A Phase 1, Randomized, Open-label, Single Dose, 2-treatment Arm (200 μg and 800 μg), 4-way Crossover Study in Healthy Participants Aged 18 to 55 to Compare the Pharmacokinetics of Salbutamol Administered Via Metered Dose Inhalers Containing Propellants HFA-152A (Test) and HFA-134A (Reference)
Phase: PHASE1
Conditions: Asthma, Healthy Participants
Sponsor: GlaxoSmithKline

CONFIDENTIAL 
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Protocol Amendment 1 Final 
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CLINICAL STUDY PROTOCOL 
Primary Study 
Intervention(s) 
Salbutamol administered via metered dose inhalers 
containing propellant HFA-152a (test). 
Other Study Intervention(s) 
Salbutamol administered via metered dose inhalers 
containing propellant HFA-134a (reference). 
Study Identifier 
219728 
EU CT Number 
2023-508279-36-00 
Approval Date 
02 May 2024 
Title 
A Phase 1, randomized, open-label, single dose, 2-
treatment arm (200 µg and 800 µg), 4-way cross-
over study in healthy participants aged 18 to 55 to 
compare the pharmacokinetics of salbutamol 
administered via metered dose inhalers containing 
propellants HFA-152a (test) and HFA-134a 
(reference). 
Compound Number/Name 
AH3365  
Brief Title 
A study to compare the pharmacokinetics of 
salbutamol administered via metered dose inhalers 
containing propellants HFA-152a (test) or HFA-
134a (reference) in healthy participants aged 18 to 
55 inclusive. 
Sponsor 
GSK Research & Development Limited 
980 Great West Road, Brentford, Middlesex, TW8 
9GS, UK 
Sponsor signatory 
Oscar Della Pasqua, MD, PhD 
Executive Director 
Clinical Pharmacology Modeling & Simulation 
Medical monitor name and contact can be found in local study contact 
information document. 
©2024 GSK group of companies or its licensor. 
 

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Protocol Amendment 1 Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments, with the terms of the clinical trial agreement and with any other study 
conduct procedures and/or study conduct documents provided by GSK. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of and will comply with GCP and all applicable regulatory 
requirements.  
• 
That I will comply with the terms of the site agreement. 
• 
To comply with local bio-safety legislation. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK study intervention and other study-related duties and functions as described 
in the protocol. 
• 
To supervise any individual or party to whom I have delegated study-related duties 
and functions conducted at the study site. 
• 
To ensure that any individual or party to whom I have delegated study-related duties 
and functions conducted at the study site are qualified to perform those study-related 
duties and functions. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality Assurance 
procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained on-site or 
elsewhere without the approval of GSK and the express physical or digital informed 
consent of the participant. 
• 
To perform no biological assays on the clinical samples other than those described in 
the protocol or its amendment(s). 
• 
To co-operate with representative(s) of GSK in the monitoring and data management 
processes of the study with respect to data entry and resolution of queries about the 
data. 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the study. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator(s)’ ownership interest 
in the sponsor or the study intervention(s), and more generally about their financial 
ties with the sponsor. GSK will use and disclose the information solely for the purpose 
of complying with regulatory requirements. 

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Hence, I: 
• 
Agree to supply GSK with any necessary information regarding ownership interest 
and financial ties (including those of my spouse and dependent children). 
• 
Agree to promptly update this information if any relevant changes occur during the 
study and for 1 year following completion of the study. 
• 
Agree that GSK may disclose any information about such ownership interests and 
financial ties to regulatory authorities. 
• 
Agree to provide GSK with an updated Curriculum Vitae and all other documents 
required by regulatory agencies for this study. 

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Protocol Amendment 1 Final 
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Study identifier 
219728 
EU CT number 
2023-508279-36-00  
Approval date 
02 May 2024 
Title 
A Phase 1, randomized, open-label, single dose, 2-
treatment arm (200 µg and 800 µg), 4-way cross-
over study in healthy participants aged 18 to 55 to 
compare the pharmacokinetics of salbutamol 
administered via metered dose inhalers containing 
propellants HFA-152a and HFA-134a (reference). 
Investigator name 
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 
 
 
 

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Protocol Amendment 1 Final 
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Protocol Amendment Summary Of Changes Table 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 1 
02 May 2024 
Original Protocol 
18 January 2024 
 
Type of Protocol 
Amendment 
Numbering 
Type of changes 
Global 
Amendment 1 
New changes for all 
Amendment 1 (02 May 2024) 
Overall rationale for the current Amendment: 
The objective of this amendment is to align the time period for collecting pregnancy 
information for female participants with the time period for post-intervention 
contraception. In addition, parameter specifications for microscopic evaluation have been 
removed. 

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LIST OF MAIN CHANGES IN THE PROTOCOL AND THEIR RATIONALE: 
Section # and 
title 
Description of change 
Brief rationale 
8.4.6 Pregnancy 
Changed time period to collect 
pregnancy information from 90 days 
to 48 hours. 
To align with the time period of post-intervention 
contraception.  
10.2 Clinical 
laboratory test 
Removal of parameter specifications 
for microscopic evaluation. 
Specific parameters will be determined in accordance 
with clinical laboratory procedures. 
11. References 
References update. 
Administrative update. 
4.3 Justification 
for dose and 8.5 
Pharmacokinetics 
Other typographical changes. 
Correction of units. 

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Protocol Amendment 1 Final 
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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 5 
List of main changes in the protocol and their rationale: ........................................... 6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 12 
1. 
PROTOCOL SUMMARY ........................................................................................ 19 
1.1. 
Synopsis ..................................................................................................... 19 
1.2. 
Schema ...................................................................................................... 20 
1.3. 
Schedule of activities (SoA) ........................................................................ 21 
2. 
INTRODUCTION .................................................................................................... 25 
2.1. 
Study rationale ............................................................................................ 25 
2.2. 
Background ................................................................................................ 25 
2.3. 
Benefit/risk assessment .............................................................................. 26 
2.3.1. 
Risk assessment .......................................................................... 27 
2.3.2. 
Benefit Assessment ..................................................................... 28 
2.3.3. 
Overall Benefit Risk Conclusion ................................................... 28 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 28 
3.1. 
Primary Estimands ...................................................................................... 29 
3.2. 
Estimands supporting secondary PK objectives .......................................... 31 
3.2.1. 
PK Parameters ............................................................................ 31 
3.2.2. 
Intra-participant variability of PK Parameters ............................... 32 
3.2.3. 
Estimands supporting secondary safety objectives ...................... 33 
4. 
STUDY DESIGN .................................................................................................... 35 
4.1. 
Overall design ............................................................................................. 35 
4.2. 
Scientific rationale for study design ............................................................. 36 
4.2.1. 
Participant input into design ......................................................... 36 
4.3. 
Justification for dose ................................................................................... 37 
4.4. 
End-of-study definition ................................................................................ 37 
5. 
STUDY POPULATION ........................................................................................... 38 
5.1. 
Inclusion criteria .......................................................................................... 38 
5.2. 
Exclusion criteria ......................................................................................... 39 
5.3. 
Lifestyle considerations ............................................................................... 41 
5.3.1. 
Meals and dietary restrictions ...................................................... 41 
5.3.2. 
Caffeine, alcohol, and tobacco ..................................................... 41 
5.3.3. 
Activity ......................................................................................... 42 
5.3.4. 
Other restrictions ......................................................................... 42 
5.4. 
Screen failures ............................................................................................ 42 
5.5. 
Criteria for temporarily delaying administration of study intervention ........... 42 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 42 
6.1. 
Study intervention(s) administered .............................................................. 43 
6.1.1. 
Medical devices ........................................................................... 44 
6.2. 
Preparation, handling, storage, and accountability ...................................... 45 
6.3. 
Assignment to study intervention ................................................................ 45 
6.4. 
Blinding ....................................................................................................... 46 

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6.5. 
Study intervention compliance .................................................................... 46 
6.6. 
Dose modification ....................................................................................... 46 
6.7. 
Continued access to study intervention after the end of the study ............... 46 
6.8. 
Treatment of overdose ................................................................................ 46 
6.9. 
Prior and concomitant therapy .................................................................... 47 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 47 
7.1. 
Discontinuation of study intervention ........................................................... 47 
7.1.1. 
Liver chemistry stopping criteria ................................................... 48 
7.1.2. 
QTc Stopping criteria ................................................................... 49 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 49 
7.3. 
Lost to follow-up.......................................................................................... 51 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 51 
8.1. 
Administrative procedures .......................................................................... 52 
8.1.1. 
Collection of demographic data .................................................... 52 
8.1.2. 
Medical and vaccination history ................................................... 52 
8.2. 
Efficacy assessments ................................................................................. 52 
8.3. 
Safety assessments .................................................................................... 52 
8.3.1. 
Physical examination ................................................................... 53 
8.3.2. 
Vital signs .................................................................................... 53 
8.3.3. 
Electrocardiograms ...................................................................... 53 
8.3.4. 
Clinical safety laboratory tests ..................................................... 53 
8.3.5. 
Pregnancy testing ........................................................................ 54 
8.4. 
Adverse Events (AEs) serious adverse events (SAEs), and other 
safety reporting ........................................................................................... 54 
8.4.1. 
Time period and frequency for collecting AE, SAE, and 
other safety information ............................................................... 54 
8.4.2. 
Method of detecting AEs and SAEs ............................................. 55 
8.4.3. 
Follow-up of AEs and SAEs ......................................................... 55 
8.4.4. 
AESIs .......................................................................................... 55 
8.4.5. 
Regulatory reporting requirements for SAEs ................................ 56 
8.4.6. 
Pregnancy ................................................................................... 56 
8.4.7. 
CV and Death Events .................................................................. 57 
8.4.8. 
Disease-related events and/or disease-related outcomes 
not qualifying as AEs or SAEs ..................................................... 57 
8.4.9. 
Contact information for reporting SAEs and pregnancies ............. 57 
8.4.10. 
Participant card ............................................................................ 57 
8.4.11. 
Medical device deficiencies ......................................................... 57 
8.5. 
Pharmacokinetics ....................................................................................... 59 
8.6. 
Pharmacodynamics .................................................................................... 59 
8.7. 
Genetics ..................................................................................................... 59 
8.8. 
Biomarkers ................................................................................................. 59 
8.9. 
Immunogenicity assessments ..................................................................... 59 
8.10. 
Health economics or medical resource utilization and health 
economics .................................................................................................. 59 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 60 
9.1. 
Statistical hypotheses ................................................................................. 60 
9.1.1. 
Multiplicity Adjustment ................................................................. 60 
9.2. 
Analysis sets ............................................................................................... 61 

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9.3. 
Statistical analyses ..................................................................................... 61 
9.3.1. 
General considerations of pharmacokinetic data .......................... 61 
9.3.2. 
Tertiary/exploratory endpoint(s) analysis...................................... 64 
......................................................................................... 65 
9.5. 
Sample size determination .......................................................................... 65 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 66 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 66 
10.1.1. 
Regulatory and ethical considerations ......................................... 66 
.................................................................... 67 
10.1.3. 
Informed consent process ............................................................ 67 
10.1.4. 
Recruitment strategy .................................................................... 68 
10.1.5. 
Data protection ............................................................................ 68 
10.1.6. 
Committees structure ................................................................... 68 
10.1.7. 
Dissemination of Clinical Study Data ........................................... 69 
10.1.8. 
Data quality assurance ................................................................ 69 
10.1.9. 
Source documents ....................................................................... 70 
10.1.10. Study and site start and closure ................................................... 70 
10.1.11. Publication policy ......................................................................... 71 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 72 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 74 
10.3.1. 
Definition of AE ............................................................................ 74 
10.3.2. 
Definition of SAE .......................................................................... 75 
10.3.3. 
Definition of TEAE ....................................................................... 76 
10.3.4. 
Recording, assessment and follow-up of AE, SAE, and 
pregnancies ................................................................................. 76 
10.4. 
Appendix 4: Contraceptive and barrier guidance ......................................... 80 
10.4.1. 
Definitions .................................................................................... 80 
10.4.2. 
Contraception guidance ............................................................... 81 
10.5. 
Appendix 5: Liver safety: suggested actions and follow-up 
assessments ............................................................................................... 83 
10.6. 
Appendix 6: Medical device AEs, ADEs, SAEs, sADEs, USADEs 
and device deficiencies: Definitions and procedures for recording, 
evaluating, follow-up, and reporting in medical device studies .................... 85 
10.6.1. 
Definition of medical device AE and ADE..................................... 85 
10.6.2. 
Definition of medical device SAE, SADE and USADE .................. 85 
10.6.3. 
Definition of device deficiency ...................................................... 86 
10.6.4. 
Recording and follow-up of medical device AE and/or SAE 
and device deficiencies ................................................................ 86 
10.6.5. 
Reporting of medical device SAEs ............................................... 87 
10.6.6. 
Reporting of SADEs ..................................................................... 88 
10.6.7. 
Reporting of medical device deficiencies for associated 
person ......................................................................................... 89 
10.7. 
Appendix 7: Standard Error (SE) Calculation for 2x2x4 Full 
Replicate Design ......................................................................................... 89 
10.8. 
Appendix 8: Reference-Scaled Acceptance Range Limit ............................ 90 
10.9. 
Appendix 9: Protocol amendment history .................................................... 90 
11. REFERENCES ....................................................................................................... 91 
CCI
CCI

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LIST OF TABLES 
PAGE 
Table 1 
Schedule of Activities ............................................................................. 21 
Table 2 
Timing of Assessments .......................................................................... 24 
Table 3 
Objectives and Endpoints ....................................................................... 28 
Table 4 
Study Intervention(s) Administered......................................................... 43 
Table 5 
Study Arm(s) .......................................................................................... 44 
Table 6 
Timeframes for submitting SAE, pregnancy and other events 
reports to GSK ....................................................................................... 56 
Table 7 
Contact information for reporting SAEs and pregnancies ....................... 57 
Table 8 
Pharmacokinetic Parameters ................................................................. 62 
Table 9 
Sample sizes with varying intra subject variability and associated 
half-widths of the 90% CI of the observed treatment ratio ...................... 65 
Table 10 
Sensitivity Table ..................................................................................... 66 
Table 11 
Protocol-required safety laboratory tests ................................................ 72 
.............. 90 
CCI

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LIST OF FIGURES 
PAGE 
Figure 1 
Study Design Overview (Cohort 1 – 200 µg dose) .................................. 20 
Figure 2 
Study Design Overview (Cohort 2 – 800 µg dose) .................................. 20 
Figure 3 
Chemical structures of HFA-134a and HFA-152a ................................... 26 
Figure 4 
Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping 
Event Algorithm ...................................................................................... 49 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition  
ADE 
Adverse device effect 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine transaminase 
AM 
Arithmetic mean 
ATS 
American Thoracic Society 
AUC(0-last) 
Area under the curve (from zero to last) 
AUC(0-∞) 
Area under the curve (from zero to infinity) 
AxMP 
Auxiliary medicinal product 
BMI 
Body mass index 
Cmax 
Maximum plasma concentration 
CA 
Competent authority 
CFC 
Chlorofluorocarbon 
CFR 
Code of Federal Regulations 
CI 
Confidence intervals 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CSR 
Clinical study report 
CVw 
Within-subject coefficient of variation 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram  
EMA 
European Medicines Agency 
ERS 
European Respiratory Society 
FDA 
Food and Drug Administration, United States of America 
FSFV 
First subject first visit 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GM 
Geometric mean 
GMR 
Geometric mean ratio 
GWP 
Global warming potential 
HBsAg 
Hepatitis B surface antigen 

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Abbreviation  
Definition  
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C virus 
HFA 
Hydrofluoroalkane  
HFA-134a 
1,1,1,2-tetrafluoroethane 
HFA-152a 
1,1-difluoroethane 
HIV 
Human immunodeficiency virus  
HR 
Heart rate 
HRT 
Hormonal Replacement Therapy 
ICE 
Intercurrent event 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
ICSR 
Individual case safety reports 
IDSL 
Integrated Data Standards Library 
IEC 
Independent Ethics Committee 
IFU 
Instructions for use 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
LDH 
Lactate Dehydrogenase 
LLOQ 
Lower Limit of Quantification  
LSLV 
Last Subject Last Visit 
MDI 
Metered Dose Inhaler 
MHR 
Maximum Heart Rate 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSDS 
Material Safety Data Sheet  
NIMP 
Non-investigational medicinal product 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PR 
Pulse Rate 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected using Fridericia’s formula 
QTL 
Quality tolerance limit 
RR 
Respiratory Rate 
RSABE 
Reference-scaled average bioequivalence 

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Abbreviation  
Definition  
SD 
Standard Deviation 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome-corona virus type 2 
SmPC 
Summary of product characteristics 
SoA 
Schedule of activities 
Tmax 
Time to reach maximum plasma concentration 
TEAE 
Treatment-emergent adverse event 
THC 
Tetrahydrocannabinol 
ULN 
Upper limit of normal 
USADE 
Unanticipated serious adverse device effect 
WHO 
World Health Organization 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of nonchildbearing potential 
 
Term 
Definition 
Adverse Drug Reaction 
An adverse event where a causal relationship between a 
medicinal product and the adverse event is at least a 
reasonable possibility, i.e., the relationship cannot be 
ruled out. 
a. In the context of a clinical trial, an ADR can be serious 
or non-serious. Serious ADRs may be subject to 
expedited reporting if they are considered unexpected 
(see SUSAR definition). 
b. For marketed products, ADRs are subject to expedited 
reporting within the country where they are authorized 
Auxiliary Medicinal Product 
(AxMP) 
a. 
Authorized AxMP 
Medicinal products used in the context of a clinical trial 
but not as investigational medicinal products, such as 
medicinal products used for background treatment, 
challenge agents, rescue medication, or used to assess 
endpoints in a clinical trial. Auxiliary medicinal products 
should not include concomitant medications, that is 
medications unrelated to the clinical trial and not relevant 
for the design of the clinical trial. 
Medicinal product authorized in accordance with 
Regulation (EC) No 726/2004, or in any Member State 
concerned in accordance with Directive 2001/83/EC, 

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Term 
Definition 
b. Unauthorized AxMP 
irrespective of changes to the labeling of the medicinal 
product. 
1. Safety reporting with regard to auxiliary medicinal 
products shall be made in accordance with Chapter 
3 of Title IX of Directive 2001/83/EC. 
a. 
Medicinal product not authorized in accordance 
with Regulation (EC) No 726/2004. 
1. Safety reporting for unauthorized auxiliary 
medicinal products will follow the same processes 
and procedures as SUSAR safety reporting. 
Background treatment 
Type of medicinal product administered to each of the 
clinical trial participant, regardless of randomization 
group, to treat the indication that is the object of the study. 
Background treatment is generally considered to be the 
current standard care for the particular indication. In 
these trials, the IMP is given in addition to the 
background treatment and safety efficacy are assessed. 
The protocol may require that the IMP plus the 
background treatment is compared with an active 
comparator or with placebo plus background treatment. 
Blinding 
A procedure in which 1 or more parties to the study are 
kept unaware of the intervention assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the 
study, and only when the data are cleaned to an 
acceptable level of quality will appropriate personnel be 
unblinded or when required in case of a SAE. 
In an open-label study, no blind is used. Both the 
investigator and the participant know the identity of the 
intervention assigned. 
Certified copy 
A copy (irrespective of the type of media used) of the 
original record that has been verified (i.e., by a dated 
signature or by generation through a validated process) 
to have the same information, including data that 
describe the context, content, and structure, as the 
original. 
Challenge agents 
A product given to trial participants to produce a 
physiological response that is necessary before the 
pharmacological action of the IMP can be assessed. 
Combination product 
Combination product comprises any combination of  

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Term 
Definition 
• 
drug  
• 
device  
• 
biological product  
Each drug, device and biological product included in a 
combination product is a constituent part.  
Comparator 
Any product used as a reference (including placebo, 
marketed product, GSK or non-GSK) for an 
investigational product being tested in a clinical trial. 
This is any product that is being used to assess the 
safety, efficacy, or other measurable value against the 
test product (IMP). 
Co-administered 
(concomitant) products 
A product given to clinical trial participants as required 
in the protocol as part of their standard care for a 
condition which is not the indication for which the IMP 
is being tested and is therefore not part of the objective 
of the study. 
Eligible 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Essential documents 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of 
the data produced 
Intervention Number 
A number identifying an intervention to a participant, 
according to intervention allocation. 
Investigational product 
A pharmaceutical form of an active substance or 
placebo being tested or used as a reference in a clinical 
trial, including products already with a marketing 
authorization but used or assembled (formulated or 
packaged) in a way different from the authorized form, 
or when used for an unauthorized indication, or when 
used to gain further information about the authorized 
form. 
Investigator 
A person responsible for the conduct of the clinical study 
at a study site. If a study is conducted by a team of 
individuals at a study site, the investigator is the 
responsible leader of the team and may be called the 
principal investigator. 
The investigator can delegate study-related duties and 
functions conducted at the study site to qualified 

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Term 
Definition 
individual or party to perform those study-related duties 
and functions. 
Legally acceptable 
representative 
An individual, judicial or other body authorized under 
applicable law to consent on behalf of a prospective 
participant to the participant’s participation in the clinical 
study. 
The terms legal representative or legally authorized 
representative are used in some settings. 
Medicinal products used to 
assess endpoints 
A product given to the participant in a Clinical Trial as a 
tool to assess a relevant clinical trial endpoint; it is not 
being tested or used as a reference in the clinical trial. 
Participant Number 
A unique identification number assigned to each 
participant who consents to participate in the study. 
Participant 
Term used throughout the protocol to denote an 
individual who has been contacted to participate or who 
participates in the clinical study as a recipient of the study 
intervention. 
Synonym: subject 
Placebo 
An inactive substance or treatment that looks the same as, 
and is given in the same way as, an active drug or 
intervention/treatment being studied. 
Randomization 
Process of random attribution of intervention to 
participants to reduce selection bias. 
Rescue medication  
Medicines identified in the protocol as those that may be 
administered to the participants when the efficacy of the 
IMP is not satisfactory, or the effect of the IMP is too 
great and is likely to cause a hazard to the patient, or to 
manage an emergency situation. 
Source data 
All information in original records and certified copies of 
original records of clinical findings, observations, or 
other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data 
are contained in source documents (original records or 
certified copies). 
Standard of Care 
Medicine(s) for a specific indication, or a component of 
the standard care for a particular medical indication, 

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Term 
Definition 
based on national and/or international consensus; there is 
no regulatory significance to this term. 
1. Products/regimens considered standard of care may 
differ country to country, depending on consensus in 
individual countries 
Study intervention 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a participant. 
Note: “Study intervention” and “study treatment” are 
used interchangeably unless otherwise specified. 
Study completion date 
The date on which the last participant in a clinical study 
was examined or received an intervention/treatment to 
collect 
final 
data 
for 
the primary 
outcome 
measures, secondary outcome measures, and AEs (that 
is, the last participant’s last visit or LSLV). 
Study monitor 
An individual assigned by the sponsor and responsible for 
assuring proper conduct of clinical studies at 1 or more 
investigational sites. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction; in a 
clinical trial, a serious adverse reaction that is considered 
unexpected, i.e., the nature or severity of which is not 
consistent with the reference safety information (e.g., 
Investigator’s 
Brochure 
for 
an 
unapproved 
investigational medicinal product). All adverse drug 
reactions (ADRs) that are both serious and unexpected 
are subject to expedited reporting 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: 
A Phase 1, randomized, open-label, single dose, 2-treatment arm (200 µg and 800 µg), 
4-way cross-over study in healthy participants aged 18 to 55 to compare the 
pharmacokinetics of salbutamol administered via metered dose inhalers containing 
propellants HFA-152a (test) and HFA-134a (reference). 
Brief Title: 
A study to compare the pharmacokinetics of salbutamol administered via metered dose 
inhalers containing propellants HFA-152a (test) or HFA-134a (reference) in healthy 
participants aged 18 to 55 inclusive. 
Rationale: 
In current MDIs, micronized particles are suspended in propellant HFA-134a which has a 
significant global warming potential. GSK is seeking to develop a low carbon footprint 
alternative propellant, HFA-152a which will address global climate change. Refer to 
Section 2.1 for further information. 
Objectives, Endpoints, and Estimands:  
The primary objective of this study is to characterize the PK of single doses of salbutamol 
in healthy participants delivered via an MDI containing propellant HFA-152a (test), and to 
compare with an MDI containing propellant HFA-134a (reference) in Cohort 1 with 200 µg 
and Cohort 2 with 800 µg. The primary PK endpoints are AUC(0-30min), AUC(0-∞) and 
Cmax. Refer to Section 3 for further information. 
Overall Design:  
This a randomized, open-label, single dose, 2-sequence, 2-treatment arm, 4-way cross-over 
(2x2x4) single-center study in healthy participants aged 18 to 55 years. Salbutamol will be 
administered as either a 200 µg or 800 µg dose, given as 2 or 8 actuations respectively at 
20 second intervals, each delivering 100 µg as the ex-valve dose of HFA-152a or 
HFA-134a. 
Number of Participants:  
The study has planned to enroll a total of 60 participants; 30 participants will be enrolled 
on to Cohort 1 (200 µg) and 30 participants will be enrolled on to Cohort 2 (800 µg). 
Within each cohort, 15 participants will be randomized to 1 of the 2 treatment sequences 
(TRRT and RTTR). 
Data Monitoring/Other Committee: Refer to Section 10.1.6. 

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1.2. 
Schema 
Figure 1 
Study Design Overview (Cohort 1 – 200 µg dose) 
 
Figure 2 
Study Design Overview (Cohort 2 – 800 µg dose) 
 

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1.3. 
Schedule of activities (SoA) 
Table 1 
Schedule of Activities  
Procedure 
Screening 
Intervention period (days)a 
Discharge or early 
discontinuation 
Follow 
upb 
Timepoints 
-28 to -1 
-1 
1 (pre-
dose) 
1 
2 
3 
4 5 6 7 
8 
9 
10 
11 
12 to 18 
Confinement 
 
X 
X 
X 
X X X X X X X 
X 
X 
X 
 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and BMI calculation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Timepoints 
-28 to -1 
-1 
1 (pre-
dose) 
1 
2 
3 
4 5 6 7 
8 
9 
10 
11 
12 to 18 
Medical history (includes substance 
usage) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (females only)d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 

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Procedure 
Screening 
Intervention period (days)a 
Discharge or early 
discontinuation 
Follow 
upb 
FSH and estradiol (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (HBsAg, anti-HCV, 
anti-HIV 1 and 2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 PCR teste 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cotinine, drug, and alcohol screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory assessmentsf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood sampling for serum potassium 
(PD) and glucose (safety)g 
 
 
X 
X 
 
 
X 
 
 X 
 
 
X 
 
 
Vital signsh 
X 
X 
X 
X 
 
 
X 
 
 X 
 
 
X 
X 
 
Timepoints 
-28 to -1 
-1 
1 (pre-
dose) 
1 
2 
3 
4 5 6 7 
8 
9 
10 
11 
12 to 18 
12-lead ECGi 
X 
X 
X 
X 
 
 
X 
 
 X 
 
 
X 
X 
 
MDI trainingj 
 
X 
X 
 
 
 
X 
 
 X 
 
 
X 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of study interventionk 
 
 
 
X 
 
 
X 
 
 X 
 
 
X 
 
 
Blood sampling for PKl 
 
 
X 
X 
X 
 
X X  X X 
 
X 
X 
 
AE reviewm 
 
 
 
X 
X X X X X X X 
X 
X 
X 
X 
SAE reviewm 
X 
X 
X 
X 
X X X X X X X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X X X X X X X 
X 
X 
X 
X 
a. 
Intervention period days: Participants will be in the clinic for 1 period, from Day-1 until Day 11 (approximately 24 hours after the last dose on Day 10). 

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b. 
Follow-up: The follow-up period is from Day 12 to Day 18. The minimum follow-up procedures that should be conducted are outlined in the follow-up column. However, further 
follow-up procedures can be conducted at the discretion of the investigator. Note. The final follow-up will be conducted via a telephone call. However, it will be at the discretion of 
the PI whether a follow-up visit would be required i.e., if further investigation is needed. 
c. 
Physical examination: Complete physical examinations will be conducted at screening. Symptom driven physical examinations are conducted at discharge/early withdrawal and 
may be conducted at any other time, per investigator discretion. 
d. 
Pregnancy testing: Female participants will be required to take a serum pregnancy test (Day-1, Screening and Discharge/Early Withdrawal). 
e. 
SARS-CoV-2 PCR testing: Sampling of nasal and throat mucosal cells for PCR testing for SARS-CoV-2 may be performed at the discretion of the site based on local guidelines. 
f. 
Clinical laboratory assessments: Including clinical chemistry [includes liver chemistries], hematology, and urinalysis will be conducted at screening, on Day-1 (admission), and at 
discharge. 
g. 
Blood sampling for serum potassium (PD) and glucose (safety): On each dosing day (Day 1, 4, 7and 10), blood samples will be taken predose at: 15 and 30 minutes and 1, 
1.5, 2 and 4 hours postdose. 
h. 
Vital signs: Systolic and diastolic blood pressure, and PR) vital signs will be recorded at screening, admission, on each dosing day (Day 1, 4,7 and 10) at predose and at the 
following time points postdose: 15, 30 minutes, 1, 2, 4 hours and at discharge. Assessed after a minimum of 5 minutes of the participant resting in the supine position with a 
completely automated device. 
i. 
12-lead ECG: 12-lead ECG will be recorded at screening, admission, on each dosing day (Day 1, 4, 7 and 10) at predose and at: 30 minutes postdose and at discharge. As the 
ECG parameters QTc and HR will be PD parameters, ECG will be measured in triplicate at predose on Days 1, 4, 7 and 10. The 3 predose measures will be recorded in the eCRF 
and will be averaged for QTc interval and HR to derive 1 baseline value which will be recorded in the eCRF. Each individual capture of the triplicate 12-lead ECG set should be 
obtained as closely as possible in succession, but no more than 5 minutes apart from first to third ECG. Postdose 12-lead ECG measurements will be single measurements on all 
dosing days. Discharge or early discontinuation 12-lead ECG measurements will be single measurements. Note. if an ECG meets potential stopping criteria, then the ECG 
measurement should be repeated in triplicate, with the averaged QT and QTcF used to determine stopping. 
j. 
MDI training: Participants will be trained using a placebo HFA-134a propellant via an MDI on Day-1 and prior to dosing on each dosing day (Day 1, 4, 7 and 10). On dosing days, 
participants should review the instructions use the placebo MDI. The investigator or delegate are to observe the participant performing a single puff using the placebo MDI and 
provide feedback as necessary until proper technique is observed before conducting the full dose using the investigational inhaler. Additional training using the placebo MDI (e.g., 
on Day 3) may be performed at the discretion of the site. 
k. 
Administration of study intervention: 8 inhalations of 100 µg (800 µg total) of study intervention or 2 inhalations of 100 µg (200 µg total) of study intervention, with the inhalations 
administered at 20-second intervals. 
l. 
PK blood sampling: on each dosing day (Day 1, 4, 7 and 10) PK blood samples will be taken at predose, at 3, 5, 10, 15-, 20-, 30-, and 45-minutes postdose; and at 1, 1.5, 2, 3, 4, 
5, 6, 8, 10-, 12-, 16- and 24-hours postdose for plasma salbutamol determination. PK collection will be from the start of study intervention (first inhalation). 
m. AE and SAE review: AEs will be collected from the start of study intervention until final follow-up telephone call. SAEs will be collected from the signing of the ICF until final follow-
up telephone call. 
 

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Table 2 
Timing of Assessments 
Assessment 
Timing of Dosing 
Study intervention 
administration 
Dosing for each participant will be around the same time (±1 hour) at each intervention period day. All postdose timepoints 
will be from the start of each study intervention i.e., the first inhalation. 
PK blood sampling 
Predose samples will be obtained between waking up and dosing. Postdose samples up to 30 minutes will be obtained with a 
time window of ±1 minute. Thereafter, postdose samples will be obtained with time margins of ±5% of the time that has 
passed since (last) dosing. 
PD blood sampling 
For PD blood samples, predose samples will be obtained between waking up and dosing. Postdose samples up to 30 minutes 
will be obtained with a time window of ±2 minutes. Thereafter, postdose samples will be obtained with time margins of ±5% of 
the time that has passed since (last) dosing. 
Safety assessments For safety assessments, predose assessments will be performed between waking up and dosing. For safety assessments up 
to 2.5 hours postdose, a time window of ±15 minutes is allowed. Thereafter, serial postdose assessments (e.g., multiple 
assessments within any given day) will be performed with time margins of ±10% of the time that has passed since (last) 
dosing. 
Note. When assessments are planned for the same scheme time, the order of the assessments should be arranged in such a way that ECG and vital signs will be done first followed 
by the PK (then PD) blood sampling, with PK blood sampling exactly on time. 
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2. 
INTRODUCTION 
2.1. 
Study rationale 
In the currently marketed Ventolin Evohaler, micronized particles of salbutamol are 
suspended in propellant HFA-134a [VENTOLIN EVOHALER, 2023]. However, HFA-
134a has significant GWP and hence its use in medicine and other applications is being 
phased out under mounting environmental pressure to replace it with a low carbon footprint 
alternative such as salbutamol HFA-152a (test). 
GSK is seeking to develop a sustainable version of the current Ventolin Evohaler to address 
global climate change. This study will evaluate the pharmacokinetics of salbutamol 
administered via MDIs containing propellants HFA-152a (test) and HFA-134a (reference). 
Hereafter, salbutamol administered via MDIs containing propellant HFA-152a (test) will 
be referred to as salbutamol HFA-152a and salbutamol administered via MDIs containing 
propellant HFA-134a (reference) will be referred to as salbutamol HFA-134a. 
2.2. 
Background 
Approximately 339 million people currently suffer from asthma, and it is the most common 
noncommunicable disease among children [GINA, 2023]. Asthma requires medical 
assessment and care when it occurs on either a persistent, or intermittent but frequently 
recurring basis. Exacerbations of asthma are episodes characterized by a progressive 
increase in symptoms of shortness of breath, cough, wheezing, or chest tightness and a 
progressive decrease in lung function, such that they represent a change from the patient’s 
usual status that is sufficient to require a change in treatment [GINA, 2023] Severe 
exacerbations are potentially life-threatening and their treatment requires close medical 
supervision [GINA, 2023]. 
Pharmacotherapy for asthma follows a stepwise process determined by symptoms and 
disease severity. The most common treatment options are short- and long-acting 
bronchodilators, corticosteroid anti-inflammatory agents, and combination products 
containing both bronchodilators and corticosteroids. Biological agents are also available 
for more severe disease in patients with eosinophilic asthma. Short-acting reliever 
medications such as salbutamol sulfate are a cornerstone of asthma therapy for as-needed 
relief of breakthrough symptoms, including worsening asthma or exacerbations 
[GINA, 2023] Salbutamol sulfate, the active ingredient in Ventolin Evohaler (HFA-134a) 
is approved in over 130 countries. 
Salbutamol sulfate is a selective β2–adrenergic receptor agonist that acts on bronchial 
smooth muscle providing short-acting (4 to 6 hour) bronchodilation with a fast onset 
(within 5 minutes) and is suitable for the relief and prevention of asthma symptoms and 
reversible airway obstruction. 
Inhaled salbutamol has been approved for human use since 1968 initially as an MDI 
containing CFC propellants. These propellants were later replaced with propellant HFA-
134a due to international treaties phasing out CFC production arising from environmental 

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concern. GSK is developing a sustainable version of its Ventolin Evohaler using an 
alternative new propellant, HFA-152a which will replace the current propellant, 
HFA-134a. The chemical structures of the 2 propellants are presented in Figure 3. 
Figure 3 
Chemical structures of HFA-134a and HFA-152a 
 
Salbutamol HFA-152a will be developed as a replacement product for the current Ventolin 
Evohaler (HFA-134a) with the same indications and posology. HFA-152a is an MDI 
delivering 100 µg of salbutamol (as salbutamol sulfate) per dose; 200 doses per device. 
Salbutamol has a duration of action of 4 to 6 hours with administration of up to 2 
inhalations (200 µg total) not exceeding 4 times daily. 
The maximum recommended total daily dose of salbutamol for chronic use delivered via 
the Ventolin MDI is 800 µg. This dose requires 8 inhalations (800 µg salbutamol). The 
exposure to HFA-152a (8x63 µL) is estimated to be 454 µg/day (6.87 µmol/day). This is 
well below the exposures of HFA-152 shown to have no adverse effects in humans. 
2.3. 
Benefit/risk assessment 
Detailed information about the known and expected benefits and risks and reasonably 
expected AEs of salbutamol delivered via MDI may be found in the patient information, 
package insert and SmPC. There is no added benefit expected for the healthy participants. 
A risk assessment has been presented in Section 2.3.1. 
CCI

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2.3.1. 
Risk assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention 
Participants will be instructed to administer 200 µg or 
800 µg of salbutamol. There is a potential risk that the 
HFA-152a propellant delivers a higher effective dose of 
salbutamol compared to the reference Ventolin Evohaler 
Hypokalemia: β-adrenergic agonist medicines may 
produce significant hypokalemia in some patients, possibly 
through intracellular shunting, which has the potential to 
produce adverse cardiovascular effects. The decrease in 
serum potassium is usually transient, not requiring 
supplementation. 
Hyperglycemia: β-adrenergic agonist medicines may 
produce a transient rise in serum glucose which is not 
expected to be clinically significant with inhalational 
administration. However, large doses of intravenous 
salbutamol have been reported to aggravate pre-existing 
diabetes mellitus and ketoacidosis. 
Cardiovascular effects: β-adrenergic agonist medicines 
may produce clinically significant cardiovascular effects in 
some patients such as changes in pulse rate or blood 
pressure. In addition, β-agonists have been reported to 
produce ECG changes, such as flattening of the T wave, 
prolongation of the QTc interval, and ST segment 
depression. The clinical relevance of these findings is 
unknown. 
Healthy participants are included who will be carefully 
screened against the defined inclusion and exclusion 
criteria (including overall cardiac health, vital signs, ECG 
interval values, and lab safety values [including serum 
potassium and glucose levels) and by ECG monitoring and 
lab PD/safety assessments (including serum potassium 
and glucose levels) as per Section 1.3. 
Study Procedures  
There are no risks associated with the study design and/or procedures. 

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2.3.2. 
Benefit Assessment 
• 
The healthy participants will receive medical assessments associated with study 
procedures, for example, physical examination, ECG and labs. They may, as a result, 
derive some benefit related to information about their general health status. 
• 
The healthy participants will be contributing to the understanding of PK and PD for 
all MDI-based therapies with salbutamol and HFA-152a. The healthy participants will 
be contributing to the process of developing a therapy which has a reduced impact on 
global warming. 
2.3.3. 
Overall Benefit Risk Conclusion 
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with salbutamol administered via 
MDI containing propellants HFA-152a and HFA-134a are justified by the anticipated 
benefits to all ongoing and future programs with HFA-152a as a propellant as well as the 
anticipated environmental and societal benefits of introducing a new propellant 
(HFA-152a) with greatly reduced GWP compared to the current propellant HFA-134a. 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
Table 3 
Objectives and Endpoints 
Objective(s) 
Endpoint(s) 
Primary 
To characterize the PK of single doses of 
salbutamol in healthy participants delivered via an 
MDI containing propellant HFA-152a (test), and to 
compare with an MDI containing propellant HFA-
134a (reference) in the following cohorts:  
Cohort 1: Salbutamol HFA-152a MDI 200 µg 
(test), HFA-134a MDI 200 µg (reference) 
Cohort 2: Salbutamol HFA-152a MDI 800 µg 
(test), HFA-134a MDI 800 µg (reference) 
• AUC(0-30min) 
• AUC(0-∞) 
• Cmax  
Secondary 
Pharmacokinetic: 
To characterize the PK of single doses of 
salbutamol in healthy participants delivered via an 
MDI containing propellant HFA-152a (test), and to 
compare with an MDI containing propellant HFA-
134a (reference) in the following cohorts:  
Cohort 1: Salbutamol HFA-152a MDI 200 µg 
(test), HFA-134a MDI 200 µg (reference) 
Cohort 2: Salbutamol HFA-152a MDI 800 µg 
(test), HFA-134a MDI 800 µg (reference) 
Pharmacokinetic: 
• Tmax 
• t1/2 
• AUC(0-last)  

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Pharmacokinetics: 
To measure the intra-participant variability in PK 
of single doses of salbutamol for healthy 
participants delivered via an MDI containing 
propellant in the following cohorts:  
Cohort 1: Salbutamol HFA-152a MDI 200 µg 
(test), Salbutamol HFA-134a MDI 200 µg 
(reference) 
Cohort 2: Salbutamol HFA-152a MDI 800 µg 
(test), Salbutamol HFA-134a MDI 800 µg 
(reference) 
Pharmacokinetics:  
• Intra-participant variability of AUC(0-30min), 
AUC(0-∞), AUC(0-last), and Cmax of HFA-
152a (test) 
• Intra-participant variability CVw of AUC(0-
30min), AUC(0-∞), AUC(0-last), and Cmax 
of HFA-134a (reference) 
Safety: 
To assess the safety and tolerability of single 
doses of salbutamol in healthy participants 
delivered via MDI HFA-152a (test) or propellant 
HFA-134a (reference) in the following cohorts:  
Cohort 1: Salbutamol HFA-152a MDI 200 µg 
(test), HFA-134a MDI 200 µg (reference) 
Cohort 2: Salbutamol HFA-152a MDI 800 µg 
(test), HFA-134a MDI 800 µg (reference) 
Safety: 
• Incidence of AEs and SAEs  
• Absolute values for 12 lead ECGs recording 
of HR and QTc intervals at each assessed 
visit 
• Change from baseline for postdose 12  
• lead ECGs recording of HR and QTc 
intervals at each assessed visit 
• Absolute values of clinical laboratory 
parameters at each assessed visit 
• Absolute values of vital signs (systolic and 
diastolic blood pressure and pulse rate) at 
each assessed visit  
Exploratory 
Pharmacodynamics: 
To characterize the PD of single doses of 
salbutamol in healthy participants delivered via an 
MDI containing propellant HFA-152a (test), and to 
compare to an MDI containing propellant HFA-
134a (reference) in the following cohorts: 
Cohort 1: Salbutamol HFA-152a MDI 200 µg 
(test), Salbutamol HFA-134a MDI 200 µg 
(reference) 
Cohort 2: Salbutamol HFA-152a MDI 800 µg 
(test), Salbutamol HFA-134a MDI 800 µg 
(reference) 
Pharmacodynamics: 
• Minimum serum potassium  
• MHR 
• Maximum QTc interval 
3.1. 
Primary Estimands 
Cohort 1: 
Test: Salbutamol HFA-152a MDI 200 µg  
Reference: Salbutamol HFA-134a MDI 200 µg  

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The primary clinical question of interest for Cohort 1 is- 
What is the GMR for Cohort 1 in primary PK parameters (AUC(0-30min), AUC(0-∞) and 
Cmax) of salbutamol HFA-152a and salbutamol HFA‑134a in healthy participants after 
administration of single dose of 200 µg? 
The primary estimand for Cohort 1 is described by the following attributes: 
• 
The population is healthy male or female participants aged 18 to 55 years. 
• 
The primary PK parameters endpoints are AUC(0-30min), AUC(0-∞) and Cmax. 
• 
Treatment condition is administration of salbutamol as a single 200 µg dose, given as 
2 actuations each separated by a 20-second interval, each delivering 100 µg of 
salbutamol (as salbutamol sulfate) as the ex‑valve dose for the HFA-152a MDI or 
HFA-134a MDI. 
• 
The ICEs and estimand strategies are as follows: 
− Study treatment discontinuation due to any reason (hypothetical strategy). 
− Occurrence of emesis or coughing on dosing (hypothetical strategy). 
− Dosing error: Considered less than or more than prescribed dose (hypothetical 
− strategy). 
− Use of prohibited or rescue medication which impacts to PK parameters 
(hypothetical strategy). 
For all ICEs, interest lies in evaluating the primary PK parameters and comparisons 
of the ratio of 2 formulations for each primary PK parameters in a hypothetical 
scenario in which the participant had not experienced an intercurrent event. This is to 
minimize potential confounding of ICEs on individual PK parameters across 
treatment periods.  
• 
The population-level summary to be estimated is: 
Ratio of adjusted GM (for logarithmic transformed values) of 2 formulations with 
90% CI for each primary PK endpoint. 
Cohort 2: 
Test: Salbutamol HFA-152a MDI 800 µg 
Reference: Salbutamol HFA-134a MDI 800 µg 
The primary clinical question of interest for Cohort 2 is – 
What is the GMR for Cohort 2 in primary PK parameters (AUC(0-30min), AUC(0-∞) and 
Cmax) of salbutamol HFA-152a and salbutamol HFA‑134a in healthy participants after 
administration of single dose of 800 µg? 

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The estimand for Cohort 2 has the same estimand attributes as Cohort 1 (population, PK 
endpoints, population-level summary measure, ICE strategy), except for the attribute for 
the treatment condition: 
• 
Treatment condition is administration of salbutamol as a single 800 µg dose, given as 
8 actuations each separated by a 20-second interval, each delivering 800 µg of 
salbutamol (as salbutamol sulfate) as the ex‑valve dose for the HFA-152a MDI or 
HFA-134a MDI. 
Rationale for primary estimands for both cohorts: The test formulation is being 
developed with an aim to have comparable PK characteristics as the reference 
formulation. Interest lies in the PK values obtained in the scenarios that had the 
participant been exposed to correct dose as prescribed, where study treatment 
discontinuation of the randomized sequence, the occurrence of emesis or coughing on 
dosing, and prohibited rescue medication usage had not occurred. 
3.2. 
Estimands supporting secondary PK objectives 
3.2.1. 
PK Parameters 
Cohort 1: 
Test: Salbutamol HFA-152a MDI 200 µg 
Reference: Salbutamol HFA-134a MDI 200 µg 
The secondary clinical question of interest for Cohort 1 is: 
What is the summarized PK profile in Cohort 1 using descriptive statistics for Tmax and 
t1/2 and GMR for AUC(0-last) between salbutamol HFA-152a and salbutamol 
HFA‑134a in healthy participants after administration of single dose of 200 µg? 
The secondary estimand for Cohort 1 has the same estimand attributes as the primary 
estimand for Cohort 1 (population, treatment condition, ICE strategy), except for the 
estimand attributes of PK endpoints and population-level summary measure: 
• 
The secondary PK parameters endpoints are Tmax, t1/2, AUC(0-last). 
• 
The population-level summary to be estimated are: 
− AM with 95% CI for Tmax and GM with 95% CI for t1/2. 
− Ratio of adjusted GM (for logarithmic transformed values) of 2 formulations with 
90% CI AUC(0-last). 
Cohort 2: 
Test: Salbutamol HFA-152a MDI 800 µg 
Reference: Salbutamol HFA-134a MDI 800 µg 

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The secondary clinical question of interest for Cohort 2 is – 
What is the summarized PK profile in Cohort 2 using descriptive statistics for Tmax and 
t1/2 and GMR for AUC(0-last) between salbutamol HFA-152a and salbutamol 
HFA‑134a in healthy participants after administration of single dose of 800 µg? 
The secondary estimand for Cohort 2 has the same estimand attributes as the primary 
estimand for Cohort 2 (population, treatment condition, ICE strategy), except for the 
estimand attributes of PK endpoints and population-level summary measure: 
• 
The secondary PK parameters endpoints are Tmax, t1/2, AUC(0-last). 
• 
The population-level summary to be estimated are: 
− AM with 95% CI for Tmax and GM with 95% CI for t1/2. 
− Ratio of adjusted GM (for logarithmic transformed values) of 2 formulations with 
90% CI AUC(0-last). 
3.2.2. 
Intra-participant variability of PK Parameters 
Cohort 1: 
Test: Salbutamol HFA-152a 200 µg 
Reference: Salbutamol HFA-134a 200 µg 
The secondary clinical question of interest for Cohort 1 is – 
What is the intra-participant variability of the PK profile of Cohort 1 using CVw for 
AUC(0-30min), AUC(0-∞), Cmax and AUC(0-last) PK parameters for salbutamol 
HFA-152a and salbutamol HFA-134a in healthy participants after administration of 
single dose of 200 µg? This secondary objective is to establish whether either the 
reference or test product is considered a high variable product at the 200 µg dose level 
(CVw > 30%). 
The secondary estimand for Cohort 1 has the same estimand attributes as the primary 
estimand for Cohort 1 (population, treatment condition, ICE strategy), except for the 
estimand attributes of PK endpoints and population-level summary measure: 
• 
The secondary PK parameters endpoints for HFA-152a (test) and HFA-134a 
(reference) are: 
− Intra-participants variability in AUC(0-30min) 
− Intra-participants variability in AUC(0-∞) 
− Intra-participants variability in Cmax 
− Intra-participants variability in AUC(0-last) 

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• 
The population-level summary to be estimated for HFA-152a (test) and HFA-134a 
(reference) are: 
− Intra(within)- participants CVw (%) for AUC(0-30min), AUC(0-∞), Cmax and 
AUC(0-last) 
Cohort 2: 
Test: Salbutamol HFA-152a 800 µg 
Reference: Salbutamol HFA-134a 800 µg 
The secondary clinical question of interest for Cohort 2 is – 
What is the intra-participant variability in PK profile of Cohort 2 using CVw for 
AUC(0-30min), AUC(0-∞), Cmax and AUC(0-last) PK parameters for salbutamol 
HFA-152a and salbutamol HFA-134a in healthy participants after administration of 
single dose of 800 µg?. This secondary objective is to establish whether either the 
reference or test product is considered a high variable product at the 800 µg dose level 
(CVw > 30%). 
The secondary estimand for Cohort 2 has the same estimand attributes as the primary 
estimand for Cohort 2 (population, treatment condition, ICE strategy), except for the 
estimand attributes of PK endpoints and population-level summary measure: 
• 
The secondary PK parameters endpoints for HFA-152a (test) and HFA-134a 
(reference) are: 
− Intra-participants variability in AUC(0-30min) 
− Intra-participants variability in AUC(0-∞) 
− Intra-participants variability in Cmax 
− Intra-participants variability in AUC(0-last) 
• 
The population-level summary to be estimated for HFA-152a (test) and HFA-134a 
(reference) are: 
− Intra(within)- participants CVw (%) for AUC(0-30min), AUC(0-∞), Cmax and 
AUC(0-last) 
Rationale for supporting secondary estimands of PK parameters for both cohorts: 
Rational for supporting secondary estimands of PK parameters for both cohorts is same 
as primary estimands. 
3.2.3. 
Estimands supporting secondary safety objectives 
Cohort 1: 
Test: Salbutamol HFA-152a MDI 200 µg 
Reference: Salbutamol HFA-134a MDI 200 µg 

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The clinical question of interest for the safety secondary objective in Cohort 1 is –  
What is the safety and tolerability profile of single doses 200 µg of salbutamol in Cohort 
1 healthy participants delivered via MDIs? 
The secondary safety estimand for Cohort 1 is described by the following attributes: 
• 
The population is healthy male or female participants aged 18 to 55 years. 
• 
The secondary safety endpoints are: 
− Incidence of AEs and SAEs 
− Absolute values for predose and postdose 12-lead ECGs recording of HR and 
QTc intervals at each assessed visit 
− Change from baseline for postdose 12-lead ECGs recording of HR and QTc 
intervals at each assessed visit 
− Absolute values of clinical laboratory parameters at each assessed visit 
− Absolute values of vital signs (systolic and diastolic blood pressure and pulse 
rate) at each assessed visit. 
• 
Treatment condition is administration of salbutamol as a single 200 µg dose, given as 
2 actuations each separated by a 20-second interval, each delivering 100 µg of 
salbutamol (as salbutamol sulfate) as the ex‑valve dose for the HFA-152a MDI or 
HFA-134a MDI. 
• 
The ICEs and estimand strategies are as follows: 
− Study treatment discontinuation due to any reason (treatment policy 
strategy). Interest lies in the group of participants irrespective of whether they 
completed the study intervention. 
− Occurrence of emesis or coughing on dosing (treatment policy strategy). 
− Dosing error: Considered less than or more than prescribed dose (treatment policy 
strategy. 
− Use of prohibited or rescue medication which is impacted to PK parameters 
(Treatment policy strategy). 
• 
The population-level summary to be estimated are: 
− Number and percentages for incidence of AEs and SAEs 
− Mean of absolute values for 12-lead ECGs recording of HR and QTc intervals at 
each assessed visit 
− Mean of change from baseline values for postdose 12-lead ECGs recording of HR 
and QTc intervals at each assessed visit 
− Mean of absolute of clinical laboratory parameters including vital signs (systolic 
and diastolic blood pressure and pulse rate) at each assessed visit 

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Cohort 2: 
Test: Salbutamol HFA-152a MDI 800 µg 
Reference: Salbutamol HFA-134a MDI 800 µg 
The clinical question of interest for the safety secondary objective in Cohort 2 is –  
What is the safety and tolerability profile of single doses 800 µg of salbutamol in Cohort 
2 healthy participants delivered via MDIs? 
The secondary safety estimand for Cohort 2 has the same estimand attributes as Cohort 1 
(population, PK endpoints, population-level summary measure, ICE strategy), except for 
the attribute for the treatment condition: 
• 
Treatment condition is administration of salbutamol as a single 800 µg dose, given as 
8 actuations each separated by a 20-second interval, each delivering 100 µg of 
salbutamol (as salbutamol sulfate) as the ex‑valve dose for the HFA-152a MDI or 
HFA-134a MDI. 
Rationale for estimands supporting secondary safety objectives in both cohorts: This 
is a study in healthy volunteers with short follow-up duration. Therefore, all adverse 
events (AEs), serious adverse events (SAEs), 12 lead ECG, laboratory parameters and 
vital signs data are of interest, regardless of ICEs to support completeness of reporting 
and transparency of the clinical study. 
4. 
STUDY DESIGN 
4.1. 
Overall design 
This is a randomized, open-label, single dose, 2-sequence, 2-treatment arm, 4-way cross-
over (2x2x4) single-center study in healthy participants aged 18 to 55 years. Salbutamol 
will be administered as either a 200 µg or 800 µg dose, given as 2 or 8 actuations 
respectively at 20 second intervals, each delivering 100 µg as the ex-valve dose of 
HFA-152a or HFA-134a. Sequential enrollment approach will be followed for the study. 
Participants in Cohort 2 will be enrolled once participants in Cohort 1 have completed the 
study. An interim analysis is planned for when last participant enrolled for the 200 µg 
(Cohort 1) completes their last visit, and final analysis will be conducted when the last 
participant of 800 µg (Cohort 2) completes their last visit. 
The study has planned to enroll a total of 60 participants to either Cohort 1 (200 µg) or 
Cohort 2 (800 µg) to ensure at least 56 participants in the PK analysis set (see Section 9 
on analysis sets). For each cohort, 30 healthy participants will be randomly assigned to a 
cohort to ensure at least 28 participants are included in the PK analysis set with 15 
randomized to each treatment sequence. 
Following treatment sequences will be applied in each cohort: 
Treatment Sequence 1: TRRT 

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Treatment Sequence 2: RTTR 
Where T is salbutamol HFA-152a (test) and R is salbutamol HFA-134a (reference). 
In Cohort 1, salbutamol will be administered as single 200 µg dose, given as 2 actuations 
each separated by a 20-second interval, each delivering 100 µg of salbutamol (as 
salbutamol sulfate) as the ex‑valve dose for the HFA-152a MDI or HFA-134a MDI. 
In Cohort 2, salbutamol will be administered as single 800 µg dose, given as 8 actuations 
each separated by a 20-second interval, each delivering 100 µg of salbutamol (as 
salbutamol sulfate) as the ex‑valve dose for the HFA-152a MDI or HFA-134a MDI. 
Participants will attend a screening visit between Day-28 and Day-1. The intervention 
period will be 10 days with dosing on Day 1, Day 4, Day 7, and Day 10. Participants will 
be discharged on Day 11. There will be a follow-up period between Day 12 and Day 18. 
4.2. 
Scientific rationale for study design 
Study population 
Healthy participants have been chosen as the study population due to the study aims and 
design and the low risk of clinically significant toxicity at anticipated exposure levels. 
Additionally, the duration of exposure is sufficiently short to not be able to provide clear 
therapeutic benefit and justify patients discontinuing current therapies. Moreover, use of 
healthy participants as opposed to patients will allow a clearer interpretation of the study 
results, as there will be no confounding factors resulting from changes in disease state 
and/or concomitant medications. 
Cross-Over and Full Replicate Design 
A cross-over design to compare the different treatments was chosen to reduce the 
influence of confounding covariates as each participant serves as their own control. The 
cross-over design requires a smaller number of participants compared to a parallel group 
design. In addition, given the broad range of exposures observed for the reference 
product across historical studies, a full replicate design has been selected whereby the 
salbutamol HFA-152a and salbutamol HFA-134a are administered twice. The full 
replicate design chosen can help characterize the extent intra-participant variability 
impacts the results. If a within-subject variability of >30% is observed for the reference 
product in this study, comparisons between the test and reference formulations will then 
be performed using a reference-scaled approach. Carryover effects are expected to be 
eliminated by introducing a washout phase of a minimum of 72 hours between study drug 
administrations (expected to be equivalent to at least 5 half-lives of salbutamol). 
4.2.1. 
Participant input into design 
Not applicable. 

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4.3. 
Justification for dose 
Justification for 200 µg dose 
The dose of 200 µg was selected as it is the maximal single dose recommended per label 
and the dose recommended for pharmacokinetic evaluation in the FDA Draft Guidance 
on Albuterol. 
Justification for 800 µg dose 
The dose of 800 µg was chosen to ensure adequate plasma concentration-time profile to 
estimate the AUC(0-∞) 
 and 
minimize within- and between-participant variability in inhaled drug dosing. In addition, 
the 800 µg dose (8 inhalations) is the maximum recommended daily dose for salbutamol, 
which has been approved in the EU. 
 
. Any differences in systemic exposure between the test and 
reference formulations at this dose level are not expected to increase the risk of known 
safety concerns with salbutamol, which (as per Section 2.3.1) are being mitigated in any 
case via careful participant screening and safety assessments. 
At the proposed dose of 8 inhalations of salbutamol sulfate, the exposure to HFA-152a 
(8x63 µL) is estimated to be 454 µg/day (6.87 µmol/day). This is well below the 
exposures shown to have no adverse effects in humans (see Section 2.2). 
Previous study experience 
Three previous studies (Study 200921, SALB1002 and SALB1003) used a single dose of 
600 µg, 1200 µg and 1200 µg respectively. Study 200921 collected PK samples for 12 
hours only, whereas SALB1002 and SALB1003 collected PK samples for 24 hours. 
 
. Where reported in these studies, 
treatments were generally well tolerated with no clinically significant laboratory safety 
abnormalities and no serious adverse events. Adverse events were those expected with 
high dose β2 agonists but reported in low numbers, these included: tremor, palpitations, 
tachycardia, flushing and headache which was usually the most frequently reported event. 
4.4. 
End-of-study definition 
A participant is considered to have completed the study if the participant has completed 
all periods of the study including the last visit. 
The end of the study is defined as the date of the last visit of the last participant in the 
study globally. 
CCI
CCI
CCI
CCI

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Sex: male or female; females may be of childbearing potential, of nonchild bearing 
potential, or postmenopausal 
2. Age : participants to be 18 to 55 years inclusive, at the time of screening 
3. BMI: 18.5 to 29.9 kg/m2 inclusive, at the time of screening 
4. Weight: 45 to 110 kg inclusive, at the time of screening 
5. Status: healthy participants 
6. At screening and Day-1, females must not be pregnant or lactating, or alternatively 
must be of nonchildbearing potential. 
7. A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and 1 of the following conditions applies: 
• 
Is a WONCBP as defined in Section 10.4.1.1 
OR 
• 
Is a WOCBP and using a contraceptive method that is highly effective, with a failure 
rate of <1%, as described in Section 10.4.1.1 during the study intervention period 
and for at least 48 hours after the last dose of study intervention. The investigator 
should evaluate potential for contraceptive method failure (e.g., noncompliance, 
recently initiated) in relationship to the first dose of study intervention. 
• 
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) as 
required by local regulations) within 7 days before the first dose of study 
intervention. Please see Section 8.3.5 for further details. 
• 
A serum pregnancy test is required. In such cases, the participant must be excluded 
from participation if the serum pregnancy result is positive. 
• 
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.5. 
• 
The investigator/delegate is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a woman with 
an early undetected pregnancy. 
8. All prescribed medication must have been stopped at least 30 days prior to admission 
to the clinical research center based on investigator judgment. An exception is made 
for hormonal contraceptives, which may be used throughout the study. 
9. All over-the-counter medication, vitamin preparations and other food supplements, 
or herbal medications (e.g., St. John’s wort) must have been stopped at least 14 days 

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prior to admission to the clinical research center based on investigator judgment. An 
exception is made for acetaminophen, which is allowed up to admission to the 
clinical research center. 
10. Ability and willingness to abstain from alcohol from 48 hours (2 days) prior to 
screening, and from 48 hours (2 days) prior to admission until discharge from the 
clinical research center. 
11. Ability and willingness to abstain from methylxanthine-containing beverages or food 
(coffee, tea, cola, chocolate, energy drinks) from 48 hours (2 days) prior to 
admission until discharge from the clinical research center. A serum pregnancy test 
is required. In such cases, the participant must be excluded from participation if the 
serum pregnancy result is positive. 
12. Good physical and mental health on the basis of medical history, physical 
examination, clinical laboratory, ECG, and vital signs, as judged by the investigator. 
13. Serum potassium and serum glucose levels within reference ranges of the clinical 
research center. 
14. Willing and able to sign the ICF. 
15. Spirometry at screening demonstrating FEV1 ≥80% predicted. 
5.2. 
Exclusion criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematologic, or neurological disorders capable of significantly altering 
the absorption, metabolism, or elimination of drugs; constituting a risk when taking 
the study intervention or interfering with the interpretation of data. 
2. History or presence of any form of asthma, including childhood asthma and exercise 
induced asthma. 
3. At screening, systolic blood pressure <90 mmHg or >140 mmHg, or diastolic blood 
pressure <50 mmHg or >90 mmHg. 
4. History of pathological tachycardia, or a pulse rate > 85 bpm at screening or Day-1. 
Note. If the pulse rate is >85 bpm, re-measurement will be allowed up to 2 times 
during the screening period and Day-1. 
5. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years. 
6. Breast cancer within the past 10 years. 
7. A QTcF value of >450 msec at screening based on a triplicate measurement taken at a 
single timepoint. 

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NOTES: 
• The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or 
manually over-read. 
• The specific formula that will be used to determine eligibility and discontinuation for 
an individual participant should be determined prior to initiation of the study and the 
same formula used throughout the study for an individual participant. In other words, 
several different formulas cannot be used to calculate the QTc for an individual 
subject and then the lowest QTc value used to include or discontinue the subject from 
the trial. 
8. Vaccine(s) within 2 weeks prior to admission, or plans to receive such vaccines during 
the study. 
9. Donation or loss of more than 450 mL of blood within 60 days prior to (the first) 
drug administration. Donation or loss of more than 1.5 L of blood (for male 
participants) or more than 1.0 L of blood (for female participants) in the 10 months 
prior to (the first) drug administration in the current study. 
10. Participation in a drug study within 30 days prior to (the first) drug administration in 
the current study. Participation in 4 or more other drug studies in the 12 months prior 
to (the first) drug administration in the current study. 
11. Current enrollment or past participation in this clinical study. 
12. ALT >1.5x ULN. 
13. Total bilirubin >1.5xULN (isolated total bilirubin >1.5xULN is acceptable if total 
bilirubin is fractionated and direct bilirubin <35%). 
14. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
15. Presence of HBsAg at screening or within 3 months prior to first dose of study 
intervention. 
16. Positive hepatitis C antibody test result at screening or within 3 months prior to first 
dose of study intervention. NOTE: Participants with positive hepatitis C antibody 
test result due to prior resolved disease can be enrolled if a confirmatory negative 
hepatitis C RNA test is obtained. 
17. Positive pre-study drug/alcohol screen, including THC. 
18. Positive HIV antibody test. 
19. Cotinine levels indicative of smoking or history or use of tobacco- or nicotine 
containing products within 6 months prior to screening. Note. Levels of ≥10 ng/mL 
in urine would exclude a participant. 
20. Average intake of more than 24 units of alcohol per week (clinical site standard: 1 
unit of alcohol equals approximately 250 mL of beer, 100 mL of wine, or 35 mL of 
spirits). 
21. Regular use of known drugs of abuse, including tetrahydrocannabinol. 

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22. Use of combustible tobacco products, and non-combustible nicotine delivery 
systems, inclusive of cigarettes, cigars, pipes, and materials used to “vape” within 6 
months prior to screening. 
23. Hypersensitivity to any of the study interventions, or components thereof, or drug or 
other allergy that, in the opinion of the investigator, contraindicates participation in 
the study. 
24. Use of any products intended to treat medical conditions that are not approved by the 
governing health authority in a given country or region (for example, herbal 
medicine, health supplements, traditional medicine, homeopathic remedies, etc.). 
25. Impairment which would prevent the correct and consistent use of an MDI, as 
determined by the investigator/delegate. 
5.3. 
Lifestyle considerations 
5.3.1. 
Meals and dietary restrictions 
• 
A fasting period of at least 4 hours is required before obtaining all clinical laboratory 
blood samples. 
• 
Participants will be advised not to consume any foods containing poppy seeds within 
48 hours prior to admission to the clinical research center as this could cause a false 
positive drug screen result. 
• 
Participants to refrain from Seville oranges, grapefruit or grapefruit juice, pomelos, 
exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days before the start of 
study intervention until after the final dose. 
• 
Meals and snacks (such as decaffeinated coffee, herbal tea, fruit, biscuits) will be 
provided according to the standard operating procedures of the clinical research 
center. 
• 
Study intervention will be administered to participants after a light breakfast. 
Participants will fast for a period of 4 hours after study intervention administration 
on all dosing days. During fasting, no fluids other than water are allowed; water is 
allowed ad libitum throughout. 
5.3.2. 
Caffeine, alcohol, and tobacco 
• 
Participants to abstain from ingesting caffeine- or xanthine-containing products (e.g., 
coffee, tea, cola drinks, chocolate, and energy drinks) for 48 hours prior to admission 
until after collection of the final PK sample on Day 11. 
• 
Participants to abstain from alcohol for 48 hours prior to admission until after 
collection of the final PK sample on Day 11. 
• 
Use of tobacco products will not be allowed from 6 months prior to screening until 
after the final follow-up telephone call. 

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5.3.3. 
Activity 
• 
Participants to abstain from strenuous exercise for 96 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during the study (e.g., watching television, reading) 
5.3.4. 
Other restrictions 
• 
Participants must not donate blood during the study until follow-up telephone call 
(other than the blood sampling planned for this study). 
5.4. 
Screen failures 
A screen failure occurs when a participant who has consented to participate in the clinical 
study is not subsequently randomized to study intervention. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure 
participants to meet the CONSORT publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure 
details (screening status, date of screen fail, screen failure rationale), eligibility criteria, 
and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Rescreened participants should be assigned a new participant number 
for every rescreening event. Previously assigned participant numbers are to be recorded 
in the participants’ eCRF. 
Note. A participant can only be rescreened once, and the GSK Medical Monitor must be 
consulted prior to rescreening. 
5.5. 
Criteria for temporarily delaying administration of study 
intervention 
Not applicable. 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
The definition of study intervention is provided in the table of definition. 

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6.1. 
Study intervention(s) administered 
Table 4 
Study Intervention(s) Administered 
Intervention 
Label 
Not applicable. Unique identifiers are not used on open-label studies. 
Intervention 
Name 
Salbutamol HFA-
152a  
Salbutamol HFA-
152a  
Salbutamol HFA-
134a  
Salbutamol HFA-
134a  
Intervention 
Description 
 
A single 800 µg 
dose, given as 8 
x 100 µg (ex-
valve) at 20-
second intervals. 
OR 
A single 200 µg 
dose, given as 2 
x 100 µg (ex-
valve) at 20-
second intervals. 
A single 800 µg 
dose, given as 8 
x 100 µg (ex-
valve) at 20-
second intervals. 
OR 
A single 200 µg 
dose, given as 2 
x 100 µg (ex-
valve) at 20-
second intervals. 
A single 800 µg 
dose, given as 8 
x 100 µg (ex-
valve) at 20-
second intervals. 
OR 
A single 200 µg 
dose, given as 2 
x 100 µg (ex-
valve) at 20-
second intervals. 
A single 800 µg 
dose, given as 8 
x 100 µg (ex-
valve) at 20-
second intervals. 
OR 
A single 200 µg 
dose, given as 2 
x 100 µg (ex-
valve) at 20-
second intervals. 
Type  
 
Drug 
Drug 
Drug 
Drug 
Dose 
Formulation 
Salbutamol 
sulfate 
HFA-152a 
suspension 
Salbutamol 
sulfate 
HFA-152a 
suspension 
Salbutamol 
sulfate 
HFA-134a 
suspension 
Salbutamol 
sulfate 
HFA-134a 
suspension 
Unit Dose 
Strength(s) 
100 µg (ex-
valve) 
100 µg (ex-
valve) 
100 µg (ex-
valve) 
100 µg (ex-
valve) 
Dosage 
Level(s) 
800 µg OR 200 
µg  
800 µg OR 200 
µg  
800 µg OR 200 
µg 
800 µg OR 200 
µg 
Route of 
Administratio
n 
Inhalation 
Inhalation 
Inhalation 
Inhalation 
Use 
 
Investigational 
Product 
Investigational 
Product 
Comparator 
Comparator 
IMP and 
NIMP/AxMP. 
IMP 
IMP 
IMP 
IMP 
Sourcing 
Provided 
centrally by the 
sponsor 
Provided 
centrally by the 
sponsor 
Provided 
centrally by the 
sponsor 
Provided 
centrally by the 
sponsor 

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Packaging 
and Labeling 
Study 
intervention will 
be provided in a 
canister fitted 
with a metering 
valve within an 
actuator. Each 
canister will be 
labeled as 
required per 
country 
requirement. 
Study 
intervention will 
be provided in a 
canister fitted 
with a metering 
valve within an 
actuator. Each 
canister will be 
labeled as 
required per 
country 
requirement. 
Study 
intervention will 
be provided in a 
canister fitted 
with a metering 
valve within an 
actuator. Each 
canister will be 
labeled as 
required per 
country 
requirement. 
Study 
intervention will 
be provided in a 
canister fitted 
with a metering 
valve within an 
actuator. Each 
canister will be 
labeled as 
required per 
country 
requirement. 
Current 
Name(s) or 
Alias(es) 
 
-- 
-- 
Ventolin 
Ventolin 
Note. The study has a full replicate design (Test and Reference are replicated twice). Salbutamol HFA-152a    
and salbutamol HFA-134a are duplicated to reinforce the 4 way cross-over. 
Table 5 
Study Arm(s) 
6.1.1. 
Medical devices 
• 
The GSK manufactured medical devices (or devices manufactured for GSK by a 
third party) provided for use in this study are MDIs.  
• 
Instructions for medical device use are provided in the pharmacy manual. 
• 
All device deficiencies (including malfunction, use error and inadequate labeling) 
shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.4.9 and Section 10.6) and appropriately managed by 
GSK. 
Arm Title 
200 µg 
800 µg 
Arm Type 
Experimental (HFA-152a) and 
Active Comparator (HFA-134a) 
administered at 200 µg. 
Experimental (HFA-152a) and 
Active Comparator (HFA-134a) 
administered at 800 µg. 
Arm 
Description 
Participants will receive a single 
200 µg dose given as 2x100 µg (ex-
valve) at 20-second intervals on Day 
1, Day 4, Day 7, and Day 10 of either 
HFA-152a or HFA-134a. 
Participants will receive a single 
800 µg dose given as 8x100 µg (ex-
valve) at 20-second intervals on Day 
1, Day 4, Day 7, and Day 10 of either 
HFA-152a or HFA-134a. 
Associated 
Intervention 
Labels 
Salbutamol HFA-152a and 
Salbutamol HFA-134a.  
Salbutamol HFA-152a and 
Salbutamol HFA-134a. 

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Note. MDIs need to be primed before use. The priming of the MDIs should not be done 
in the vicinity of the participants, as unintended inhalation of micronized particles of 
salbutamol may affect the salbutamol plasma concentrations of the participants. Please 
refer to the pharmacy manual for full IFU. 
6.2. 
Preparation, handling, storage, and accountability 
• 
The investigator or designee must confirm appropriate conditions (e.g., temperature) 
have been maintained during transit for all study intervention received, and any 
discrepancies are reported and resolved before use of the study intervention. 
• 
Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply, prepare, or administer study intervention. 
• 
For further guidance and information about equipment requirements and product 
usage, please refer to the pharmacy manual. 
• 
All study intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
• 
The investigator, or authorized site staff is responsible for study intervention 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records) 
• 
Further guidance and information for the final disposition of unused study 
interventions are provided in the pharmacy manual. 
• 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, medical monitor and/or GSK 
study contact. 
• 
A MSDS/equivalent document describing occupational hazards and recommended 
handling precautions either will be provided to the investigator, where this is 
required by local laws, or is available upon request from GSK. 
6.3. 
Assignment to study intervention 
Participants will be independently randomized in Cohort 1 (200 µg) and Cohort 2 
(800 µg). Within each cohort, participants will be randomly assigned with 1:1 ratio in 2 
possible sequences (TRRT or RTTR [T for test and R for reference]) in 2x2x4 cross-over 
design as mentioned in Section 4.1. 
The randomization schedule, order of treatment sequence assignment, will be generated 
using the GSK validated randomization system Randall NG. The randomization schedule 
is made up of randomization numbers mapped to treatment sequences. Randomization 
numbers are assigned in sequential order. Each participant will be assigned 1 
randomization number to determine which treatment sequence will be followed. 

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Knowledge of treatment assignment will be revealed at time of participant is randomized, 
but not sooner. 
Once the randomization number has been assigned, it must not be re-assigned to another 
participant. 
6.4. 
Blinding 
This is an open-label study; however, the specific intervention to be taken by a 
participant will be assigned at random, and the order of treatment sequence assignment 
will remain concealed. Once the randomization is conducted, the treatment sequence 
assignment will be revealed. 
6.5. 
Study intervention compliance 
When participants are dosed at the site, they will receive study intervention directly from 
the investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. 
In addition, the GSK Medical Monitor may provide training and support to site personnel 
regarding inhaler technique in order to support study intervention compliance. 
Participants will be required to perform predose MDI training as outlined in the SoA. The 
study will use placebo MDIs so an assessment of co-ordination of inhalation and 
actuation can be performed, and participants are familiar with the cold freon effect ahead 
of dosing. 
6.6. 
Dose modification 
Not applicable. 
6.7. 
Continued access to study intervention after the end of the 
study 
Not applicable. 
6.8. 
Treatment of overdose 
An overdose is any dose of study intervention given to a participant that exceeds the 
planned, randomized dose for an individual within a given dose group. 
GSK does not recommend specific treatment for an overdose. 

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6.9. 
Prior and concomitant therapy 
Participants must abstain from taking prescription medications from 30 days prior to 
admission until completion of the follow-up visit or early discontinuation. An exception 
is made for hormonal contraceptives, which may be used throughout the study. 
Participants must abstain from taking nonprescription drugs (including vitamins, 
recreational drugs, and dietary or herbal supplements) from 14 days prior to admission 
until completion of the follow-up visit or early discontinuation. 
Vaccination is not allowed from 2 weeks prior to admission until discharge. 
Paracetamol/Acetaminophen, at doses of 2 grams/day, is permitted for use any time 
during the study, except during the 24 hours predose or postdose. The reason that 
acetaminophen is not permitted during the 24 hours predose or postdose is because 
acetaminophen may decrease the excretion rate of salbutamol, which could result in a 
higher serum level (https://go.drugbank.com/drugs/DB01001). Other concomitant 
medications may be considered on a case-by-case basis by the investigator in consultation 
with the medical monitor. 
Other medication to treat AEs may only be prescribed if deemed necessary by the 
investigator. If medication is used, the name of the drug, the dose, and dosage regimen 
will be recorded in the eCRF. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study intervention 
‘Discontinuation’ of study intervention refers to any participant who has not received all 
planned doses of the study intervention. In rare instances, it may be necessary for a 
participant to permanently discontinue study intervention. If study intervention is 
permanently discontinued, the participant should, if possible, continue other study 
procedures (e.g., safety), planned in the study protocol at the discretion of the 
investigator. If the participant does not agree to continue in-person visits, a modified 
follow-up must be arranged to ensure the collection of endpoints and safety information 
(e.g., telephone contact). See the SoA for data to be collected at the time of 
discontinuation of study intervention and follow-up and for any further evaluations that 
need to be completed. 

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The primary reason for premature discontinuation of the study intervention will be 
documented in the eCRF based on the list below: 
Reasons  
Additional items/Sub-reasons  
AE  
 
Lost to follow-up  
Participant Relocated  
Participant was Incarcerated  
Other 
Unknown  
Participant Reached Protocol-Defined 
Stopping Criteria  
Liver chemistry stopping criteria  
QTc Stopping criteria  
Physician Decision  
Specify  
Pregnancy  
 
Protocol Deviation  
Specify  
Site Terminated by Sponsor  
 
Sponsor Terminated Study Treatment 
 
Study Terminated by Sponsor  
 
Withdrawal by Participant  
Burden of Procedure 
Participant Relocated 
COVID-19 Pandemic 
Other  
Other  
Specify  
Death  
 
7.1.1. 
Liver chemistry stopping criteria 
Discontinuation of study intervention for abnormal liver tests is required by the 
investigator when a participant meets one of the conditions outlined in Figure 4 or in the 
presence of abnormal liver chemistries not meeting protocol-specified stopping rules if 
the investigator believes that it is in best interest of the participant. 
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met: 

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Figure 4 
Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm 
 
Abbreviations: ALT=alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; ULN = 
upper limit of normal. 
Refer to Section 10.5 for required Liver Safety Actions and Follow-up Assessments. 
7.1.2. 
QTc Stopping criteria 
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QT interval corrected using Fridericia’s formula [QTcF] after enrollment, the 
investigator or qualified designee will determine if the participant can continue the study 
intervention and if any change in participant management is needed. This review of the 
ECG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE. 
A subject that meets the bulleted criteria below based on the average of triplicate ECG 
readings will be withdrawn from study intervention. 
• 
QTcF > 500 msec 
• 
Change from baseline: QTcF >60 msec 
• 
QT uncorrected > 600 msec 
7.2. 
Participant discontinuation/withdrawal from the study 
A participant may withdraw from the study at any time at the participant’s own request 
for any reason (or without providing any reason). 

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A participant may be withdrawn at any time at the discretion of the investigator for 
safety, behavioral, or compliance reasons. 
Investigators will attempt to contact participants who do not return for scheduled visits or 
follow-up. 
At the time of discontinuing from the study, if possible, an ED visit should be conducted, 
as shown in the SoA (Section 1.3). See SoA (Section 1.3) for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need to 
be completed. 
The participant will be permanently discontinued from the study intervention and the 
study at that time. 
All data and samples collected up to and including the date of withdrawal of/last contact 
with the participant will be included in the study analyses. If the participant withdraws 
consent for disclosure of future information, the sponsor may retain and continue to use 
any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, the participant may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 
The primary reason for participant discontinuation/withdrawal from the study will be 
documented in the eCRF based on the list below: 
Reasons  
Additional items/Sub-reasons  
AE  
 
Lost to follow-up  
Participant Relocated  
Participant was Incarcerated 
Other 
Unknown  
Participant Reached Protocol-
Defined Stopping Criteria  
  
Liver chemistry stopping criteria 
QTc Stopping criteria  
Physician Decision  
Specify  
Pregnancy 
 
Protocol Deviation  
Specify  
Site Terminated by Sponsor  
 
Study Terminated by Sponsor  
 
Withdrawal by Participant  
Burden of Procedure 
Participant Relocated 
COVID-19 Pandemic 
Other  
Other  
Specify  
Death  
 

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Participants who are withdrawn from the study because of AEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will 
follow participants who are withdrawn from the study due to an AE/SAE until the event 
is resolved (see Section 10.3.4.5) 
7.3. 
Lost to follow-up 
A participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
1. The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
2. Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls, and if necessary, an email to the participant’s last known email address). These 
contact attempts should be documented in the participant’s medical record. 
3. Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. This scenario will be noted as treatment 
discontinuation and/or study withdrawal with the primary reason for this being lost 
to follow-up in the eCRF. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
1. Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
2. Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
3. All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. Subjects who have signed informed consent 
but are not eligible to proceed should be recorded in the eCRF with a status of 
‘screen failure’. 
4. Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the timeframe defined in the SoA. 
5. In the event of a significant study-continuity issue (e.g., caused by a pandemic), 
alternate strategies for participant visits, assessments, study intervention distribution 
and monitoring may be implemented by the sponsor or the investigator, as per local 
health authority/ethics requirements. 

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6. The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
500 mL. 
7. Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Administrative procedures 
8.1.1. 
Collection of demographic data 
Record demographic data such as date of birth, sex, race, and ethnicity in the 
participant’s eCRF. 
Collection of sex, race and ethnicity data is necessary to assess and monitor the diversity 
of the trial participants, and to determine if the trial participants are truly representative of 
the impacted population. 
8.1.2. 
Medical and vaccination history 
Obtain the participant’s medical/vaccination history by interviewing the participant and/or 
review of the participant’s medical records. Record any pre-existing conditions, signs 
and/or symptoms present prior to study start in the eCRF. 
8.2. 
Efficacy assessments 
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). 
MDI Training 
MDI training using placebo demonstrator devices will be performed at the timepoints 
specified in the SoA. The correct inhalation technique will be reinforced by the 
investigator/delegate prior to treatment administration. 
Spirometry 
Spirometry should be obtained using spirometry equipment that is calibrated and 
maintained in accordance with the manufacturers guidance and meets ATS and ERS 
guidelines [Graham, 2019]. 
Spirometry will be performed as part of the enrolment criteria where participants pre-
bronchodilator FEV1 should be ≥80% of predicted to be eligible to enroll onto the study. 
8.3. 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 

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8.3.1. 
Physical examination 
• 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. 
8.3.2. 
Vital signs 
• 
Vital signs that will be measured include pulse rate and blood pressure. 
• 
Blood pressure and pulse measurements will be assessed after a minimum of 5 
minutes of the participant resting in the supine position with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
• 
If an absolute value for vital signs parameters is clinically significant as judged by 
the investigator, then the value will be recorded as an AE. 
8.3.3. 
Electrocardiograms 
• 
Twelve lead ECG(s) will be obtained at screening, intervention period, and at 
discharge or early discontinuation as outlined in the SoA (Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTc intervals.  
• 
The ECG will be obtained after the participant has been resting for at least 5 minutes 
in the supine position. Refer to Section 7.1.2 for QTc withdrawal criteria and any 
additional QTc readings that may be necessary. 
• 
If an absolute value for parameters is clinically significant as judged by the 
investigator, then the value will be recorded as an AE. 
8.3.4. 
Clinical safety laboratory tests 
• 
See Section 10.2 for the list of clinical laboratory tests to be performed in accordance 
with lab manual and the SoA (Section 1.3). 
• 
The investigator must review the laboratory results, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory results must be retained with source documents. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 1 day after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator (who may opt to discuss this with 
the GSK medical monitor). 
− In the absence of a diagnosis, abnormal laboratory findings assessments or other 
abnormal results the investigator considers clinically significant will be recorded 
as an AE or SAE, if they meet the definition of an AE or SAE (refer to Section 
10.3.1 and  Section  10.3.2). 

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− If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the etiology should be identified, and 
the sponsor notified. 
− If laboratory values from non-protocol-specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator e.g., SAE or AE, then the 
results must be recorded. 
− The addresses of clinical laboratories performing the laboratory assessments are 
documented in the Protocol Supporting Documentation. 
8.3.5. 
Pregnancy testing 
• 
Female participants of childbearing potential must perform a blood pregnancy test 
before the administration of any dose of study intervention. Pregnancy testing must 
be done even if the participant is menstruating at the time of the study visit. The 
study intervention may only be administered if the pregnancy test is negative. 
• 
Refer to Section 8.4.6 for the information on study continuation for participants who 
become pregnant during the study. 
• 
Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
• 
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted during study intervention period as detailed in the SoA. 
• 
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure. 
• 
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator, or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study. 
8.4. 
Adverse Events (AEs) serious adverse events (SAEs), and 
other safety reporting 
For definitions relating to safety information see Section 10.3. 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and other safety 
information and remain responsible for following up all AEs (see Section 8.4.2). This 
includes events reported by the participant. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.4.1. 
Time period and frequency for collecting AE, SAE, and other 
safety information 
All SAEs will be collected from the signing of the ICF until final follow-up telephone 
call at the time points specified in the SoA. 

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SAEs assessed as related to study participation (e.g., study intervention, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to a GSK 
product (non-IMP) will be recorded from the time a participant consents to participate in 
the study. 
All AEs will be collected from the start of study intervention until final follow-up 
telephone call at the timepoints specified in the SoA. 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded as medical history/current medical conditions, not as 
AEs. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under 
no circumstance should this exceed 24 hours, as indicated in Section 10.3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
A poststudy AE/SAE is defined as any event that occurs outside of the AE/SAE reporting 
period defined in Section 8.4.3. 
Investigators are not obligated to actively seek information on AEs or SAEs after 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, after a participant has been discharged from the study, the investigator 
must record it in the medical records. If the investigator considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
8.4.2. 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.3.4.5 and Section 10.6.4.4. 
8.4.4. 
AESIs 
Not applicable. 

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8.4.5. 
Regulatory reporting requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met. See Section 8.4.3 
for reporting timeframes. 
• 
For SAEs, the investigator must always provide an assessment of causality at the 
time of the initial report, as defined in the Section 10.3.4.3. 
• 
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the sponsor 
will review and then file it along with the IB, IFU, or package insert will notify the 
IRB/IEC, if appropriate according to local requirements. 
Table 6 
Timeframes for submitting SAE, pregnancy and other events reports 
to GSK 
Type of event 
Initial reports 
Follow-up of relevant information on 
a previous report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours* ‡ 
Paper/Electronic AEs 
Report  
24 hours* 
Paper/Electronic AEs 
Report 
Pregnancies  
24 hours* 
Paper pregnancy 
notification report  
24 hours * 
Paper pregnancy follow-
up report  
* Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
‡ Paper AEs Report will be dated and signed by the investigator (or designee). For each SAE, the investigator(s) must 
document in the medical notes that they have reviewed the SAE and have provided an assessment of causality. 
8.4.6. 
Pregnancy 
Female participants who become pregnant after the first study intervention dose must not 
receive subsequent doses of the study intervention but may continue other study 
procedures at the discretion of the investigator. 
• 
Details of all pregnancies in female participants will be collected after the start of 
study intervention and until 48 hours after the last study intervention. 
• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
female participant pregnancy. 
• 
Any pregnancy or pregnancy complication or elective termination of a pregnancy for 
medical reasons will be reported as an AE or SAE. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant/pregnant female 
partner and the neonate, and the information will be forwarded to the sponsor. See 
Table 6 for reporting timeframes. 

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• 
Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
• 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
8.4.7. 
CV and Death Events 
CV Events 
Not applicable. 
Death Events 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within 1 week 
of when the death is reported. 
8.4.8. 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs 
Not applicable. 
8.4.9. 
Contact information for reporting SAEs and pregnancies 
Table 7 
Contact information for reporting SAEs and pregnancies 
Study contact for questions regarding SAEs and pregnancies 
 
Contact GSK’s local and/or medical contacts 
Contacts for reporting SAEs and pregnancies. 
Available 24/24 hours and 7/7 days 
fax # +44(0) 20 81814780. 
Available during working hours 
oax37649@gsk.com 
8.4.10. 
Participant card 
Not applicable. 
8.4.11. 
Medical device deficiencies 
Medical devices are being provided for use in this study as the study intervention. To 
fulfill regulatory reporting obligations worldwide, the investigator is responsible for the 

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detection and documentation of events meeting the definitions of device deficiency that 
occur during the study with such devices. 
The definition of a medical device deficiency can be found in Section 10.6. 
NOTE: Deficiencies fulfilling the definition of an AE/SAE will follow the processes 
outlined in Section 10.6 of the protocol.  
8.4.11.1. 
Time Period for Detecting Medical Device Deficiencies 
• Medical device deficiencies that result in an incident 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 device deficiency at any time after a participant has 
been discharged from the study, and such a deficiency 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 deficiencies is provided in Section 10.6. 
8.4.11.2. 
Follow-up of Medical Device Deficiencies 
• Follow-up applies to all participants, 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. 
8.4.11.3. 
Prompt Reporting of Device Deficiencies to the Sponsor 
• Device deficiencies will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical 
device deficiency. 
• The medical device deficiency report form will be sent to the sponsor by 
email/facsimile equipment. If email/facsimile equipment is unavailable, then 
notification by telephone with a copy of data collection tool sent by overnight courier 
service should be utilized. 
• The sponsor will be the contact for the receipt of device deficiency reports. 
8.4.11.4. 
Regulatory Reporting Requirements for Device Deficiencies 
• The investigator will promptly report all 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. 

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• The investigator, or responsible person according to local requirements (e.g., the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC. 
8.5. 
Pharmacokinetics 
Whole blood samples of approximately 4.5 mL will be collected for measurement of 
plasma concentrations of salbutamol as specified in the SoA (Section 1.3). 
Instructions for the collection and handling of plasma samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
Details of PK blood sampling collection, processing, storage, and shipping procedures are 
provided in the Lab Manual prepared by GSK. 
8.6. 
Pharmacodynamics 
The following PD parameters will be evaluated and compared: serum potassium 
weighted means and minimum serum potassium. 
Blood samples of approximately 3.5 mL will be collected for measurement of potassium 
concentrations in serum as specified in the SoA (Section 1.3). 
Serum potassium concentrations will be assessed by the 
 
 
8.7. 
Genetics 
Not applicable. 
8.8. 
Biomarkers 
Not applicable. 
8.9. 
Immunogenicity assessments 
Not applicable. 
8.10. 
Health economics or medical resource utilization and health 
economics 
Neither health economics or medical resource utilization and health economics 
parameters are evaluated in this study. 
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9. 
STATISTICAL CONSIDERATIONS 
The statistical analysis plan will include a more technical and detailed description of the 
statistical analyses described in this section. This section is a summary of the planned 
statistical analyses of the most important endpoints including primary and key secondary 
endpoints. 
Any deviation from the statistical analysis plan will be reported in the section “Changes  
in Planned Analysis” in the CSR. 
9.1. 
Statistical hypotheses 
This study is designed to estimate the relative bioavailability of salbutamol HFA-152a 
(test) and Salbutamol HFA-134a (reference) in following cohorts: 
Cohort 1: Salbutamol HFA-152a 200 µg, Salbutamol HFA-134a 200 µg. 
Cohort 2: Salbutamol HFA-152a 800 µg, Salbutamol HFA-134a 800 µg. 
In each cohort, for each PK parameters endpoints (AUC(0-30min.), AUC(0-∞), Cmax 
and AUC(0-last)), point estimates and corresponding 90% CIs will be constructed for 
GMR(T/R). 
90% Confidence Interval of GMR (T/R): The GMR is calculated by taking the ratio of 
the geometric means of the salbutamol HFA-152a (T) to the salbutamol HFA-134a (R). 
The 90% confidence interval of this GMR is a range that provides a measure of the 
uncertainty in this ratio. 
An additional assessment will be performed by comparing the 90% CIs for the 
GMR(T/R) in AUC(0-30min), AUC(0-∞), Cmax and AUC(0-last) PK parameters to the 
bioequivalence acceptance range (refer to Section 10.8, Table 12). 
9.1.1. 
Multiplicity Adjustment 
No multiplicity adjustment will be performed for the primary or secondary endpoints. 

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9.2. 
Analysis sets 
Analysis Set 
Definition/Criteria  
Analyses 
Evaluated  
Screened 
• 
All participants who were screened for eligibility.  
All Screened, 
Reason for Screen 
Failures 
Enrolled 
• 
All participants who screen passed and entered in 
the study (who were randomized). 
• 
Note screening failures (who never passed 
screening even if rescreened) and participants 
screened but never enrolled into the study (met 
eligibility but not needed) are excluded from the  
• 
enrolled analysis set as they did not enter the 
study.  
Study Population 
FAS 
• 
 All randomized participants who received at least a 
single dose period of study intervention 
• 
 Data will be reported according to the randomized 
study intervention. 
Exploratory PD 
objective 
Safety  
• 
All participants who received at least one 
puff/actuation of study intervention. 
Estimand for 
secondary safety 
objective  
PK  
• 
All participants in the FAS who had at least 1 non-
missing PK assessment (NQ values will be 
considered as non-missing values). 
• 
Data will be reported according to the actual study 
intervention. 
Estimand for primary 
and secondary 
objective of PK 
parameters  
9.3. 
Statistical analyses 
9.3.1. 
General considerations of pharmacokinetic data 
PK analysis will be the responsibility of 
 
 Plasma concentration-time data will be analyzed 
by noncompartmental methods with WinNolin 8.3. Calculations will be based on the 
actual sampling times recorded during the study. 
The PK parameters data will be summarized using descriptive statistics (N, n, AM, 95% 
CI of AM, GM, 95% CI of GM, SD, SD (loge) median, between- subject coefficient of 
variation (CVb in %), minimum and maximum), and will be listed and summarized in 
tabular and/or graphical form. 
Listings and graphical presentation will also be produced for PK parameters endpoints. 
Discrete data will be summarized by counts and percentages as appropriate. 
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9.3.1.1. 
Definition of PK endpoints 
The definitions of PK parameters are described in Table 8. 
Table 8 
Pharmacokinetic Parameters 
Parameters  
Descriptions  
AUC(0-30min) 
Area under the plasma concentration-time curve up to 30 minutes 
postdose 
AUC(0-∞) 
Area under the plasma concentration-time curve from time 0 to 
infinity calculated as: AUC(0-∞) = AUC(0-last)+C(last)/k(el), where 
Clast is the last measurable plasma concentration and K(el) is the 
elimination rate constant 
AUC(0-last) 
Area under the plasma concentration-time curve up to last time 
with concentrations above the LLOQ 
Cmax 
Maximum observed plasma concentration 
Tmax 
Time to Cmax 
t1/2 
Apparent terminal phase half-life 
9.3.1.2. 
Main Analytical Approach 
The primary analysis for PK parameters AUC(0-30min), AUC(0-∞) and Cmax will 
evaluate the primary estimand in PK analysis set. 
If for the reference product, SDWR <0.294 or CVw <30%, then ABE approached will be 
used, refer Section 10.8, Table 12 for the acceptance range limit of BE. 
If for the reference product, SDWR ≥ 0.294 or CVw ≥30%, then RSABE approached will 
be used, refer Section 10.8, Table 12 for the acceptance range limit of BE. 
The extent of the widening is defined based upon the within-subject variability seen in 
the bioequivalence study using scaled-average-bioequivalence according to [U, L]=exp 
[±k·SWR], where U is the upper limit of the acceptance range, L is the lower limit of the 
acceptance range, k is the regulatory constant set to 0.760 as per EMA and 0.893 
according to FDA and SWR is the within-subject standard deviation of the log-
transformed values of Cmax and AUC of the reference product (refer Section 10.8, Table 
12). 
9.3.1.3. 
Statistical model for primary analysis 
For each cohort, following loge-transformation, AUC(0-30min.), AUC(0-∞) and Cmax 
will be analyzed using mixed effect model approach with fixed effect for period, 
treatment group and participants as random effects. The point estimates and their 
associated 90% CI will then be back-transformed to provide point estimates and 90% CI 
for the ratios (GMR) of HFA-152a MDI (test)/HFA-134a MDI (reference). 

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If an intercurrent event (ICE) (as described in Section 3.1) happens during a specific 
treatment period, and this event affects the measurement of individual pharmacokinetic 
(PK) concentrations (pharmacokinetic data), then the data points for those affected 
individuals in the treatment period will be set to missing. 
9.3.1.4. 
Secondary endpoint(s) analyses 
The secondary analysis for PK parameters AUC(0-30min), AUC(0-∞) and Cmax will 
evaluate the secondary estimand in PK analysis set. 
In each cohort, analytical approach for the statistical analysis of AUC(0-last) is same as 
primary PK parameters as mentioned in Section 9.3.1.2. 
Statistical model for estimating the intra-participants (within) variability. 
For each cohort, following loge-transformation, AUC(0-30min.), AUC(0-∞), Cmax and 
AUC(0-last) will be analyzed using mixed effect model approach with fixed for period, 
treatment group and participants as random effects. SD in log scale and coefficient of 
variation (CVWR)for intra (within)-participants will be computed. 
Statistical model for estimating the inter-participants (intra participants for test and 
reference) variability. 
For each cohort, following loge-transformation, AUC(0-30min.), AUC(0-∞), Cmax and 
AUC(0-last) will be analyzed using mixed effect model approach with fixed for period, 
treatment group and treatment group as random effects. SD in log scale and coefficient of 
variance (CV) for inter-participants will be calculated. 
• 
Total participants variability will be calculated as sum of intra (within)-participants 
and inter-participants variability. 
If an intercurrent events (ICEs) (as described in Section 3.2.1 and Section 3.2.2) happens 
during a specific treatment period, and this event affects the measurement of individual 
pharmacokinetic (PK) concentrations (pharmacokinetic data), then the data points for 
those affected individuals in the treatment period will be set to missing. 
9.3.1.5. 
Safety analyses 
All safety analyses will be performed on the Safety analysis set. 
Safety and tolerability will be assessed through AEs, SAEs, clinical laboratory, vital 
signs, and ECGs, and any other parameter that is relevant for safety assessment. Safety 
data will be presented in tabular and/or graphical format and summarized descriptively 
according to GSK’s IDSL standards. 
Treatment policy strategy for the ICEs (as described in Section 3.2.3) will be used for 
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Safety analysis is described in further detail in below sections. 
9.3.1.6. 
Adverse Events 
All reported AEs will be coded using the standard GSK dictionary, (MedDRA) and 
grouped by body system and preferred terms. Counts and percentages for AEs, and SAEs 
will be produced by system organ class and preferred terms. AEs and SAEs will also be 
presented for both the overall follow-up period and on-treatment period. The number and 
percentages will be provided for all AEs, study treatment – related AEs, and SAEs, 
deaths, fatal AEs, non-fatal SAEs, and AEs leading to study treatment or study 
withdrawal. AEs and SAEs will be summarized by severity. 
9.3.1.7. 
Clinical laboratory 
A summary of all data outside the reference range of the clinical laboratory will be 
provided. Absolute values of clinical laboratory data will be presented descriptively 
(arithmetic mean, SD, median, minimum, and maximum), where applicable. 
9.3.1.8. 
Vital signs and electrocardiograms 
Absolute values for vital signs (systolic and diastolic blood pressure and pulse rate) will 
be summarized descriptively (arithmetic mean, SD, median, minimum, and maximum). 
Absolute and changes from baseline values for ECG parameters detailed in Section 8.3.3 
will be presented descriptively (arithmetic mean, SD, median, minimum, and maximum), 
where applicable. 
9.3.2. 
Tertiary/exploratory endpoint(s) analysis 
9.3.2.1. 
Pharmacodynamic analysis 
For each cohort, the following PD parameters will be evaluated and compared between 
Salbutamol HFA-152a MDI (test) and Salbutamol HFA-134a MDI (reference): minimum 
serum potassium, MHR and maximum QTcF interval. 
Following loge-transformation, minimum serum potassium, MHR and maximum QTcF 
interval will be analyzed using mixed effect model approach with fixed effect for period, 
treatment group and participants as random effects. The point estimates and their 
associated 90% CI will then be back-transformed to provide point estimates and 90% CI 
for the ratios (GMR) of HFA-152a MDI (test)/HFA-134a MDI (reference). 
The exploratory PD parameters data will be summarized using descriptive statistics (N, n, 
AM, GM, SD, SD in log scale CV %, median, minimum, and maximum), and will be 
summarized in tabular and/or graphical form. 

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9.5. 
Sample size determination 
Up to 60 healthy participants will be enrolled to either Cohort 1 (200 µg) or Cohort 2 
(800 µg) to achieve at least 56 participants in the PK analysis set. 
For each cohort, 30 healthy participants will be randomly assigned to a cohort to ensure 
at least 28 participants are included in the PK analysis set with 15 randomized to each 
treatment sequence. 
The target number of participants in each cohort is chosen to achieve half width 
(refer Table 9) of the 90% CI, in the estimate of the geometric mean ratios for the 
primary endpoints (AUC (0-30 min.), AUC(0-inf) and Cmax). 
In the previously conducted 219430 pilot PK study, there was considerable interest in 
AUC(0-30 min) due to larger than expected observed differences between test and 
reference product, in addition to observing potentially higher amounts of intra-subject 
variability that would classify the product as highly variable (~30%). Though, less 
variability was observed among AUC(0-inf) and Cmax. Due to uncertainty of what the 
true CVw may be for both the reference and test products, this current study therefore has 
considered a more conservative assumption accounting for up to 50% intra subject 
variability (CVw) in PK parameters, with a particular interest in AUC(0-30 min). 
Therefore, a sample size 28 in each cohort, assuming intra subject variability (CVw) of 
50% in AUC(0-30 min.), the half width of the upper bound of the 90% CI for observed 
GMR (T/R) is 16.44% (refer Table 9). 
For example, if the geometric ratio between test and reference is 1.06 for n=28 and 
CVw = 50%, then the upper bound of the 90% CI for observed treatment ratio is 
1.06*(1+0.1644) = 1.23 and the lower bound is 1.06/(1+0.1644) = 0.91 (refer Table 10). 
Table 9 
Sample sizes with varying intra subject variability and associated 
half-widths of the 90% CI of the observed treatment ratio 
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Table 10 
Sensitivity Table 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1. 
Regulatory and ethical considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS international ethical guidelines. 
− Applicable ICH GCP guidelines 
− Applicable laws and regulations 
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• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.  
• Substantial amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following, as applicable: 
− Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, 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. 
10.1.3. 
Informed consent process 
• The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participants and answer all questions 
regarding the study. 
• Potential participants must be informed that their participation is voluntary. They will 
be required to physically or digitally sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, privacy and data protection requirements, where applicable, and the 
IRB/IEC or study center. 
• The medical record must include a statement that physical or digital informed consent 
was obtained before the participant was enrolled in the study and the date the physical 
or digital consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
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• A physical or digital copy of the ICF(s) must be provided to the participant. 
In case of unexpected pregnancy, participant must be informed that PI such as date of 
birth, sex of the baby will be collected as part of safety follow-up. Consent for the baby 
may be obtained from the participant and/or their partner as per local regulations. 
If partners of male participants become pregnant during the study, consent will need to be 
obtained or notification given as per local regulation to the partner before collecting their 
PI such as LMP, year of birth or the PI such as date of birth, sex of their baby as part of 
safety follow-up. 
10.1.4. 
Recruitment strategy 
Participants will be identified for potential recruitment using clinical database, and 
IEC/IRB-approved newspaper/radio/social media advertisements, prior to consenting to 
take part in this study. 
10.1.5. 
Data protection 
• Participants will be assigned a unique identifier by the investigator. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
• GSK will ensure protection of the personal data of the investigator and site staff 
which is collected within the framework of and for the purpose of the study. 
• The participant must be informed that their personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant that their data will be used as described in 
the informed consent. 
• The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
10.1.6. 
Committees structure 
Not applicable. 

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10.1.7. 
Dissemination of Clinical Study Data 
• The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study Register in compliance with 
applicable regulations/GSK policy. GSK will aim to register protocols summaries 
prior to study start and target results summaries submission within 12 months of 
primary/study completion date. Where external regulations require earlier disclosure, 
GSK will follow those timelines. 
• Where required by regulation, summaries will also be posted on applicable national 
or regional clinical study registers. 
• Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the study report, and provided reasonable access to 
statistical tables, figures, and relevant reports. GSK will also provide the investigator 
with the full summary of the study results, including a summary of trial results 
understandable to laypersons. The investigator is encouraged to share the plain 
language summary with the study participants, as appropriate. The full study report 
will be made available upon request, after decision on marketing authorization by 
regulatory authorities.  
• GSK will provide the investigator with the randomization codes and participant-level 
line listings for their site only after completion of the full statistical analysis. 
• GSK intends to make anonymized participant-level data from this study available to 
external researchers for scientific analyses or to conduct further research that can help 
advance medical science or improve patient care. This helps ensure the data provided 
by study participants are used to maximum effect in the creation of knowledge and 
understanding. 
10.1.8. 
Data quality assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 
• Guidance on completion of eCRFs will be provided in eCRF completion guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
• QTLs will be predefined in the Action Item Key Decision Log to identify systematic 
issues that can impact participant right, safety and/or reliability of study results. These 
predefined parameters will be monitored during the study, and important deviations 
from the QTLs and remedial actions taken will be summarized in the CSR. 
• Monitoring details describing strategy, including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring, 
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requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the monitoring plan. 
• The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final 
CSR/equivalent summary unless local regulations or institutional policies require a 
different retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to another 
location or party without written notification to the sponsor. 
• When copies of source documents are shared externally for review by a central reader 
mechanism (e.g., endpoint adjudication committee; expert reader), documents are 
stored by the external body for 25years. 
10.1.9. 
Source documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data and its origin can be found in source data 
acknowledgment or monitoring guidelines. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The sponsor or designee will perform monitoring to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.10. 
Study and site start and closure 
Start of study and first act of recruitment 
The start of study and the first act of recruitment are defined as FSFV (first ICF signature 
date). 
Study/Site Termination 
GSK or designee reserves the right to close the study site or terminate the study at any 
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completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or temporarily suspended, the sponsor shall 
promptly inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
temporary suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up. 
10.1.11. 
Publication policy 
The results of this study may be published in peer reviewed scientific literature and/or 
presented at scientific meetings. The sponsor will comply with the requirements for 
publication of study results in accordance with standard editorial and ethical practice and 
as per the sponsor’s internal policy. Authorship will be determined by mutual agreement 
and in line with ICMJE authorship requirements. 

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10.2. 
Appendix 2: Clinical laboratory tests 
• 
The tests detailed in Table 11 will be performed by 
 
 
• 
Local laboratory results are only required in the event that 
 
 results are not available in time for either study intervention administration 
and/or response evaluation. If a local sample is required, it is important that the 
sample for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used to make either a study intervention decision or response 
evaluation, the results must be recorded. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• 
Investigators must document their review of each laboratory safety report. 
Table 11 
Protocol-required safety laboratory tests  
Laboratory Tests 
Parameters 
Hematology 
• 
Platelet count 
• 
Red blood cell (RBC) count 
RBC indices 
• 
Mean corpuscular volume (MCV) 
• 
Mean corpuscular hemoglobin (MCH) 
• 
%Reticulocytes 
Absolute WBC count 
with differential: 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
• 
Hemoglobin 
• 
Hematocrit 
Clinical 
chemistry1 
• 
Blood urea 
nitrogen 
(BUN)/Urea 
• 
Potassium** 
• 
Creatinine* 
• 
Sodium 
• 
Calcium 
• 
Glucose fasting** 
• 
CPK 
• 
Aspartate aminotransferase (AST)/serum 
glutamic-oxaloacetic transaminase (SGOT) 
• 
Alanine aminotransferase (ALT)/serum glutamic-
pyruvic transaminase (SGPT) 
• 
Alkaline phosphatase 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Total protein 
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Laboratory Tests 
Parameters 
Routine 
urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, 
leukocyte esterase] by dipstick 
• 
Microscopic examination. Please note, this will only be performed if there 
is an abnormality in accordance with Clinical Laboratory standard 
procedures. 
• 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy 
testing 
• 
Highly sensitive serum hCG pregnancy test. 
Other screening 
tests 
• 
FSH and estradiol. 
• 
Cotinine, alcohol, and drug screen (to include at minimum: amphetamines 
[including XTC], methadone, barbiturates, cocaine, opiates, cannabinoids 
and benzodiazepines) 
• 
Serology [(HIV antibody 1/2 antibody test, hepatitis B surface antigen 
[HBsAg], and hepatitis C virus antibody)] 
• 
PCR testing for SARS-CoV-2 may be performed at the discretion of the 
physician and based on local guidelines. 
NOTES 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up are given in Section [7.1.1 Liver 
Chemistry Stopping Criteria] and Section10.5: Liver Safety: Suggested Actions and Follow-up Assessments [and 
Study Intervention Rechallenge Guidelines]]. All events of ALT [or AST] ≥3 × upper limit of normal (ULN) and total 
bilirubin ≥2 × ULN (> 35% direct bilirubin) or ALT [or AST] ≥3 × ULN and international normalized ratio (INR) 
> 1.5 (if INR measured), which may indicate severe liver injury (possible Hy’s law), must be reported to [sponsor] 
in 24 hours (excluding studies of hepatic impairment or cirrhosis). 
* To assess the kidney function, use eGFR 2021 calculator (CKD-Epi creatinine equation). eGFR (based on CKD-Epi) 
will be measured at all time points when creatinine is measured.  
** Blood sampling for serum potassium and glucose on each dosing day (Day 1, 4, 7 and 10) and at the following time 
points: predose and 15 and 30 minutes, 1, 1.5, 2 and 4 hours post dose. 
 

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10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting 
10.3.1. 
Definition of AE 
AE definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
• 
NOTE: 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 a study intervention. 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
Events that occur as a result of protocol-mandated procedures (i.e., invasive 
procedures, modification of participant’s previous therapeutic regimen). 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
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• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. Pre-existing 
diseases will be recorded in the medical history section of the eCRF. 
• 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before signing the informed consent) that did not worsen from baseline. 
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. 
Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study participant 
f. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) 
g. Is a suspected transmission of any infectious agent via an authorized medicinal 
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h. Other situations: 
• 
Possible Hy’s Law case: ALT ≥3x ULN AND total bilirubin ≥ 2x ULN (>35% 
direct bilirubin) or INR >1.5 must be reported as SAE 
• 
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
− Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
10.3.3. 
Definition of TEAE 
TEAE Definition: 
• 
A TEAE is an event that emerges during treatment, having been absent pre-
treatment or worsens relative to the pre-treatment state. 
10.3.4. 
Recording, assessment and follow-up of AE, SAE, and 
pregnancies  
10.3.4.1. 
AE and SAE recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE information. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the required form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
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. 
10.3.4.2. 
Assessment of intensity 
The investigator will make an assessment of intensity for each AE, SAE and device 
deficiency reported during the study and assign it to one of the following categories:  
• 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 

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therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
• 
Moderate:  
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
• 
Severe:  
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.  
10.3.4.3. 
Assessment of causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency. The investigator will use 
clinical judgment to determine the relationship. 
• 
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. 
• 
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. 
• 
For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
• 
The investigator must review and provide an assessment of causality for each 
AE/SAE and document this in the medical notes There may be situations in which an 
SAE has occurred and the investigator has minimal information to include in the 
initial report to GSK. However, it is very important that the investigator always 
makes an assessment of causality for every event before the initial transmission of 
the SAE data to GSK. 
• 
The investigator may change their 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. 
10.3.4.4. 
Assessment of outcomes 
The investigator will assess the outcome of all serious and non-serious unsolicited AEs 
recorded during the study as: 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 

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• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only). 
10.3.4.5. 
Follow-up of AEs, SAEs, pregnancies or any other events of interest  
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any postmortem findings 
including histopathology. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
After the initial AE/SAE/pregnancy or any other event of interest, the investigator is 
required to proactively follow each participant at subsequent visits/contacts. All SAEs, 
will be followed until the event is resolved, stabilized, otherwise explained, or the 
participant is lost to follow-up. 
Other non-serious AEs must be followed until the participant is lost to follow-up. 
Follow-up during the study 
AEs documented at a previous visit/contact and defined as not recovered/not resolved or 
recovering/resolving will be reviewed at subsequent visits/contacts until follow-up visit 
or until the participant is lost to follow-up. 
If a participant dies during their participation in the study or during a recognized follow-
up period, GSK will be provided with any available postmortem findings, including 
histopathology. 
Follow-up of pregnancies 
Pregnant participants will be followed to determine the outcome of the pregnancy. At the 
end of the pregnancy, whether full-term or premature, information on the status of the 
mother and child will be forwarded to GSK using the paper pregnancy follow-up report 
and the AE Report if applicable. Generally, the follow-up period does not need to be 
longer than 6 to 8 weeks after the estimated date of delivery. 
Regardless of the reporting period for SAEs in this study, if the pregnancy outcome is an 
SAE, it should always be reported as such. 
Furthermore, the investigator must report any SAE occurring as a result of a poststudy 
pregnancy that is considered by the investigator to be reasonably related to the study 
intervention, to GSK as described in the Section 10.3.4.7. 

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10.3.4.6. 
Updating of SAE and pregnancy information after removal of write 
access to the participant’s eCRF 
When additional SAE or pregnancy information is received after write access to the 
participant’s eCRF is removed, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be sent to the Study contact for reporting SAEs (refer to 
Section 8.4.1). 
10.3.4.7. 
Reporting of SAEs and pregnancies  
SAE Reporting to GSK via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor by telephone. 
• 
If the site during the course of the study or poststudy becomes aware of any serious, 
non-serious AEs, pregnancy exposure, related to any GSK non-IMP they will report 
these events to GSK or to the concerned CA via the national spontaneous reporting 
system. These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in Section 8.4.9. 
SAE Reporting to GSK via Paper Data Collection Tool 
• 
Email/facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor. 
• 
In rare circumstances and in the absence of email/facsimile equipment, notification 
by telephone is acceptable with a copy of the SAE 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 data collection tool within the designated reporting 
timeframes. 
• 
Contacts for SAE reporting can be found in Section 8.4.9. 

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10.4. 
Appendix 4: Contraceptive and barrier guidance 
10.4.1. 
Definitions 
10.4.1.1. 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Adolescents of childbearing potential: Tanner stage ≥2 (post-thelarche) irrespective 
of the occurrence of menarche or following menarche. 
2. From the time of menarche until becoming postmenopausal unless permanently 
sterile (see below) 
Note: Menarche is the first onset of menses in a young female. Menarche is normally 
preceded by several changes associated with puberty including breast development and 
pubic hair growth.  
10.4.1.2. 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
1. Premenarchal: Tanner stage 1 (prepubertal) 
2. Permanently sterile due to one of the following procedures: 
a. 
Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. 
Documented bilateral oophorectomy 
For permanently sterile individuals due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry. If reproductive 
status is questionable, additional evaluation should be considered. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• 
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception HRT. However, in 
the absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement threshold if required (>40 IU/L or mIU/mL) or remove to allow for 
flexibility with different local thresholds for defining postmenopausal state is 
required. 

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• 
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception guidance 
Female participants of childbearing potential with fertile male partners must use one of 
the following contraceptive methods from at least 4 weeks prior to first study intervention 
until 48 hours postdose of last study intervention. 
• 
Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception. 
• 
Use of a highly effective contraceptive (see list below) plus partner use of a condom. 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of 
<1% per year when used consistently and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS)c 
Bilateral tubal occlusion/ligation 
Azoospermic partner (vasectomized or due to a medical cause) 
• 
Azoospermia is a highly effective contraceptive method provided that the partner 
is the sole sexual partner of the woman of childbearing potential and the absence 
of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. 
• 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per 
year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 

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Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
Sexual abstinence 
• 
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
a. Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for those participating in clinical 
studies. 
a. Failure rate of <1% per year when used consistently and correctly. Typical use 
failure rates differ from those when used consistently and correctly. 
b. Male condoms must be used in addition to hormonal contraception. If locally 
required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive methods are limited to those which inhibit ovulation as 
the primary mode of action. 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method (LAM) are not acceptable methods of contraception. Male condom and 
female condom should not be used together (due to risk of failure from friction) 
 

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10.5. 
Appendix 5: Liver safety: suggested actions and follow-up 
assessments  
Phase 1 Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology. 
Phase 1 Liver Chemistry Stopping Criteria and Required Follow-Up Assessments 
Liver Chemistry Stopping Criteria  
ALT-absolute 
 
ALT≥3xULN 
If ALT≥3xULN AND total bilirubin2xULN (>35% direct bilirubin) or 
international normalized ratio (INR) >1.5, report as an SAE1,2. 
 
Required Actions, Monitoring and Follow-up Assessments  
Actions 
Follow-Up Assessments 
• 
Immediately discontinue study intervention 
• 
Report the event to GSK within 24 hours 
• 
Complete the liver event form and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAE2 
• 
Perform liver event follow-up assessments 
as described in the Follow-Up Assessment 
column 
• 
Do not restart or rechallenge participant with 
study intervention 
• 
Monitor the participant until liver 
chemistries resolve, stabilize, or return to 
within baseline (see MONITORING) 
MONITORING: 
If ALT≥3xULN AND total bilirubin  2xULN 
or INR >1.5: 
• 
Viral hepatitis serology3 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
aminotransferases values show 
downward trend 
• 
Obtain blood sample for pharmacokinetic 
(PK) analysis, within 72 hours of 
identified liver event4 
• 
Obtain serum CPK and LDH, GGT, 
glutamate dehydrogenase (GLDH) and 
serum albumin. 
• 
Fractionate bilirubin if total bilirubin 
2xULN 
• 
Obtain complete blood count with 
differential to assess eosinophilia 
• 
Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the liver event form 
• 
Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, recreational drugs, and other 
over-the-counter medications 
• 
Record alcohol use on the liver event 
alcohol intake form 
If ALT≥3xULN AND total bilirubin 2xULN 

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Liver Chemistry Stopping Criteria  
• 
Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, total bilirubin and INR) and 
perform liver event follow-up assessments 
within 24 hours 
• 
Monitor participant twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• 
A specialist or hepatology consultation is 
recommended 
If ALT≥3xULN AND total bilirubin < 2xULN 
and INR ≤1.5: 
• 
Perform liver chemistries (include ALT, 
AST, alkaline phosphatase, total bilirubin 
and INR) and perform liver event follow-up 
assessments within 24-72 hours 
• 
Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
or INR >1.5 obtain the following in addition 
to the assessments listed above: 
• 
Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins 
• 
Liver imaging (ultrasound, magnetic 
resonance, or computed tomography) 
and /or liver biopsy to evaluate liver 
disease, complete Liver Imaging form. 
• 
Liver biopsy may be considered and 
discussed with local specialists if 
available, for instance: 
− In participants when serology raises 
the possibility of autoimmune hepatitis 
(AIH) 
− In participants when suspected DILI 
progresses or fails to resolve on 
withdrawal of study intervention 
− In participants with acute or chronic 
atypical presentation. 
• 
If liver biopsy is conducted, then 
complete liver biopsy form 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is 
unavailable, record the absence/presence of detectable urinary bilirubin on dipstick, which is indicative of direct 
bilirubin elevations suggesting liver injury.  
2. 
All events of ALT 3xULN and total bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR >1.5, which may 
indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE, the INR threshold value stated will 
not apply to participants receiving anticoagulants. 
3. 
Includes: hepatitis A immunoglobulin (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing) 
and hepatitis E IgM antibody  
4. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
PK blood sample draw. If the date or time of the last dose is unclear, provide the participant’s best approximation. 
If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period 
indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the lab manual. 

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10.6. 
Appendix 6: Medical device AEs, ADEs, SAEs, sADEs, 
USADEs and device deficiencies: Definitions and 
procedures for recording, evaluating, follow-up, and 
reporting in medical device studies 
• 
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 6.1.1 for the list 
of sponsor medical devices. 
10.6.1. 
Definition of medical device AE and ADE 
Medical device AE and ADE definition  
• 
A medical device AE is any untoward medical occurrence, in a clinical study 
participant, 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 except for events in 
users or other persons, which only include events related to investigational 
devices. 
• 
An 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 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. 
10.6.2. 
Definition of medical device SAE, SADE and USADE 
A Medical Device SAE is any serious AEs that: 
a. 
Led to death  
b. Led to serious deterioration in the health of the participant, 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 participant 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. 
• 
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. 

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• 
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). 
c. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
SADE definition 
• 
A SADE is defined as an ADE that has resulted in any of the consequences 
characteristic of an SAE. 
• 
Any 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. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is 
defined as a serious ADE that by its nature, incidence, severity or outcome has not 
been identified in the current version of the risk analysis report. (see Section 2.3). 
10.6.3. 
Definition of device deficiency 
Device deficiency definition 
• 
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequacy of the information supplied by 
the manufacturer. 
10.6.4. 
Recording and follow-up of medical device AE and/or SAE and 
device deficiencies 
10.6.4.1. 
Medical device AE, SAE, and device deficiency recording 
• 
When an AE/SAE/device deficiency occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE/device deficiency information 
in the participant’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 participant’s 
medical records to GSK in lieu of completion of the AE/SAE/device deficiency 
form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 

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• 
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 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 device 
deficiency. This includes any amendment to the device design to prevent 
recurrence. 
• 
If the site during the course of the study becomes aware of any serious, non-serious 
incident (including device deficiencies and malfunctions) related to any GSK non-
IMP product they will report these events to GSK or to the concerned CA via the 
national spontaneous reporting system. These will be classified as spontaneous 
ICSRs. 
10.6.4.2. 
Assessment of intensity 
Refer to Section 10.3.4.2 
10.6.4.3. 
Assessment of causality 
Refer to Section 10.3.4.3 
10.6.4.4. 
Follow-up of medical device AE/SAE and 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 GSK to 
elucidate the nature and/or causality of the AE/SAE/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 participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK 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 GSK within 24 hours of 
receipt of the information. 
10.6.5. 
Reporting of medical device SAEs 
Medical Device SAE Reporting to GSK via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next table) to report the event within 24 hours. 

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• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form or to the 
medical monitor by telephone. 
• If the site during the course of the study or poststudy becomes aware of any serious, 
non-serious AEs, pregnancy exposure, related to any GSK device they will report 
these events to GSK or to the concerned CA via the national spontaneous reporting 
system. These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in Section 8.4.9. 
Medical Device SAE Reporting to GSK via Paper Data Collection Tool 
• 
Email/Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor. 
• 
In rare circumstances and in the absence of email/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 Section 8.4.9. 
10.6.6. 
Reporting of SADEs 
SADE Reporting to GSK 
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 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 device deficiency. 
• 
The sponsor will review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These 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 Section 8.4.9. 

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10.6.7. 
Reporting of medical device deficiencies for associated person 
• 
Reporting to GSK  
If an Associated Person (i.e., e.g., spouse, caregiver, site staff) experiences a device 
deficiency, the medical device deficiency information, and any associated AE/SAE 
information will be reported to GSK. The associated person will be provided with the 
authorization to contact physician letter.  
If follow-up information is required, authorization to contact physician (or other 
licensed medical practitioner) must be signed to obtain consent. 
• 
Medical device deficiencies that are not related to an AE or SAE should be 
reported via email to gsk-rd.complaints@gsk.com, using the medical device 
deficiency report form.  
• 
If the medical device deficiency is related to a non-serious AE and not linked to an 
SAE, please send the medical device deficiency report form with details of the 
associated AE via email to gsk-rd.complaints@gsk.com only. 
• 
If the device incident is linked to an SAE, please email the medical device 
deficiency report form, within 24 hours. Refer to Section 8.4.9 for reporting.  
• 
GSK will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported 
to the regulatory authorities and IRBs/IECs as required by national regulations. 
10.7. 
Appendix 7: Standard Error (SE) Calculation for 2x2x4 Full 
Replicate Design 
CCI

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10.8. 
Appendix 8: Reference-Scaled Acceptance Range Limit 
10.9. 
Appendix 9: Protocol amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment 
is located directly before the TOC. 
Amendment [1] 
Overall rationale for the Amendment 
The objective of this amendment is to align the time period for collecting pregnancy 
information for female participants with the time period for post-intervention 
contraception. In addition, parameter specifications for microscopic evaluation have been 
removed. 
CCI

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11. 
REFERENCES 
GINA 
2023: 
https://ginasthma.org/wp-content/uploads/2023/07/GINA-Main-Report-
2023-FINAL-22-07-01-WMS.pdf. 
GlaxoSmithKline UK. VENTOLIN EVOHALER, Summary of Product Characteristics 
2023, from emc: https://www.medicines.org.uk/emc/product/850/smpc#about-medicine 
Graham BL, Steenbruggen I, Miller MR, et.al. Standardization of spirometry 2019 update. 
An official American thoracic society and European respiratory society technical 
statement. AJRCCM. 2019 Oct 15;200(8):e70-88. 

Signature Page for  219728 TMF-19365570 v1.0
Signature Page for TMF-19365570 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 02-May-2024 15:40:08 GMT+0000
PPD