... 11
List of Appendices.............................................................................................................. 11
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.......................................... 12
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE............................. 16
1.
INTRODUCTION............................................................................................ 18
1.1.
Background Information................................................................................... 18
1.2.
Rationale for Conducting this Study.................................................................. 19
2.
STUDY OBJECTIVES..................................................................................... 21
2.1.
Primary Objective............................................................................................. 21
2.2.
Secondary Objectives........................................................................................ 21
2.3.
Exploratory Objectives ..................................................................................... 21
3.
STUDY DESIGN ............................................................................................. 22
3.1.
Overall Study Design and Flow Chart............................................................... 22
3.1.1.
Order of Assessments ....................................................................................... 27
3.1.2.
End of Study..................................................................................................... 27
3.1.3.
Expected Duration of the Study ........................................................................ 27
3.2.
Rationales for Study Design and Dose Selection............................................... 28
3.2.1.
Rationale for Study Design ............................................................................... 28
3.2.2.
Dose Rationale.................................................................................................. 28
3.3.
Risk-benefit Assessment................................................................................... 28
3.3.1.
Risk Assessment for COVID-19 Pandemic ....................................................... 29
3.3.2.
Benefits ............................................................................................................ 30
4.
STUDY POPULATION ................................................................................... 31
4.1.
Selection of Study Population ........................................................................... 31
4.1.1.
Inclusion Criteria .............................................................................................. 31
4.1.2.
Exclusion Criteria ............................................................................................. 31
4.2.
Restrictions During the Study ........................................................................... 34
4.2.1.
Reproductive Restrictions ................................................................................. 35
4.2.1.1.
Women of Non-Childbearing Potential ............................................................. 35
4.2.1.2.
Women of Childbearing Potential ..................................................................... 35
4.2.1.3.
Male Subjects ................................................................................................... 36
4.3.
Replacement of Subjects................................................................................... 36
5.
STUDY CONDUCT......................................................................................... 37
5.1.
Subject Enrollment and Randomization ............................................................ 37
5.1.1.
Procedures for Randomization .......................................................................... 37


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5.2.
Procedures for Handling Incorrectly Randomized Subjects............................... 38
5.3.
Blinding and Procedures for Unblinding the Study............................................ 38
5.3.1.
Methods for Ensuring Blinding......................................................................... 38
5.3.2.
Methods for Unblinding the Study.................................................................... 38
5.4.
Study Intervention ............................................................................................ 39
5.4.1.
Investigational Products.................................................................................... 39
5.4.2.
Medical Devices ............................................................................................... 40
5.4.3.
Supply of Investigational Medicinal Product..................................................... 40
5.4.4.
Dose and Treatment Regimens.......................................................................... 41
5.4.5.
Labeling ........................................................................................................... 42
5.4.6.
Storage and Handling Procedures...................................................................... 42
5.5.
Concomitant and Post-study Treatment(s)......................................................... 42
5.6.
Study Intervention Compliance......................................................................... 43
5.6.1.
Drug Accountability, Dispensing, and Destruction............................................ 43
5.7.
Discontinuation of Study Intervention and Withdrawal from Study................... 43
5.7.1.
Procedures for Withdrawal of a Subject from the Study.................................... 44
5.8.
Premature Termination of the Study.................................................................. 44
5.9.
Duration of Post-treatment Follow-up Period.................................................... 45
6.
COLLECTION OF STUDY VARIABLES....................................................... 46
6.1.
Recording of Data............................................................................................. 46
6.2.
Enrollment and Screening Procedures............................................................... 46
6.3.
Safety and Eligibility Measurements................................................................. 46
6.3.1.
Adverse Events................................................................................................. 46
6.3.1.1.
Definition of Adverse Events............................................................................ 46
6.3.1.2.
Definitions of Serious Adverse Event ............................................................... 46
6.3.1.3.
Other Significant Adverse Events ..................................................................... 47
6.3.1.4.
Recording of Adverse Events............................................................................ 47
6.3.1.5.
Reporting of Serious Adverse Events................................................................ 50
6.3.1.6.
Regulatory Reporting Requirements for Serious Adverse Events ...................... 51
6.3.1.7.
Medical Device-related Safety Events............................................................... 51
6.3.1.8.
Medical Device Deficiencies............................................................................. 52
6.3.2.
Laboratory Assessments ................................................................................... 53
6.3.2.1.
Hematology...................................................................................................... 53
6.3.2.2.
Serum Clinical Chemistry................................................................................. 53
6.3.2.3.
Urinalysis ......................................................................................................... 54
6.3.2.4.
Pregnancy Testing ............................................................................................ 54
6.3.2.5.
Viral Serology .................................................................................................. 54
6.3.2.6.
Drugs of Abuse, Alcohol and Cotinine.............................................................. 54
6.3.2.7.
COVID-19 Testing ........................................................................................... 54
6.3.3.
Physical Examination........................................................................................ 55
6.3.4.
Electrocardiograms........................................................................................... 55
6.3.4.1.
Safety 12-lead ECGs......................................................................................... 55
6.3.5.
Vital Signs........................................................................................................ 55
6.3.6.
Spirometry........................................................................................................ 56


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6.4.
Pharmacokinetics.............................................................................................. 56
6.4.1.
Collection of Pharmacokinetic Samples ............................................................ 56
6.4.1.1.
Plasma Samples................................................................................................ 56
6.4.2.
Pharmacokinetic Drug Assays........................................................................... 56
6.5.
Pharmacodynamics........................................................................................... 56
6.6.
Pharmacogenetics ............................................................................................. 57
6.7.
Biomarkers ....................................................................................................... 57
6.8.
Immunogenicity................................................................................................ 57
6.9.
Metabolites....................................................................................................... 57
6.10.
Taste Assessment.............................................................................................. 57
7.
BIOLOGICAL SAMPLES PROCEDURES ..................................................... 58
7.1.
Total Blood Volume ......................................................................................... 58
7.2.
Handling, Storage, and Destruction of Biological Samples................................ 58
7.2.1.
Pharmacokinetic Samples ................................................................................. 58
7.3.
Labeling and Shipment of Biohazard Samples .................................................. 58
7.4.
Chain of Custody of Biological Samples........................................................... 58
7.5.
Withdrawal of Informed Consent for Donated Biological Samples.................... 59
8.
REGULATORY AND ETHICAL CONSIDERATIONS.................................. 60
8.1.
Regulatory and Ethical Considerations.............................................................. 60
8.2.
Data Protection ................................................................................................. 60
8.3.
Informed Consent Process................................................................................. 61
8.4.
Insurance .......................................................................................................... 61
9.
DATA QUALITY ASSURANCE AND DATA MANAGEMENT................... 62
9.1.
Quality Control and Source Data Verification................................................... 62
9.2.
Audit/Inspections.............................................................................................. 62
9.3.
Study Monitoring.............................................................................................. 62
9.4.
Data Collection................................................................................................. 62
9.4.1.
Case Report Forms and Source Documents....................................................... 63
9.4.2.
Access to Source Documents ............................................................................ 63
9.5.
Data Management............................................................................................. 63
10.
EVALUATION AND CALCULATION OF VARIABLES .............................. 65
10.1.
Safety Variables................................................................................................ 65
10.1.1.
Adverse Events................................................................................................. 65
10.1.2.
Laboratory Assessments ................................................................................... 66
10.1.3.
Physical Examination........................................................................................ 66
10.1.4.
Resting 12-lead Electrocardiogram ................................................................... 67
10.1.5.
Vital Signs........................................................................................................ 67
10.2.
Pharmacokinetic Variables................................................................................ 67
10.2.1.
Plasma Parameters............................................................................................ 67
10.2.2.
Calculation or Derivation of Pharmacokinetic Parameters................................. 68


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10.3.
Pharmacodynamic Variable(s) .......................................................................... 69
10.4.
Pharmacogenetics ............................................................................................. 69
10.5.
Exposure - Response Analyses.......................................................................... 69
10.6.
Taste Assessment.............................................................................................. 69
11.
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION.......... 70
11.1.
Description of the Analysis Sets........................................................................ 70
11.1.1.
Safety Analysis Set........................................................................................... 70
11.1.2.
Pharmacokinetic Analysis Set........................................................................... 70
11.1.3.
Randomized Set................................................................................................ 70
11.2.
Methods of Statistical Analyses ........................................................................ 71
11.2.1.
General Principles............................................................................................. 71
11.2.2.
Missing Data..................................................................................................... 72
11.2.3.
Subject Characteristics...................................................................................... 72
11.2.3.1.
Demographic and Baseline Data ....................................................................... 72
11.2.4.
Prior and Concomitant Medication and Drug Administration............................ 73
11.2.4.1.
Prior and Concomitant Medication.................................................................... 73
11.2.4.2.
Study Intervention Administration .................................................................... 73
11.2.5.
Safety and Tolerability...................................................................................... 73
11.2.6.
Pharmacokinetics.............................................................................................. 74
11.3.
Protocol Deviations........................................................................................... 78
11.4.
Determination of Sample Size........................................................................... 79
12.
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR............................................................................................. 80
12.1.
Medical Emergencies and AstraZeneca Contacts .............................................. 80
12.2.
Pregnancy......................................................................................................... 80
12.2.1.
Maternal Exposure............................................................................................ 80
12.2.2.
Paternal Exposure............................................................................................. 81
13.
LEGAL AND ADMINISTRATIVE ASPECTS................................................ 82
13.1.
Archiving of Study Documents......................................................................... 82
13.2.
Publication of Study Results ............................................................................. 82
13.3.
Clinical Study Report........................................................................................ 82
14.
REFERENCE LIST.......................................................................................... 83
15.
APPENDICES.................................................................................................. 84
List of Tables
Table 2-1
Primary Objectives and Outcome Measures............................................. 21
Table 2-2
Secondary Objectives and Outcome Measures ......................................... 21
Table 3-1
Schedule of Assessments ......................................................................... 24
Table 3-2
Expected Duration of the Study ............................................................... 27


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Table 5-1
Investigational Products........................................................................... 39
List of Figures
Figure 3-1
Study Flow Chart..................................................................................... 23
List of Appendices
Appendix A
Additional Safety Information.................................................................. 84
Appendix B
International Airline Transportation Association 6.2 Guidance Document86
Appendix C
Actions Required in Cases of Combined Increase of Aminotransferase 
and Total Bilirubin - Hy’s Law ................................................................ 87
Appendix D
Medical Device AEs, ADEs, SAEs, SADEs, USADEs and Medical 
Device Deficiencies: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting in Medical Device Studies............ 92


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Please note definitions of abbreviations for pharmacokinetic variables are presented in
Section 10.2.1 of this protocol.
Abbreviation or 
special term
Explanation
ABE
average bioequivalence
AE
Adverse event (see definition in Section 6.3.1)
AIM
Aerosol inhalation monitor
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AMP
Amphetamine
AST
Aspartate aminotransferase
ATS/ERS
American Thoracic Society/European Respiratory Society
BAR
Barbiturates
BGF
Budesonide, glycopyrronium, formoterol
BMI
Body mass index
BP
Blood pressure
bpm
Beats per minute
BUP
Buprenorphine
BZO
Benzodiazepines
CFR
Code of Federal Regulations
CI
Confidence interval 
ClinBase™
Parexel's electronic source data capturing and information management system
CO2
Carbon dioxide
COC
Cocaine
COPD
Chronic obstructive pulmonary disease
COVID-19
Corona virus disease of 2019
CRF
Case report form
CRO
Contract research organization
CRP
C-reactive protein
CSP
Clinical study protocol 
CSR
Clinical study report 
CV
Co-efficient of variation
CV%
Percentage co-efficient of variation
DAE
Adverse event leading to discontinuation (of IMP)
DCF
Data clarification form


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Abbreviation or 
special term
Explanation
DMP
Data management plan
DVS
Data validation specification
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EU
European Union
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in the first second
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
GGT
Gamma glutamyl transpeptidase (transferase)
GMP
Good Manufacturing Practice
GMR
Geometric mean ratio
gSD
Geometric standard deviation
GWP
Global warming potential
Hb
Hemoglobin
HBsAg
Hepatitis B surface antigen
HCT
Hematocrit
HFA
hydrofluoroalkane
HFO
hydrofluoroolefin
HIV
Human immunodeficiency virus
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
ICS
Inhaled corticosteroid
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IMP
Investigational medicinal product
IRB
Institutional Review Board
LABA
Long-acting β2 agonist
LAMA
Long-acting muscarine agonist
LLOQ
Lower limit of quantification
MCH
Mean corpuscular hemoglobin


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Abbreviation or 
special term
Explanation
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDI
Metered dose inhaler
MDMA
Methylenedioxymethamphetamine
MDR
Medical Device Regulation
MedDRA
Medical Dictionary for Regulatory Activities
MET
Methamphetamine
MTD
Methadone Metabolites
n
Number of subjects
NC
Not calculated
NGP
Next generation propellant
NIMP
Non-investigational medicinal products
NQ
Not quantified
OAE
Other significant adverse events
OPI
Opiates
OTC
Over-the-counter
OXY
Oxycodone
PCP
Phencyclidine
PCR
Polymerase chain reaction
PI
Principal Investigator
PK
Pharmacokinetic(s)
PR(PQ)
ECG interval measured from the onset of the P wave to the onset of the QRS 
complex
QRS
ECG interval measured from the onset of the QRS complex to the J point
QT
ECG interval measured from the onset of the QRS complex to the end of the T 
wave
QTcB
QT interval corrected for heart rate using Bazett's formula
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RBC
Red blood cell
RR
The time between corresponding points on 2 consecutive R waves on ECG
RSABE
Reference-scaled average bioequivalence
RT
Reverse transcriptase
SADE
Serious adverse device effect
SAE
Serious adverse event (see definition in Section 6.3.1.2).
SAP
Statistical Analysis Plan


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Abbreviation or 
special term
Explanation
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
Standard deviation
SoA
Schedule of assessments
SOC
System Organ Class
SOP
Standard operating procedure
SRC
Safety Review Committee
SUSAR
Suspected unexpected serious adverse reaction
swr
within-subject standard deviation
T4
Thyroxine
TBL
Total bilirubin
TCA
Tricyclic anti-depressant
THC
Marijuana
TOST
Two one-sided test
TSH
Thyroid stimulating hormone
UADE
Unanticipated adverse device effect
UK
United Kingdom
ULN
Upper limit of normal
USA
United States of America
WAD
Windows Allowance Document
WBC
White blood cell
WOCBP
Women of childbearing potential


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INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
Sponsor:
AstraZeneca AB
151 85 Södertälje
Sweden
Sponsor’s Lead 
Physician:
Tel: 
Email: 
Sponsor’s 
Biostatistician:
Email: 
Principal 
Investigator:
Tel: 
Email: 
Contract 
Research 
Organization:
Tel: 
Fax: 
Clinical 
Laboratory:
Phone: 
Fax: 
Email: 
Analytical 
Laboratory
(pharmacokinetic 
sample analysis):
All laboratories used to analyze samples taken for this study will be detailed in the 
Laboratory Manual.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Adverse Event 
Reporting:
AstraZeneca Patient Safety Data Entry Site
Tata Consultancy Services
Fax: 
Email: 
A list and contact details of investigators and other key study team members are provided in 
the Project Plan in the electronic Trial Master File. A list of all participating investigators will 
be provided in the Clinical Study Report.
PPD
PPD


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1.
INTRODUCTION
1.1.
Background Information
AstraZeneca has developed BGF MDI HFA as a maintenance treatment in adult patients with 
COPD with moderate to severe airflow obstruction who are not adequately treated by a 
combination of an ICS and a LABA or a combination of a LABA and a LAMA.
The drug substances in BGF MDI HFA are budesonide, glycopyrronium bromide 
(glycopyrrolate), and formoterol fumarate dihydrate. Budesonide is a synthetic glucocorticoid 
receptor agonist with well-established anti-inflammatory properties that exhibits potent 
glucocorticoid and weak mineralocorticoid activity. Glycopyrronium bromide is a synthetic 
LAMA, and glycopyrronium is the active moiety of this bromide salt form (9 μg of 
glycopyrronium bromide is equivalent to 7.2 μg of glycopyrronium). Glycopyrronium exerts 
its bronchodilatory effect via muscarinic receptors located on smooth muscle cells within the 
trachea and bronchi. Formoterol fumarate dihydrate is a synthetic LABA used as its fumarate 
salt in dihydrate form (5 μg of formoterol fumarate dihydrate is equivalent to 4.8 μg of 
formoterol fumarate). Formoterol fumarate is a potent and selective LABA that acts locally in 
the lung as a bronchodilator when inhaled. Formoterol fumarate stimulates β2 adrenoreceptors 
in the airways, inducing airway smooth muscle relaxation and reducing or preventing 
bronchoconstriction. More information on budesonide, glycopyrronium, and formoterol 
fumarate can be found in the Investigator’s Brochure 2022.
The BGF MDI HFA product is formulated with HFA-134a propellant, a liquified compressed 
gas, in which the budesonide, glycopyrronium bromide, and formoterol fumarate dihydrate are 
suspended. HFA-134a is a common propellant in pharmaceutical MDI products that provides 
the force to generate an aerosol to deliver a product inhalation or dose. This drug product is an 
MDI 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 an 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. More 
information on the BGF MDI HFA product is described in the Investigator’s Brochure 2022.
The current HFA propellant is known to have a relatively high GWP compared with some 
alternative propellants and contributes substantially to the sponsor, AstraZeneca’s carbon 
footprint. The reformulation of AstraZeneca’s MDI products with an NGP that has much 
lower GWP will allow patients to continue to use MDI type treatments while contributing to 
AstraZeneca’s sustainability efforts.


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Development of BGF MDI HFO Product
In an effort to reduce the carbon footprint of the BGF MDI HFA product, AstraZeneca has 
investigated replacements for HFA-134a propellant with a focus on lower GWP materials 
with similar properties to HFA-134a to mitigate any impact on the MDI drug product 
performance, stability, and robustness. AstraZeneca has identified HFO-1234ze propellant as 
a suitable for replacement of HFA-134a in the BGF MDI HFA product. HFO-1234ze has a 
near zero GWP and very low photochemical reactivity. In addition, it has very similar 
physical properties to HFA-134a which will ensure comparable performance of the BGF MDI 
product. HFO-1234ze, which is available for industrial uses such as refrigeration, has been 
further purified by the manufacturer by fractional distillation to provide a suitable grade 
propellant for clinical studies.
A comprehensive nonclinical toxicology program that includes a range of studies to support 
HFO-1234ze regulatory applications is well advanced. Further information on HFO-1234ze 
can be found in Appendix A of the Investigator’s Brochure 2022.
Additionally, 1 clinical study (D5985C00001) assessing the relative bioavailability between 
3 BGF MDIs formulated with 3 different propellants, ie, HFO (test), HFC (test) and HFA 
(reference), in healthy male adults (age 18 to 60 years) has been completed. Systemic 
exposure to budesonide, glycopyrronium, and formoterol was similar for BGF MDI HFO, 
BGF MDI HFC and the reference product BGF MDI HFA. Safety and tolerability data from 
the study did not raise any safety concerns. There were no deaths, SAEs, or AEs that led to 
discontinuation of BGF MDI reported during the study. There were no notable differences 
between the treatments given regarding number of volunteers reporting AEs, number of 
events, assessed relationship, or severity. No clinically relevant trends were observed for vital 
signs, physical examination, laboratory results, spirometry, and taste assessment, and no 
abnormal clinically significant 12-lead safety and digital ECG, as well as cardiac telemetry 
findings were reported. The combination of BGF when administered as single doses in 
3 different propellant formulations demonstrated an acceptable safety profile and was well 
tolerated in the studied population.
The aim of the current study is to assess the bioequivalence of the total systemic exposure of 
budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with 
BGF MDI HFA.
1.2.
Rationale for Conducting this Study
The current propellant in BGF MDI HFA (HFA-134a) is known to have a relatively high 
GWP compared to CO2 and contributes substantially to AstraZeneca’s carbon footprint. In 
order to address this issue AstraZeneca is evaluating a potential alternative propellant (HFO) 
with a much lower GWP which will allow patients to continue to use MDI type treatments 
while contributing to AstraZeneca’s sustainability efforts. The reformulation of AstraZeneca’s 


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MDI products with the new propellant that has much lower GWP will allow patients to 
continue to use MDI type treatments while contributing to AstraZeneca’s sustainability 
efforts. As part of the clinical development program for gaining regulatory approval of BGF 
MDI HFO, this study is being conducted to demonstrate that it provides equivalent total 
systemic exposure for budesonide, glycopyrronium, and formoterol compared with the 
currently approved BGF MDI HFA.


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2.
STUDY OBJECTIVES
2.1.
Primary Objective
Table 2-1
Primary Objectives and Outcome Measures
Primary Objective
Outcome Measures
To assess the bioequivalence of the total systemic 
exposure of budesonide, glycopyrronium, and 
formoterol administered as BGF MDI HFO compared 
with BGF MDI HFA
AUCinf, AUClast, Cmax for test and reference 
treatment
BGF = budesonide, glycopyrronium, formoterol; HFA = hydrofluoroalkane; HFO = hydrofluoroolefin; 
MDI = metered dose inhaler; PK = pharmacokinetic(s).
2.2.
Secondary Objectives
Table 2-2
Secondary Objectives and Outcome Measures
Secondary Objectives
Outcome Measures
To characterize the PK profiles of budesonide, 
glycopyrronium, and formoterol administered as BGF 
MDI HFO and BGF MDI HFA
tmax, λz, t½λz, MRTinf, CL/F, and Vz/F
To assess the safety and tolerability of single doses of 
BGF MDI HFO and BGF MDI HFA in healthy 
subjects
•
AEs and SAEs.
•
Vital signs (systolic and diastolic BP, pulse rate, 
body temperature, and respiratory rate).
•
12-lead ECG.
•
Physical examination.
•
Laboratory assessments (hematology, clinical 
chemistry, and urinalysis).
AE = adverse event; BGF = budesonide, glycopyrronium, formoterol; BP = blood pressure; 
ECG = electrocardiogram; HFA = hydrofluoroalkane; HFO = hydrofluoroolefin; MDI = metered dose inhaler; 
MRT = mean residence time; PK = pharmacokinetic(s); SAE = serious adverse event.
Refer to Section 10.2 for PK variables, Section 6.3 for safety variables.
2.3.
Exploratory Objectives
Not applicable.


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3.
STUDY DESIGN
3.1.
Overall Study Design and Flow Chart
This is a Phase I, randomized, double-blind, single-dose, single-center, cross-over study to 
assess the PK and safety of BGF MDI in healthy subjects (male or female). Pharmacokinetic 
profiles of each active ingredient (budesonide, glycopyrronium, and formoterol) will be 
determined after administration of BGF MDI HFO (test) and BGF MDI HFA (reference). The 
study will comprise:

A screening period up to 28 days prior to first dosing;

Three Treatment Periods: subjects will be resident at the Clinical Unit from the morning 
on the day before dosing with BGF MDI on Day -1 of Treatment Period 1, until 24 hours 
following the final dose on Day 2 of Treatment Period 3, with a washout period of 
3 to 7 days between each dose; and

Follow-up: final safety Follow-up Phone Call within 3 to 7 days after the last 
administration of BGF MDI in Treatment Period 3.
Each subject will receive 3 single dose treatments of BGF MDI following an overnight fast of 
at least 8 hours:

Treatment A: BGF MDI HFO 160/7.2/4.8 µg ex-actuator; 4 inhalations as a single dose -
test formulation; administered during 1 treatment period.

Treatment B: BGF MDI HFA 160/7.2/4.8 µg ex-actuator; 4 inhalations as a single dose -
reference formulation; administered during 2 treatment periods.
Subjects will receive treatments in 1 of 3 possible treatment sequences: ABB, BAB, BBA.
The reference formulation will be administered during 2 of the 3 treatment periods in order to 
estimate intra-subject variability. There will be a minimum of a 3 to 7-day washout between 
administration of each treatment.
A total of 108 healthy male and female subjects will be randomized to ensure at least 
96 evaluable subjects.
No fluids will be allowed apart from water which can be given until 1 hour prior to 
administration of the IMPs and then from 2 hours after administration of the IMPs. A meal 
will be given 4 hours after administration of the IMPs.
Details of IMP administration are provided in Section 5.4.4.
The study flow-chart with the flow of events for all treatments, depending on the subject’s 
assigned randomization (see Section 5.1) is presented in Figure 3-1. The SoA displaying 
assessments/tasks and time points is presented in Table 3-1.


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Figure 3-1
Study Flow Chart
Up to 28 days
between V1 and V2
Screening
V1
Treatment Period 1
V2.1
Single dose treatment with 
a minimum 3- to 7-day 
washout between 
treatment visits
Treatment Period 2
V2.2
Treatment Period 3
V2.3
Follow-up Phone Call at least 3 days, but no longer 
than 7 days, after last dose
V = visit.
This is a partial-replicate 3-period cross-over study. Subjects will be randomly assigned to 1 of 3 treatment 
sequences: ABB, BAB, BBA, where Treatment A: BGF MDI HFO (test), Treatment B: BGF MDI HFA 
(reference).


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Table 3-1
Schedule of Assessments
Screening
Treatment Periods 1, 2, and 3 a
Early Termination Visit (within 
3 to 7 days post final dose)
Follow-up Phone Call (within 
3 to 7 days post final dose)
Day -1
Day 1 to 2
Informed Consent
X
Assignment of enrollment
number
X
Inclusion/exclusion criteria
X
X b
Demographic data
X
Medical history
X
Urinary drug/cotinine and 
serum alcohol screen
X
X b
Concomitant medication
X
X
X
X
Serology
X
COVID-19
X
X b
FSH (postmenopausal
women only)
X
Pregnancy testing (females 
only)
X
(serum)
X
(serum/urine)
X c
(urine)
X
(urine)
Randomization
X
(Day 1 of Treatment 
Period 1)
Study residency
Check-in
X
(morning)
Check-out
X
Day 2 (24 hours 
post-dose in 
Treatment Period 3)


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Screening
Treatment Periods 1, 2, and 3 a
Early Termination Visit (within 
3 to 7 days post final dose)
Follow-up Phone Call (within 
3 to 7 days post final dose)
Day -1
Day 1 to 2
Inhalation Practice
Device and inhalation 
training with placebo and 
with AIM trainer
X
X
X
(prior to dosing)
IMP administration
Day 1 (0 hours of 
each treatment 
period)
Safety and tolerability
Adverse events
X d
X
X
X
X
Vital signs (BP, pulse rate, 
body temperature, and 
respiratory rate)
X
X
X e
X
12-lead ECG
X
X c
X
Spirometry
X
Clinical laboratory 
evaluations
X
X c
X
Urinalysis
X
X c
X
Physical examination
X
X f
X c
X
Body weight
X
X c
X
Pharmacokinetics
Plasma for budesonide, 
glycopyrronium, and 
formoterol
X
(pre-dose and 2, 5, 
10, 20, 30, and 
45 minutes post-dose 
and 1, 2, 4, 8, 12 and 
24 hours post-dose)


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AIM = aerosol inhalation monitor; BP = blood pressure; COVID = corona virus disease; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
IMP = investigational medicinal product; SAE = serious adverse event.
a
There will be a 3 to 7-day washout period between each dose administration.
b
Day -1 of Treatment Period 1.
c
Assessments will only be performed on Day 2 of Treatment Period 3 before subject is discharged from the Clinical Unit.
d
Serious adverse events will also be collected during screening.
e
Single measurement 2 hours post-dose.
f
A brief physical examination will be performed.


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3.1.1.
Order of Assessments
It is important that PK sampling occurs as close as possible to scheduled time. In order to 
achieve this, other assessments scheduled at the same time may be initiated prior to the 
time point. Another aspect for the proposed timing is that physiological assessments such as 
heart rate or BP as well as inquiring for AEs should not be accidentally influenced by physical 
interventions such as a venous puncture. The sequence at a particular time point is:
1
Electrocardiograms
2
Vital signs (BP and pulse rate, body temperature, and respiratory rate)
3
Safety and PK blood sampling (order of standard blood sampling to be followed)
Pre-dose assessments (except for pre-dose PK assessments) may be performed up to 
60 minutes prior to dosing. In the event of a delay due to technical or logistical issues with the 
vital signs assessment, PK blood sampling should be prioritized.
Details of acceptable tolerance windows for safety and PK assessments will be included in a 
WAD which will be agreed upon and signed off before the start of the study.
3.1.2.
End of Study
The end of study is defined as the last subject’s Follow-up Phone Call from the Clinical Unit.
3.1.3.
Expected Duration of the Study
Each subject will be involved in the study for approximately 55 days.
Table 3-2
Expected Duration of the Study
Screening
Up to 28 days prior to first dosing.
Treatment Periods 1, 2, and 3
Three Treatment Periods: Subjects will be resident at the Clinical Unit from 
the morning on the day before dosing with BGF MDI on Day -1 of 
Treatment Period 1 until Day 2 of Treatment Period 3, 24 hours following 
the final dose, with 3- to 7-day washout periods.
Follow-up
Phone call within 3 to 7 days after the last administration of BGF MDI.
Total Duration
Up to 55 days.
BGF = budesonide, glycopyrronium, formoterol; MDI = metered dose inhaler.


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3.2.
Rationales for Study Design and Dose Selection
3.2.1.
Rationale for Study Design
The primary objective of this study is to assess the total systemic exposure bioequivalence for 
budesonide, glycopyrronium, and formoterol between BGF MDI HFO and BGF MDI HFA. 
For this reason, subjects will be randomized to prevent bias in allocation of treatments in each 
treatment period. The study is double-blind to minimize any bias from the subjects, 
investigator, or sponsor that may affect the study results. A partial-replicate design, ie, 
reference product administered on 2 occasions will allow determination of within-subject 
variability and possible expansion of the bioequivalence criteria limits. The design of the 
study is consistent with regulatory guidance regarding the conduct of bioequivalence studies.
3.2.2.
Dose Rationale
The dose to be administered (ie, 4 inhalations as a single dose) is higher than the approved 
therapeutic dose (2 inhalations) in order to increase drug exposure and calculate reliable PK 
parameters.
This study will employ a partial-replicate design in which the reference treatment is 
administered on 2 occasions in order to assess within-subject variability and potentially widen 
the 90% CI limits (see Section 11).
3.3.
Risk-benefit Assessment
A detailed description of the chemistry, pharmacology, efficacy, safety, known and expected 
benefits, and potential risks of BGF MDI is provided in the Investigator’s Brochure 2022. 
Overall, BGF MDI is well tolerated, especially considering that this study includes only 
single-dose administrations.
Since the test product is a reformulation based on a change in the excipient propellant gas:

The active ingredients are the same.

Treatment is expected to be as safe as it was previously.

Inhaler device of reformulated drug is same as previous inhaler.

NGPs are not expected to be environmentally damaging.

One clinical trial with the NGP-based products has been completed with acceptable safety 
results.
Hydrofluoroolefin (HFO)
Hydrofluoroolefin was negative in a battery of genotoxicity tests. It was also very well 
tolerated in single-dose (mouse and rat) and repeat-dose (rat and dog) toxicology studies. 
Refer to the Investigator’s Brochure 2022 for more details on nonclinical studies with HFO.


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Additionally, safety and tolerability data from the clinical study assessing the relative 
bioavailability between 3 BGF MDIs formulated with 3 different propellants (see Section 1.1), 
did not raise any safety concerns. The combination of BGF when administered as single doses 
in 3 different propellant formulations demonstrated an acceptable safety profile and was well 
tolerated in the studied population.
The significant safety margins achieved in the toxicology studies, and the safety data from the 
clinical relative bioavailability study completed to date support the proposed clinical trial.
3.3.1.
Risk Assessment for COVID-19 Pandemic
AstraZeneca is committed to supporting the safety and well-being of the study subjects, 
investigators, and site staff. All local regulations and site requirements are being applied in the 
countries that are affected by the COVID-19 pandemic, including COVID-19 testing of 
subjects if applicable. As the COVID-19 situation evolves, investigators must use their best 
judgment to minimize risk to subjects during the conduct of the study.
Measures to mitigate the additional risks caused by COVID-19 are:

This study is going to start enrolling only when the sponsor and CRO in collaboration 
deem it is safe to start the study. In addition, the study will not start until the local 
confinement measures or other safety restrictions linked to the COVID-19 pandemic is
lifted by the local authorities.

Current national laws and local recommendations for prevention of pandemic will be 
strictly adhered to.

Subjects will be closely monitored for any signs and symptoms of COVID-19, including 
fever, dry cough, dyspnea, sore throat, and fatigue throughout the study. Once clinical 
signs of infection are reported by subjects, the investigator needs to determine whether 
samples can be collected, and safety data can be recorded on site. If not, AEs and 
concomitant medications will be obtained via phone calls. Daily body temperature 
measurements during in-house stay and outpatient visits will be implemented.

The investigator will not dose subjects upon identification of any signs of COVID-19 
infection.

Confirmation of COVID-19 infection by optional laboratory assessment will be 
conducted based on availability (test capacity and turnaround time) of approved tests and 
on investigator’s discretion. This would include serology testing at screening and virus 
testing prior to any admission.

The probability of virus transmission will be controlled as much as possible by:

Advising the subject to adhere to local requirements for reduction of the public 
exposure while ambulatory.

If applicable, all subjects will be contacted by phone one day prior to every visit for 
assessing COVID-19 symptoms and signs and are asked not to attend the site in case 
of suspected reports. In addition, subjects are asked for any contact with a person 


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who has tested positive for SARS-CoV-2. If applicable, subjects will be referred to 
the local health care system for further follow-up and treatment.

Physical distancing and person-to-person contact restrictions will be applied during 
site visits and in-house confinement.

Where physical distancing is not possible, personal protective equipment will be used 
by subjects (surgical face mask, gloves) and staff (for example, but not limited to 
masks, gloves, protectors, medical suits) if deemed appropriate by the investigator
and site staff and guided by local requirements.

Logistical improvements of the site and structural measures of the study site building 
will be implemented to further improve physical distancing.
3.3.2.
Benefits
No benefit for individuals in this study is expected.


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4.
STUDY POPULATION
4.1.
Selection of Study Population
The investigator should keep a subject screening log of all potential subjects who consented 
and were subjected to screening procedures.
Subjects who fail to meet the inclusion criteria or meet any exclusion criterion should not, 
under any circumstances, be randomized into the study. There can be no exceptions to this 
rule.
This study will be conducted in healthy male and female subjects. The study may not 
necessarily be balanced regarding gender. The study was not formally powered to detect 
differences between genders for the primary endpoint. It is not planned to perform 
sub-analyses on gender. One repeat measurement per scheduled timepoint is allowed per 
discretion of the investigator.
4.1.1.
Inclusion Criteria
For inclusion in the study subjects should fulfill the following criteria:
1
Provision of signed and dated, written informed consent prior to any study specific 
procedures.
2
Healthy male and female subjects aged 18 to 60 years with suitable veins for cannulation 
or repeated venepuncture.
3
Females must have a negative pregnancy test at screening and on admission to the unit, 
must not be lactating, confirmed at screening and fulfill the criteria detailed in 
Section 4.2.1.
4
Have a BMI between 18 and 35 kg/m2 inclusive and weigh at least 50 kg and no more 
than 120 kg inclusive.
5
Subjects must have a FEV1 ≥ 80% of the predicted normal value and an 
FEV1/FVC > 70% regarding age, height, and ethnicity at the Screening Visit.
6
Subjects must demonstrate proper inhalation technique and have the ability to properly 
use an MDI device after training.
4.1.2.
Exclusion Criteria
Subjects will not enter the study if any of the following exclusion criteria are fulfilled:
1
History of any clinically significant disease or disorder which, in the opinion of the 
investigator, may either put the volunteer at risk because of participation in the study, or 
influence the results or the volunteer’s ability to participate in the study.


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2
History or presence of gastrointestinal, hepatic, or renal disease, or any other condition 
known to interfere with absorption, distribution, metabolism, or excretion of drugs.
3
Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of 
the first administration of IMP.
4
History of narrow angle glaucoma not adequately treated and/or change in vision that may 
be relevant. All medications approved for control of intraocular pressures are allowed, 
including topical ophthalmic non-selective βblockers and prostaglandin analogues.
5
History of 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 the prostate or full resection of the 
prostate within 6 months prior to Visit 1 are excluded from the study.
6
Unresectable cancer that has not been in complete remission for at least 5 years.
Note: Patients with squamous cell and basal cell carcinoma of the skin are allowed in the 
study.
7
Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis 
results at screening, as judged by the investigator.
8
Any clinically significant abnormal findings in physical examination, or vital signs at 
screening, as judged by the investigator.
9
Any clinically significant abnormalities on 12-lead ECG at screening, as judged by the 
investigator.
Note: Subjects with ECG QTcF interval (corrected for heart rate using Fridericia’s 
formula [QTcF]) > 480 msec will be excluded. Subjects with high degree atrioventricular 
block II or III, or with sinus node dysfunction with clinically significant pauses who are 
not treated with a pacemaker will also be excluded.
10 Any positive result on screening for serum hepatitis B surface antigen, hepatitis C 
antibody, and HIV antibody.
11 Subject has a positive RT-PCR test for SARS-CoV-2 prior to randomization.
12 Subject has clinical signs and symptoms consistent with SARS-CoV-2 infection, eg, 
fever, dry cough, dyspnea, sore throat, fatigue, or laboratory confirmed acute infection 
with SARS-CoV-2.
13 Subject who had severe course of COVID-19 (extracorporeal membrane oxygenation, 
mechanically ventilated, Intensive Care Unit stay).
14 Recent (within 14 days prior to admission to the Clinical Unit) exposure to someone who 
has COVID-19 symptoms or tested positive for SARS-CoV-2.
15 Has a current occupation that involves routine exposure to potential COVID-19 patients 
or sources of SARS-CoV-2 infection (eg, healthcare worker).
16 History of any respiratory disorders such as asthma, COPD, or idiopathic pulmonary 
fibrosis.


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17 For the duration of the study, subjects must agree to adhere to local requirements for 
reduction of the public SARS-CoV-2 exposure.
18 While admitted to the Clinical Unit, physical distancing and person-to-person contact 
restrictions will be applied and explained to subjects. Where physical distancing is not 
possible subjects will be asked to use surgical face masks and/or gloves if deemed 
appropriate by the investigator and Clinical Unit staff and guided by local requirements.
19 Known or suspected history of drug abuse, as judged by the investigator.
20 Receipt of any investigational drug within 30 days or 5 half-lives (whichever is longer) 
prior to randomization.
Note: subjects consented and screened, but not randomized in this study or a previous 
Phase I study, are not excluded.
21 Plasma donation within 1 month of screening or any blood donation/loss more than 
500 mL during the 3 months prior to screening.
22 History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged 
by the investigator or history of hypersensitivity to drugs with a similar chemical structure 
or class to BFG.
23 Current smokers or those who have smoked or used nicotine products (including 
e-cigarettes) within the 3 months prior to screening.
24 Positive screen for drugs of abuse or cotinine at screening or on admission to the Clinical 
Unit or positive screen for alcohol on admission to the Clinical Unit.
25 Use of drugs with enzyme-inducing properties such as St John’s Wort within 3 weeks 
prior to the first administration of IMP.
26 Use of any prescribed or non-prescribed medication including antacids, analgesics (other 
than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 
600 times the recommended daily dose) and minerals during the 2 weeks prior to the first 
administration of IMP or longer if the medication has a long half-life.
27 Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as 
judged by the investigator.
28 Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) as 
judged by the investigator. Excessive intake of caffeine defined as the regular 
consumption of more than 600 mg of caffeine per day (eg, > 5 cups of coffee) or would 
likely be unable to refrain from the use of caffeine-containing beverages during 
confinement at the investigational site.
29 Involvement of any AstraZeneca, Parexel or study site employee or their close relatives.
30 Subjects who have previously received BGF MDI HFO.
31 Judgment by the investigator that the subject should not participate in the study if they 
have any ongoing or recent (ie, during the screening period) minor medical complaints 


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that may interfere with the interpretation of study data or are considered unlikely to 
comply with study procedures, restrictions, and requirements.
32 Subjects who cannot communicate reliably with the investigator.
33 Vulnerable subjects, eg, kept in detention, protected adults under guardianship, 
trusteeship, or committed to an institution by governmental or juridical order.
4.2.
Restrictions During the Study
The following restrictions apply for the specified times during the study period:
1
On Day 1 of each treatment period, subjects will be fasted for 8 hours prior to dosing until 
4 hours after dosing. No fluids will be allowed apart from water which can be given until 
1 hour prior to dosing and then from 2 hours after dosing.
2
Subjects should not lie fully supine (unless specified for certain assessments) for 4 hours 
after dosing.
3
Subjects should not engage in any strenuous activity from 72 hours prior to check-in until 
after their final Follow-up Phone Call.
4
Subjects should abstain from alcohol for 72 hours prior to check-in until after their last 
PK sampling visit. Subjects should also abstain from alcohol for 72 hours before their 
final Follow-up Phone Call.
5
Subjects should abstain from caffeine-containing foods and beverages for 24 hours prior 
to check-in until discharge from the Clinical Unit.
6
Subjects should abstain from grapefruit or grapefruit juice, Seville oranges, quinine 
(eg, tonic water) from 7 days prior to check-in on Day -1 until after their Follow-up 
Phone Call.
7
Subjects will receive a standard diet, which excludes all alcohol and grapefruit-containing 
products. No additional food or beverages must be consumed while in the Clinical Unit.
8
Subjects should abstain from consuming high energy drinks (eg, Red Bull®), and food 
containing poppy seeds and any OTC medication or herbal preparations until after their 
final Follow-up Phone Call has been completed. Subjects should also limit their caffeine 
intake to equivalent of 3 servings of coffee per day (1 serving = 12 oz soda, 6 oz coffee, 
or 8 oz tea). Subjects should consume no more than 2 units of alcohol per day and 
completely abstain from alcohol from 72 hours prior to admission to the Clinical Unit.
Additional related restrictions may be implemented based on local guidance and/or Clinical 
Unit requirements.
For medication restrictions, please refer to Section 5.5.


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4.2.1.
Reproductive Restrictions
4.2.1.1.
Women of Non-Childbearing Potential
Women of non-childbearing potential are defined as female subjects who are permanently 
surgically sterilized or postmenopausal.
Permanent sterilization includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy at least 6 weeks before screening but excludes bilateral tubal ligation. Bilateral 
oophorectomy alone is acceptable only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment.
Females are considered postmenopausal if they have had amenorrhea for at least 12 months or 
more following cessation of all exogenous hormonal treatments and without an alternative 
medical cause and the FSH level is in the postmenopausal range.
4.2.1.2.
Women of Childbearing Potential
A woman is considered of childbearing potential, ie, fertile, following menarche and until 
becoming postmenopausal unless permanently sterile. Female subjects of childbearing 
potential must use one highly effective form of birth control. A highly effective method of 
contraception is defined as one that can achieve a failure rate of less than 1% per year when 
used consistently and correctly. At enrollment, WOCBP who are sexually active with a 
non-sterilized male partner should be stable on their chosen method of highly effective birth 
control, and willing to remain on the birth control until at least 14 days after last dose of study 
intervention. Cessation of contraception after this point should be discussed with a responsible 
physician. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable 
methods of contraception. Female condom and male condom should not be used together. All 
WOCBP must have a negative serum pregnancy test result at Screening Visit.
Highly effective birth control methods are listed below:

Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:

Oral

Intravaginal

Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:

Oral

Injectable

Implantable

Intrauterine device


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
Intrauterine hormone-releasing system

Bilateral tubal occlusion

Vasectomized partner (only acceptable provided that the partner is the sole sexual partner 
of the subject and that the vasectomized partner has received medical assessment of the 
surgical success)

Sexual abstinence defined as complete abstinence from intercourse when it is the 
preferred and usual lifestyle of the subject (however, periodic abstinence eg, calendar, 
ovulation, symptothermal, post-ovulation methods, and withdrawal are not acceptable 
methods of contraception).
Pregnancy Testing
Women of childbearing potential can be included only after a negative highly sensitive serum 
pregnancy test. Additionally, serum or urine pregnancy testing will be done as per the SoA 
(Table 3-1).
Pregnancy
If the subject becomes pregnant during the study this should be reported to the investigator. 
The investigator should also be notified of pregnancy occurring during the study but 
confirmed after completion of the study. The pregnancy will be followed, and the status of 
mother and/or child will be reported to the sponsor after delivery.
A pregnancy notification form and follow-up will be completed.
4.2.1.3.
Male Subjects
There is no restriction on fathering children or donating sperm during the study.
4.3.
Replacement of Subjects
Subjects who are withdrawn from the study due to any reason will not be replaced.


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5.
STUDY CONDUCT
5.1.
Subject Enrollment and Randomization
The investigator will ensure:
!
Signed informed consent is obtained from each potential subject before any study specific 
procedures are performed.
!
Each potential subject is assigned a unique enrollment number at screening upon signing 
the Informed Consent.
!
The eligibility of each subject is in accordance with the inclusion and exclusion criteria.
!
Each eligible subject is assigned a unique randomization code.
Randomization codes will be assigned strictly sequentially as subjects become eligible for 
randomization (codes to be used without leading zero(s)). Randomization numbers will be 
generated within the AstraZeneca randomization system (Calyx).
The following specific format must be followed for unique enrollment number; reduced 
enrollment number “
” in ClinBaseTM and on labels, full enrollment number “
” 
for outputs.
If a subject withdraws his/her participation in the study, then his/her enrollment/randomization
code cannot be reused. For each treatment sequence, an additional set of random numbers will 
be generated with Calyx.
5.1.1.
Procedures for Randomization
Upon completion of the randomization request form, the randomization will be produced by 
Calyx.
The number of subject identifiers generated for the study will account for the number of 
randomized subjects per the sample size calculation (N = 108, see Section 11.4). For this 
study, a total of n x 3 subject identifiers will be randomly assigned to 1 of 3 possible treatment 
sequences: ABB, BAB, BBA, where:
!
Treatment A: BGF MDI HFO 160/7.2/4.8 μg ex-actuator; 4 inhalations as a single dose -
test formulation; administered during 1 treatment period.
!
Treatment B: BGF MDI HFA 160/7.2/4.8 μg ex-actuator; 4 inhalations as a single dose -
reference formulation; administered during 2 treatment periods.
PPD
PPD


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5.2.
Procedures for Handling Incorrectly Randomized Subjects
Subjects who fail to meet the inclusion criteria or meet any exclusion criterion should not, 
under any circumstances, be randomized into the study. There can be no exceptions to this 
rule.
Where a subject, who does not meet the selection criteria, is randomized in error and this is 
identified before dosing, the subject should be withdrawn from the study.
If a subject, who does not meet the selection criteria, has been dosed before the error is 
identified, the subject should be advised to continue safety assessments to ensure their safety.
5.3.
Blinding and Procedures for Unblinding the Study
5.3.1.
Methods for Ensuring Blinding
This study is double blinded with regard to treatment (BGF MDI administered with 2 different 
propellants [Treatment A or B]), ie, the sponsor, the investigator, all clinical staff involved in 
the clinical study, the subjects, and the study monitor will remain blinded, unless safety 
concerns or a regulatory requirement necessitate unblinding).
The PK analyst will remain blinded during the study conduct.
The PK analyst will be unblinded to perform the final PK analyses after all subjects have 
completed the study, final bioanalytical results are available and all required study data are 
considered clean. This may occur prior to database lock.
The following personnel will have access to the randomization lists from study start:

The AstraZeneca staff carrying out the labeling and packaging of subject specific 
treatments.

Pharmacy staff preparing the study medication.

Bioanalytical staff analyzing plasma samples.
The randomization lists should be kept in a secure location until database lock.
5.3.2.
Methods for Unblinding the Study
The treatment code should not be broken, except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomization or regulatory 
requirements exist (eg, for SAEs). If an emergency unblinding becomes necessary, the 
investigator should notify the sponsor prior to unblinding, if possible, unless identification of 
the IMP is required for emergency therapeutic measures. If an investigator or subject is 
prematurely unblinded, the subject must be withdrawn from the clinical study and procedures 
accompanying withdrawal are to be performed. The decision to break the blind will be made 


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on a case-by-case basis and, if possible, such emergencies are to be discussed with 
AstraZeneca prior to disclosure of the treatment allocation. If the blind is broken, the date, 
time, and reason together with the identity of the person responsible must be recorded in 
ClinBase™and any associated AE report.
The investigator will document and report the action to AstraZeneca staff.
Details of the code breaking procedure will be provided in the Safety Review and 
Management Plan.
5.4.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to or medical device(s) utilized by a study subject 
according to the CSP.
5.4.1.
Investigational Products
Details on the identity of the IMPs are presented in Table 5-1.
Table 5-1
Investigational Products
Arm Name
BGF MDI HFO
BGF MDI HFA
Intervention name
Budesonide/Glycopyronium/ 
Formoterol fumarate pressurized 
inhalation suspension, HFO
Budesonide/Glycopyronium/ 
Formoterol fumarate pressurized 
inhalation suspension, HFA 
Type 
Combination product
Combination product
Dose formulation
MDI
MDI
Unit dose strength(s) 
(delivered dose)
160/7.2/4.8 μg per actuation
160/7.2/4.8 μg per actuation
Dosage level
4 inhalations
4 inhalations
Route of administration
Oral inhalation
Oral inhalation
Use
Experimental
Comparator
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the sponsor
Provided centrally by the sponsor


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Arm Name
BGF MDI HFO
BGF MDI HFA
Packaging and labeling
Study intervention will be provided in 
an MDI. Each MDI will be labeled as 
required per country requirements.
Study intervention will be provided in 
an MDI. Each MDI will be labeled as 
required per country requirements
BGF = budesonide, glycopyrronium, formoterol; HFA = hydrofluoroalkane; HFO = hydrofluoroolefin; 
IMP = investigational medicinal product; MDI = metered dose inhaler; NIMP = non-investigational medicinal 
product.
Dosing instructions and dispensing details will be provided by AstraZeneca.
Budesonide, glycopyrronium, and formoterol MDI is a combination product (drug + device).
Details of the batch numbers will be included in the Trial Master File and the final CSR.
Subject inhalation training will be performed using the Vitalograph AIM inhalation training 
device supplied by Parexel. As part of this training, subjects will use a placebo Vitalograph 
HFA MDI. These devices are commercially available in many countries, including the USA, 
and used specifically for training with the AIM device. In addition to the above, subjects will 
perform inhalation training with BGF MDI containing placebo (HFA propellant based), 
supplied by AstraZeneca. Per inclusion criterion, subjects must demonstrate the proper 
inhalation technique and have the ability to properly use an MDI device after training.
Non-IMP supplies will include placebo inhalers for inhalation training. Inhalation training will 
also be conducted using the AIM training device.
5.4.2.
Medical Devices
The AstraZeneca manufactured device constituents’ part of the combination product provided 
for use in this study are:

Metered dose inhaler (approved)
Instructions for medical device use are provided in the Investigator’s Brochure 2022 and 
Combination Products Product of Summary Characteristics.
All medical device deficiencies (including malfunction, use error and inadequate labeling) 
shall be documented and reported by the investigator throughout the clinical investigation (see 
Section 6.3.1.8) and appropriately managed by the sponsor.
5.4.3.
Supply of Investigational Medicinal Product
The IMPs will be supplied by AstraZeneca as individual subject kits.


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A technical agreement or Item Requirement Schedule between the investigator and 
AstraZeneca will be in place to cover all pharmacy related activities, detailing roles, and 
responsibilities prior to receipt of the IMP(s) at the Clinical Unit.
A release document signed by a legally authorized Qualified Person in EU/UK or Pharmacist 
in USA at the Clinical Unit will be placed in the appropriate section of the Trial Master File to 
document labeling and dispensing of the IMP(s) to the subject.
Dispensing and retention of reserve bioequivalence samples of IMP will be performed in 
accordance with the FDA Code of Federal Regulations 21, Part 320 Bioavailability and 
Bioequivalence requirements.
5.4.4.
Dose and Treatment Regimens
Each subject will receive single doses (4 inhalations as a single dose) of BGF MDI HFO or 
BGF MDI HFA on Day 1 of each treatment period.
In each treatment period, the IMP will be administered after an overnight fast of at least 
8 hours.
Each subject will receive 3 single dose treatments of BGF MDI:

Treatment A: BGF MDI HFO 160/7.2/4.8 µg ex-actuator; 4 inhalations as a single dose -
test formulation; administered during 1 treatment period.

Treatment B: BGF MDI HFA 160/7.2/4.8 µg ex-actuator; 4 inhalations as a single dose -
reference formulation; administered during 2 treatment periods.
No fluids will be allowed apart from water which can be given until 1 hour prior to 
administration of the IMP and then from 2 hours after administration of the IMP. A meal will 
be given 4 hours after administration of the IMP.
Other restrictions, including posture control are described in Section 4.2. Data of subjects may 
be excluded from the PK analysis set as described in Section 11.1.2.
Specific precautions will be taken to prevent any contamination of collected PK samples by 
the particles of IMP inhalations. Administration of IMP will take place in a room separate 
from the room where blood samples will be drawn. During administration, subjects and clinic 
personnel will wear protective clothing and gloves according to the routines at the Clinical 
Unit. The protective clothing and gloves will be discarded immediately after administration in 
the room used for inhalation if the personnel are going directly to the blood draw area, to 
avoid subsequent contamination of blood samples. Subjects will also wash their hands and 
face with soap and water or a disposable wipe after self-administration of IMP. Subjects must 
wear a surgical mask for approximately 30 minutes before and after dosing.


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All devices must be primed in a separate room (ie, a different room than will be used to 
administer IMP to subjects) by study personnel before the first use. Study personnel must 
wear laboratory coats and gloves during IMP inhaler priming and must remove their 
laboratory coats and gloves immediately after priming is completed in the room where 
priming was conducted.
At the Screening Visit, on admission/Day -1, and pre-dose on Day 1 of each treatment period, 
subjects will be instructed by site staff on the inhalation technique for MDI using the 
Vitalograph AIM device. In addition, at the same visits, the subjects will be trained to use the 
placebo BGF MDI inhalers to ensure adequate demonstration of MDI techniques.
Each dose will consist of 4 actuations from the MDI. Each actuation must take place within 
approximately 30 seconds from the previous. At the time of dosing, a healthcare provider will 
be present to ensure that the required number of actuations of the MDI device is properly 
self-administered by the subject and that the subject inhales the full dose by observing that 
none of the IMP plume escapes the subject’s mouth. The sponsor will provide the Clinical 
Unit with instructions for use. The dosing time (recorded as the time of the fourth inhalation) 
must be documented on the eCRF.
5.4.5.
Labeling
Bulk labels for IMP will be prepared in accordance with GMP and local regulatory guidelines. 
The labels will fulfill GMP Annex 13 requirements.
5.4.6.
Storage and Handling Procedures
The IMP will be stored in a secure facility, details of storage conditions will be provided on 
the label of the IMP.
AstraZeneca will be permitted upon request to audit the supplies, storage, dispensing 
procedures, and records, provided that the blind of the study is not compromised.
5.5.
Concomitant and Post-study Treatment(s)
If a subject is being considered for enrollment into the study and also being considered for 
COVID-19 vaccination, the subject must not be randomized until at least 7 days after the last 
dose of vaccine or booster.
Apart from paracetamol/acetaminophen, hormone replacement therapy, and systemic 
contraceptives, no concomitant medication or therapy will be allowed.
The subjects should be instructed that no other medication is allowed, including herbal 
remedies, vitamin supplements, and OTC products, without the consent of the investigator.


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Medication, which is considered necessary for the subject’s safety and well-being, may be 
given at the discretion of the investigator during the residential period.
When any medication is required, it should be prescribed by the investigator. Following 
consultation with AstraZeneca Lead Physician, the investigator should determine whether or 
not the subject should continue in the study. Administration of concomitant medications that 
may influence the measurement of the PK endpoints may be documented as a CSP deviation 
after consultation of the investigator with AstraZeneca Lead Physician.
5.6.
Study Intervention Compliance
Dosing will take place at the Parexel Early Phase Clinical Unit.
The administration of all study intervention will be recorded in ClinBase™.
Compliance will be assured by direct supervision and witnessing of self-administration of 
study intervention.
5.6.1.
Drug Accountability, Dispensing, and Destruction
The study intervention provided for this clinical study will be used only as directed in the 
CSP.
In accordance with GCP, the Clinical Unit will account for all supplies of BGF MDI HFO and 
BGF MDI HFA. Details of receipt, storage, assembly/dispensing and return will be recorded.
All used and unused supplies of BGF MDI HFO and BGF MDI HFA will either be destroyed 
by Parexel or returned at the end of the study in accordance with instruction by the sponsor. 
The certificate of delivery and destruction must be signed, in accordance with instruction by 
AstraZeneca. Destruction must not take place unless the responsible person at AstraZeneca 
has approved it.
5.7.
Discontinuation of Study Intervention and Withdrawal from 
Study
Dosing for any individual subject will be stopped if the subject experiences a possibly 
drug-related SAE or a possibly drug-related significant non-serious AE, which in the opinion 
of the investigator warrants discontinuation of the subject from the active CSP for his or her 
well-being.
Healthy subjects may be discontinued from study intervention in the following situations:

Healthy subject decision. The healthy subject is at any time free to discontinue treatment, 
without prejudice to further treatment.

Severe non-compliance to CSP.


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It may be necessary for a subject to permanently discontinue study intervention. If study 
intervention is permanently discontinued, the subject should be encouraged to remain in the 
study and complete the remainder of the study visits and procedures. See the SoA (Table 3-1) 
for data to be collected at the time of discontinuation of study intervention and follow-up and 
for any further evaluations that need to be completed.
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
If a subject experience any of the changes listed below, the study intervention must be 
discontinued:

Development of exclusion criteria or other safety reasons as judged by the investigator 
during the treatment period.

Pregnancy or breastfeeding.

Paradoxical bronchospasm.
The appropriate AE form in the eCRF must be completed.
5.7.1.
Procedures for Withdrawal of a Subject from the Study
If a subject withdraws or is withdrawn from the study, the subject will be encouraged to return 
to the Clinical Unit for an Early Termination Visit to ensure the subjects safety.
5.8.
Premature Termination of the Study
The study will be terminated prematurely if:

The investigator and the sponsor assess that the number and/or severity of AEs justify 
discontinuation of the study. 
For instance, when there is 1 case of fatal SAE or 2 cases of other SAEs, in both 
situations considered at least possibly related to the IMP by the investigator and the 
sponsor.

The sponsor considers the applied doses of the study drug to be no longer relevant.

The sponsor decides to discontinue the study.

New data become available and raise concern about the safety of IMP so that continuation 
would pose potential risks to the subjects.
Premature termination of the study must be mutually agreed upon by the investigator and the 
sponsor and must be documented. However, study results will be reported according to the 
requirements outlined in this CSP as far as applicable.


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5.9.
Duration of Post-treatment Follow-up Period
The Follow-up Phone Call should occur within 3 to 7 days after the last administration.


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6.
COLLECTION OF STUDY VARIABLES
6.1.
Recording of Data
Standard measures to assess PK, safety and tolerability apply during the study. For the single 
doses of BGF MDI planned to be given during this study, no safety issues are expected.
For timing of assessments refer to the SoA (Table 3-1).
6.2.
Enrollment and Screening Procedures
Viral serology and urine drugs of abuse, alcohol and cotinine will be assessed for eligibility. 
Follicle-stimulating hormone (females only), pregnancy testing (females only) and use of 
concomitant medication will also be assessed and reported.
6.3.
Safety and Eligibility Measurements
Safety and tolerability variables will include:

Adverse events

Vital signs (systolic and diastolic BP, pulse rate, body temperature, and respiratory rate)

12-lead ECG

Physical examination

Laboratory assessments (hematology, clinical chemistry, and urinalysis)
6.3.1.
Adverse Events
6.3.1.1.
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (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 intervention has been administered.
6.3.1.2.
Definitions of Serious Adverse Event
A SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-up), 
that fulfills one or more of the following criteria:

Results in death.


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
Is immediately life-threatening.

Requires in-patient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions.

Is a congenital anomaly or birth defect.

Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A of this CSP.
Adverse events for malignant tumors reported during a study should generally be assessed as 
SAEs. If no other seriousness criteria apply, the “Important Medical Event” criterion should 
be used. In certain situations, however, medical judgment on an individual event basis should 
be applied to clarify that the malignant tumor event should be assessed and reported as a 
non-serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfill the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as non-serious; examples include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
6.3.1.3.
Other Significant Adverse Events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs or where relevant DAEs and withdrawal from 
the study. Based on the expert’s judgment, significant AEs of particular clinical importance 
may, after consultation with the Global Safety Physician, be considered OAEs and reported as 
such in the CSR. A similar review of other data from laboratory tests, vital signs, ECGs, and 
other safety assessments will be performed for identification of OAEs.
Examples of these are marked hematologic and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment.
6.3.1.4.
Recording of Adverse Events
Time Period for Collection of Adverse Events
Adverse events will be collected from the start of screening throughout the treatment period 
up to and including the Follow-up Phone Call.
Serious adverse events will be recorded from the time of informed consent.


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If the investigator becomes aware of an SAE with a suspected causal relationship to the IMP
that occurs after the end of the clinical study in a subject treated by him or her, the investigator 
shall, without undue delay, report the SAE to the sponsor.
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in ClinBase™.
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.
Variables
The following variables will be collected for each AE:

AE term (diagnosis/verbatim)

The date and time when the AE started and stopped

Intensity

Whether the AE is serious or not

Investigator causality rating against the IMP (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date investigator became aware of serious AE

Adverse event is serious due to

Date of hospitalization

Date of discharge from hospital

Probable cause of death

Date of death

Autopsy performed (yes/no)

Causality assessment in relation to study procedure(s)

Causality assessment to other medication'
The following intensity ratings will be used:

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).


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It is important to distinguish between serious and severe AEs:

Severity is a measure of intensity whereas seriousness is defined by the criteria in 
Section 6.3.1.2.

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. On 
the other hand, a stroke that results in only a limited degree of disability may be 
considered a mild stroke but would be an SAE.
Causality Collection
The investigator will assess causal relationship between IMP and/or investigational medicinal 
devices and each AEs and/or incident, and answer “yes” or “no” to the question “Do you 
consider that there is a reasonable possibility that the event may have been caused by the 
investigational product?”
For SAEs, causal relationship will also be assessed for other medication, any additional drug 
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 A of this CSP. For 
medical devices, a guide to the interpretation of the causality question can be found in
Appendix D.
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 personnel: “Have you had any health problems since you were last asked?” or 
revealed by observation will be collected and recorded in ClinBase™.
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.
Adverse Events Based on Examinations and Tests
The results from CSP-mandated laboratory tests, vital signs, ECGs, and other safety 
assessments will be summarized in the CSR.
Deterioration as compared to baseline in CSP-mandated laboratory values, vital signs, ECGs,
and other safety assessments should therefore only be reported as AEs if they fulfill any of the 
SAE criteria or are the reason for discontinuation of treatment with the IMP or are considered 
to be clinically relevant as judged by the investigator (which may include, but not limited to, 


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consideration as to whether treatment, or non-planned visits were required, or other action was 
taken with the study intervention, eg, dose adjustment or drug interruption).
If deterioration in a laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result, 
or vital sign will be considered as additional information.
Wherever possible the reporting investigator should use the clinical, rather than the laboratory 
term (eg, anemia versus low Hb value).
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-CSP-mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
Hy's Law
Cases where a subject shows elevation in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 x ULN together with TBL ≥2 x ULN may need to be 
reported as SAEs. Please refer to Appendix C for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.
Adverse Events Associated with Use of ICS, LAMAs, and LABAs
Certain AEs have been identified as associated to the class of drugs being studied. Known 
effects of LAMAs and LABAs include cardiovascular effects, ocular disorders, urinary 
retention, gastrointestinal disorders, and anticholinergic effects for LAMAs and 
cardiovascular and tremor effects for LABAs. Local corticosteroid effects include oral 
candidiasis, hoarseness, oropharyngeal candidiasis, dysphonia, and throat irritation. Systemic 
corticosteroid effects include fractures, osteoporosis/osteopenia, adrenal suppression, and 
adrenal cortical hypofunctions. These AEs will be captured as described and presented in 
summary tabulation in the CSR.
6.3.1.5.
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the IMP, or to the 
study procedure(s). All SAEs will be recorded in ClinBase™.
If any SAE occurs in the course of the study, then the investigator or other site personnel will 
inform appropriate AstraZeneca representatives immediately, or no later than 24 hours of 
when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca patient safety data entry site within 


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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 will be undertaken immediately.
Investigators or other site personnel will inform AstraZeneca representatives of any follow-up 
information on a previously reported SAE immediately, or no later than 24 hours of when he 
or she becomes aware of it.
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site staff how to proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
6.3.1.6.
Regulatory Reporting Requirements for Serious Adverse Events
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
intervention under clinical investigation are met.
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, IRB, and investigators.
For all studies, investigator safety reports must be prepared for SUSARs according to local 
regulations (for studies utilizing medical devices – according to European Medical Device 
Regulation 2017/745 for clinical device research) 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 (eg, summary or listing of SAEs) from the sponsor will review and then 
file it along with the IB and will notify the IRB, if appropriate according to local 
requirements.
6.3.1.7.
Medical Device-related Safety Events
The definitions of medical device-related safety events can be found in Appendix D. Medical 
Device deficiencies are covered in Section 6.3.1.8.


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6.3.1.8.
Medical Device Deficiencies
Drug/device combination products are being provided for use in this study. In order to fulfill
regulatory reporting obligations worldwide, the investigator is responsible for the detection 
and documentation of events meeting the definitions of medical device deficiency that occur 
during the study with such medical devices.
The definition of a medical device deficiency for device constituent of a combination product 
is an inadequacy of a medical device with respect to its identity, quality, durability, reliability, 
safety, or performance. Medical device deficiencies include malfunctions, use errors, and 
information supplied by the manufacturer.
The AstraZeneca medical device complaint report will be used to collect the deficiency.
NOTE: Incidents and deficiencies fulfilling the definition of an AE/SAE will also follow the 
processes outlined in Appendix D of the CSP.
6.3.1.8.1.
Time Period for Detecting Medical Device Deficiencies

Medical device incidents or malfunctions of the medical device will be detected, 
documented, and reported during all periods of the study in which the medical device is 
used.

If the investigator learns of any medical device deficiency at any time after a subject has 
been discharged from the study, and such incident is considered reasonably related to a 
medical device provided for the study, the investigator will promptly notify the sponsor.
The method of documenting medical device deficiency is provided in Appendix D.
6.3.1.8.2.
Follow-up for Medical Device Deficiencies

Follow-up applies to all subjects, including those who discontinue study intervention.

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.

New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator.
6.3.1.8.3.
Prompt Reporting of Medical Device Deficiencies to Sponsor

Medical device deficiencies will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the CSP definition of a medical device 
deficiency.

The medical device deficiency Paper Report Form will be sent to the sponsor by email. If 
email is unavailable, then telephone should be utilized.

The sponsor will be the contact for the receipt of medical device deficiency reports.


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6.3.1.8.4.
Regulatory Reporting Requirements for Device Deficiencies

The investigator will promptly report all medical device deficiencies occurring with any 
medical device provided for use in the study in order for the sponsor to fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (eg, the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of medical device deficiencies to the IRB.

For further guidance on the definition of an SAE, see Appendix D of the CSP.
6.3.2.
Laboratory Assessments
6.3.2.1.
Hematology
Hematology
White blood cell (WBC) count
Neutrophils absolute count 
Red blood cell (RBC) count
Lymphocytes absolute count 
Hemoglobin (Hb)
Monocytes absolute count 
Hematocrit (HCT)
Eosinophils absolute count 
Mean corpuscular volume (MCV)
Basophils absolute count 
Mean corpuscular hemoglobin (MCH)
Platelets
Mean corpuscular hemoglobin concentration (MCHC)
Reticulocytes absolute count 
6.3.2.2.
Serum Clinical Chemistry
Serum Clinical Chemistry
Sodium
Alkaline phosphatase (ALP)
Potassium
Alanine aminotransferase (ALT)
Urea
Aspartate aminotransferase (AST)
Creatinine
Gamma glutamyl transpeptidase (GGT)
Albumin
Total Bilirubin (TBL)
Calcium
Unconjugated bilirubin
Phosphate
Follicle-stimulating hormone (FSH) b
Glucose (fasting)
Thyroxine (T4) a
C-reactive protein (CRP)
Thyroid stimulating hormone (TSH)a
a
Screening only
b
Postmenopausal women


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6.3.2.3.
Urinalysis
Urinalysis
Glucose
Protein
Blood
Microscopy (if positive for protein or blood): RBC, WBC, Casts (Cellular, Granular, Hyaline)
6.3.2.4.
Pregnancy Testing
Pregnancy test (females only)
Human-beta chorionic gonadotrophin
6.3.2.5.
Viral Serology
Viral Serology
Human immunodeficiency virus (HIV) I and II
Hepatitis C Virus antibody
Hepatitis B surface antigen (HBsAg)
6.3.2.6.
Drugs of Abuse, Alcohol and Cotinine
Drugs of Abuse, Alcohol, and Cotinine Testing
Amphetamine (AMP)/Ecstasy
Benzodiazepines (BZO)
Ethanol
Methadone Metabolites (MTD)
Cannabinoids
Barbiturates (BAR)
Cocaine (COC)
Phencyclidine (PCP)
Opiates (OPI)
Urine Creatinine
Cotinine a
Methylenedioxymethamphetamine (MDMA)
Tricyclic anti-depressants (TCA)
Oxycodone (OXY)
Buprenorphine (BUP)
Methamphetamine (MET)
a
Screening only
Drugs of abuse screen will be done via a urine sample. Alcohol screen will be done via a 
serum sample.
6.3.2.7.
COVID-19 Testing
COVID-19 Testing (Nasopharyngeal Swab)
SARS-CoV-2 RT-PCR
Rapid SARS-CoV-2 done at admission


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6.3.3.
Physical Examination
Full
The complete physical examinations will include an assessment of the general appearance, 
respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, and 
throat), lymph nodes, thyroid, musculoskeletal and neurological systems.
Brief
The brief physical examinations will include an assessment of the general appearance, skin, 
abdomen, cardiovascular, and respiratory system.
6.3.4.
Electrocardiograms
Safety 12-lead ECGs will be performed at the time points specified in the SoA (Table 3-1).
Safety 12-lead ECGs will allow the site investigator to review the ECG tracings at bedside and 
determine any potential abnormalities and risks.
6.3.4.1.
Safety 12-lead ECGs
A 10-second 12-lead safety ECG will be obtained after the subject has been resting in the 
supine position for at least 5 minutes at all time points listed in SoA (Table 3-1) and whenever 
it is required by the investigator. All ECGs will be evaluated with respect to rhythm; heart 
rate; and PR, RR, QRS, QT, and QTcF intervals from the 12-lead safety ECG, and the 
investigator will judge the overall interpretation as normal or abnormal. If abnormal, it will be 
decided whether the abnormality is clinically significant or not, and the abnormality will be 
recorded. The investigator or delegate will evaluate the safety ECG in real time.
The date/time and the physician interpretation (normal, abnormal clinically significant, 
abnormal not clinically significant) for the safety ECGs will be recorded in the ClinBase™ 
and stored as source documents.
6.3.5.
Vital Signs
The following variables will be collected after the subject has rested in the supine position for 
at least 5 minutes:

Systolic BP (mmHg)

Diastolic BP (mmHg)

Pulse rate (beats per minute [bpm])

Body temperature (°C)

Respiratory rate (breaths per minute)
The measurement of vital signs will be carried out according to the relevant Parexel SOPs.


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6.3.6.
Spirometry
Spirometry will be performed by a technologist or a qualified designee to ensure subjects 
achieve optimal lung function and using standardized equipment that meets or exceeds the 
ATS/ERS joint recommendations.
The subject will be in a seated position during spirometry. The following variables will be 
recorded:

Forced expiratory volume in one second

Forced expiratory volume in one second percentage of predicted value

Forced vital capacity

FEV1/FVC ratio
Spirometry must meet both acceptability and repeatability criteria according to ATS/ERS 
2019 recommendations (Graham et al. 2019). Calculated predicted spirometry results will be 
obtained using the Global Lung Initiative equations (Quanjer et al. 2012).
6.4.
Pharmacokinetics
6.4.1.
Collection of Pharmacokinetic Samples
6.4.1.1.
Plasma Samples
Blood samples for the determination of plasma concentrations of budesonide, 
glycopyrronium, and formoterol will be collected for each treatment period as specified in the 
SoA (Table 3-1).
Samples will be collected, handled, labeled, stored, and shipped as detailed in the Laboratory 
Manual.
6.4.2.
Pharmacokinetic Drug Assays
Blood samples for determination of budesonide, glycopyrronium, and formoterol 
concentrations in plasma will be analyzed by LabCorp on behalf of AstraZeneca, using a 
validated assay. Additional analyses may be conducted on the biological samples to further 
investigate the presence and/or identity of drug metabolites.
Full details of the analytical method and analyses performed will be described in a separate 
bioanalytical report.
6.5.
Pharmacodynamics
Not applicable.


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6.6.
Pharmacogenetics
Not applicable.
6.7.
Biomarkers
Not applicable.
6.8.
Immunogenicity
Not applicable.
6.9.
Metabolites
Not applicable.
6.10.
Taste Assessment
Not applicable.


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7.
BIOLOGICAL SAMPLES PROCEDURES
All biological samples will be collections will be performed by trained staff and in accordance 
with the Clinical Unit’s SOPs.
7.1.
Total Blood Volume
The maximum volume to be drawn from each subject, including repeat samples, must not 
exceed 500 mL in total in any 55-day period of a study.
7.2.
Handling, Storage, and Destruction of Biological Samples
Samples will be disposed of, on instruction from AstraZeneca, after the CSR has been 
finalized, unless samples are retained for additional or future analyses.
7.2.1.
Pharmacokinetic 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 anonymized by pooling. Additional analyses 
may be conducted on the anonymized, pooled and/or individual PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be reported 
separately from the CSR.
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 CSR but 
separately in a bioanalytical report.
7.3.
Labeling and Shipment of Biohazard Samples
Samples will be labeled and shipped in accordance with the Laboratory Manual and the 
Biological Substance, Category B regulations (materials containing or suspected to contain 
infectious substances that do not meet Category A criteria), see Appendix B of this CSP
‘IATA 6.2 Guidance Document’.
Any samples identified as Infectious Category A materials will not be shipped and no further 
samples will be taken from the subject unless agreed with AstraZeneca and appropriate 
labeling, shipment and containment provisions are approved.
7.4.
Chain of Custody of Biological Samples
A full chain of custody will be maintained for all samples throughout their lifecycle.


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The investigator will ensure full traceability of collected biological samples from the subjects 
while in storage at the Clinical Unit until shipment and will keep documentation of receipt of 
arrival.
The sample receiver will keep full traceability of samples while in storage and during use, 
until used, disposed of, or until further shipment or disposal (where appropriate) and will keep 
documentation of receipt of arrival.
Samples retained for further use will be registered in the AstraZeneca biobank system during 
the entire life cycle.
7.5.
Withdrawal of Informed Consent for Donated Biological Samples
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed if not already analyzed and the action documented.
As collection of donated biological samples is an integral part of the study then the subject is 
withdrawn from further study participation.
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the action 
documented, and the signed document returned to the Clinical Unit.


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8.
REGULATORY AND ETHICAL CONSIDERATIONS
8.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the CSP and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki (Fortaleza, Brazil, October 2013) and Council for 
International Organizations of Medical Sciences International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulations

The CSP, CSP amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB by the investigator and reviewed and approved by the IRB 
before the study is initiated.

Any amendments to the CSP will require IRB and applicable Regulatory Authority 
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects.

AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO, but the accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB, European 
Regulation 536/2014 for clinical studies (if applicable), European Medical Device 
Regulation 2017/745 for clinical device research (if applicable), and all other applicable 
local regulations.
8.2.
Data Protection

Subjects will be assigned a unique identifier. Any subject records or datasets that are 
transferred to the sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.

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 and use of 
their data must also be explained to the subject in the informed consent.

The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities.
All clinical study findings and documents will be regarded as confidential. The investigator 
and members of his/her research team must not disclose such information without prior 
written approval from the sponsor.
The anonymity of participating subjects must be maintained. Subjects will be specified in 
outputs and other documents containing subject data by their subject number, not by name. 


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Documents that identify the subject (eg, signed ICF) will be maintained in confidence by the 
investigator.
Study data will be stored in accordance with local and global data protection laws.
8.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding the 
study.

Subjects must be informed that their participation is voluntary, and they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the 
study. Subjects or their legally authorized representative defined as ‘an individual, or 
judicial, or other body authorized under applicable law to consent on behalf of a 
prospective subject to the subject's participation in the procedure(s) involved in the 
research’, 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 of 1996 requirements, where applicable, and the IRB 
or Clinical Unit.

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 authorized 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 authorized
representative.
Subjects who are rescreened are required to sign a new ICF.
8.4.
Insurance
The sponsor has covered this clinical study by means of an insurance of the clinical study 
according to national requirements. The name and address of the relevant insurance company, 
the certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's Site File.


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9.
DATA QUALITY ASSURANCE AND DATA MANAGEMENT
9.1.
Quality Control and Source Data Verification
Source data verification will be conducted with due regard to subject confidentiality.
The Clinical Unit will allow the study monitor and sponsor representative direct access to all 
study documents, medical files, and source documents to enable verification of the study data, 
while maintaining the anonymity of the subject and confidentiality of the data.
Internal quality control will be performed at all stages of the study by the Clinical Unit.
9.2.
Audit/Inspections
The Clinical Unit facilities and all study data/documentation may be audited/inspected by 
independent auditor/inspector/any representatives of regulatory authorities. The investigator
must allow the applicable persons access to all relevant facilities and data/documents. The 
investigator must be available to discuss any findings/issues.
If an audit was performed, the audit certificate will be included in the CSR.
9.3.
Study Monitoring
The conduct of the study will be monitored by an independent Parexel monitor to ensure 
compliance with applicable regulatory requirements and GCP. The summary of the 
documentation of the monitoring visits will form part of the study documentation and will be 
archived as such.
9.4.
Data Collection
The ClinBase™ system is an electronic source data capturing and information management 
system. The system combines all aspects of source data capturing with process control and 
clinical study management. All clinical and laboratory data, except those which are 
paper-based or provided by external vendor, will be collected in ClinBase™. Only 
paper-based data will be subject to data entry. For electronic source data, no data entry will be 
performed.
The responsible study monitor will check data at the monitoring visits to the Clinical Unit. 
The investigator will ensure that the data collected are accurate, complete, and legible. Data 
will be monitored within ClinBase™ by the study monitor before being exported. Any 
changes made during monitoring will be documented with a full audit trail within ClinBase™.


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9.4.1.
Case Report Forms and Source Documents
All data obtained using paper collection methods during the clinical study will be recorded in 
ClinBase™. All source documents from which ClinBase™ entries are derived should be 
placed in the subject’s personal records.
The original ClinBase™ entries for each subject will be checked against source documents by 
the study monitor. Instances of missing or uninterpretable data will be discussed with the 
investigator for resolution.
9.4.2.
Access to Source Documents
During the course of the clinical study, a study monitor will make Clinical Unit visits to 
review CSP compliance, compare ClinBase™ entries and individual subject’s personal 
records, assess IMP accountability and ensure that the clinical study is being conducted 
according to pertinent regulatory requirements. ClinBase™ entries will be verified against 
source documents. The review of medical records will be handled confidentially to ensure 
subject anonymity.
Checking of the ClinBase™ entries for completeness and clarity and verifying with source 
documents, will be required to monitor the clinical study for compliance with GCP and other 
regulations. Moreover, regulatory authorities of certain countries, IECs/IRBs may wish to 
carry out source data inspections on site, and the sponsor’s clinical quality assurance group 
may wish to carry out audits. Direct access to source data will be required for these 
inspections and audits; they will be carried out giving due consideration to data protection and 
subject confidentiality. The investigator assures the sponsor of the necessary support at all 
times.
9.5.
Data Management
Parexel will utilize standardized and validated procedures and systems to collect, process and 
file the clinical data of this study. Any system used will be compliant with FDA 21 CFR 
Part 11 requirements.
A DMP will be prepared to describe the processes and dataflow within the clinical study. 
Timelines, versions for the computer systems and the coding will be defined in the DMP, and 
if applicable, sponsor specific requests will also be documented within. The DMP will be 
finalized before first dose where possible but before database lock.
A DVS will be created to outline the validation checks to be performed during the study. The 
DVS must be finalized before data validation.
After the data has been monitored by the responsible study monitor all data received will be 
reviewed, logged, and filed.


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The raw data intended for further processing will be checked by standard routines or 
according to the DVS and queries will be generated and sent to the investigator for review and 
resolution. Corrections resulting from these queries will be confirmed on the DCFs. This 
process will be repeated until no further discrepancies are found. The data will then be 
declared as clean. Applicable documentation will be stored in the study files.
Only trained study staff will have access to the clinical database and every change in data will 
have a full audit trail.


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10.
EVALUATION AND CALCULATION OF VARIABLES
10.1.
Safety Variables
10.1.1.
Adverse Events
All AEs will be coded using MedDRA vocabulary and will be listed for each subject. A 
treatment emergent adverse event is defined as an AE with onset (start date/time) after dosing 
the first dose of IMP in Treatment Period 1.
Adverse events will be assigned to a treatment based on the start date/time of the AE in 
relation to dosing in that period; for tabulation purposes the AE will then be assigned to the 
treatment received in the respective treatment period as follows:

Screening: all AEs with start date/time prior to dosing in Treatment Period 1.

Treatment Period 1: AEs with start date/time at the time of or after dosing in Treatment 
Period 1 until the time of dosing in Treatment Period 2.

Treatment Period 2: AEs with start date/time at the time of or after dosing in Treatment 
Period 2 until the time of dosing in Treatment Period 3.

Treatment Period 3: AEs with start date/time at the time of or after dosing in Treatment 
Period 3 until the final Follow-up Phone Call.
Adverse events with missing start dates/times will be handled as follows:

If the start date is completely missing but the end date is known and shows that the AE 
ended on or after the first dose date, then the start date will be imputed as the first day of 
dosing; if the end date is known and shows that the AE ended before the first dose date, 
then the screening date will be used for the start date. If the end date is non-informative 
(ie, is missing or does not contain enough information), the start date will be imputed as 
the first date of dosing.

If only the start day is missing the day will be imputed as the first day on which a dose 
was given in that month unless the end date is known and shows that the AE ended before 
a dose was given in that month; in which case the date will be imputed as 01. If the end 
date is non-informative (ie, is missing or does not contain enough information), the start 
date will be imputed as the first date of dosing in the known month. If the month is not a 
dosing month the date will be imputed as 01.

If the start day and month are missing the date will be imputed as the first day of dosing 
in the known year unless the end date is known and shows that the AE ended before a 
dose was given in that year; in which case the start day and month will be imputed as 
01Jan or with the date of screening if this is later. If the end date is non-informative (ie, is 
missing or does not contain enough information), the start date will be imputed as the first 
date of dosing in the known year. If the year is not a year of dosing, then the date will be 
imputed as 01Jan or with the date of screening if this is later.

Missing times will be imputed as 00:00 h or with the time of dosing for events starting on 
a dosing day.


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Adverse events will be summarized by treatment (where treatments will be pooled across 
treatment periods) and overall for all subjects, including tabulations by causality and severity 
(mild, moderate, and severe). All tabulations will be presented by SOC and preferred term. 
Furthermore, separate listings of SAEs, DAEs, and AEs that led to death will be presented.
The following information will be included in the listings: verbatim term, SOC, preferred term
and lowest level term, start date/time, end date/time, time from last dose, causality, action 
taken, whether the AE was classified as serious, and the outcome.
All tabulations will include the number and percentage of subjects. In addition, a separate 
tabulation will be presented showing the number of events by treatment and preferred term.
Finally, an overview of all AEs will be presented, separately for the number and percentage of 
subjects and the number of events. This will include categories for any AE, AEs with outcome 
of death, and SAEs.
10.1.2.
Laboratory Assessments
Hematology and clinical chemistry values will be listed by subject and time point including 
changes from baseline and repeat/unscheduled measurements. Summary tabulations including 
absolute values and changes from baseline will be presented by time point for the safety 
analysis set. The baseline for the measurements will be the screening assessment performed 
prior to dosing in Treatment Period 1. Shift tables will also be presented.
The listings will include the following information: test name, date of measurement, reference 
range, result and flags for any measurements that are outside the reference range (eg, 
AstraZeneca, program, or laboratory ranges). Clinical laboratory data will be reported in 
System International units in the CSR.
Additional listings will be presented for the following:

Urinalysis (macroscopic and microscopic, if applicable).

Pregnancy testing (including FSH).

The results of viral serology and the drugs of abuse and alcohol screen will not be listed 
in the CSR.
10.1.3.
Physical Examination
The baseline/screening results of the physical examination will be documented in medical 
history for each subject.
Any new or aggravated clinically relevant abnormal medical physical examination finding 
compared to the baseline assessment will be reported as an AE.


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10.1.4.
Resting 12-lead Electrocardiogram
12-Lead ECG results will be listed for each subject, with interpretation by the investigator as 
“Normal”, “Abnormal CS” (clinically significant) and “Abnormal NCS” (not clinically 
significant).
10.1.5.
Vital Signs
The results of the vital signs measurements will be listed by subject and time point including 
the date/time of the assessment, changes from baseline and repeat/unscheduled measurements. 
The baseline for vital signs measurements will be the screening assessment. Descriptive 
statistics will be presented by treatment and time point for both observed values and changes 
from baseline.
10.2.
Pharmacokinetic Variables
Where possible, the PK parameters will be assessed for budesonide, glycopyrronium, and 
formoterol using plasma concentrations.
10.2.1.
Plasma Parameters
Primary PK parameters
AUCinf
Area under plasma concentration-time curve from zero to infinity
AUClast
Area under the plasma concentration-curve from zero to the last quantifiable 
concentration
Cmax
Maximum observed plasma (peak) drug concentration
Secondary PK parameters
tmax
Time to reach peak or maximum observed concentration or response following 
drug administration
t½λz
Half-life associated with terminal slope (λz) of a semi-logarithmic 
concentration-time curve
MRTinf
Mean residence time of the unchanged drug in the systemic circulation from zero 
to infinity
λz
Terminal rate constant, estimated by log-linear least squares regression of the 
terminal part of the concentration-time curve
CL/F
Apparent total body clearance of drug from plasma after extravascular 
administration
Vz/F
Volume of distribution (apparent) at steady state following extravascular 
administration (based on terminal phase)
Additionally, Test (Treatment A) to Reference (Treatment B) ratios for AUCinf, AUClast, and 
Cmax will be calculated for each individual subject.


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The following diagnostic parameters for plasma PK analysis will be listed, but not 
summarized:
λz upper and λz lower
The time interval (h) of the log-linear regression to determine t½
λzN
Number of data points used for λz determination
Rsq_adj
Statistical measure of fit for the regression used for λz determination adjusted for 
the number of used data points (n obs)
AUCextr
Extrapolated area under the curve from tlast to infinity, expressed as percentage 
of AUCinf
Additional PK parameters may be determined where appropriate.
10.2.2.
Calculation or Derivation of Pharmacokinetic Parameters
The PK analyses of the plasma concentration data for budesonide, glycopyrronium, and 
formoterol will be performed by AstraZeneca R&D.
PK parameters will be derived using non-compartmental methods with Phoenix® 
WinNonlin® Version 8.2, or higher. All descriptive and inferential statistical computations 
will be performed using SAS® Version 9.4, or higher.
PK analysis will, where possible, be carried out using actual times recorded in the raw data. If 
actual times are missing, nominal times will be used.
Plasma concentrations which are NQ prior to the first quantifiable concentration will be set to 
a value of zero. After the first quantifiable concentration, any NQ plasma concentrations will 
be set to missing for all concentration profiles. Where 2 or more consecutive concentrations 
are NQ at the end of a profile, the profile will be deemed to have terminated and therefore any 
further quantifiable concentrations will be set to missing for the calculation of the PK 
parameters unless it is considered to be a true characteristic of the profile of the drug.
If an entire concentration-time profile is NQ, the profile will be excluded from the PK 
analysis.
Terminal elimination half-life, calculated as (ln2)/λz, will be estimated by log-linear least 
squares regression of the terminal part of the concentration-time curve. For the determination 
of λz, the start of the terminal elimination phase for each subject will be defined by visual 
inspection and will be the first point at which there is no systematic deviation from the 
log-linear decline in plasma concentrations. A minimum of 3 data points will be used in 
calculating λz, and the duration of time over which λz is recommended to be at least 3 times 
the subsequently estimated terminal half-life. Where an elimination half-life is estimated over 
less than 3 times the subsequently estimated terminal half-life, it will be flagged and 
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is the observed last quantifiable drug concentration. The AUCinf values where the percentage 
extrapolation is greater than 20% will be flagged in the data listings.
AUCs (including AUCinf and AUClast) will be calculated using the linear trapezoidal method 
when concentrations are increasing and the logarithmic trapezoidal method when 
concentrations are decreasing.
The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive plasma concentrations above the LLOQ, with at least 1 of these concentrations 
following Cmax.
10.3.
Pharmacodynamic Variable(s)
Not applicable.
10.4.
Pharmacogenetics
Not applicable.
10.5.
Exposure - Response Analyses
Not applicable.
10.6.
Taste Assessment
Not applicable.


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11.
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION
11.1.
Description of the Analysis Sets
11.1.1.
Safety Analysis Set
The safety analysis set will include all subjects who received at least 1 inhalation of any BGF 
MDI.
Unless otherwise stated, the safety analysis set will be used for the presentation of all 
demographic and disposition data, as well as all safety analyses. Exposure to IMP will also be 
presented using the safety analysis set.
11.1.2.
Pharmacokinetic Analysis Set
The PK analysis set will consist of all subjects in the safety analysis set for whom at least 
1 primary PK parameter that can be calculated and who have no important CSP deviations 
thought to impact the analysis of the PK data.
Subjects may be excluded from the PK analysis set as a result of the following:

Data from subjects for whom the pre-dose concentration is > 5% of Cmax for BGF MDI 
in a specific treatment period.
A subject may be excluded from the analysis only for the specific treatment period in which 
the AE occurred.
The exclusion of any subjects or time points from the calculation of the PK parameters will be 
documented by the PK Scientist including the reason(s) for exclusion.
The available concentration data and PK parameter data for any subjects excluded from the 
PK analysis set will be listed only. Concentration data for subjects excluded from the PK 
analysis set will be presented in the individual figures of concentration versus time plots.
11.1.3.
Randomized Set
The Randomized Set will consist of all subjects randomized into the study.


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11.2.
Methods of Statistical Analyses
11.2.1.
General Principles
The statistical methodology below describes the statistical analysis as it is foreseen when the 
study is being planned.
If circumstances should arise during the study rendering the analysis inappropriate, or if in the 
meantime improved methods of analysis should come to light, different analyses may be 
performed. A SAP will not be written for the study. Any deviations from the statistical 
methodology defined in this CSP, reasons for such deviations and all alternative/additional 
statistical analyses that may be performed will be described in the CSR. Such changes to 
analyses may be written into an abbreviated SAP, if appropriate. The verification and review 
of all statistical modeling assumptions will be documented appropriately.
All original and derived parameters as well as demographic and disposition data will be listed 
and described using summary statistics. All safety data (scheduled and unscheduled) will be 
presented in the data listings.
Demographic and baseline data will be summarized for all randomized subjects. 
Pharmacokinetic data will be summarized by treatment. Safety and tolerability data will be 
summarized by treatment, if applicable.
Frequency counts (n and percentages) will be made for each qualitative variable. Descriptive 
statistics (n, mean, SD, median, minimum and maximum) will be calculated for each 
quantitative variable (unless otherwise stated). Descriptive statistics will only be presented if 
n ≥ 3.
The following rules will apply to any repeated safety assessments occurring within each 
treatment period:

If the repeated measurement of a specific parameter occurs prior to IMP administration 
(Day 1), then the last obtained value prior to dosing will be used in the descriptive 
statistics and in the calculation of changes from baseline.

If the repeated measurement of a specific parameter occurs after IMP administration 
(Day 1), then the first (non-missing) value after dosing will be used in descriptive 
statistics and in the calculation of changes from baseline.
The planned sequence for measurement of multiple assessments at the same time point is 
described in Section 3.1.1.


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For safety assessments performed at screening and the last visit, the following rules will apply 
for any repeated assessments:

If the repeated assessment occurs at screening the last available value will be used in the 
summary statistics.

If the repeated assessment occurs at the Day 2 Treatment Period 3 visit the first 
non-missing assessment will be used in the summary statistics.
All statistical analyses and production of tables, figures and listings will be performed using 
SAS® version 9.4 or later.
11.2.2.
Missing Data
Missing dates and times in the AE data will be handled as described in Section 10.1.1. 
Concentrations that are NQ in the PK data will be handled as described in Section 10.2.2.
There will be no imputations of other missing data. All subjects will be included into the 
safety analyses as far as the data permit.
11.2.3.
Subject Characteristics
A randomization listing will be presented and include the following: each subject’s 
randomization number, the subject’s full enrollment number, the treatment to which the 
subject has been randomized and the country where the Clinical Unit is located.
Subjects and/or data excluded from the PK analysis set will be listed including the reason for 
exclusion. Subject disposition will be summarized and will include the following information: 
number of subjects randomized and dosed, number and percentage of subjects completing the 
study and the number and percentage of subjects who were withdrawn (including reasons for 
withdrawal). Disposition data will be presented based on all subjects randomized.
Subject discontinuations will be listed including the date of study exit, duration of treatment 
and reason for discontinuation. A listing of informed consent response will also be presented.
11.2.3.1.
Demographic and Baseline Data
Demographic variables (age, gender, race, ethnicity, height, weight, and BMI) will be listed 
by subject. Demographic characteristics (age, gender, race, and ethnicity) and subject 
characteristics (height, weight, and BMI) will be summarized separately for all randomized 
subjects. The denominator for percentages will be the number of randomized subjects.
Medical history data will be listed by subject including visit, description of the 
disease/procedure, MedDRA SOC, MedDRA preferred term, start date and stop date (or 
ongoing if applicable).


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A summary of the number and percentage of subjects who had relevant medical histories will 
be presented by treatment sequence and for all subjects for the medical history preferred term.
11.2.4.
Prior and Concomitant Medication and Drug Administration
11.2.4.1.
Prior and Concomitant Medication
Prior medications are those that started and stopped prior to the first dose of IMP; all 
medications taken after first dosing are considered as concomitant (including medications that 
started prior to dosing and continued after). Prior medication started within 3 months prior to 
the first dose of IMP will be recorded also in the concomitant medication module of 
ClinBase™.
Prior and concomitant medication will be listed by subject and will include the following 
information: reported name, preferred term, the route of administration, dose, frequency, start 
date/time, duration, and indication. Prior and concomitant medication will be coded according 
to the sponsor’s drug dictionary.
11.2.4.2.
Study Intervention Administration
Study intervention dates and times will be listed for each subject and treatment period.
11.2.5.
Safety and Tolerability
All safety data (scheduled and unscheduled) will be presented in the data listings continuous 
variables will be summarized using descriptive statistics (n, mean, SD, minimum, median, 
maximum) by treatment group. Categorical variables will be summarized in frequency tables 
(frequency and proportion) by treatment/dose group. The analysis of the safety variables will 
be based on the safety analysis set.
Adverse events will be summarized by preferred term and SOC using MedDRA vocabulary. 
Furthermore, listings of SAEs and DAEs will be made. Adverse events that occur before 
dosing will be reported separately.
Tabulations and listings of data for vital signs, clinical laboratory tests, ECGs, will be 
presented. Any new or aggravated clinically relevant abnormal medical physical examination 
finding compared to the baseline assessment will be reported as an AE. Data will be 
summarized for the observed values at each scheduled assessment, together with the 
corresponding changes (and/or percentage change) from the baseline when baseline is defined. 
Clinical laboratory data will be reported in the units provided by the clinical laboratory for the 
SRC meeting, and in Système International units in the CSR.
Out-of-range values for safety laboratory will be flagged in individual listings as well as 
summarized descriptively using agreed reference ranges (eg, laboratory ranges).


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11.2.6.
Pharmacokinetics
A listing of PK blood sample collection times, as well as derived sampling time deviations 
will be provided. Plasma concentrations and PK parameters will be summarized by treatment 
group and analyte (budesonide, glycopyrronium, and formoterol) using appropriate descriptive 
statistics. Where possible, the following descriptive statistics will be presented: n, geometric 
mean, geometric CV, arithmetic mean, arithmetic SD, median, minimum, and maximum. For 
tmax, only n, median, minimum, and maximum will be presented.
The geometric mean is calculated as the exponential of the arithmetic mean calculated using 
log-transformed data.
The CV% is calculated as 
where s is the SD of the log-transformed data.
Concentration data will be presented to the same number of significant figures as the data 
received from the bioanalytical laboratory; for PK parameters, the listings will be presented 
according to the following rules:

Cmax – will be presented to the same number of significant figures as received from the 
bioanalytical laboratory

tmax, λz lower and λz upper time limit – will be presented as received in the data, usually 
to 2 decimal places

AUCinf, AUClast, t½λz, λz, CL/F, MRTinf, Vz/F, AUCextr, R sq adj will be presented to 
3 significant figures

λzN – will be presented as an integer (no decimals)
For PK concentration data all descriptive statistics will be presented to 4 significant figures 
with the exception of the minimum and maximum which will be presented to 3 significant 
figures.
For PK parameters data the descriptive statistics will be presented according to the following 
rules:

Cmax, AUCinf, AUClast, t½λz, λz, CL/F, MRTinf, Vz/F – all descriptive statistics will 
be presented to 4 significant figures with the exception of the minimum and maximum 
which will be presented to 3 significant figures

tmax, λz lower and λz upper – all descriptive statistics will be presented as received in the 
data, usually to 2 decimal places

λzN, N – present as an integer




1
exp
100
2 

s


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Plasma concentrations that are NQ or if there are missing values (eg, no result [NR]) will be 
handled as follows:

Where there is NR, these will be set to missing.

At a time point where less than or equal to 50% of the values are NQ, all NQ values will 
be set to the LLOQ, and all descriptive statistics will be calculated.

At a time point where more than half of the values are NQ, the mean, SD, geometric 
mean and CV% will be set to NC. The maximum value will be reported from the 
individual data, and the minimum and median will be set to NQ.

If all values are NQ at a time point, no descriptive statistics will be calculated for that 
time point. Not calculated will be written in the field for SD and CV% and NQ will be 
written in fields for mean, geometric mean, minimum, median, and maximum.

The number of NQ values (n below LLOQ) will be reported for each time point.
Three observations > LLOQ are required as a minimum for a plasma concentration to be 
summarized. Two observations are presented as a minimum and maximum with the other 
summary statistics as NC.
Data from subjects excluded from the PK analysis set will be included in the data listings, but 
not in the descriptive statistics or in the inferential statistics.
Plasma concentrations for each analyte (budesonide, glycopyrronium, and formoterol) will be 
listed by treatment occasion, subject and time point. Plasma concentrations will also be 
summarized by treatment occasion and for each analyte using protocol scheduled times and 
appropriate descriptive statistics.
The statistical analysis will be performed for the PK analysis set. Pharmacokinetic parameters 
will be calculated using non-compartmental analysis.
For each analyte, individual plasma concentrations versus actual time will be plotted in linear 
and semi-logarithmic scale with all treatment occasions overlaid on the same plot and separate 
plots for each subject. Combined individual plasma concentration versus actual times will be 
plotted in linear and semi-logarithmic scale for each treatment occasion and analyte. 
Geometric mean plasma concentration (± gSD) versus nominal sampling time will be plotted 
in linear and semi-logarithmic (no SD presented) scale with all treatment occasions overlaid 
on the same figure.
For mean plots, below the limit of quantification values will be handled as described for the 
summary tabulations; for individual plots plasma concentrations which are NQ prior to the 
first quantifiable concentration will be set to a value of zero (linear plots only). After the first 
quantifiable concentration, any NQ plasma concentrations will be regarded as missing. All 


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plots will be based on the PK analysis set, with the exception of individual plots by subject 
which will be based on the safety analysis set.
Bioequivalence
Bioequivalence will be assessed between test treatment BGF MDI HFO and reference 
treatment BGF MDI HFA based on the PK analysis set.
USA Approach:
To establish the bioequivalence of the test treatment BGF MDI HFO and reference treatment 
BGF MDI HFA, the GMR and 90% CIs will be analyzed for PK parameters Cmax, AUClast, 
and AUCinf of analytes budesonide, glycopyrronium, and formoterol.
The TOST will be performed via a linear mixed effects model, with log-transformed PK 
parameter as dependent variable; sequence and period as fixed effects; subject and treatment 
nested within-subject as random effects. The estimated GMR with 90% CIs will be provided.
For any of Cmax, AUClast, or AUCinf, if the swr of the reference treatment is < 0.294 (ie, 
within-subject CV is < 30%), then the ABE method will be used. The acceptance criteria for 
90% CIs of GMR are the fixed limits 80% to 125%.
For any of Cmax, AUClast, or AUCinf, if swr is ≥ 0.294 that shows high intra-subject 
variability, then the RSABE method will be used. The acceptance limits for 90% CIs of GMR 
are expanded to [U, L] = e ± k·swr, where k = 0.893.
Geometric mean ratio must lie within 80% and 125%, regardless of the expanded acceptance 
limits for 90% CIs.
The acceptance criteria for GMR and the acceptance criteria for 90% CIs of GMR must be 
satisfied for each PK parameter and each analyte to conclude the bioequivalence.
Proposed SAS Code for PK Bioequivalence Analysis with Replicate Designs:
The FDA guidance for Industry document “Statistical approaches to establish bioequivalence” 
specifies the bioequivalence analysis of replicated design using a linear mixed effects model, 
with log-transformed PK parameter as dependent variable; sequence and period as fixed 
effects; subject and treatment (nested within-subject) as random effects 
(FDA Guidance 2001).


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EU Approach:
To establish the bioequivalence of the test treatment BGF MDI HFO and reference treatment 
BGF MDI HFA, the GMR and 90% CIs will be analyzed for PK parameters Cmax, and 
AUClast of analytes budesonide, glycopyrronium, and formoterol.
The TOST will be performed via an analysis of variance model, with log-transformed PK 
parameter as dependent variable; sequence, period, treatment, and subject within sequence as 
fixed effects. The estimated GMR with 90% CIs will be provided.
For Cmax, if the swr of the reference treatment 
 the 
ABE method will be used. The acceptance criteria for 90% CIs of GMR are the fixed limits 
 
 
The ABE method will be applied for AUClast. The acceptance criteria for 90% CIs of GMR 
are the fixed limits 
Geometric mean ratio must lie within 
 regardless of the expanded acceptance 
limits for 90% CIs.
The acceptance criteria for GMR and the acceptance criteria for 90% CIs of GMR must be 
satisfied for each PK parameter and each analyte to conclude the bioequivalence.
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Proposed SAS Code for PK Bioequivalence Analysis with Replicate Designs:
The EU approach compatible with Committee for Medicinal Products for Human Use
guideline specifies the bioequivalence analysis of replicated design using an analysis of 
variance model, with log-transformed PK parameter as dependent variable; sequence, period, 
treatment and subject within sequence as fixed effects (Annex I EMA, EMA Guideline 2010).
 
 
11.3.
Protocol Deviations
Protocol deviations are considered any deviation from the CSP relating to a subject, and 
include the following:
!
Inclusion/exclusion criteria deviations
!
Dosing deviations (eg, incorrect treatment received, subject was not fasted as per the CSP
requirements prior to and after dosing)
!
Time window deviations for safety and/or PK assessments
!
Subjects receiving prohibited concomitant medications
!
Other procedural and study conduct deviations recorded by the Clinical Unit on a CSP
deviation log
The criteria for the assessment and reporting of CSP deviations will be stipulated in a separate 
study specific CSP deviation specification document. This will include a WAD which 
stipulates tolerance windows for safety and PK assessments. Measurements performed within 
these tolerance windows will not be considered as CSP deviations and will not be reported.
All CSP deviations will be discussed at the data review meeting prior to database hard lock in 
order to define the analysis sets for the study.
Important CSP deviations will be listed by subject.
Protocol deviations will be handled in accordance with Parexel SOPs.
CCI
CCI


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For handling of CSP amendments, see Section 8.1.
11.4.
Determination of Sample Size
The sample size for this study was based on 
 
 
 
 
 
The number of subject identifiers generated for the study will account for the number of 
randomized subjects per the sample size calculation (N = 108). For this study, a total of 
108 subject identifiers will be randomly assigned to 1 of 3 possible treatment sequences: 
ABB, BAB, BBA.
CCI
CCI


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12.
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR
12.1.
Medical Emergencies and AstraZeneca Contacts
In case of medical emergency, the primary contact is the PI. The PI may contact the Sponsor’s 
Lead Physician. If the PI cannot be reached, the site’s staff will contact the PI’s deputy or may 
contact Sponsor’s Lead Physician.
Name
Role in the Study
Contact Details
Principal Investigator
Tel: 
Email: 
Sponsor’s Lead Physician
AstraZeneca AB
Tel: 
Email: 
12.2.
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the study subject has received any study intervention.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
Please refer to Section 4.2.1.2 and Section 4.2.1.3 for further details.
12.2.1.
Maternal Exposure
If a subject becomes pregnant during the course of the study, BGF MDI should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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anomalies/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital anomaly) 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 1 day (ie, 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 CSP process for SAE reporting) and within 30 days for all other 
pregnancies.
The same timelines apply when outcome information is available.
Please refer to Section 4.2.1.2 for further details.
12.2.2.
Paternal Exposure
There is no restriction on fathering children or donating sperm during the study.


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13.
LEGAL AND ADMINISTRATIVE ASPECTS
13.1.
Archiving of Study Documents
All source documents generated in connection with the study will be retained in the limited 
access file storage area, respecting the privacy and confidentiality of all records that could 
identify the subjects. Direct access is allowed only for authorized people for monitoring and 
auditing purposes. Source documents will be handled, stored, and archived according to in 
house procedures.
The Investigator's Site File will be archived by the CRO for 15 years after completion of the 
study.
13.2.
Publication of Study Results
All of the study information and data collected during the study are confidential and the 
property of AstraZeneca. After completion of the study, AstraZeneca may prepare a joint 
publication with the investigator. The investigator must undertake not to submit any data from 
this CSP for publication without prior consent of AstraZeneca at a mutually agreed time.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
13.3.
Clinical Study Report
An integrated CSR will be prepared in accordance with the standards of the ICH guideline for 
structure and content of CSRs (ICH E3). Copies of the CSR will be provided to the IRB and 
the national Regulatory Authority in accordance with regulatory requirements and Parexel
SOPs. In the event of premature termination of the study or other conditions specified in 
ICH E3, an abbreviated CSR may be prepared.


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14.
REFERENCE LIST
Annex I EMA
Annex I EMA/582648/2016. Available at: 
https://www.ema.europa.eu/en/documents/other/31-annex-i-statistical-analysis-methods-
compatible-ema-bioequivalence-guideline_en.pdf. Accessed 17 May 2022.
EMA Guideline 2010
EMA Guideline on the Investigation of Bioequivalence 2010. Available at: 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-
bioequivalence-rev1_en.pdf. Accessed 17 May 2022.
FDA Guidance 2001
FDA Guidance for Industry document “Statistical approaches to establishing bioequivalence” 
(2001). Available at: https://www.fda.gov/media/70958/download. Accessed 17 May 2022.
Graham et al. 2019
Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, Hallstrand 
TS, Kaminsky DA, McCarthy K, McCormack MC, Oropez CE, Rosenfeld M, Stanojevic S, 
Swanney MP, Thompson BR. Standardization of Spirometry 2019 Update. An Official 
American Thoracic Society and European Respiratory Society Technical Statement. Am J 
Respir Crit Care Med. 2019 Oct 15;200(8):e70-e88.
Investigator’s Brochure 2022
Budesonide, Glycopyrronium and Formoterol Fumarate Inhalation Aerosol (BGF MDI); 
Budesonide and Formoterol Fumarate Inhalation Aerosol (BFF MDI); Budesonide Inhalation 
Aerosol (BD MDI); Glycopyrronium Inhalation Aerosol (GP MDI) (Also known as PT010 
[BGF MDI], PT009 [BFF MDI], PT008 (BD MDI); PT001 (GP MDI); Edition Number 8.0, 
15 April 2022.
Quanjer et al. 2012
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson JL, 
Ip MS, Zheng J, Stocks J; ERS Global Lung Function Initiative. Multi-ethnic reference values 
for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir 
J. 2012 Dec;40(6):1324-43.
Tothfalusi and Endrenyi 2011
Tothfalusi L, Endrenyi L. Sample sizes for designing bioequivalence studies for highly 
variable drugs. J Pharm Sci. 2012;15(1):73-84.


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15.
APPENDICES
Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event
Life-threatening
“Life-threatening” means that the subject was at immediate risk of death from the adverse
event (AE) as it occurred, or it is suspected that use or continued use of the product would 
result in the subject’s death. “Life-threatening” does not mean that had an AE occurred in a 
more severe form it might have caused death (eg, hepatitis that resolved without hepatic 
failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious adverse event (SAE), 
although the reasons for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions 
and/or surgical operations planned before or during a study are not considered AEs if the 
illness or disease existed before the subject was enrolled in the study, provided that it did not 
deteriorate in an unexpected way during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an Important Medical Event; 
medical judgment must be used.

Angioedema not severe enough to require intubation but requiring intravenous
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse


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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 
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 etiology 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 no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as “not related”.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


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Appendix B
International Airline Transportation Association 6.2 
Guidance Document
Labeling and Shipment of Biohazard Samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious
_substances.htm). For transport purposes, the classification of infectious substances according 
to risk groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005). Infectious substances are now classified either as Category A, Category B or Exempt. 
There is no direct relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are for example, Ebola and Lassa 
Fever viruses:

Are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are for example, hepatitis A, B, C, D, and E
viruses, and human immunodeficiency virus (HIV) types 1 and 2. They are assigned the 
following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

Are to be packed in accordance with UN 3373 and IATA 650.
Exempt refers to all other materials with minimal risk of containing pathogens.

Clinical trial samples will fall into Category B or Exempt under IATA regulations.

Clinical trial samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging.
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm)

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry ice content.

An IATA compliant courier and packaging materials should be used for packing and 
transportation. Packing should be done by an IATA certified person, as applicable.

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.


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Appendix C
Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated alanine aminotransferase (ALT) from a central laboratory 
and/or elevated total bilirubin (TBL) from a local laboratory.
The investigator will also review adverse event (AE) data (for example, for AEs that may 
indicate elevations in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than Drug-Induced Liver Injury (DILI) caused by the investigational medicinal product 
(IMP).
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting serious adverse events (SAEs) and AEs according to the outcome of the review and 
assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law
Aspartate aminotransferase (AST) or ALT ≥3 x upper limit of normal (ULN) together with
TBL ≥2 x ULN at any point during the study following the start of study medication 
irrespective of an increase in alkaline phosphatase (ALP).
Hy’s Law (HL)
Aspartate aminotransferase or ALT ≥3 x ULN together with TBL ≥2 x ULN, where no 
other reason, other than the IMP, can be found to explain the combination of increases, eg, 
elevated ALP indicating cholestasis, viral hepatitis, another drug.


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:

Aspartate aminotransferase ≥3 x ULN

Alanine aminotransferase ≥3 x ULN

Total bilirubin ≥2 x ULN
The investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative.

Determine whether the subject meets PHL criteria (see Section 2 within this appendix for 
definition) by reviewing laboratory reports from all previous visits.

Promptly enter the laboratory data into the laboratory CRF module(s).
Follow-up
Potential Hy’s Law Criteria Not Met
If the subject does not meet PHL criteria the investigator will:

Inform the AstraZeneca representative that the subject has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the clinical study protocol (CSP).
Potential Hy’s Law Criteria Met
If the subject does meet PHL criteria the investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team.

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criteria “Important Medical Event” and causality assessment “yes/related” 
according to CSP process for SAE reporting.

For subjects that met PHL criteria prior to starting IMP, the investigator is not required to 
submit a PHL SAE unless there is a significant change1 in the subject’s condition.
1 A “significant” change in the subject’s condition refers to a clinically relevant change in any of the individual 
liver biochemistry parameters (ALT, AST or TBL) in isolation or in combination, or a clinically relevant change 


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
The Study Physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up (including any further laboratory testing) and 
the continuous review of data.

Subsequent to this contact the investigator will:
o
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.
o
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests 
available in the HL laboratory kit should be used (if applicable).
o
Complete the 3 liver CRF modules as information becomes available.
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from the date the PHL criteria were met. The AstraZeneca Global Clinical Lead or equivalent 
and Global Safety Physician will also be involved in this review together with other subject 
matter experts as appropriate.
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the AST or ALT and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets any criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF module(s)

If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE CRF entries accordingly with the new information (reassessing event term; 
causality and seriousness criteria) following the AstraZeneca standard processes
in associated symptoms. The determination of whether there has been a significant change will be at the 
discretion of the investigator, this may be in consultation with the Study Physician if there is any uncertainty.


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If it is agreed that there is no explanation that would explain the AST or ALT and TBL 
elevations other than the IMP:

Send updated SAE (report term “Hy’s Law”) according to AstraZeneca standard 
processes

The “Medically Important” seriousness criterion should be used if no other 
seriousness criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
“related” should be assigned
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether the case meets the criteria for HL, then it is assumed that there is 
no alternative explanation until such time as an informed decision can be made:

Provide any further update to the previously submitted SAE of PHL (report term now 
“Hy’s Law case”), ensuring causality assessment is “related to IMP” and seriousness 
criterion is “medically important”, according to CSP process for SAE reporting.

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory. For studies using a local 
laboratory, the list may be modified based on clinical judgment. Any test results need to be 
recorded.


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Hy’s Law laboratory kit for central laboratories (18 December 2018)
Additional standard biochemistry and 
coagulation tests
GGT (gamma glutamyl transpeptidase (transferase))
LDH (lactate dehydrogenase)
Prothrombin time
INR (international normalized ratio)
Viral hepatitis
IgM anti-HAV 
IgG anti-HCV
IgM and IgG anti-HBc
HCV RNA 1
HBsAg
IgM anti-HEV
HBV deoxyribonucleic acid
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
1
HCV RNA is only tested when anti-HCV is positive or inconclusive.
REFERENCES
Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in 
drug‐induced liver injury. Clinical Pharmacology & Therapeutics 2011;89(6):806–15.
FDA Guidance for Industry (issued July 2009) “Drug-induced liver injury: Premarketing 
clinical evaluation”.


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Appendix D
Medical Device AEs, ADEs, SAEs, SADEs, USADEs and 
Medical Device Deficiencies: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting in Medical 
Device Studies

The definitions and procedures detailed in this appendix are in accordance with 
International Organization for Standardization 14155 and European Medical Device 
Regulation (MDR) 2017/745 for clinical device research (if applicable), in particular 
Medical Device Coordination Group (MDCG) 2020-10/1 Safety reporting in clinical 
investigations of medical devices.

Both the investigator and the sponsor will comply with all local reporting requirements 
for medical devices.

The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 5.4 for details of 
sponsor medical devices.
Definition of Medical Device AE and ADE
Medical Device AE and ADE Definition

An adverse event (AE) is any untoward medical occurrence in a clinical study subject, 
users, or other persons, temporally associated with the use of study intervention, whether 
or not considered related to the investigational medical device. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of an 
investigational medical device. This definition includes events related to the 
investigational medical device or comparator and events related to the procedures 
involved.

An adverse device effect (ADE) is defined as an AE related to the use of an 
investigational medical device. This definition includes any AE resulting from 
insufficient or inadequate instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device as well as any event 
resulting from use error or from intentional misuse of the investigational medical device.
Definition of Medical Device SAE, SADE and USADE
A Medical Device Serious Adverse Event (SAE) is an/any SAE that:

Led to death.

Led to serious deterioration in the health of the subject, that either resulted in:

A life-threatening illness or injury. The term “life-threatening” in the definition of 
“serious” refers to an event in which the subject was at risk of death at the time of the 
event. It does not refer to an event, which hypothetically might have caused death if it 
were more severe.

A permanent impairment of a body structure or a body function.


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
Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE.

Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.

Chronic disease (MDR 2017/745).

Led to fetal distress, fetal death, or a congenital anomaly or birth defect.
SADE Definition

A serious adverse device effect (SADE) is defined as an ADE that has resulted in any of 
the consequences characteristic of an SAE.

Any medical device deficiency that might have led to an SAE if appropriate action had 
not been taken, intervention had not occurred, or circumstances had been less fortunate.
USADE Definition

An unanticipated SADE (USADE) (also identified as UADE in United States Regulations 
21 CFR 813.3), is defined as a SADE that by its nature, incidence, severity, or outcome 
has not been identified in the current risk analysis (see Section 3.4 for risk-benefit 
assessment of the device).
Definition of Medical Device Deficiency
Medical Device Deficiency Definition

A medical device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Medical device 
deficiencies include malfunctions, use errors, and information supplied by the 
manufacturer.
Recording and Follow-up of AE and/or SAE and Medical Device Deficiencies
AE, SAE, and Medical Device Deficiency Recording

When an AE/SAE/medical device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory reports, 
and diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/medical device deficiency 
information in the subject’s medical records, in accordance with the investigator’s normal 
clinical practice and on the appropriate form.

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to the Sponsor in lieu of completion of the AE/SAE/medical device deficiency 
form.


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
There may be instances when copies of medical records for certain cases are requested by 
the sponsor. In this case, all subject identifiers, with the exception of the subject number, 
will be redacted on the copies of the medical records before submission to the sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.

For medical device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a medical 
device deficiency. This includes any amendment to the medical device design to 
prevent recurrence.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE/SAE/medical device 
deficiency reported during the study and assign it to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. “Severe” is a category used for rating the 
intensity of an event; both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
Assessment of Causality
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE/medical device deficiency. A “reasonable possibility” of a 
relationship conveys that there are facts, evidence, and/or arguments to suggest a causal 
relationship, rather than a relationship, cannot be ruled out. The investigator will use clinical 
judgment to determine the relationship. Alternative causes, such as underlying disease(s), 
concomitant therapy, and other risk factors, as well as the temporal relationship of the event to 
study intervention administration will be considered and investigated. The investigator will 
also consult the Investigator’s Brochure and/or Product Information, for marketed products in 
his/her assessment.
For each AE/SAE/medical device deficiency, the investigator must document in the medical 
notes that he/she has reviewed the AE/SAE/medical device deficiency and has provided an 
assessment of causality. There may be situations in which an SAE has occurred, and the 


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investigator has minimal information to include in the initial report to the sponsor. However, it 
is very important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor.
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. The causality 
assessment is one of the criteria used when determining regulatory reporting requirements.
For the purpose of harmonizing reports, each SAE will be classified according to 5 different 
levels of causality. The sponsor and the investigators will use the following definitions to 
assess the relationship of the SAE to the investigational2 device or procedures.
Not related: Relationship to the device or procedures can be excluded when:

the event has no temporal relationship with the use of the investigational device or the 
procedures.

the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible.

the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the serious event.

the event involves a body-site or an organ not expected to be affected by the device or 
procedure.

the serious event can be attributed to another cause (eg, an underlying or concurrent 
illness/clinical condition, an effect of another device, drug, treatment, or other risk 
factors).

the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable.
In order to establish the non-relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event.

Unlikely: The relationship with the use of the device seems not relevant and/or the event 
can be reasonably explained by another cause, but additional information may be 
obtained.

Possible: The relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible (eg, an underlying or 
concurrent illness/ clinical condition or/and an effect of another device, drug, or 
treatment). Cases where relatedness cannot be assessed or no information has been 
obtained should also be classified as possible.
2 Investigational device: any device object of the clinical investigation, including the comparators


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
Probable: The relationship with the use of the investigational device seems relevant 
and/or the event cannot be reasonably explained by another cause, but additional 
information may be obtained.

Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when:

the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures.

the event has a temporal relationship with investigational device use/application or 
procedures.

the event involves a body-site or organ that:
o
the investigational device or procedures are applied to.
o
the investigational device or procedures have an effect on.

the serious event follows a known response pattern to the medical device (if the 
response pattern is previously known).

the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible).

other possible causes (eg, an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled out.

harm to the subject is due to error in use.

the event depends on a false result given by the investigational device used for 
diagnosis, when applicable.
In order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event.
Follow-up of AE/SAE/Medical Device Deficiency

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE/SAE/medical device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a subject dies during participation in the study or during a recognized follow-up period, 
the investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology.

New or updated information will be recorded in the originally completed form.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.


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Reporting of SAEs
SAE Reporting to the Sponsor via Paper Data Collection Tool

Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the study physician.

In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE paper data collection tool sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE paper data collection tool within the designated reporting time frames.

Contacts for SAE reporting can be found in the Safety Handling Plan.
Reporting of SADEs
SADE Reporting to the Sponsor
NOTE: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs that must fulfill the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to medical 
devices being used in clinical studies.

Any medical device deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the 
definition of a medical device deficiency.

The sponsor will review all medical device deficiencies and determine and document in 
writing whether they could have led to an SAE. These medical device deficiencies will be 
reported to the regulatory authorities and IRBs/IECs as required by national regulations.

Contacts for SAE reporting can be found in the Safety Handling Plan.


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