A Randomized, Double-blind, Single-site, Two-way Crossover Phase 1 Study to Assess the Effect of Repeated Doses of Test Propellant (HFA-152a) on Mucociliary Clearance as Compared to Reference Propellant (HFA-134a) in Healthy Male and Female Participants
Phase: PHASE1
Conditions: Asthma
Sponsor: GlaxoSmithKline

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1 
 
CLINICAL STUDY PROTOCOL 
Primary Study 
Intervention(s) 
HFA-152a (1 – Difluoroethane) and HFA-134A 
(1,1,1,2 – Tetrafluoroethane) 1 – Difluoroethane and 
1,1,1,2 – Tetrafluoroethane 
Other Study Intervention(s) 
NA 
Study Identifier 
221781 
Approval Date 
14 May 2024 
Title 
A randomized, double-blind, single-site, two-way 
crossover Phase 1 study to assess the effect of 
repeated doses of Test propellant (HFA-152a) on 
mucociliary clearance as compared to Reference 
propellant (HFA-134a) in healthy male and female 
participants 
Compound Number/Name 
AH3365 - Salbutamol 
Brief title 
Study of the effect of HFA-152a and HFA-134a 
propellants on mucociliary clearance in healthy 
participants 
Acronym 
NA 
Sponsor 
GlaxoSmithKline Research & Development Limited 
980 Great West Road, Brentford, Middlesex, TW8 
9GS, UK 
Sponsor signatory 
Oscar Della Pasqua 
Executive Director, Head Clinical Pharmacology 
Lifecyle Management 
Medical monitor name and contact can be found in local study contact 
information document. 
©2024. GSK group of companies or its licensor. Trademarks are property of their 
respective owners. 

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Protocol Investigator Agreement 
• 
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 clinical study site agreement. 
• 
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 cooperate 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. 

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Study identifier 
221781 
Approval date 
14 May 2024 
 
 
Title 
A randomized, double-blind, single-site, two-way 
crossover Phase 1 study to assess the effect of 
repeated doses of Test propellant (HFA-152a) on 
mucociliary clearance as compared to Reference 
propellant (HFA-134a) in healthy male and female 
participants 
Investigator name 
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 
 
 

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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 10 
1. 
PROTOCOL SUMMARY ........................................................................................ 16 
1.1. 
Synopsis ..................................................................................................... 16 
1.2. 
Study Schema ............................................................................................ 17 
1.3. 
Schedule of Activities (SoA) ........................................................................ 17 
2. 
INTRODUCTION .................................................................................................... 21 
2.1. 
Background and Study Rationale ................................................................ 21 
2.2. 
Benefit/Risk Assessment ............................................................................ 22 
2.2.1. 
Risk Assessment ......................................................................... 22 
2.2.2. 
Benefit Assessment ..................................................................... 25 
2.2.3. 
Overall Benefit-Risk Conclusion ................................................... 25 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 26 
4. 
STUDY DESIGN .................................................................................................... 28 
4.1. 
Overall Design ............................................................................................ 28 
4.2. 
Scientific Rationale for Study Design .......................................................... 29 
4.2.1. 
Participant Input to the Design ..................................................... 30 
4.3. 
Justification for Dose and Duration of the Treatment .................................. 30 
4.4. 
End-of-Study Definition ............................................................................... 30 
5. 
STUDY POPULATION ........................................................................................... 31 
5.1. 
Inclusion Criteria ......................................................................................... 31 
5.2. 
Exclusion Criteria ........................................................................................ 32 
5.3. 
Randomization criteria ................................................................................ 34 
5.4. 
Lifestyle Considerations .............................................................................. 35 
5.4.1. 
Meals and Dietary Restrictions .................................................... 35 
5.4.2. 
Caffeine Alcohol and tobacco ...................................................... 35 
5.4.3. 
Exercise ....................................................................................... 35 
5.4.4. 
Other Restrictions ........................................................................ 36 
5.5. 
Screen Failures........................................................................................... 36 
5.6. 
Criteria for Temporarily Delaying Administration of Study 
Intervention ................................................................................................. 36 
6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY ................................ 37 
6.1. 
Study Intervention Administered ................................................................. 37 
6.1.1. 
Medical Devices ........................................................................... 37 
6.2. 
Preparation, Handling, Storage, and Accountability .................................... 38 
6.3. 
Assignment to Study Intervention ............................................................... 38 
6.4. 
Blinding ....................................................................................................... 39 
6.5. 
Study Intervention Compliance ................................................................... 40 
6.6. 
Dose Modifications ..................................................................................... 40 
6.7. 
Continued Access to Study Intervention after the End of the Study ............ 40 
6.8. 
Treatment of Overdose ............................................................................... 40 
6.9. 
Prior and Concomitant Medications ............................................................ 40 

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7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 41 
7.1. 
Discontinuation of Study Intervention .......................................................... 41 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 42 
7.1.2. 
QTc Stopping Criteria .................................................................. 42 
7.1.3. 
Bronchospasm Stopping Criteria ................................................. 43 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 43 
7.3. 
Lost to Follow-up ........................................................................................ 44 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 45 
8.1. 
Administrative Procedures .......................................................................... 46 
8.1.1. 
Collection of Demographic Data .................................................. 46 
8.1.2. 
Medical and Vaccination History .................................................. 46 
8.2. 
Efficacy and/or Immunogenicity Assessments ............................................ 46 
8.2.1. 
Inhaler training ............................................................................. 46 
8.3. 
Safety Assessments ................................................................................... 46 
8.3.1. 
Physical Examinations ................................................................. 46 
8.3.2. 
Vital Signs .................................................................................... 46 
8.3.3. 
Electrocardiograms ...................................................................... 47 
8.3.4. 
Spirometry ................................................................................... 47 
8.3.5. 
Clinical Safety Laboratory Tests .................................................. 47 
8.3.6. 
Pregnancy Testing ....................................................................... 48 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting ......................................................................................... 48 
8.4.1. 
Follow-up of AEs and SAEs ......................................................... 48 
8.4.2. 
Time period and frequency for collecting AE, SAE, and 
other safety information ............................................................... 48 
8.4.3. 
Method of detecting AEs and SAEs ............................................. 49 
8.4.4. 
Adverse event of special interests ............................................... 49 
8.4.5. 
Regulatory reporting requirements for SAEs ................................ 49 
8.4.6. 
Pregnancy ................................................................................... 50 
8.4.7. 
Cardiovascular and Death Events ................................................ 50 
8.4.8. 
Disease-related events and/or disease-related outcomes 
not qualifying as AEs or SAEs ..................................................... 51 
8.4.9. 
Contact information for reporting SAEs and pregnancies ............. 51 
8.4.10. 
Participant Card ........................................................................... 51 
8.4.11. 
Medical device deficiencies ......................................................... 51 
8.4.11.1. Time Period for Detecting Medical Device 
Deficiencies ................................................................ 52 
8.4.11.2. Follow-up of Medical Device Deficiencies ................... 52 
8.4.11.3. Prompt Reporting of Device Deficiencies to the 
Sponsor ...................................................................... 52 
8.4.11.4. Regulatory Reporting Requirements for Device 
Deficiencies ................................................................ 52 
8.5. 
Pharmacokinetics ....................................................................................... 52 
8.6. 
Pharmacodynamics .................................................................................... 53 
8.7. 
Imaging Assessments ................................................................................. 53 
8.7.1. 
Assessment of MCC using nebulized 99mTc and 
scintigraphy Assessments ........................................................... 53 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 54 
9.1. 
Statistical Hypotheses................................................................................. 54 

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9.1.1. 
Multiplicity adjustment .................................................................. 54 
9.2. 
Analysis Sets .............................................................................................. 54 
9.3. 
Statistical Analyses ..................................................................................... 55 
9.3.1. 
General considerations ................................................................ 55 
9.3.1.1. 
Definition of MCC endpoints ....................................... 55 
9.3.1.2. 
Main Analytical Approach ........................................... 56 
9.3.1.3. 
Sensitivity Analysis ..................................................... 56 
9.3.1.4. 
Supplementary/supportive Analysis ............................ 56 
9.3.1.5. 
Secondary Endpoints Analyses .................................. 56 
9.3.1.6. 
Sensitivity Analysis for secondary endpoint ................ 57 
9.3.2. 
Safety Analysis ............................................................................ 57 
9.3.2.1. 
Adverse Events .......................................................... 57 
9.3.2.2. 
Clinical Laboratory ...................................................... 58 
9.3.2.3. 
Vital signs and ECG ................................................... 58 
9.4. 
Interim Analyses ......................................................................................... 58 
9.5. 
Sample Size Determination ........................................................................ 58 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 61 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 61 
10.1.1. 
Regulatory and ethical considerations ......................................... 61 
10.1.2. 
Financial disclosure ..................................................................... 62 
10.1.3. 
Informed consent process ............................................................ 62 
10.1.4. 
Recruitment strategy .................................................................... 62 
10.1.5. 
Data protection ............................................................................ 63 
10.1.6. 
Committees structure ................................................................... 63 
10.1.7. 
Dissemination of Clinical Study Data ........................................... 63 
10.1.8. 
Data quality assurance ................................................................ 64 
10.1.9. 
Source documents ....................................................................... 65 
10.1.10. Study and site start and closure ................................................... 65 
10.1.11. Publication policy ......................................................................... 66 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 66 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 68 
10.3.1. 
Definition of AE ............................................................................ 68 
10.3.2. 
Definition of SAE .......................................................................... 69 
10.3.3. 
Definition of Cardiovascular events .............................................. 70 
10.3.4. 
Definition of TEAE ....................................................................... 70 
10.3.5. 
Recording, assessment and follow-up of AE, SAE, and 
pregnancies ................................................................................. 70 
10.3.5.1. AE and SAE recording ................................................ 70 
10.3.5.2. Assessment of intensity .............................................. 71 
10.3.5.3. Assessment of causality ............................................. 71 
10.3.5.4. Assessment of outcomes............................................ 72 
10.3.5.5. Follow-up of AEs, SAEs, pregnancies or any 
other events of interest ............................................... 72 
10.3.5.6. Updating of SAE and pregnancy information 
after removal of write access to the 
participant’s eCRF ...................................................... 73 
10.3.5.7. Reporting of SAEs and pregnancies ........................... 73 
10.4. 
Appendix 4: Contraceptive and barrier guidance ......................................... 74 
10.4.1. 
Definitions .................................................................................... 74 

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10.4.1.1. Woman of Childbearing Potential (WOCBP) ............... 74 
10.4.1.2. Woman of Nonchildbearing Potential 
(WONCBP) ................................................................. 74 
10.4.2. 
Contraception guidance ............................................................... 75 
10.5. 
Appendix 5: Genetics .................................................................................. 76 
10.6. 
Appendix 6: Liver safety: suggested actions and follow-up 
assessments ............................................................................................... 76 
10.7. 
Appendix 7: Medical device AEs, ADEs, SAEs, sADEs, USADEs 
and device deficiencies: Definitions and procedures for recording, 
evaluating, follow-up, and reporting in medical device studies .................... 78 
10.7.1. 
Definition of medical device AE and ADE..................................... 78 
10.7.2. 
Definition of medical device SAE, SADE and USADE .................. 79 
10.7.3. 
Definition of device deficiency ...................................................... 80 
10.7.4. 
Recording and follow-up of medical device AE and/or SAE 
and device deficiencies ................................................................ 80 
10.7.4.1. Medical device AE, SAE, and device deficiency 
recording .................................................................... 80 
10.7.4.2. Assessment of intensity .............................................. 80 
10.7.4.3. Assessment of causality ............................................. 81 
10.7.4.4. Follow-up of medical device AE/SAE and 
device deficiency ........................................................ 81 
10.7.5. 
Reporting of medical device SAEs ............................................... 81 
10.7.6. 
Reporting of SADEs ..................................................................... 82 
10.7.7. 
Reporting of medical device deficiencies for associated 
person ......................................................................................... 82 
10.8. 
Appendix 8: Country-specific requirements ................................................. 83 
10.9. 
Appendix 9. Risk Assessment for Gamma Scintigraphy Studies 
using nebulized 99mTc ................................................................................. 83 
11. REFERENCES ....................................................................................................... 85 
 

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LIST OF TABLES 
PAGE 
Table 1 
Schedule of Activities ............................................................................. 18 
Table 2 
Summary of Potential Risks of Clinical Significance ............................... 23 
Table 3 
Objectives and endpoints ....................................................................... 26 
Table 4 
Study Intervention Administered ............................................................. 37 
Table 5 
Timeframes for submitting SAE, pregnancy and other events 
reports to GSK ....................................................................................... 50 
Table 6 
Contact information for reporting SAEs and pregnancies ....................... 51 
Table 7 
Half-width Expected for Different Sample Size and Intra-Subjects 
Variability ............................................................................................... 59 
Table 8 
Lower and Upper Bound GMR for Different Values of GMR ................... 60 
Table 9 
Protocol-required safety laboratory tests ................................................ 67 
 

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LIST OF FIGURES 
Figure 1 
Schematic of the Study .......................................................................... 29 
Figure 2 
Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping 
Event Algorithm ...................................................................................... 42 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADE 
Adverse device effect 
AE 
Adverse event 
ALT 
Alanine transaminase 
ARSAC 
Administration of Radioactive Substances Advisory Committee 
AUC 
Area under the curve 
AUC(0-4h) 
Area under the percent radiolabeled particle retention -time curve up 
to 4 hours 
BID 
Bis in die (twice daily) 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus disease 2019 
CSR 
Clinical study report 
CV 
Coefficient of variation 
CVb 
Between-subject coefficient of variation 
CVw 
Within subject coefficient of variation 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ED 
Early discontinuation 
EMA 
European Medicine Agency 
FEV1 
Forced expiratory volume in 1 second 

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Abbreviation 
Definition 
FSFV 
First subject first visit 
FSH 
Follicle stimulating hormone 
FVC 
Forced vital capacity 
GCP 
Good clinical practices 
GM 
Geometric mean 
GMR 
Geometric mean ratio 
GSK 
GlaxoSmithKline 
GWP 
Global Warning Potential 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HFA-134a 
1,1,1,2 – Tetrafluoroethane (Reference propellant) 
HFA-152a  
1 – Difluoroethane (Test propellant) 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HRT 
Hormonal Replacement Therapy 
ICE 
Intercurrent event 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
ICSR 
Individual case safety reports 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
LSLV 
Last subject last visit 

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Abbreviation 
Definition 
MCC 
Mucociliary clearance 
MDI 
Metered dose inhaler 
MDR 
(European) medical device regulation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSDS 
Material Safety Data Sheet 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PR 
Pulse rate 
QT 
QT interval 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected using Fredericia formula 
ROI 
Region of interest 
SADE 
Severe adverse device effect 
SAE 
Severe adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome-corona virus type 2 
SD 
Standard deviation 
SoA 
Schedule of activities 
TEAE 
Treatment-emergent adverse event 
THC 
Tetrahydrocannabinol 
TP 
Treatment period 
ULN 
Upper limit of normal 
USADE 
Unexpected severe adverse device effect 

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Abbreviation 
Definition 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of nonchildbearing potential 
 
Term 
Definition 
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 a double-blind study, the participant, the investigator 
and sponsor staff who are involved in the treatment or 
clinical evaluation of the participants and the review or 
analysis of data are all unaware of the intervention 
assignment. 
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. 
Combination product 
Combination product comprises any combination of  
• 
drug  
• 
device  
• 
biological product  
Each drug, device and biological product included in a 
combination product is a constituent part.  
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. 

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Term 
Definition 
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 
individual or party to perform those study-related duties 
and functions 
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 (vaccine(s)/product(s)/control). 
Synonym: subject 
Participant number 
A unique identification number assigned to each 
participant who consents to participate in the study. 
Primary Completion Date 
The date on which the last participant in a clinical study 
was examined or received an intervention to collect final 
data for the primary outcome measure. 
Whether the clinical study ended according to 
the protocol or was terminated does not affect this date. 
For clinical studies with more than one primary outcome 
measure with different completion dates, this term refers 
to the date on which data collection is completed for all 
the primary outcome measures.  
Randomization 
Process of random attribution of intervention to 
participants to reduce selection bias. 
Self-contained study 
Study with objectives not linked to the data of another 
study. 
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). 
Study completion date 
The date on which the last participant in a clinical study 
was examined or received an intervention/treatment to 

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Term 
Definition 
collect final data for the primary outcome 
measures, secondary outcome measures, and AEs (that 
is, the last participant's last visit or LSLV). 
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 monitor 
An individual assigned by the sponsor and responsible 
for assuring proper conduct of clinical studies at 1 or 
more investigational sites. 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A randomized, double-blind, single-site, two-way crossover Phase 1 
study to assess the effect of repeated doses of Test propellant (HFA-152a) on mucociliary 
clearance as compared to Reference propellant (HFA-134a) in healthy male and female 
participants 
Brief Title: Study of the effect of HFA-152a and HFA-134a propellants on mucociliary 
clearance in healthy participants  
Rationale: A new Ventolin formulation (low carbon Ventolin) is under development, in 
which the 1,1,1,2 – Tetrafluoroethane (HFA-134a) propellant is substituted by 1,1-
Difluoroethane (aka HFA-152a), to reduce the effect on climate change. The purpose of 
this study is to investigate the effect of the new propellant HFA-152a (Test, T) on 
mucociliary clearance (MCC) in comparison to that of the current propellant HFA-134b 
(Reference, R) in healthy participants, as requested by regulatory requirements. Refer to 
Section 2.1. 
Objectives, Endpoints, and Estimands: The primary objective of the study is to assess 
MCC after 7-day administration of HFA-152a (Test) or HFA-134a (Reference) 
propellants to healthy male and female participants. The primary endpoint is the area 
under the percent radiolabeled particle retention-time curve up to 4 hours (AUC[0-4h]) 
after nebulized 99mTc-sulphur colloid inhalation measured on Day 7. For additional 
information on the primary, secondary, and exploratory objectives, endpoints and 
estimands, refer to Section 3. 
Overall Design: This is a randomized, double-blind, single-site, 2-way crossover study 
to investigate the effect of HFA-152a and HFA-134a propellants on MCC in healthy 
participants. Refer to Section 4.1. 
Number of Participants: The study has planned to enrol a total of 24 healthy 
participants to ensure at least 20 participants with at least 10 randomized to each 1 of 2 
treatment sequences (T-R and R-T). Refer to Section 9.5. 
Data Monitoring/Other Committee: Refer to Section 10.1.6. 

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1.2. 
Study Schema 
 
Notes: Training MDI concerns the initial training of the inhalation from MDI (propellants); additional training will be 
provided during the treatment periods. Between Day 1 to Day 6 of Period 1, the ROI encompassing the right 
lung will be defined based on a single 57Co transmission scan of the participant chest. Green triangles represent 
propellant administrations (4 inhalations BID for 6 days + single morning administration on Day 7). Tc Training 
inhalation concerns the training of inhalation of nebulized saline solution (without radiolabeled 99mTc); Yellow 
boxes represent inhalation of the nebulized labelled 99mTc for the assessment of MCC. Abbreviations: BID=twice 
daily, Co=Cobalt, MDI=metered dose inhaler, ROI=region of interest, Tc=Technetium. 
1.3. 
Schedule of Activities (SoA) 
The Schedules of Activities (SoA) are presented in the following Table 1. 

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Table 1 
Schedule of Activities 
Visit 
Screening 
Treatment Period 1 
Washout 
Treatment Period 2 
Follow up 
or early 
withdrawal 
Visit Window 
Day -21 to 
Day-7 
Day -1 
Day 1 to 
Day 6 
Day 7 
Day 8 
7 days ± 2 
days 
Day -1 
Day 1 to 
Day 6 
Day 7 
Day 8 
8 days ± 2 
days after 
last TP 
(discharge) 
Confinementa 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Admission 
 
X 
 
 
 
 
X 
 
 
 
 
Discharge from 
site 
 
 
 
 
X 
 
 
 
 
X 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion 
criteria 
X 
X 
 
 
 
 
X 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Physical 
examinationb 
X 
 
 
 
 
 
 
 
 
 
X 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
Height and BMI 
calculation 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
(includes 
substance 
usage) 
X 
 
 
 
 
 
 
 
 
 
 
Pulmonary 
testsc  
X 
X 
 
 
X 
 
X 
 
 
X 
 
FSH  
X 
 
 
 
 
 
 
 
 
 
 
Serology 
(HBsAg, anti-
HCV, anti-HIV 1 
and 2) 
X 
 
 
 
 
 
 
 
 
 
 

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Visit 
Screening 
Treatment Period 1 
Washout 
Treatment Period 2 
Follow up 
or early 
withdrawal 
Visit Window 
Day -21 to 
Day-7 
Day -1 
Day 1 to 
Day 6 
Day 7 
Day 8 
7 days ± 2 
days 
Day -1 
Day 1 to 
Day 6 
Day 7 
Day 8 
8 days ± 2 
days after 
last TP 
(discharge) 
Drug and 
alcohol screen, 
cotinine test 
X 
X 
 
 
 
 
X 
 
 
 
 
Clinical 
laboratory 
assessmentsd 
X 
 
 
X 
 
 
 
 
X 
 
X 
Vital signse 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
X 
X 
X 
 
 
X 
X 
X 
 
X 
MDI trainingg 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
criteriah 
 
X 
 
 
 
 
X 
 
 
 
 
Administration 
of study 
intervention 
(propellants)i 
 
 
X 
X 
 
 
 
X 
X 
 
 
57Co 
transmission 
scanj  
 
 
X 
 
 
 
 
 
 
 
 
Inhalation 
trainingk (saline 
without 99mTc) 
 
 
 
X 
 
 
 
 
X 
 
 
Nebulized 99mTc 
administration 
and percent 
radiolabeled 
particle 
retention 
measurementsl 
 
 
 
X 
 
 
 
 
X 
 
 

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Visit 
Screening 
Treatment Period 1 
Washout 
Treatment Period 2 
Follow up 
or early 
withdrawal 
Visit Window 
Day -21 to 
Day-7 
Day -1 
Day 1 to 
Day 6 
Day 7 
Day 8 
7 days ± 2 
days 
Day -1 
Day 1 to 
Day 6 
Day 7 
Day 8 
8 days ± 2 
days after 
last TP 
(discharge) 
AE reviewm 
 
 
 
 
 
 
 
 
 
 
 
SAE reviewn 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
review 
X 
X 
X 
X 
 
 
X 
X 
X 
 
X 
a. 
Participants will be in the clinic for 2 periods, from Day -1 until Day 8; they will be discharged from site on Day 8, 24 h after nebulized 99mTc in both TP 1 and TP 2.  
b. 
Complete physical examinations will be conducted at screening and at the follow-up visit. Symptom-driven physical examinations may be conducted on Day -1 and 8 of 
each TP, at follow up, or any other time, per the investigator’s discretion. 
c. 
FVC, FEV1  
d. 
Clinical laboratory assessments (including clinical chemistry, hematology, and urinalysis): at screening, on Day 7 of each TPs, and at discharge. 
e. 
Vital signs (systolic and diastolic blood pressure, and pulse rate): vital signs will be recorded at screening, admission, on each propellant morning dosing day at pre-dose 
and at the following time point post-dose:  20±10 min post-dose, 24 hours post last dose in each period and at  follow up visit. Participants will be discharged by the 
investigator based on normal vitals, or in case of abnormal values judged to be not clinically significant and not representing a safety concern. 
f. 
12-lead ECG: 12-lead ECG will be recorded as single assessments at screening, admission, on each morning dosing day of each TP at pre-dose, and at the following time 
points post-dose: 20±10 min post-dose, and at follow up. Participants will be discharged from the study by the investigator based on normal ECG or in case of abnormal 
values judged to be not clinically significant and not representing a safety concern. In case of QT abnormalities, ECGs will be repeated in triplicate assessments.  
g. 
Inhaler Training will be performed at screening, at least 7 days before the start of the multiple dosing, and again during the mornings of Day 1 to Day 7 of each treatment 
period. Once the participant is comfortable with using the training device, practice completing a sequence of 8 puffs. Provide feedback as necessary until proper technique 
is observed before conducting the full dose administration using the investigational inhaler. 
h. 
At the start of treatment period 1 and 2, the randomization criteria (aka treatment period criteria) (see section 5.3) should be reviewed to ensure no changes in participant’s 
health status. Please see section 5.3 for further details  
i. 
Propellants will be given 4 actuations BID (morning and evening, 12±3 hours apart) by oral inhalation using MDI. Note: Propellant devices need to be primed before use. 
j. 
Single transmission scan of the chest using 57Co. 
k. 
Training to nebulized 99mTc inhalation: Participants will be trained to nebulized 99mTc inhalation by using saline inhalation (without 99mTc) on Day 7 of each TP, before 
propellant dosing.  
l. 
Administration of nebulized 99mTc inhalation given 30±10 min after the last propellant intake. Measurement of retained radioactivity will be performed immediately after 
nebulized 99mTc administration (scintigraphic time=”0”) and then at 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min after nebulized 99mTc administration. 
m. All AEs will be collected from the start of study intervention until final discharge from the study (including washout period). All SAEs will be collected from the signing of the 
Informed consent form (ICF) until final discharge from the study (including washout period). 
 

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2. 
INTRODUCTION 
2.1. 
Background and Study Rationale 
Ventolin (aka salbutamol, albuterol) is a beta2-adrenergic receptor agonist providing 
short-acting (4 to 6 hour) bronchodilation with fast onset (within 5 minutes) in reversible 
airways obstruction. It is indicated in the treatment or prevention of bronchospasm in 
chronic conditions such as asthma and COPD and in the prevention of exercise-induced 
bronchospasm [Ventolin, 2021]. Ventolin is frequently administered via an MDI 
currently formulated with hydrofluorocarbon 1,1,1,2 – Tetrafluoroethane (aka HFA-
134a) as propellant. This propellant agent is characterized by a large GWP, being 
responsible for trapping solar heat in the atmosphere, thus contributing to climate change. 
To reduce this impact, GSK is developing a new Ventolin formulation (low carbon 
Ventolin), in which the HFA-134a propellant is substituted by 1,1-Difluoroethane (aka 
HFA-152a). HFA-152a is characterized by a >10-fold lower GWP compared to HFA-
134b. The new propellant is also characterized by shorter atmospheric life (1.4 years vs. 
14 years), which further reduces its potential effect on climate change. 
 
 
 
 
To assure that these changes are not leading to potential modifications of Ventolin 
clinical efficacy or safety and tolerability characteristics, a development program was 
planned, incorporating in vitro and in vivo assessments. In particular, following the 
publication of the relevant guidance from EMA [EMA, 2009; Lee, 2009; Lu, 2015; 
EMA, 2017; EMA, 2023] comparative studies aiming at assessing relative 
bioavailability, similar PD effects (methacholine challenge), and long-term safety of the 
2 formulations (Test=HFA-152a and Reference=HFA-134b) are being implemented. 
The available guidance, related to the requirements for clinical documentation for orally 
inhaled products, also indicate the need to assess the effect of the new propellant on MCC 
[EMA, 2009], which was specifically required by EMA for low carbon Ventolin. MCC is 
an innate host defence mechanisms freeing up the airways from dust, bacteria, and other 
irritants [Munkholm, 2014; Bustamante-Marin, 2017]. This MCC assessment can 
therefore be considered part of the safety and tolerability characterization of the 
propellant and, in turn of the new Ventolin formulation. The fact that MCC after the 
exposure to the new Test propellant is similar to that observed after the Reference 
propellant, which has been in clinical use for many years, would provide additional 
confidence on the safety and tolerability characterization of the new Ventolin 
formulation. 
The purpose of this study is to investigate the effect of the new propellant HFA-152a 
(Test) on MCC in comparison to that of the current propellant HFA-134b (Reference) in 
healthy male and female participants using the percent radiolabeled particle retention 
following inhalation of a radiolabeled compound (colloidal 99mTc sulphur) after a short 
repeated exposure to the Test and Reference propellants [Bennett, 2015; Bennett, 2013; 
Bennett, 2022]. 
CCI
CCI
CCI
CCI

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2.2. 
Benefit/Risk Assessment 
More detailed information about the known risks and reasonably expected AEs on used 
propellants may be found in the corresponding MSDS. 
2.2.1. 
Risk Assessment 
Ventolin formulated with the Reference propellant, has been on the market for many 
years and, thus, has a well characterized tolerability profile. The change in propellant 
from HFA-134a to HFA-152a is supported by a nonclinical toxicology program for 
HFA-152a conducted by the propellant manufacturer in accordance with ICH guidelines. 
In human exposure studies, HFA-152a was well tolerated, and was rapidly cleared from 
the blood [Kuehl, 2022]. The Sponsor’s assessment of known and potential risks of this 
study are summarized in Table 2. Concerning exposure to radiolabeled compounds, see 
Section 10.9. 
99mTc sulphur colloid injection is marketed in the USA for intravenous, subcutaneous, 
intraperitoneal and oral administration for imaging studies. Full details on adverse 
reactions using the approved routes of administration can be found in the prescribing 
information for 99mTc sulphur colloid injection. The most frequently reported adverse 
reactions, across all categories of use and routes of administration, include rash, allergic 
reaction, urticaria, anaphylaxis/anaphylactic shock, and hypotension. Less frequently 
reported adverse reactions are fatal cardiopulmonary arrest, seizures, dyspnea, 
bronchospasm, abdominal pain, flushing, nausea, vomiting, itching, fever, chills, 
perspiration, numbness, and dizziness. Local injection site reactions, , have also been 
reported.  
99mTc sulphur colloid injection can be used to identify pulmonary aspiration, therefore 
although it is not licensed to be administered into the lungs, this route is known to be 
tolerated. Additionally, the use of inhaled 99mTc sulphur colloid in 0.9% sodium chloride 
to assess lung MCC has been safely performed in clinical studies since the 1980s 
[Bennett, 2015]. 
 

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Table 2 
Summary of Potential Risks of Clinical Significance 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study intervention [Test and Reference propellants and radiolabeled compound] 
Local respiratory 
irritation 
The risk would be that the Test propellant has a local tolerability 
profile different from that of the Reference propellant, which has 
been on the market for many years and, thus, has a well-known 
tolerability profile.  
During the clinical conduct, close monitoring of all participants according to 
the Schedule of Assessment will be performed to evaluate the occurrence 
and severity of any local irritation and actions taken according to the 
protocol and stopping criteria if breached.  
No local respiratory irritation was observed in a pilot PK study of the new 
formulation of Ventolin and other studies evaluating HFA-152a have found 
the propellant to be well tolerated by study participants. 
Risks related to 
exposure to 
radiolabelled 
99mTc and 57Co 
The risk would be that the amount of radioactivity carries a risk 
of later developing serious and possibly fatal conditions.  
Over both administrations, the estimated radiation dose that each 
participant will receive is 1.22 mSv defined using the principle of “as low as 
reasonably practicable. If repeat transmission scans (up to 2) are required, 
the maximum possible radiation dose that each participant will receive is 
1.42 mSv. While any increase in the amount of radiation that is received 
above natural radiation carries a risk of later developing serious and 
possibly fatal conditions, the risk associated with the maximum possible 
dose of radiation in this study is very small indeed and is considered to be 
acceptable. 
Extrapolation from epidemiological studies indicated that the lifetime risk of 
inducing a fatal cancer in a healthy individual from the total exposure of 
1.0 mSv is approximately 1 in 20 000, which indicates that the additional 
risk from this amount of radiation exposure is minimal, compared with the 
lifetime risk for being diagnosed with cancer in the UK (1 in 2).  
See Section 10.9. 
Subjects at risk (women of child-bearing potential, age <30 years, age 
>55 years) have been excluded from the study. 

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Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Risks related to 
sulphur colloid 
inhalation 
The risk would be that colloidal particle inhalation may give rise 
to local tolerability issues, bronchospasm and although unlikely, 
of allergic or anaphylactic reactions.  
During the clinical conduct, close monitoring of all participants according to 
the Schedule of Assessment will be performed to evaluate the occurrence 
and severity of any local irritation and actions taken according to the 
protocol and stopping criteria if breached. 
In addition to hypersensitivity reactions, inhaled particulates can rarely 
trigger bronchospasm. In the unlikely event that a patient suffers an 
episode of bronchospasm after inhaling any of the study interventions they 
will be promptly and appropriately managed according to clinical judgement 
e.g., administration of inhaled or nebulized bronchodilator such as 
salbutamol or ipratropium, and they will be withdrawn from the study. 
Oxygen will be given if required to maintain oxygen saturations >90%. If 
judged clinically necessary by the investigator participants could be 
transferred to hospital for ongoing treatment and monitoring.  
 

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2.2.2. 
Benefit Assessment 
This study is performed with Test and Reference propellants in healthy participants.  
While not a direct benefit, participants in this study will contribute to the process of 
developing a new, more environmentally friendly formulation of Ventolin that 
contributes less greenhouse gas emissions. 
Participants may benefit from information about their general health status through medical 
evaluations/assessments associated with this study (i.e., physical examinations and blood 
testing [hematology and biochemistry data]). 
2.2.3. 
Overall Benefit-Risk Conclusion 
This study is performed with Test and Reference propellants in healthy participants. The 
tolerability profile of the Reference propellant HFA-134a, which has been part of the 
Ventolin formulation for many years, is well characterized. The change in propellant 
from HFA-134a to HFA-152a is supported by a nonclinical toxicology program. The test 
propellant was well tolerated in human exposure studies thus far, and in GSK’s PK study 
was rapidly cleared from the blood. The test propellant is under evaluation by other 
companies as well (see Study to Assess the Effect of the New HFA-152a Propellant on 
Mucociliary Clearance - Full Text View - ClinicalTrials.gov, accessed 21/11/2023).  
The risk related to the exposure to radioactivity is characterized and manageable. The 
maximum possible dose of radiation in this study is very small indeed and is considered 
to be acceptable. The risk related to nebulized 99mTc sulphur colloid inhalation is 
characterized and manageable. 
Women of child-bearing potential (WOCBP) are excluded to protect from risk associated 
with administration of radioactivity. Adult subjects (from 18 up to 55 years) are typically 
used in this kind of studies; exclusion of subjects younger than 30 years is justified based 
on the recommendations of the ARSAC for the exposure to radiation. 
Taking into account the measures taken to minimize any risk to participants in this study 
(exclusion of WOCBP, exclusion of subjects of younger age), the potential risks 
recognized 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 salbutamol inhaler with a new propellant (HFA-152a) with 
greatly reduced GWP, compared to the current propellant HFA-134a.  

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3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
The study objectives and endpoints are presented in Table 3. 
Table 3 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
To assess MCC expressed as integrated 
measurements of retained radioactivity in the 
right lung up to 4 h after 7-day administration 
of Test and Reference propellants to healthy 
male and female participants 
• 
AUC0-4h after nebulized 99mTc inhalation on Day 7 
Secondary 
(MCC) To assess MCC expressed as retained 
radioactivity in the right lung at individual 
times after 7-day administration of Test and 
Reference propellants to healthy male and 
female participants 
• 
Percent radiolabeled particle retention at 1 h after nebulized 
99mTc inhalation on Day 7 
• 
Percent radiolabeled particle retention at 1.5 h after 
nebulized 99mTc inhalation on Day 7 
• 
Percent radiolabeled particle retention at 3 h after nebulized 
99mTc inhalation on Day 7 
(Safety) To assess the safety and tolerability 
after 7-day administration of Test and 
Reference propellants in healthy male and 
female participants. 
• 
Incidence of AEs and SAEs 
Primary Estimand  
The primary clinical question of interest is: 
What is the GMR in primary parameter AUC0-4h after repeated dosing for 7 days of 
HFA-152a, aka 1 – Difluoroethane (Test propellant) and HFA-134a, aka 1,1,1,2 – 
Tetrafluoroethane (Reference propellant) in healthy participants? 
The estimand is described by the following attributes: 
• 
Population:  
Healthy male or female participants aged 30 to 55 years. 
• 
Endpoint:  
AUC(0-4h) in the right lung after nebulized 99mTc inhalation on Day 7. 
• 
Treatment condition:  
Administration of repeated doses of Test propellant (HFA-152a) or Reference 
propellant (HFA-134a) for 6 days, given as 4 inhalations BID and last administration 
on the morning of Day 7. 
• 
Intercurrent events (ICEs) and estimand strategies: 
1. Treatment discontinuation due to any reasons (Principal stratum strategy) 

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2. Participants unable to take all doses as prescribed (Principal stratum strategy) 
3. Dosing error in propellants (Principal stratum strategy) 
The principal stratum strategy is a commonly accepted strategy for MCC studies. For 
all ICEs, interest lies in evaluating primary parameter and comparison of the ratio of 
2 formulations for AUC(0-4h) after nebulized 99mTc inhalation in a principal stratum 
strategy for participants completed the study and who achieved 100% compliance 
with no dosing error. 
• 
Population-level summary:  
Ratio of adjusted GM for AUC(0-4h) (for logarithmic transformed values) following 
repeated dosing of the 2 formulations (HFA-152a and HFA-134a), with 90% CI.  
Rationale for estimand: The Test formulation is being developed with the aim to 
have comparable AUC(0-4h) after nebulized 99mTc inhalation characteristics as the 
reference formulation, under the scenario where participants are required to have the 
desired levels of exposure to study intervention. Interest lies in the AUC(0-4h) 
values obtained in the scenarios had the participant been exposed to correct dose as 
prescribed, completed the study and 100% compliance.  
Estimands Supporting Secondary MCC Objectives  
The secondary clinical question of interest is:  
What is the mean difference in percent radiolabeled particle retention at 1, 1.5, and 
3 hours after nebulized 99mTc inhalation, after repeated dosing for 7 days of HFA-152a , 
aka 1 – Difluoroethane (Test propellant) and HFA-134a, aka 1,1,1,2 – Tetrafluoroethane 
(Reference propellant) in healthy participants? 
This secondary MCC estimand has the same estimand attributes as the primary estimand 
(population, treatment condition, ICEs strategy, rationale for the estimand), except for the 
following attributes: 
• Endpoint:  
− 
Right lung percent radiolabeled particle retention at 1 h after nebulized 99mTc 
inhalation on Day 7 
− 
Right lung percent radiolabeled particle retention at 1.5 h after nebulized 99mTc 
inhalation on Day 7 
− 
Right lung percent radiolabeled particle retention at 3 h after nebulized 99mTc 
inhalation on Day 7 
• Population-level summary:  
Adjusted mean difference in percent radiolabeled particle retention at 1, 1.5 and 3 h 
following repeated dosing of the 2 formulations (HFA-152a and HFA-134a), with 
90% CI. 
Estimands Supporting Secondary Safety Objectives 
The clinical question of interest for the safety secondary objective is:  

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What is the safety and tolerability profile of HFA-152a (Test propellant) compared to 
HFA-134a (Reference propellant) in healthy participants? 
This secondary safety estimand has the same estimand attributes as the primary estimand 
(population, treatment condition), except for the following attributes: 
• 
Endpoint:  
Incidence of AE and SAEs. 
• 
ICEs and estimand strategies: 
1. Treatment discontinuation due to any reasons – (Treatment policy strategy)  
2. Participants unable to take all doses as prescribed (Treatment policy strategy) 
3. Dosing error in propellants (Treatment policy strategy) 
• 
Population-level summary:  
Number and percentages for incidence of AEs and SAEs  
Rationale for estimand:  This is a study in healthy volunteers with short follow-up 
duration. Therefore, all AEs and SAEs 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, double-blind, single-site, 2-way crossover study to assess the effect 
of repeated doses of Test propellant (HFA-152a, aka 1 – Difluoroethane) on MCC as 
compared to Reference propellant (HFA-134a, aka 1,1,1,2 – Tetrafluoroethane) in 
healthy male and female participants. 
The study has planned to enrol a total of 24 healthy participants to ensure at least 
20 participants are included in the principal stratum analysis set with at least 
10 participants randomized to each treatment sequence. 
Participants will be randomly assigned to 1 of 2 treatment sequences in 2 TPs using a 
cross-over design. The following treatment sequences will be tested: 
• Treatment Sequence 1: T-R 
• Treatment Sequence 2: R-T 
Where T is HFA-152a, aka 1 – Difluoroethane (Test) and R is HFA-134a, aka 1,1,1,2 – 
Tetrafluoroethane (Reference). 
In each study period, Test or Reference propellants will be administered by oral 
inhalation BID on Days 1-6 and as a single dose on the morning of Day 7. MCC will be 
determined using gamma-scintigraphy following the administration of nebulized colloidal 
99mTc-sulphur colloid by inhalation after the final dose of the propellant on Day 7. The 

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study will comprise a Screening Period of up to 21 days prior to first dosing; 2 TPs of 8 
days each, with a 7±2 days Washout Period between the 2 TPs; and a final safety Follow-
up Visit up to 8 ± 2 days after the final dose administration in TP2 (maximal duration 
56 days). 
A schema of the study is provided in Figure 1. 
Figure 1 
Schematic of the Study 
 
Notes: Training MDI concerns the initial training of the inhalation from MDI (propellants); additional training will be 
provided during the treatment periods. Between Day 1 to Day 6 of Period 1, the ROI encompassing the right 
lung will be defined based on a single 57Co transmission scan of the participant chest. Green triangles 
represent propellant administrations (4 inhalations BID for 6 days + single morning administration on Day 7). Tc 
Training inhalation concerns the training of inhalation of nebulized saline solution (without radiolabeled 99mTc); 
Yellow boxes represent inhalation of the nebulized labelled 99mTc for the assessment of MCC.  
Abbreviations: BID=twice daily, Co=Cobalt, MDI=metered dose inhaler, ROI=region of interest, Tc=Technetium. 
4.2. 
Scientific Rationale for Study Design 
A reformulated ‘low carbon’ Ventolin is under development, in which the HFA-134a 
propellant is replaced by 1,1-Difluoroethane (aka HFA-152a), to reduce the effect on 
climate change. In addition to other assessments (relative bioavailability, PD similarity in 
the methacholine challenge model, and long-term safety study characterization of the 
Test vs Reference formulation), during interactions with EMA; the assessment of the 
effect of the new propellant HFA-152a (Test) on MCC in comparison to that of the 
current propellant HFA-134b (Reference) was required. Considering that MCC is an 
important host defence mechanism freeing up the airways from dust, bacteria and other 
irritants, the assessment of MCC is part of the safety characterization of the new (Test) 
propellant. The demonstration that the Test propellant has similar effect on MCC 
compared to the Reference Propellant (tested in years of commercial use of Ventolin) 
will provide additional confidence concerning the safety and tolerability of the new 
formulation of Ventolin. 
The study is based on a randomized 2-way crossover design as the potential, differential 
effect of the Test and Reference propellants can be suitably tested in the same subjects, 
Test Propellant
1
2
3
4
5
6
7
8
Day
Reference Propellant
1
2
3
4
5
6
7
8
Day
99mTc
Test Propellant
1
2
3
4
5
6
7
8
Day
Reference Propellant
1
2
3
4
5
6
7
8
Day
Random
ization
Washout 
7±2 Days
Washout 
7±2 Days
Screening
Sequence 1
Sequence 2
99mTc
99mTc
99mTc
Tc Training 
inhalation 
Tc Training 
inhalation 
Tc Training 
inhalation 
Tc Training 
inhalation 
Training 
MDI
Scan ROI  
57Co
+
-1
Follow up
Scan ROI  
57Co

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i.e., the design is suited to reduce the influence of confounding covariates as each 
participant serves as their own control. The crossover design typically requires a smaller 
number of participants compared to a parallel group design. Carryover effects are 
expected to be eliminated by introducing a suitable washout phase; considering the very 
short residence of the propellant in the body [Kuehl, 2022], a washout period of 7±2 days 
is considered appropriate. 
Healthy participants have been chosen as the study population due to the study design, 
and the low risk of clinically significant toxicity at anticipated exposure levels. In 
addition, the study involves the administration of propellants only, and no patient benefit 
is expected from the administration of propellants, so that the study can be suitably 
performed in healthy participants. 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. Subjects at risk for radioactivity administration (WOCBP, subjects 
<30 years, see section 2.2) have been excluded. 
As the assessment of safety and tolerability is among the secondary objectives of the 
study, it is preferred that the study is double blinded, i.e., both the investigators and the 
healthy participants do not know the actual propellant used in a particular occasion, to 
allow for a more objective identification and collection of the AEs after administration. 
4.2.1. 
Participant Input to the Design 
Not applicable. 
4.3. 
Justification for Dose and Duration of the Treatment 
Effects on MCC are not expected to be elicited after a single dose of propellants, so MCC 
assessment will be conducted after a short-term (7-day) repeated dosing of the 
propellants. For the chronic therapy of asthma, Ventolin can be administered as 
2 inhalations up to 4 times a day, resulting in a maximum of 8 inhalations/day [Ventolin 
HFA, 2021]. Therefore, in this MCC study, the propellants will be given as 4 inhalations 
BID (i.e., matching the maximal daily exposure of the propellant in the clinical use of 
Ventolin), for a total 13 administrations, i.e., final administration on the morning of 
Day 7 of each treatment period. Of note, no salbutamol will be included in the 
formulation for this assessment. The amount of propellant given per single actuation is 
the same for both propellants . For the dose of radiolabelled material, see Section 8.7 and, 
Section 10.9. 
4.4. 
End-of-Study Definition 
A participant is considered to have completed the study if the participant has completed 
the 2 treatment periods of the study including the last visit or the last scheduled procedure 
shown in the SoA (see Section 1.3). 

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The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA for the last participant in the study. 
The Ethics Committee should be notified of the conclusion of the study within 90 days of 
the end of the study, or within 15 days if the study is terminated early, clearly explaining 
the reasons for the termination. The ARSAC Practitioner will also be notified of the end 
of trial or early termination of the trial within an appropriate timeframe. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
It is aimed to enroll up to 24 healthy male and female participants to have at least 20 
completers. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all following criteria apply: 
1. Sex: male or female. 
2. Age: 30 to 55 years, inclusive, at screening 
3. BMI: 18.0 to 32.0 kg/m2, inclusive, at screening 
4. Weight: ≥50 kg 
5. Nonsmokers or ex-smokers for more than 6 months with a smoking history of 
<10 pack years 
6. Status: healthy participants 
7. Spirometry data;  
• FEV1≥80% of predicted values; 
•  FEV1:FVC ratio >70%. 
8. Females must be of nonchildbearing potential, as defined in Section 10.4.1.2. 
9. A female participant is eligible to participate if: 
• She is a WONCBP, as defined in Section 10.4. 
• She agrees not to donate eggs (ova, oocytes) for the purpose of reproduction 
during the study intervention period and at least 30 days after the last dose of 
study intervention. She must also not be involved in the process of donating eggs 
prior to consenting to the study.  
10. Male participants are eligible to participate if they agree to the following during the 
study intervention period and for at least 90 days after the last dose of study 
intervention: 
• Refrain from donating sperm 

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• Either be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 
• Or must agree to use a male condom when having sexual intercourse with a 
WOCBP who is not currently pregnant. The female partner should additionally 
use a highly effective contraceptive method with a failure rate of <1% per year as 
described in Section 10.4. 
11. All prescribed medication must have been stopped at least 30 days prior to admission 
to the clinical research center based on investigator judgment (see Section 6.9). An 
exception is made for HRT, and occasional paracetamol which may be used 
throughout the study. 
12. Ability and willingness to abstain from alcohol from 48 hours (2 days) prior to 
screening, and from 48 hours (2 days) prior to each admission until discharge from 
the clinical research center at each study period. 
13. Ability and willingness to abstain from methylxanthine-containing beverages or food 
(coffee, tea, cola, chocolate, energy drinks) from 48 hours (2 days) prior to each 
admission to the clinical research center at each study period. 
14.  Good physical and mental health on the basis of medical history, physical 
examination, clinical laboratory, ECG, and vital signs, as judged by the investigator. 
15. Capable of giving written informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol.  
16. Capable of using inhaler device with no physical or other issues which would impair 
the participant’s ability to successfully use a pMDI inhaler as instructed in this study. 
17. Ability to comply with the protocol. Subjects have capacity and no issues which 
would impair their ability to comply with all aspects of the protocol during the study. 
The investigator 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. 
5.2. 
Exclusion Criteria  
Individuals who meet any of the following exclusion criteria at screening will not be 
eligible to participate in the study: 
1. Radiation exposure, including that from the present study, excluding background 
radiation but including diagnostic x-rays and other medical exposures, exceeding 
5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally 
exposed worker, as defined in the Ionising Radiation Regulations 2017, shall 
participate in the study. 
2. History or presence of any form of asthma, including childhood asthma and exercise 
induced asthma. 
3. Respiratory disorders other than asthma. A history of respiratory diseases to include 
(but not limited to): pneumothorax, pulmonary fibrotic disease, bronchopulmonary 

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dysplasia, chronic bronchitis, cystic fibrosis, bronchiectasis, interstitial lung disease, 
emphysema, COPD, tuberculosis, known alpha 1 antitrypsin deficiency and other 
respiratory abnormalities other than asthma that, in the opinion of the investigator, 
could put the participant at risk through study participation or could affect the study 
analyses and data interpretation. 
4. History or presence of any cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematologic, or neurological disorders that could, in the 
opinion of the investigator, put the participant at risk through study participation or 
that would affect the study analyses and data interpretation.  
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. Also, any other history of previous 
malignancy that could, in the opinion of the investigator, put the participant at risk 
through study participation or which could affect the study analyses and data 
interpretation. 
6. Recent history of mild conditions potentially affecting MCC (viral infections, cough, 
cold, active hayfever etc.) in the last 14 days (see also Section 5.5). 
7. Recent use of drugs for treating conditions potentially affecting MCC (viral 
infections, cough, cold, etc.) in the last 30 days (see also Section 5.5). 
8. Systolic blood pressure <90 mmHg or >140 mmHg, or diastolic blood pressure 
<50 mmHg or >90 mmHg at screening or Day -1 of each treatment period. 
9. History of pathological tachycardia, or a pulse rate >100 bpm at screening or Day -1. 
10. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
11. Vaccine(s) within 2 weeks prior to admission or plans to receive such vaccines 
during the study. 
12. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day or participation in a clinical study within 90 days of study start, or 5 half-
lives of study drug if that is longer.  
13. Current enrollment or past participation in this clinical study. 
14. 12-Lead ECG abnormality: Significant abnormality in the 12-lead ECG performed at 
screening that, in the investigator's opinion, would affect safety evaluations or place 
the subject at risk. 
15. QTc >450 msec (or >480 msec in participants with bundle branch block) performed 
at screening. 
Notes: The QTc is the QT interval corrected for heart rate according to QTcF. It is 
either machine-read or manually over-read. The specific formula used to determine 
eligibility and discontinuation for an individual participant should be determined 
prior to initiation of the study and used throughout the study for the individual 
participant. In other words, several different formulas cannot be used to calculate the 
QTc for an individual participant and then the lowest QTc value used to include or 
discontinue the participant from the trial. 

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16. ALT >1.5× ULN at screening. 
17. Total bilirubin >1.5×ULN at screening. Participants with Gilbert’s syndrome can be 
included with total bilirubin >1.5×ULN as long as direct bilirubin is <1.5×ULN 
18. Presence of HBsAg at screening or within 3 months prior to first dose of study 
intervention. 
19. 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. 
20. Positive hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study intervention. Note: Test is optional and participants with negative 
hepatitis C antibody test are not required to also undergo hepatitis C RNA testing. 
21. Positive HIV antibody test. 
22. Positive pre-study drug/alcohol screen, including THC. 
23. Regular use of known drugs of abuse, including THC. 
24. Cotinine levels indicative of smoking or history or use of tobacco- or nicotine 
containing products within 6 months prior to screening.  
25. Use of combustible tobacco products, and noncombustible nicotine delivery systems, 
inclusive of cigarettes, cigars, pipes, and materials used to “vape” within 6 months 
prior to screening. 
26. Average intake of more than 21 units of alcohol per week in males and 14 units per 
week in females (clinical site standard: unit of alcohol equals approximately 250 mL 
of beer, 100 mL of wine, or 35 mL of spirits) based on breath alcohol test. 
27. 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. 
28. Presence or history of clinically significant allergy requiring treatment, as judged by 
the investigator. 
29. 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 e.g.,xample, herbal 
medicine, health supplements, traditional medicine, homeopathic remedies, etc.) 
within 14 days prior to first dose of propellant in treatement period 1. 
30. Subjects who are study site employees, or immediate family members of a study site 
or sponsor employee. 
31. Failure to satisfy the investigator of fitness to participate for any other reason. 
5.3. 
Randomization criteria 
Participants meeting any of the following criteria must not be randomized. Similarly, the 
following criteria 1 and 2 should also be reviewed and confirmed again at the start of 

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treatment period 2 to ensure no changes since the participant completed treatment 
period 1. 
1. Occurrence of a culture-documented or suspected bacterial or viral infection of the 
upper or lower respiratory tract, sinus or middle ear occurring between screening and 
randomization that, in the opinion of the investigator, may put the safety of the 
participant at risk or impact the participant’s ability to participate in the study or that 
may impact analyses and interpretation of the study results. See Section 5.5 for 
information on rescreening. 
2. Any other change in health status since screening or short course of medications 
taken since screening, which could, in the opinion of the investigator, put the safety 
of the participant at risk through study participation, impact the participant’s ability 
to participate or confound the interpretation of the study results. See Section 5.5 for 
information on rescreening. 
5.4. 
Lifestyle Considerations 
5.4.1. 
Meals and Dietary Restrictions 
There are no meal or dietary restrictions, except those reported under Section 5.4.2. On 
Days -1 to Day 6 and Day 8 meals will be provided at appropriate times. On Day 7, 
breakfast will be provided after safety bloods have been taken and prior to administration 
of any study treatment. Lunch will be provided after completion of all scintigraphy 
imaging at approximately 4 hours post dose. The evening meal will be provided at 
approximately 10 hours post dose. Water consumption will be controlled.  
5.4.2. 
Caffeine Alcohol and tobacco 
• Due to the potential effects on pulmonary function, during the study, participants will 
abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee, tea, 
cola drinks, and chocolate) from 48 hours prior to each admission until discharge 
from the site at the end of each treatment period 
• During the study, participants will abstain from alcohol from 48 hours prior to 
admission until discharge from the site at the end of each treatment period. 
• Use of tobacco products will not be allowed from 6 months prior to screening until 
after the final follow up visit. 
5.4.3. 
Exercise 
Participants will abstain from strenuous exercise for 96 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light recreational 
activities during the clinical study (e.g., watching television, reading). 

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5.4.4. 
Other Restrictions 
• Participants must not donate blood during the study until discharge (other than the 
blood sampling planned for this study). Participants should refrain from donating 
sperm or eggs during the study intervention period and for at least 90 days or 30 days, 
respectively, after the last dose of study intervention. 
5.5. 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical 
study is not subsequently entered into the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations, and any 
SAEs. 
Screen failure data will be included in the datasets. For all participants (including screen 
failures) a source data review will be performed.  
Participants who were considered screen failure for recent history of mild temporary 
conditions potentially affecting MCC (exclusion criterion 6) or for taking drugs for 
treating mild temporary conditions affecting MCC (exclusion criterion 7) may be 
rescreened and enrolled at later times if time allows. Rescreened participants should be 
assigned a new participant number for every screening/rescreening event. Previously 
assigned participant numbers are to be recorded in the participants’ eCRF. 
5.6. 
Criteria for Temporarily Delaying Administration of Study 
Intervention 
Not applicable 

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6. 
STUDY INTERVENTIONS AND CONCOMITANT 
THERAPY 
The definition of study intervention is provided in the table of definitions. 
6.1. 
Study Intervention Administered 
Study intervention is presented in Table 4. 
Table 4 
Study Intervention Administered 
Intervention Label 
Test Treatment 
Reference Treatment 
MCC gamma 
scintigraphy 
assessment 
Intervention Name 
Test propellant: HFA-
152a, aka 1 – 
Difluoroethane 
Reference propellant (HFA-
134a, aka 1,1,1,2 – 
Tetrafluoroethane 
Nebulized 
radiolabelled 
saline solution 
Intervention Description 
repeated doses: 6 days, 4 
inhalations twice daily 
(BID)+last administration 
on the morning of Day 7 
repeated doses: 6 days, 4 
inhalations twice daily 
(BID)+last administration on 
the morning of Day 7 
Saline solution 
containing 
radiolabeled 
99mTc colloidal 
sulphur  
Route of administration  
Oral inhalation  
Oral inhalation 
Oral inhalation 
Use 
Propellant for Ventolin 
Propellant for Ventolin 
Enable 
assessment of 
MCC via 
scintigraphy 
imaging 
Source 
GSK 
GSK 
Clinical site 
 
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. 
Labelled as per 
the country 
requirements 
The study intervention will be administered with the participant in the upright, seated 
position. Dosing for each individual participant will be at around the same time in the 
morning and in the evening (time interval 12±3 hour) BID on each dosing day. 
6.1.1. 
Medical Devices 
• 
The GSK manufactured medical devices (or devices manufactured for GSK by a 
third party, if applicable) provided for use in this study are MDI, which is used to 
administer the study intervention. 
• 
MDIs need to be primed before use. The priming of MDIs should not be done in the 
vicinity of the participants, as unintended inhalation needs to be avoided. 
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• 
Instructions for medical device use are provided in a separate 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 10.7) and appropriately managed by GSK. 
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.  
• 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, institution, the head of the medical institution (where applicable), 
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.  
• 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 
The GSK Randomization Officer will use the Randall NG system to generate 
randomization codes. With central randomization, knowledge of the randomized 
treatment group for previous participants does not predict which treatment group will be 
assigned to the next randomized participant. Randomization and study intervention 
assignment will be facilitated by the Interactive response technologies through the central 
RAMOS NG. Following confirmation of fulfilment of study entry criteria, study site 
personnel will be required to register participants using RAMOS NG for assignment of a 
unique identifier which comprises of 4 digits (e.g., 1001 and increasing) (designating the 
participant’s randomization code and treatment sequence assignment) for each participant 
in the study. 
On Day 1, participants will be assigned a unique number (randomization number) in 
ascending numerical order. The randomization number encodes the participant’s 
assignment to one of the 2 treatment sequences of the study, according to the 
randomization schedule generated prior to the study by the statistics department at GSK. 

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6.4. 
Blinding 
This is a double-blind study in which investigators and participants are blinded to study 
intervention.  
Type of Study 
 
Blinding of laboratory testing  
The laboratory in charge of sample testing will be blinded 
to the study intervention assignment. Codes will be used 
to link the participant and study to each sample. There will 
be no link between the study intervention groups and the 
identity of the participant. 
Emergency unblinding 
This is a double-blind study in which participants 
investigators/outcomes assessors, and investigational site 
staff are blinded to the study interventions. In case of an 
emergency, the investigator has the sole responsibility for 
determining if unblinding of a participants’ intervention 
assignment is warranted. Participant safety must always 
be the first consideration in making such a determination. 
If the investigator decides that unblinding is warranted, the 
investigator may, at the investigator’s discretion, contact 
GSK to discuss the situation prior to unblinding a 
participant’s intervention assignment unless this could 
delay emergency treatment for the participant. If a 
participant’s intervention assignment is unblinded, GSK 
must be notified within 24 hours of this occurrence. The 
date and reason for the unblinding must be recorded in 
the eCRF. 
If the investigator is unable to access RAMOS they can 
contact the GSK helpdesk based on the information 
provided in the pharmacy manual.  
A physician other than the investigator (e.g., an 
emergency room physician) or participant/participant’s 
caregiver or family member may also request emergency 
access to the participant’s study intervention information 
as per participant card. 
A participant may continue in the study if that participant’s intervention assignment is 
unblinded. The primary reason for discontinuation (the event or condition which led to 
the unblinding) will be recorded in the eCRF. 
GSK’s Global Safety staff may unblind the intervention assignment for any participant 
with an SAE. If the SAE requires that an expedited regulatory report be sent to one or 
more regulatory agencies, a copy of the report, identifying the participant’s intervention 
assignment, may be sent to investigators in accordance with local regulations and/or GSK 
policy. 

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6.5. 
Study Intervention Compliance 
Participants 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. To adhere to study intervention, participants will be 
required to perform pre-dose MDI training as described in the SoA and in study specific 
training manual. The study will adopt MDI training systems 
or similar) 
which provide flow and co-ordination coaching. An overdose is any dose of propellant 
given to a participant that exceeds the planned dose for an individual within a given dose 
group.  In the event of an overdose, the [investigator or designee] should:  
• Closely monitor the participant for any AE/SAE and laboratory abnormalities for 
1 week.  
• 
Document the quantity of the excess dose in the eCRF. 
6.6. 
Dose Modifications 
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.  
GSK does not recommend specific treatment for an overdose. 
6.9. 
Prior and Concomitant Medications 
The use of all prescribed medication is not allowed from 30 days prior to admission to the 
clinical research center until discharge from the study at the final follow up visit  or ED. 
An exception is made for HRT, which are allowed throughout the study and occasional 
use of up to 4 g/day paracetamol. The use of all over-the-counter medication, vitamin 
preparations and other food supplements, or herbal medications (e.g., St. John’s wort) is 
not allowed from 30 days prior to admission to the clinical research center until discharge 
from the study at the final follow up visit. 
Vaccination (including vaccination against SARS-CoV-2) is not allowed from 2 weeks 
prior to admission until discharge. Acetaminophen (paracetamol), at doses of 
4 grams/day, is permitted for use any time during the study, except during the 24 hours 
pre-dose or post-dose on each dosing day. Other concomitant medications may be 
considered on a case-by-case basis by the investigator in consultation with the GSK 
Medical Monitor. 
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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 sequences 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 in a particular period, all reasonable attempts will be made to 
ensure the collection of endpoints and safety information (e.g., telephone contact) in that 
period and follow-up. 
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. The primary 
reason for premature discontinuation of the study intervention will be documented in the 
eCRF based on the list below: 
Reason 
Additional Items/Sub-reasons 
AE 
 
Lost to follow-up 
Participant  relocated 
Participant was incarcerated  
Other, specify  
Unknown 
Participant achieved protocol-defined stopping criteria  
Liver chemistry stopping criteria  
QTc stopping criteria 
Bronchospasm stopping criteria 
Physician decision 
Specify 
Protocol deviation 
Specify 
Site terminated by the Sponsor 
 
Study treatment terminated by the Sponsor 
 
Study terminated by the Sponsor 
 
Withdrawal by participant 
Burden of procedure 
Participant relocated 
COVID-19 pandemic 
Other, specify 
Other 
Specify 
Death 
 

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7.1.1. 
Liver Chemistry Stopping Criteria  
Discontinuation of study intervention and any further treatments for abnormal liver tests 
is required by the investigator when a participant meets one of the conditions outlined in 
Figure 2 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. 
Figure 2 
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 10.6 for required liver safety actions and follow-up. 
7.1.2. 
QTc Stopping Criteria 
If a clinically significant finding is identified (including, but not limited to, changes from 
screening value in QTcF after enrolment, and based on rounded values), 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. 
If an ECG meets any of the below-reported potential stopping criteria, then the ECG 
measurement should be repeated in triplicate, with the averaged QT and QTcF values 
used to determine stopping: 
QTcF >500 msec 
QT uncorrected >600 msec 
Change from baseline QTcF >60 msec 

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For participants with underlying bundle branch block, follow the discontinuation criteria 
listed below: 
Baseline QTc with Bundle Branch 
Block 
Discontinuation QTc with Bundle 
Branch Block 
<450 msec 
>500 msec 
450 – 480 msec 
≥530 msec 
Note: Baseline referred to Day -1 of the relevant treatment  
7.1.3. 
Bronchospasm Stopping Criteria 
In the unlikely event that a participant suffers an episode of significant bronchospasm 
after inhaling any of the study interventions, participants will be discontinued from any 
further study interventions and withdrawn from the study. This assessment of 
bronchospasm will be made by the investigator. Significant bronchospasm is defined as 
symptomatic requiring treatment and/or showing a decrease in FEV1 >30% from baseline 
(baseline will be considered to be the most recent pre-therapy measurement i.e., Day -1 
test of the relevant treatment period). Treatment of bronchospasm should include an 
inhaled or nebulised bronchodilator such as salbutamol and/or ipratropium and oxygen to 
maintain peripheral oxygen saturation >90%. If, at any time, it is believed that participant 
safety would be improved by transfer to hospital, this will be arranged.  
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). 
A participant may be withdrawn at any time at the discretion of the investigator for 
safety, behavioral, or compliance reasons. 
During the clinical conduct, close monitoring of all participants according to the 
Schedule of Assessment will be performed to evaluate the occurrence and severity of any 
local irritation; appropriate actions will be taken, including the removal from the study. 
If during the study a participant becomes ill and/or tests positive for SARS-CoV-2 dosing 
will be stopped. The participant will be isolated from other study participants and referred 
for treatment, if required. The participant will be discharged from the clinical unit if safe 
to do so and will be asked to quarantine at home according to local guidelines. 
Investigators will attempt to contact participants who do not return for scheduled visits or 
follow-up (if applicable). 
At the time of discontinuing from the study, if possible, an ED visit should be conducted, 
as shown in the SoA. See SoA 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.  

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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: 
Reason 
Additional Items/Sub-reasons 
AE 
 
Lost to follow-up 
Participant relocated,  
Participant was  incarcerated  
Other, specify 
Unknown 
Participant achieved protocol-defined stopping criteria  
Liver chemistry stopping criteria  
QTc stopping criteria 
Bronchospasm stopping criteria 
Physician decision 
Specify 
Protocol deviation 
Specify 
Site terminated by the Sponsor 
 
Study terminated by the Sponsor 
 
Withdrawal by participant 
Burden of procedure 
Participant relocated 
COVID-19 pandemic 
Other, specify 
Other 
Specify 
Death 
 
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 10.3.5.5). 
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. 

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The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
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. 
• 
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, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• 
Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study.  
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. Subjects who have signed informed consent 
but are not eligible to proceed should be recorded in the eCRF with a status of 
‘screen failure’. 
• 
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 (see Section 1.3). 
• 
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. 
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. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 

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8.1. 
Administrative Procedures 
8.1.1. 
Collection of Demographic Data 
Record demographic data such as year of birth, sex, race, and ethnicity in the 
participant’s eCRF.  
Collection of age, 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 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 the first dose of study intervention in the eCRF. 
8.2. 
Efficacy and/or Immunogenicity Assessments 
Planned timepoints for all assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Inhaler training 
Participants’ MDI proficiency will be reviewed by the investigator or delegate. Inhaler 
proficiency will be assessed during the Screening Visit and during subsequent treatment 
period visits at the timepoints specified in the SoA (Section 1.3). If a participant is unable 
to demonstrate inhaler use in a satisfactory and repeatable manner, they will be excluded 
from the study. 
8.3. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal (including liver and spleen), 
dermatologic, and neurological systems. Height and weight (on an empty bladder 
and wearing light clothing) will also be measured and recorded.  
8.3.2. 
Vital Signs 
• 
Pulse rate and blood pressure will be recorded. 
• 
Blood pressure and pulse measurements will be assessed with a completely 
automated device after the participant has been resting for at least 5 minutes in the 

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supine position. 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 
• Screening and post-dose will be conducted via single 12-lead ECG(s) as outlined in 
the SoA (see 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. 
• All ECGs will be performed in single assessment. In case of any QT abnormalities 
ECGs will be repeated in triplicate. 
• 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. 
Spirometry 
Spirometry will be performed at the study site to assess FEV1 and FVC. 
To enroll in this study, participants must demonstrate a baseline FEV1 ≥80% of predicted 
and a FEV1:FVC ratio >70% at screening. At least 3 acceptable spirometry maneuvers 
(from a maximum of 8 attempts) should be achieved on each occasion that spirometry 
assessments are performed, in accordance with the American Thoracic Society/European 
Respiratory Society standards [Graham, 2019]. The highest of 3 technically acceptable 
measurements will be recorded at each visit. Global Lung Function Initiative equations 
will be used [Quanjer, 2012] to determine predicted values. Predicted values will be 
corrected for gender, age, height and race. 
8.3.5. 
Clinical Safety Laboratory Tests 
• Clinical laboratory tests will be performed in accordance with laboratory 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 should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the investigator or 
medical monitor. 
− 
In the absence of a diagnosis, abnormal laboratory findings assessments or other 
abnormal results the investigator considers clinically significant will be recorded 

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as an AE or SAE, if they meet the definition of an AE or SAE (refer to Section 
10.3).  
− 
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 nonprotocol-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. 
8.3.6. 
Pregnancy Testing 
Not applicable, as only women of nonchildbearing potential (WONCBP) are eligible to 
participate 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 10.3). 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. 
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 10.3.5.5 and Section 10.7.4.4. 
8.4.2. 
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 discharge from the 
study (see SoA, Section 1.3).  
All AEs will be collected from the start of study intervention until final discharge from 
the study (see SoA, Section 1.3). 

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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 8.4.1. 
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. 
8.4.3. 
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. 
8.4.4. 
Adverse event of special interests 
Not Applicable. 
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 Table 5 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 10.3.5.3. 
• 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 investigational directions for use, or package insert will 
notify the IRB/IEC, if appropriate according to local requirements. 
• The ARSAC practitioner will be notified of any SAE that is considered related to the 
exposure of radioactivity. 

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Table 5 
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 
• Details of all pregnancies in female partners of male participants will be collected after 
the start of study intervention and until 90 days 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 partner of male participant (after obtaining the necessary signed informed 
consent from the female partner) 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 pregnant female partner will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the pregnant 
female partner and the neonate, and the information will be forwarded to the sponsor. 
See Table 5 for reporting timeframes. 
• 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 8.4.5. While the investigator is not obligated to actively seek this information 
in former  pregnant female partners, he or she may learn of an SAE through 
spontaneous reporting. 
• Any male participant whose partner becomes pregnant while participating in the 
study will discontinue study intervention or be withdrawn from the study. 
8.4.7. 
Cardiovascular and Death Events 
Cardiovascular Events 
Not Applicable. 

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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 one 
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 6 
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 
The investigator or delegate must provide the participant with a “participant card” 
containing information about the clinical study. The participant must be instructed to 
always keep the participant card in their possession for the duration of the study. In an 
emergency, this card serves to inform the responsible attending physician that the 
participant is in a clinical study and that relevant information may be obtained by 
contacting the investigator(s) or their back up.  
8.4.11. 
Medical device deficiencies 
Medical devices are being provided for use in this study to administer the study 
intervention. To fulfill regulatory reporting obligations worldwide, the investigator is 
responsible for the 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 10.7. 
Note. Deficiencies fulfilling the definition of an AE/SAE will follow the processes 
outlined in Section 10.7 of the protocol.  

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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 10.7. 
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 or designee to 
fulfill the legal responsibility to notify appropriate regulatory authorities and other 
entities about certain safety information relating to medical devices being used in 
clinical studies. 
• 
The investigator, or responsible person according to local requirements (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 
No PK data will be collected in this study. 

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8.6. 
Pharmacodynamics 
No PD data will be collected in this study. 
8.7. 
Imaging Assessments 
8.7.1. 
Assessment of MCC using nebulized 99mTc and scintigraphy 
Assessments 
After Day 7 Test or Reference Propellant inhalation, MCC will be assessed in each TP. 
Sulphur colloid containing NMT 20 MBq 99mTc will be delivered to the lungs via the 
PARI LC PLUS nebulizer with PARI TubroBO SX compressor using relaxed tidal 
breathing (with a nose clip) according to the study specific dosing instructions. 
Immediately after nebulization (prior to the acquisition of any scintigraphic images), 
participants will rinse their mouth with at least 120mL of water and will expel the rinse to 
minimize the amount of radioactivity that may be swallowed, after which  a further 
volume of 120mL  of water is to be taken and drunk to clear any radioactivity from the 
oropharynx and esophagus. 
From the start time of the nebulization, a record of coughs will be kept for each subject 
up until completion of the final scintigraphy assessment at approximately 4 h following 
completion of the nebulization. 
To enable the gamma scintigraphic assessment of MCC, up to 2 anatomical markers 
containing 99mTc will be taped to the skin, so they are visible within the gamma camera 
field of view without overlapping regions of interest. Immediately post-nebulization (and 
the subsequent rinsing and consumption of water), posterior and anterior images will be 
collected (T0), with subsequent images collected at defined intervals over a 4-hour 
period, as indicated in the SoA (Section 1.3). Where necessary, any items external to the 
body of the subject will be retained and imaged (as soon as is feasible around the imaging 
schedule of the participant) e.g., apron, tissues, mucociliary excretions, if it is believed to 
benefit for the subsequent data analysis. 
All images will be acquired using a gamma camera with a 54 × 40 cm field of view and 
fitted with a low energy parallel hole collimator.  For all images, subjects will be in a 
standing position in front of the gamma camera, in both posterior and anterior 
orientations.  
The gamma scintigraphic images collected up to 4 h following the controlled inhalation 
of nebulized 99mTc-sulphur colloid, will be used to derive the percent of radioactivity that 
is retained in the right lung (as a percent of initial amount of radioactivity delivered at 
T0) across all imaging time points (as indicated in the SoA).  
The imaging schedule provided in the SoA may be altered based on emerging 
scintigraphic data (for e.g., additional images may be acquired if deemed necessary for 
the purposes of the data analysis). Actual image times will always be recorded. 
Adjustments to the schedule may also be made to allow time to alter the position of the 
anatomical markers, or to adjust the camera positioning in order to maintain image 
quality.  

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Whole lung clearance is strongly dependent on the site of particle deposition within the 
lung. To characterize regional deposition by providing a clear outline of the lungs, and in 
order to correct for the attenuation of gamma rays by overlying tissues, each participant 
will undergo a transmission scan of the thorax using a flood field source containing 57Co. 
The transmission scans will be planned to be performed on Day 1 to Day 6 of TP 1, as 
per the SoA (Section 1.3). 
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 
No formal hypothesis testing will be performed for the primary and secondary endpoints. 
This study is designed to estimate MCC of orally inhaled HFA-152a MDI (Test 
propellant) and HFA-134a MDI (Reference propellant). For this aim, the GMR will be 
calculated by taking the ratio of the GMs of the Test (T) to the Reference propellant (R) 
for primary endpoint; 90% Confidence Interval of GMR (T/R) will also be calculated. 
9.1.1. 
Multiplicity adjustment 
The primary or secondary endpoints will be analyzed in a descriptive manner with no 
formal hypothesis testing and therefore no multiplicity adjustments will be applied. 
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 
• 
Study Population 

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Analysis Set  
Definition / Criteria  
Analyses Evaluated  
as they did not enter the 
study.  
MCC (Principal Stratum) 
• 
All participants who were able 
to adhere to all doses of study 
intervention as prescribed and 
completed the study 
• 
Estimand for primary and 
secondary objective of MCC 
parameters 
Safety 
• 
All participants who received 
at least one dose of study 
intervention.  
• 
Estimand for secondary safety 
objective 
9.3. 
Statistical Analyses 
9.3.1. 
General considerations 
Calculations will be based on the actual sampling times recorded during the study. From 
the retained radioactivity data, the following parameters will be estimated: retained 
radioactivity at all different timepoints and AUC0-4h of the retained radioactivity. 
The MCC parameters data will be summarized using descriptive statistics (N, n, 
arithmetic mean, 95% CI of arithmetic mean, GM, 95% CI of GM, SD, SD (loge) median, 
CVb in %, minimum and maximum), and will be listed and summarized in tabular and/or 
graphical form. Where appropriate, listings and graphical presentation will also be 
produced for MCC parameters endpoints. 
Discrete data (safety) will be summarized by counts and percentages as appropriate. 
9.3.1.1. 
Definition of MCC endpoints 
The definitions of MCC parameters are described in the following table: 
Parameter 
Description 
AUC0-4h (primary) 
Area under the right lung percent 
radiolabeled particle retention -time curve 
up to 4 h after dosing with nebulized 
99mTc on Day 7 
R1h (secondary) 
Right lung Percent radiolabeled particle 
retention at 1 h after dosing with 
nebulized 99mTc on Day 7 
R1.5h (secondary) 
Right lung Percent radiolabeled particle 
retention at 1.5 h after dosing with 
nebulized 99mTc on Day 7 
R3h (secondary) 
Right lung Percent radiolabeled particle 
retention at 3 h after dosing with 
nebulized 99mTc on Day 7 

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9.3.1.2. 
Main Analytical Approach 
The primary MCC parameter is area under the percent radiolabeled particle retention-
time curve up to 4 hours (AUC[0-4h]) after nebulized 99mTc inhalation. The primary 
analysis will evaluate the primary estimand in the MCC analysis set. In cases where 
reliable estimation of AUC(0-4h) is not possible due to last nonreportable measurable 
radioactivity retention data, the corresponding AUC(0-4h) data will be treated as missing 
data.  
Loge-transformed data of AUC(0-4h) will be analyzed using mixed effect model 
approach with fixed effect such as 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 , aka 1 – 
Difluoroethane (Test)/ HFA-134a, aka 1,1,1,2 – Tetrafluoroethane (Reference).  
Strategies for handling ICEs is described in Section 3. Further details of the planned 
analysis of primary estimands will be described in the SAP. 
9.3.1.3. 
Sensitivity Analysis 
If missing data is more than 10% then a sensitivity analysis will be conducted by using 
AUC0-4h estimated by linear extrapolation method of the log-transformed data. 
9.3.1.4. 
Supplementary/supportive Analysis  
No supplementary/supportive analysis will be performed. 
9.3.1.5. 
Secondary Endpoints Analyses  
The secondary MCC endpoints are as follows: 
• Right lung percent radiolabeled particle retention at 1 h after dosing with nebulized 
99mTc on Day 7 
• Right lung percent radiolabeled particle retention at 1.5 h after dosing with nebulized 
99mTc on Day 7 
• Right lung percent radiolabeled particle retention at 3 h after dosing with nebulized 
99mTc on Day 7 
The secondary endpoint analysis, like the primary analysis, will assess the secondary 
estimand in the MCC population. In cases where the measurement is not performed, it 
will be treated as missing data.  
Secondary endpoints will be analyzed using mixed effect model approach with fixed 
effect such as period, treatment group and participants as random effects. The point 
estimates of mean difference and their associated 90% CI will be provided for HFA-152a, 
aka 1 – Difluoroethane (Test) and HFA-134a, aka 1,1,1,2 – Tetrafluoroethane 
(Reference). 

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ICEs will be managed in the same way as primary endpoint. 
Further details of the planned analysis of secondary estimands will be described in the 
SAP. 
9.3.1.6. 
Sensitivity Analysis for secondary endpoint 
If the distribution of the secondary endpoints’ (percent radiolabeled particle retention at 
1, 1.5, 3 h after dosing with nebulized 99mTc on Day 7) data does not follow normal 
distribution, then loge transformation will be applied. 
Loge transformed data of secondary endpoints will be analyzed using mixed effect model 
approach with fixed effect such as 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 ratio (GMR) of HFA-152a, aka 1 – 
Difluoroethane (Test) / HFA-134a, aka 1,1,1,2 – Tetrafluoroethane (Reference). 
If missing data of percent radiolabeled particle retention at either timepoint (1h, 1.5h, and 
3h) is >10% then sensitivity analysis will be performed using log-linear/linear (depending 
if data are normally or log-normally distributed, respectively) interpolation/ extrapolation 
imputation of available measurements similarly to what reported under Section 9.3.1.3). 
9.3.2. 
Safety Analysis 
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 SDTM standards. 
Treatment policy strategy (as described in Section 3) for the ICE of study treatment 
discontinuation due to any reason will be used for summarizing safety data of the study. 
Safety analysis is described in further detail in below sections. 
9.3.2.1. 
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 overall 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.  

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9.3.2.2. 
Clinical Laboratory 
A summary of all data outside the reference range of the clinical laboratory will be provided 
to monitor participants’ safety. Absolute values of clinical laboratory data will be presented 
descriptively (arithmetic mean, SD, median, minimum, and maximum), where applicable. 
9.3.2.3. 
Vital signs and ECG 
Absolute and changes from baseline 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. 
9.4. 
Interim Analyses 
No interim analysis will be performed for this study. 
9.5. 
Sample Size Determination 
Up to 24 healthy participants will be randomly assigned to ensure at least 20 participants 
are included in the MCC analysis set with at least 10 randomized to each treatment 
sequence. 
The target number of participants is chosen to achieve half width (refer to Table 7) of the 
90% CI, in the estimate of the GMR for the primary endpoint.  
An MCC study [Donno, 1988] reported a CVw of 8.5% for the AUC(0-6h) parameter. 
The within-participant CVw for the AUC(0-4h) parameter was thus assumed to range 
from 8.5% to 11.5%. 
Using a sample size 20 and CVw of 10.5% in AUC(0-4h), the half width of the upper 
bound of 90% CI for observed treatment ratio of AUC(0-4h) between 2 treatment arms is 
5.93 % (Table 7). Considering for example, that the GMR between Test and Reference is 
1.05 for n = 20 and CVw = 10.5%, then the upper bound of the 90% CI for observed 
treatment ratio is 1.05*(1+0.0593)=1.11 and the lower bound is 1.05/(1+0.0593)=0.99 
(Table 8). 

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Table 7 
Half-width Expected for Different Sample Size and Intra-Subjects 
Variability 
Sample size 
Intra subject variability SD (CVw%) 
Half-width (%) of the upper bound of 
90% CI for Observed Treatment 
Ratio 
16 
0.0849 (8.5%) 
5.44 
18 
 
5.07 
20 
 
4.77 
22 
 
4.52 
16 
0.0948 (9.5%) 
6.09 
18 
 
5.68 
20 
 
5.35 
22 
 
5.06 
16 
0.1047 (10.5%) 
6.76 
18 
 
6.30 
20 
 
5.93 
22 
 
5.61 
16 
0.1146 (11.5%) 
7.42 
18 
 
6.92 
20 
 
6.51 
22 
 
6.16 
Abbreviations: CI=confidence interval; CVw=coefficient of variation within subjects. 

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Table 8 
Lower and Upper Bound GMR for Different Values of GMR 
GMR (T/R) 
Lower and Upper bound for observed GMR (T/R) 
 
Lower Bound 
Upper Bound 
0.9 
0.85 
0.95 
0.95 
0.90 
1.01 
1 
0.94 
1.06 
1.05 
0.99 
1.11 
1.1 
1.04 
1.17 
Note: n = 20 & CVw = 10.5% 
Abbreviations: CVw=coefficient of variation within subjects, GMR=geometric mean ratio, R=reference, T=test 

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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 
− 
Health and Safety. The Ionising Radiations Regulations 2017. Statutory 
Instrument 2017 No. 1075. 
− 
Health and Safety. The Ionising Radiations (Medical Exposure) Regulations 
2017. Statutory Instrument 2017 No. 1322. 
• 
The protocol, protocol amendments, ICF, 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. Any amendments relating to the 
administration of radioactive substances will be reviewed by the ARSAC practitioner 
prior to submission to ARSAC as required by the current ARSAC Notes for 
Guidance. The ARSAC practitioner will also be notified of any substantial 
amendments to the PIS and ICF and/or protocol. 
• 
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, if applicable 
− 
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 

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• The ARSAC practitioner for this study will administer the radiation at
 
Administration will be conducted in accordance with the ARSAC practitioner’s 
current licence and 
 current ARSAC Employer licence. Additionally, a 
research application will be submitted to ARSAC to obtain approval for the conduct 
of the study before test product administration. 
• The protocol will be reviewed and the final version will be approved by the ARSAC 
practitioner. 
10.1.2. 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
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. 
• 
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. 
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. 
CCI
CCI

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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. 
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 

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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, 
involvement of central reading mechanism) methods, responsibilities, and 
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.  

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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 e.g. 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 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• 
Discontinuation of further study intervention development 
For site termination: 

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• 
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, ARSAC practitioner and ARSAC, 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. 
10.2. 
Appendix 2: Clinical laboratory tests 
• 
The clinical safety laboratory tests detailed in Table 9 will be performed by the local 
laboratory. 
• 
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. 

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Table 9 
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 
• Urea 
• Potassium 
• Creatinine* 
• Sodium 
• Calcium 
• Glucose 
fasting 
• Creatine 
phosphokinase
(CPK) 
• Aspartate aminotransferase (AST)/serum 
glutamic-oxaloacetic transaminase (SGOT)1 
• Alanine aminotransferase (ALT)/serum 
glutamic-pyruvic transaminase (SGPT)1 
• Alkaline phosphatase2 
• Total bilirubin1 
• Direct bilirubin, only if total bilirubin is elevated 
• Total protein 
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 at investigator discretion. 
• Culture at investigator discretion (if positive: specify pathogen) 
Other screening 
tests 
• FSH and estradiol (as needed in WONCBP only) 
• 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)] 
• Testing for SARS-CoV-2 may be performed at the discretion of the 
physician and based on local guidelines. 

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NOTES 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 10.6: Liver 
Safety: Suggested Actions and Follow-up Assessments [and Study Intervention Rechallenge Guidelines]. All 
events of ALT [or AST] 3 × ULN and total bilirubin 2 × ULN (>35% direct bilirubin) or ALT [or AST] 3 × ULN 
and INR >1.5 (if INR measured), which may indicate severe liver injury (possible Hy’s law), must be reported to 
[sponsor] in 24hours (excluding studies of hepatic impairment or cirrhosis). 
2. 
If alkaline phosphatase is elevated, consider fractionating. 
* To assess the kidney function, use eGFR 2009 calculator (CKD-Epi creatinine equation). eGFR (based on CKD-Epi) 
will be measured at all time points when creatinine is measured. 
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). 

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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 
convenience admission to a hospital, admission for routine examination.). 
• 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, 

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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 
product. 
h. Other situations: 
• Possible Hy’s Law case: ALT ≥3x ULN AND total bilirubin ≥2x ULN (>35% 
direct bilirubin) or INR (if INR is measured) >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 Cardiovascular events  
Not Applicable. 
10.3.4. 
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. 
10.3.5. 
Recording, assessment and follow-up of AE, SAE, and 
pregnancies  
10.3.5.1. 
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 

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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. 
10.3.5.2. 
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 
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.   
10.3.5.3. 
Assessment of causality 
• The investigator is obligated to assess the relationship between the study 
interventions as described in Table 4 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 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 make 
an assessment of causality for every event before the initial transmission of the SAE 
data to GSK. 

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• Where multiple interventions are administered in the same visit, the investigator 
should specify, when possible, if the AE/SAE could be causally related to a specific 
study intervention. When a causal relationship to a specific study intervention cannot 
be determined, the investigator should indicate the AE/SAE to be related to all 
interventions 
• 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. 
10.3.5.4. 
Assessment of outcomes 
The investigator will assess the outcome of all serious and nonserious unsolicited AEs 
recorded during the study as: 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved 
• Recovered with sequelae/resolved with sequelae 
• Fatal (SAEs only). 
10.3.5.5. 
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 if available. 
• 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 nonserious AEs must be followed until follow-up visit or until the participant is 
lost to follow-up. 

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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, if available. 
Follow-up of pregnancies 
Pregnant partners of male 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 10.3.5.7. 
10.3.5.6. 
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). 
10.3.5.7. 
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. 

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• 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, 
nonserious AEs, pregnancy exposure, related to any GSK non-IMP they will report 
these events to GSK or to the concerned competent authority (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. 
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): 
• Adolescents of childbearing potential: Tanner stage ≥2 (post-thelarche) irrespective 
of the occurrence of menarche or following menarche. 
• 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: 
• Permanently sterile due to one of the following procedures: 
a. Documented hysterectomy 

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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. 
• 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 or (HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more 
than 1 FSH measurement is required. 
• 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 partners of childbearing potential with fertile male participants must use a highly 
effective contraceptive (see list below) plus participant use of a condom from the start of 
first study intervention until  90 days post-dose of last study intervention. 
• 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 participant (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 WOCBP 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. 

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Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationc 
• oral 
• intravaginal 
• transdermal 
• injectable 
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. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
[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) 
10.5. 
Appendix 5: Genetics 
Not Applicable. Genetics are not evaluated in this study. 
10.6. 
Appendix 6: Liver safety: suggested actions and follow-up 
assessments  
Phase 1 Liver chemistry stopping criteria have been designed to assure participant 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 INR (if 
measured) >1.5, report as an SAE1,2. 
Required Actions, Monitoring and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study intervention 
• Viral hepatitis serology3 

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Liver Chemistry Stopping Criteria  
• 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 3×ULN AND total bilirubin 2×ULN 
or INR >1.5: 
• 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 3×ULN AND total bilirubin <2×ULN 
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 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
aminotransferases values show 
downward trend 
• Obtain serum creatine phosphokinase 
(CPK) and lactate dehydrogenase (LDH), 
• 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 3×ULN AND total bilirubin 2×ULN 
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: 

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Liver Chemistry Stopping Criteria  
o 
In participants when serology raises 
the possibility of autoimmune 
hepatitis (AIH) 
o 
In participants when suspected DILI 
progresses or fails to resolve on 
withdrawal of study intervention 
o 
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 2×ULN (>35% direct bilirubin) or ALT 3×ULN 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.  
10.7. 
Appendix 7: Medical device AEs, ADEs, SAEs, sADEs, 
USADEs and device deficiencies: Definitions and 
procedures for recording, evaluating, follow-up, and 
reporting in medical device studies 
• 
The definitions and procedures detailed in this appendix are in accordance with ISO 
14155 and the European MDR 2017/745 for clinical device research (if applicable).  
• 
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. 
10.7.1. 
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 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 a medical device. This definition includes events related 
to the medical device or comparator and events related to the procedures involved 

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except for events in users or other persons, which only include events related to 
devices. 
• 
An ADE is defined as an AE related to the use of a medical device. This definition 
includes any AE resulting from insufficient or inadequate instructions for use or 
any malfunction of the medical device as well as any event resulting from use 
error or from intentional misuse of the medical device. 
10.7.2. 
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. 
• 
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 2.2). 

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10.7.3. 
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. 
10.7.4. 
Recording and follow-up of medical device AE and/or SAE and 
device deficiencies 
10.7.4.1. 
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. 
• 
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, nonserious 
incident (including device deficiencies and malfunctions) related to any GSK non-
IMP product they will report these events to GSK or to the concerned competent 
authority via the national spontaneous reporting system.  These will be classified as 
spontaneous ICSRs. 
10.7.4.2. 
Assessment of intensity 
Refer to Section 10.3.5.2. 

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10.7.4.3. 
Assessment of causality 
Refer to Section 10.3.5.3. 
10.7.4.4. 
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 postmortem findings 
including histopathology, if available. 
• 
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. 
10.7.5. 
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. 
• 
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 
table) or to the medical monitor by telephone. 
• 
If the site during the course of the study or poststudy becomes aware of any serious, 
nonserious AEs, pregnancy exposure, related to any GSK device they will report 
these events to GSK or to the concerned competent authority 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. 

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• 
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. 
10.7.6. 
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. 
10.7.7. 
Reporting of medical device deficiencies for associated person 
• 
Reporting to GSK  
If an Associated Person (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 nonserious 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. 

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• 
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. 
10.8. 
Appendix 8: Country-specific requirements 
Not Applicable. 
10.9. 
Appendix 9. Risk Assessment for Gamma Scintigraphy 
Studies using nebulized 99mTc 
This is a gamma scintigraphy study using a nebulized 99mTc labelled sulphur colloid 
product containing not more than 20 MBq, so participants will be exposed to ionising 
radiation. The effective dose per administration will be 0.5 mSv and 0.03 mSv per 99mTc 
anatomical marker. The effective dose per transmission scan will be 0.1 mSv. 
The effective dose that each participant will receive from each administration of 20 MBq 
99mTc (including 2 anatomical markers) will not exceed 0.56 mSv. Over both 
administrations the estimated radiation dose that each participant will receive is 
1.22 mSv*. This is approximately 5.5 months of the average radiation exposure 
received in the UK each year (2.7 mSv; data obtained from UK Health Security Agency 
Ionising Radiation Exposure of the UK Population: 2010 Review [PHE, 2016]) and is 
equivalent to slightly less than the radiation dose that would result from 3 x-rays of the 
abdomen (0.47 mSv per procedure). It is believed that any increase in the amount of 
radiation that is received above natural radiation carries a risk of later developing serious 
and possibly fatal conditions. The risk associated with the maximum possible dose of 
radiation in this study is very small indeed and is considered to be acceptable. 
The dose of radioactivity has been determined in accordance with the current approved 
ARSAC Employer Licence Application for 
 
 and the current Practitioner Licence for the ARSAC practitioner. The 
associated radiation exposure will fall within International Commission on Radiological 
Protection (ICRP) (1992) Guidelines for Category IIb studies (1 to 10 mSv). 
*Note: Transmission scans can be repeated up to 2 times, if the first is considered not 
suitable for use due to unforeseen circumstances. Each transmission scan results in 
0.1 mSv of radiation. Accordingly the maximum amount of radiation that any 
participant may receive (if the scan is repeated a maximum of 2 times) will be 1.42mSv. 
This is not expected to result in a significant increase in risk. 
CCI
CCI

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Radiation Exposure per Participant 
Effective Dose (mSv) 
Transmission Scan (57Co) 
0.1 
99mTc Sulphur Colloid 
0.5 
99mTc anatomical marker (per 
marker)
0.03 
Total per administration* 
0.56 
Total over 2 administrations** 
1.22 
*Representative of one radiolabelled dose with the use of 2 anatomical markers 
**Representative of both radiolabelled doses with the use of 2 anatomical markers per dose, and a transmission scan 
Extrapolation of data from epidemiological studies of cancers induced by radiation 
exposure indicates that the risk factor for an adult UK population of both sexes (age 
range 18 to 64) is 5 × 10-2 per Sv [NRPB, 1993]. From this it can be estimated that the 
lifetime risk of inducing a fatal cancer in a healthy individual from a total exposure of 
1.0 mSv is approximately 1 in 20,000. The lifetime risk for being diagnosed with cancer 
in the UK is around 1 in 2 [Cancer Research, 2021], indicating that this additional risk 
from this amount of radiation exposure is minimal. 
CCI

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11. 
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Date of signature: 14-May-2024 20:18:37 GMT+0000
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