Clinical trial NCT05791565
Conditions: Asthma
Keywords: Cross-over Healthy volunteers Salbutamol Pharmacokinetics
Sponsor: GlaxoSmithKline
Start date: 2023-04-03; Completion date: 2023-05-21
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will be conducted to compare the PK of salbutamol administered via metered dose inhalers (MDI) containing propellants 1,1-difluroethane (HFA-152a) and 1,1,1,2-tetrafluoroethane (HFA-134a) in healthy participants.

Detailed description:

Arms: arm 1: Participants will receive Salbutamol HFA-152a MDI in treatment period 1 followed by Salbutamol HFA-134a MDI in treatment period 2. There will be a minimum washout period of 72 hours between each treatment period. arm 2: Participants will receive Salbutamol HFA-134a MDI in treatment period 1 followed by Salbutamol HFA-152a MDI in treatment period 2. There will be a minimum washout period of 72 hours between each treatment period.
Interventions: intervention 1: Salbutamol HFA-152a intervention 2: Salbutamol HFA-134a
Intervention descriptions: intervention 1: Salbutamol HFA-152a will be administered. intervention 2: Salbutamol HFA-134a will be administered.

Protocol documents:
Prot_000.pdf: 
Protocol
Study ID:  219430
Official Title of Study: A Single Dose Two-way Cross-over Study in Healthy 
Participants to Compare the Pharmacokinetics (PK) of Salbutamol Administered 
Via Metered Dose Inhalers Containing Propellants HFA-152a and HFA-134a
NCT ID: NCT05791565
Date of Document: 11 February 2023 (This date has been redacted on Page 3)


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Protocol (Final 2.0) 
10 Feb 2023 
1 
 
Clinical Study Protocol 
Primary Study 
Intervention(s) 
Salbutamol administered via metered dose inhalers 
containing propellant HFA-152a (Test) 
Other Study Intervention(s) 
Salbutamol administered via metered dose inhalers 
containing propellant HFA-134a (Reference) 
Study Identifier 
219430  
EudraCT Number  
2022-003406-77 
Approval Date 
10 Feb 2023 
Title 
A single dose two-way cross-over study in healthy 
participants to compare the pharmacokinetics (PK) 
of salbutamol administered via metered dose 
inhalers containing propellants HFA-152a and 
HFA-134a 
Compound Number/Name 
AH3365 (Salbutamol) 
Brief Title 
Green (Sustainable) Ventolin - PK study in healthy 
volunteers 
Sponsor 
GlaxoSmithKline Research & Development Limited 
980 Great West Road, Brentford, Middlesex, TW8 
9GS, UK 
Sponsor Signatory 
Jeff Min, MD, MSCE 
Clinical Development Director 
Clinical Sciences Respiratory 
Medical monitor name and contact information can be found in the Study Team 
Contact List. 
 
©2022 GSK group of companies or its licensor. 
 
PPD


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Protocol (Final 2.0) 
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2 
Protocol Amendment 1 Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments, with the terms of the clinical trial agreement and with any other 
study conduct procedures and/or study conduct documents provided by GSK. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of and will comply with GCP and all applicable regulatory 
requirements.  
• 
That I will comply with the terms of the site agreement. 
• 
To comply with local bio-safety legislation. 
• 
To ensure that all persons assisting me with the study are adequately informed 
about the GSK study intervention and other study-related duties and functions 
as described in the protocol. 
• 
To supervise any individual or party to whom I have delegated study-related 
duties and functions conducted at the study site. 
• 
To ensure that any individual or party to whom I have delegated study-related 
duties and functions conducted at the study site are qualified to perform those 
study-related duties and functions. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if 
required by local regulations, obtain the laboratory’s current certification or 
Quality Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained 
on-site or elsewhere without the approval of GSK and the expressphysical or 
digitalinformed consent of the participant.  
• 
To perform no biological assays on the clinical samples other than those 
described in the protocol or its amendment(s).To co-operate with 
representative(s) of GSK in the monitoring and data management processes of 
the study with respect to data entry and resolution of queries about the data. 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the study. 
• 
That I have been informed that certain regulatory authorities require the 
sponsor to obtain and supply, as necessary, details about the investigator(s)’ 
ownership interest in the sponsor or the study intervention(s), and more 
generally about their financial ties with the sponsor. GSK will use and disclose 
the information solely for the purpose of complying with regulatory 
requirements. 
Hence, I: 


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Protocol (Final 2.0) 
10 Feb 2023 
3 
• 
Agree to supply GSK with any necessary information regarding ownership 
interest and financial ties (including those of my spouse and dependent 
children). 
• 
Agree to promptly update this information if any relevant changes occur during 
the study and for 1 year following completion of the study. 
• 
Agree that GSK may disclose any information about such ownership interests 
and financial ties to regulatory authorities. 
• 
Agree to provide GSK with an updated Curriculum Vitae and all other 
documents required by regulatory agencies for this study. 
Study identifier 
 219430 
 
EudraCT number 
2022-003406-77 
Approval date 
10 Feb 2023 
 
 
Title 
Principal Investigator 
Investigator name 
Salah Hadi, MD 
 
Signature 
 
Date of signature 
(DD Month YYYY) 
 
 
PPD


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Protocol (Final 2.0) 
10 Feb 2023 
4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 1 
10 February 2023 
Original Protocol 
09 December 2022 
Amendment 1 (10 Feb 2023) 
This amendment is considered substantial based on the criteria defined in EU 
Clinical Trial Regulation No 536/2014 of the European Parliament and the Council 
of the European Union because it concerns the Investigational Medicinal Product 
and therefore impacts the scientific value of the study. 
Overall rationale for the current Amendment: 
 
 
. Protocol Amendment 1 addresses 
the removal of the 
 study arm and change in study 
design from 3-way to 2-way crossover. 
Protocol Amendment 1 also addresses clarification required by the Ethics Committee 
Board. 
List of main changes in the protocol and their rationale:
Section # and title 
Description of change 
Brief rationale 
Title page 
The title was adapted to a 
2-way cross-over study with 1 
test formulation. 
To reflect the new design of the study. 
Section 1, Protocol 
Summary 
The protocol summary has 
been updated to relflect that 
the study has a 2-way cross-
over design with 1 test 
reference. 
To reflect the new design of the study. 
Section 1.2, Schema, 
Figure 1 
The study design overview has 
been updated to reflect that the 
study has a 2-way cross-over 
design with 1 test reference.  
To reflect the 2-way cross-over design 
and the removal of test Formulation 2 
from the study design. 
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Protocol (Final 2.0) 
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Section # and title 
Description of change 
Brief rationale 
Section 1.3, Schedule 
of activities,Table 1 
The schedule of activities has 
been adapted to reflect that 
subjects will remain in the clinic 
for 6 days instead of 9 and will 
have 2 treatments instead of 3.  
To reflect that there will be 2 treatment 
periods instead of 3. 
Section 2.2.2, 
Background 
information on the 
product 
Text which describes the 
 
formulation has been removed.  
To reflect the removal of test 
Formulation 2 from the study design. 
Section 2.3, 
Benefit/Risk 
assessment 
The text was adapted to reflect 
that there is 1 test formulation.  
To reflect the removal of test 
Formulation 2 from the study design. 
Section 2.3.3, Overall 
benefit-risk 
conclusion 
The text was adapted to reflect 
that there is 1 test formulation.  
To reflect the removal of test 
Formulation 2 from the study design. 
Section 3, Objectives 
The objectives have been 
rephrased to reflect that there 
is 1 test reference.  
To reflect the removal of test 
Formulation 2 from the study design. 
Section 3.1, Primary 
Estimand 
The text was adapted to reflect 
the statistics for 1 instead of 2 
test formulations.  
To reflect the removal of test 
Formulation 2 from the study design. 
Section 3.2, 
Secondary Estimand 
(1) 
The text was adapted to reflect 
that there is 1 test formulation.   
To reflect the removal of test 
Formulation 2 from the study design. 
Section 3.3, 
Secondary Estimand 
(2) 
The text was adapted to reflect 
that there is 1 test formulation.   
To reflect the removal of test 
Formulation 2 from the study design. 
Section 3.4, 
Secondary Estimand 
(3) 
The text was adapted to reflect 
that there is 1 test formulation.   
To reflect the removal of test 
Formulation 2 from the study design. 
Section 4.1, Overall 
design 
The text was adapted to reflect 
that there will be 2 treatment 
sequences instead of 6 and 
clarification to equal 
assignment of treatment 
sequence to subjects.  
To reflect the removal of test 
Formulation 2 from the study design. 
Section 4.4, End-of-
study definition 
The text was adapted to reflect 
that there are 2 treatments 
instead of 3 treatments in total.  
To reflect the removal of test 
Formulation 2 from the study design. 
Section 6.1, Study 
Treatment Formulation 2 
To reflect the removal of test 
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Section # and title 
Description of change 
Brief rationale 
intervention(s) 
administered,Table 4 
containing 
 has been 
deleted from Table 4.  
Formulation 2 from the study design. 
Section 6.3, 
Assignment to study 
intervention 
Text has been adapted to 
reflect that there will be 2 
treatment sequences instead of 
6. 
To reflect the removal of test 
Formulation 2 from the study design. 
Section 6.4, Blinding 
Text has been adapted to 
reflect that there will be 2 
treatment sequences instead of 
6, and 2 treatment periods 
instead of 3. Also a 2-way 
cross-over design will be used 
instead of a Williams squares 
design. 
To reflect the 2-way cross-over design 
and the removal of test Formulation 2 
from the study design. 
Section 6.9, Prior and 
concomitant therapy 
Text has been adapted to 
reflect that day of discharge will 
be Day 5 instead of Day 8. 
To reflect a change in study design. 
Section 6.9, Prior and 
concomitant therapy 
Text has been adapted to 
explain why paracetamol is not 
allowed during the 24 hours 
predose or post dose on the 
dosing days.  
To address a comment from the Ethics 
Committee. 
Section 9, Statistical 
considerations 
Text has been adapted to 
clarify the statistical analysis 
plan will be finalized prior to 
database lock. 
This information was added as 
requested by the Independent Ethics 
Committee. 
Section 9.1, Statistical 
hypotheses 
The text was adapted to reflect 
that there are 2 treatments 
instead of 3 treatments in total.  
To reflect the removal of test 
Formulation 2 from the study design. 
Section 9.3.1, 
Pharmacokinetic 
analysis 
The text was adapted to reflect 
that there are 2 treatments 
instead of 3 treatments in total.  
To reflect the removal of test 
Formulation 2 from the study design. 
Section 9.3.2, Safety 
analysis 
The text was adapted to reflect 
that presentation of the safety 
data will not be according to 
GSK’s IDSL standards. 
Removal of text to reflect that the
process will be followed, which will be 
described in the statistical analysis 
plan.  
Section 9.5, Sample 
size determination 
The calculations for the sample 
size sensitivity were updated.  
To reflect the removal of test 
Formulation 2 from the study design.  
Section 10.2, 
Appendix 2: Clinical 
laboratory tests, 
The footnote in Table 9 was 
adapted to reflect that there are 
To reflect the removal of test 
Formulation 2 from the study design.  
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Protocol (Final 2.0) 
10 Feb 2023 
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Section # and title 
Description of change 
Brief rationale 
Table 9 
2 dosing days instead of 3.  
Section 10.4.2, 
Contraception 
guidance 
The contraceptive period for 
male participants has been 
changed from 90 days after 
last study interventions to 48 
hours after last study 
intervention. 
To address a comment from the Ethics 
Comittee 
Section 10.8, 
Appendix 8: Protocol 
amendment history 
A reference to the protocol 
amendment summary of 
changes was added to this 
section.  
To reflect that a protocol amendment 
has been prepared for this study. 
 
 


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Protocol (Final 2.0) 
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8 
TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 4 
List of main changes in the protocol and their rationale: ........................................... 4 
LIST OF ABBREVIATIONS ........................................................................................... 14 
1. 
PROTOCOL SUMMARY ........................................................................................ 18 
1.1. 
Synopsis ..................................................................................................... 18 
1.2. 
Schema ...................................................................................................... 26 
1.3. 
Schedule of activities (SoA) ........................................................................ 26 
2. 
INTRODUCTION .................................................................................................... 29 
2.1. 
Study rationale ............................................................................................ 29 
2.2. 
Background ................................................................................................ 29 
2.2.1. 
Background information on the disease to be treated .................. 30 
2.2.2. 
Background information on the product ....................................... 30 
2.2.3. 
Quality development .................................................................... 32 
2.2.4. 
Nonclinical development .............................................................. 32 
2.2.5. 
Clinical development .................................................................... 32 
2.3. 
Benefit/risk assessment .............................................................................. 34 
2.3.1. 
Risk assessment .......................................................................... 35 
2.3.2. 
Benefit assessment ..................................................................... 37 
2.3.3. 
Overall benefit-risk conclusion ..................................................... 37 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ................................................... 38 
3.1. 
Primary Estimand: ...................................................................................... 39 
3.2. 
Secondary Estimand (1): ............................................................................ 40 
3.3. 
Secondary Estimand (2): ............................................................................ 42 
3.4. 
Secondary Estimand (3): ............................................................................ 43 
4. 
STUDY DESIGN .................................................................................................... 44 
4.1. 
Overall design ............................................................................................. 44 
4.2. 
Scientific rationale for study design ............................................................. 45 
4.2.1. 
Participant input into design ......................................................... 45 
4.2.2. 
COVID-19 risk mitigation ............................................................. 45 
4.3. 
Justification for dose ................................................................................... 46 
4.4. 
End-of-study definition ................................................................................ 47 
5. 
STUDY POPULATION ........................................................................................... 47 
5.1. 
Inclusion criteria .......................................................................................... 47 
5.2. 
Exclusion criteria ......................................................................................... 48 
5.3. 
Lifestyle considerations ............................................................................... 50 
5.3.1. 
Meals and dietary restrictions ...................................................... 50 
5.3.2. 
Caffeine, alcohol, and tobacco ..................................................... 50 
5.3.3. 
Activity ......................................................................................... 50 
5.3.4. 
Other restrictions ......................................................................... 50 
5.4. 
Screen failures ............................................................................................ 50 
5.5. 
Criteria for temporarily delaying administration of study intervention ........... 51 
6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY ................................ 51 


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6.1. 
Study intervention(s) administered .............................................................. 51 
6.1.1. 
Medical devices ........................................................................... 52 
6.2. 
Preparation, handling, storage, and accountability ...................................... 52 
6.3. 
Assignment to study intervention ................................................................ 53 
6.4. 
Blinding ....................................................................................................... 53 
6.5. 
Study intervention compliance .................................................................... 54 
6.6. 
Dose modification ....................................................................................... 54 
6.7. 
Continued access to study intervention after the end of the study ............... 54 
6.8. 
Treatment of overdose ................................................................................ 54 
6.9. 
Prior and concomitant therapy .................................................................... 55 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 55 
7.1. 
Discontinuation of study intervention ........................................................... 55 
7.1.1. 
Liver chemistry stopping criteria ................................................... 56 
7.1.2. 
QTc stopping criteria .................................................................... 57 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 58 
7.3. 
Lost to follow-up.......................................................................................... 59 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 60 
8.1. 
Administrative procedures .......................................................................... 60 
8.1.1. 
Collection of demographic data .................................................... 60 
8.1.2. 
Medical and vaccination history ................................................... 60 
8.2. 
Efficacy and/or immunogenicity assessments ............................................. 60 
8.3. 
Safety assessments .................................................................................... 61 
8.3.1. 
Physical examination ................................................................... 61 
8.3.2. 
Vital signs .................................................................................... 61 
8.3.3. 
Electrocardiograms ...................................................................... 61 
8.3.4. 
Clinical safety laboratory tests ..................................................... 61 
8.3.5. 
Pregnancy testing ........................................................................ 62 
8.4. 
Adverse Events (AEs), serious adverse events (SAEs), and other 
safety reporting ........................................................................................... 62 
8.4.1. 
Time period and frequency for collecting AE, SAE, and 
other safety information ............................................................... 62 
8.4.2. 
Method of detecting AEs and SAEs ............................................. 63 
8.4.3. 
Follow-up of AEs and SAEs ......................................................... 63 
8.4.4. 
Regulatory reporting requirements for SAEs ................................ 63 
8.4.5. 
Pregnancy ................................................................................... 64 
8.4.6. 
Contact information for reporting SAEs and pregnancies ............. 65 
8.4.7. 
Medical device Deficiencies ......................................................... 65 
8.5. 
Pharmacokinetics ....................................................................................... 66 
8.6. 
Pharmacodynamics .................................................................................... 66 
8.7. 
Genetics ..................................................................................................... 67 
8.8. 
Biomarkers ................................................................................................. 67 
8.9. 
Immunogenicity assessments ..................................................................... 67 
8.10. 
Health economics or medical resource utilization and health 
economics .................................................................................................. 67 
8.11. 
Timing of assessments ............................................................................... 67 
8.11.1. 
Timing of dosing .......................................................................... 67 
8.11.2. 
PK blood sampling ....................................................................... 67 
8.11.3. 
PD blood sampling ....................................................................... 67 
8.11.4. 
Safety assessments ..................................................................... 67 


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9. 
STATISTICAL CONSIDERATIONS ........................................................................ 68 
9.1. 
Statistical hypotheses ................................................................................. 68 
9.2. 
Analysis sets ............................................................................................... 68 
9.3. 
Statistical analyses ..................................................................................... 69 
9.3.1. 
Pharmacokinetic analysis ............................................................ 69 
9.3.2. 
Safety analysis ............................................................................ 70 
9.3.3. 
Pharmacodynamic analysis ......................................................... 71 
9.4. 
Interim analyses .......................................................................................... 71 
9.5. 
Sample size determination .......................................................................... 71 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 72 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 72 
10.1.1. 
Regulatory and ethical considerations ......................................... 72 
10.1.2. 
Financial disclosure ..................................................................... 73 
10.1.3. 
Informed consent process ............................................................ 73 
10.1.4. 
Recruitment strategy .................................................................... 74 
10.1.5. 
Data protection ............................................................................ 74 
10.1.6. 
Committees structure ................................................................... 74 
10.1.7. 
Dissemination of Clinical Study Data ........................................... 75 
10.1.8. 
Data quality assurance ................................................................ 75 
10.1.9. 
Source documents ....................................................................... 76 
10.1.10. Study and site start and closure ................................................... 76 
10.1.11. Publication policy ......................................................................... 77 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 77 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 79 
10.3.1. 
Definition of AE ............................................................................ 79 
10.3.2. 
Definition of SAE .......................................................................... 80 
10.3.3. 
Solicited events............................................................................ 81 
10.3.4. 
Unsolicited AE ............................................................................. 81 
10.3.5. 
Definition of TEAE ....................................................................... 82 
10.3.6. 
Recording, assessment and follow-up of AE, SAE, and 
pregnancies ................................................................................. 82 
10.3.7. 
Reporting of SAEs and pregnancies ............................................ 85 
10.4. 
Appendix 4: Contraceptive and barrier guidance ......................................... 86 
10.4.1. 
Definitions .................................................................................... 86 
10.4.2. 
Contraception guidance ............................................................... 87 
10.5. 
Appendix 5: Liver safety: suggested actions and follow-up 
assessments ............................................................................................... 87 
10.6. 
Appendix 6: Medical device AEs, ADEs, SAEs, SADEs, USADEs 
and device deficiencies: Definitions and procedures for recording, 
evaluating, follow-up, and reporting in medical device studies .................... 89 
10.6.1. 
Definition of medical device AE and ADE..................................... 90 
10.6.2. 
Definition of medical device SAE, SADE and USADE .................. 90 
10.6.3. 
Definition of device deficiency ...................................................... 91 
10.6.4. 
Recording and follow-up of medical device AE and/or SAE 
and device deficiencies ................................................................ 91 
10.6.5. 
Reporting of medical device SAEs ............................................... 92 
10.6.6. 
Reporting of SADEs ..................................................................... 93 
10.6.7. 
Reporting of medical device deficiencies for associated 
person ......................................................................................... 93 


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10.7. 
Appendix 7: Country-specific requirements ................................................. 94 
10.8. 
Appendix 8: Protocol amendment history .................................................... 94 
11. REFERENCES ....................................................................................................... 94 
 


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LIST OF TABLES 
PAGE 
Table 1 
Schedule of Activities ............................................................................. 27 
Table 2 
Structural information for salbutamol sulfate ........................................... 31 
Table 3 
Objectives and Endpoints ....................................................................... 38 
Table 4 
Study Intervention(s) Administered......................................................... 51 
Table 5 
Timeframes for submitting SAE and pregnancy reports to GSK ............. 64 
Table 6 
Contact information for reporting SAEs and pregnancies ....................... 65 
Table 7 
Pharmacokinetic parameters .................................................................. 69 
Table 8 
Sample size sensitivity table................................................................... 72 
Table 9 
Protocol-required safety laboratory tests ................................................ 77 


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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 26 
Figure 2 
Chemical structures of HFA-134a and HFA-152a ................................... 31 
Figure 3 
Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping 
Event Algorithm ...................................................................................... 57 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADE 
Adverse device effect 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical code 
AUC 
Area under the curve 
AxMP 
Auxiliary medicinal product 
BMI 
Body mass index 
CA 
Competent authority 
CCMO 
Centrale Commissie Mensgebonden Onderzoek 
CFC 
Chlorofluorocarbon 
CFR 
Code of Federal Regulations 
CI 
Confidence intervals 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CRO 
Clinical Research Organization 
CSR 
Clinical study report 
ECG 
Electrocardiogram  
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration, United States of America 


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Abbreviation 
Definition 
FEV1 
Forced expiratory volume in 1 second 
FSFV 
First subject first visit 
FSH 
Follicle stimulating hormone 
GC 
Gas chromatography 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
GMR 
Geometric mean ratio 
GSK 
GlaxoSmithKline 
GWP 
Global warming potential 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HFA 
Hydrofluoroalkane  
HFA-134a 
1,1,1,2-tetrafluoroethane 
HFA-152a 
1,1-difluoroethane 
HIV 
Human immunodeficiency virus   
HR 
Heart rate 
HRT 
Hormonal replacement therapy 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICSR 
Individual case safety reports 
IDSL 
Integrated Data Standards Library 
IEC 
Independent ethics committee 
IFU 
Instructions for use 


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Abbreviation 
Definition 
IgG 
Immunoglobulin G 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRT 
Interactive response technology 
LC-MS-MS 
Liquid chromatography tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantification  
MDI 
Metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
MSDS 
Material Safety Data Sheet  
NIMP 
Noninvestigational medicinal product 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic(s) 
PFT 
Pulmonary function testing 
PK 
Pharmacokinetic(s) 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected using Fridericia’s formula 
QTL 
Quality tolerance limit 
RAMOS NG 
Randomization and Medication Ordering System Next 
Generation 
RR 
Respiratory rate 
SADE 
Serious adverse device effect 


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Abbreviation 
Definition 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome-corona virus type 2 
SMG 
Safety and medical governance 
SmPC 
Summary of product characteristics 
SoA 
Schedule of activities 
SPO2 
Saturation of peripheral oxygen 
TEAE 
Treatment-emergent adverse event 
THC 
Tetrahydrocannabinol 
ULN 
Upper limit of normal 
USADE 
Unanticipated serious adverse device effect 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of nonchildbearing potential 


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Protocol (Final 2.0) 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
A single dose two-way cross-over study in healthy participants to compare the 
pharmacokinetics (PK) of salbutamol administered via metered dose inhalers containing 
propellants HFA-152a and HFA-134a 
Brief Title: 
Green (Sustainable) Ventolin - PK study in healthy volunteers  
Rationale:  
In a metered dose inhaler (MDI), micronized particles of salbutamol are suspended in a 
propellant, currently hydrofluoroalkane 1,1,1,2-tetrafluoroethane (HFA-134a). However, 
this propellant has significant global warming potential and hence its use in medicine and 
other applications is being phased out under mounting environmental pressure to replace 
it with a low carbon footprint alternative such as hydrofluoroalkane 1,1-difluoroethane 
(HFA-152a). 
GSK is seeking to develop a sustainable version of Ventolin Evohaler (salbutamol sulfate 
suspension in propellant hydrofluoroalkane, HFA-134a) to address global climate 
change.  


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Objectives, Endpoints, and Estimands:  
 
Objectives 
Endpoints 
Primary 
To characterise the PK of single doses of 
salbutamol in healthy participants 
delivered via an MDI containing 
propellant HFA-152a, and to compare to 
an MDI containing propellant HFA-134a 
• 
AUC(0-30min) 
• 
AUC(0-∞) 
• 
AUC(0-t) 
• 
Cmax 
Secondary 
Pharmacokinetics: To characterise the 
PK of single doses of salbutamol in 
healthy participants delivered via an MDI 
containing propellant HFA-152a, and to 
compare to an MDI containing propellant 
HFA-134a 
• 
Tmax 
• 
t1/2 
Pharmacodynamics (PD): To 
characterise the PD of single doses of 
salbutamol in healthy participants 
delivered via an MDI containing 
propellant HFA-152a, and to compare to 
an MDI containing propellant HFA-134a 
 
• 
Minimum and 0-4h weighted mean 
serum potassium  
• 
Maximum and 0-4h weighted mean 
heart rate  
• 
Maximum and 0-4h weighted mean 
QTc interval  
Safety: To characterise the safety and 
tolerability of single doses of salbutamol 
in healthy participants delivered via an 
MDI containing propellant HFA-152a, 
and to compare to an MDI containing 
propellant HFA-134a 
 
• 
Incidence of AEs and SAEs 
• 
Pre- and post-dose 12-lead ECGs 
recording of HR, PR, QRS, QT and 
QTc intervals (absolute and change 
from baseline values) 
• 
Clinical laboratory assessment 
(absolute values) 
• 
Vital signs (systolic and diastolic 
blood pressure and pulse rate) 
(absolute values) 
 
Primary Estimand: 
The primary clinical question of interest is: What is the geometric mean ratio (GMR) of 
the PK parameters of Salbutamol HFA-152a MDI vs Salbutamol HFA‑134a MDI after 
administration of single doses of salbutamol in healthy participants. 
 
The estimand is described by the following attributes: 


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Protocol (Final 2.0) 
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• Population:  
Healthy male or female participants aged 18 to 55 years 
• Endpoints:  
AUC (0-∞), AUC (0-30min), AUC (0-t) and Cmax 
• Treatment Conditions:  
• Salbutamol will be administered as a single 800 µg dose, given as 8 actuations 
each separated by a 20-second interval, each delivering 100 µg as the ex‑valve 
dose for the test treatment and a reference treatment. 
The comparison of interest is: The ratio of Salbutamol HFA-152a MDI vs 
Salbutamol HFA‑134a MDI.  
• Intercurrent events: 
 
Treatment discontinuation due to any reasons - Hypothetical Strategy  
o Interest lies in the comparisons of ratio of two formulations in a hypothetical 
scenario where no participant discontinued from the study. The individual PK 
concentrations affected by occurrence of the intercurrent event would be 
treated as missing from the occurrence of the intercurrent event until the end 
of the study and consequently affected individual PK parameters will be 
missing. 
 
Occurrence of emesis or coughing on dosing - Hypothetical strategy  
o Interest lies in the comparisons of ratio of two formulations in a hypothetical 
scenario where no participant experiences an episode of coughing or emesis 
within a treatment that is judged by the investigator to have impacted inhaled 
drug delivery to the airways or swallowed drug absorption from the 
gastrointestinal tract. The individual PK concentrations affected by 
occurrence of the intercurrent event would be treated as missing from the 
occurrence of the intercurrent event until the end of the treatment (period) and 
consequently affected individual PK parameters will be missing for that 
treatment (period). 
 
Dosing error: Considered less than or more than prescribed dose and wrong 
treatment - Hypothetical strategy 
o Where the investigator is interested in the treatment effects in a hypothetical 
scenario where all participants have taken dose correctly as prescribed. The 
individual PK data affected by occurrence of the intercurrent event would be 
treated as missing from the occurrence of the intercurrent event until the end 
of the treatment (period) and consequently affected individual PK parameters 
will be missing for that treatment (period). 
 


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• Rationale for estimand: The test formulation is developed to have comparable 
PK characteristics and treatment effects. Interest lies in the PK values obtained 
while the participant is exposed to correct dose as prescribed, prior to the 
discontinuation of the randomized sequence and prior to the occurrence of emesis 
or coughing on dosing. 
• Population-level summary: Ratio of geometric mean (for logarithmic 
transformed values) and 90% CI for the ratio of the geometric means for 
AUC(0-∞), AUC (0-t), AUC(0-30min), and Cmax. 
Secondary Estimand (1): 
The clinical question of interest for the secondary objective is: What is the summarized 
PK profile using descriptive statistics for tmax and t1/2 after administration of single doses 
of salbutamol in healthy participants. 
The estimand is described by the following attributes: 
• Population:  
Healthy male or female participants aged 18 to 55 years 
•  Endpoints: 
tmax and t1/2 
• Treatment conditions:  
Salbutamol will be administered as a single 800 µg dose, given as 8 actuations 
each separated by a 20-second interval, each delivering 100 µg as the ex‑valve 
dose for the test treatment and a reference treatment. Descriptive summary by 
treatment groups are:  
o Salbutamol HFA-152a MDI  
o Salbutamol HFA‑134a MDI  
 
• Intercurrent events: 
Treatment discontinuation due to any reasons - Hypothetical strategy  
o Interest lies in the descriptive summary by treatment groups in a hypothetical 
scenario where no participant discontinued from the study. The individual PK 
concentrations affected by occurrence of the intercurrent event would be 
treated as missing from the occurrence of the intercurrent event until the end 
of the study and consequently affected individual PK parameters will be 
missing. 
 
Occurrence of emesis or coughing on dosing - Hypothetical strategy  
o Interest lies in the descriptive summary by treatment groups in a hypothetical 
scenario where no participant experiences an episode of coughing or emesis 


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Protocol (Final 2.0) 
10 Feb 2023 
22 
within a treatment that is judged by the investigator to have impacted inhaled 
drug delivery to the airways or swallowed drug absorption from the 
gastrointestinal tract. The individual PK concentrations affected by 
occurrence of the intercurrent event would be treated as missing from the 
occurrence of the intercurrent event until the end of the treatment (period) and 
consequently affected individual PK parameters will be missing for that 
treatment (period). 
 
Dosing error: Considered less than or more than prescribed dose and wrong 
treatment - Hypothetical strategy 
o Where the investigator is interested in the treatment effects in a hypothetical 
scenario where all participants have taken dose correctly as prescribed. The 
individual PK data affected by occurrence of the intercurrent event would be 
treated as missing from the occurrence of the intercurrent event until the end 
of the treatment (period) and consequently affected individual PK parameters 
will be missing for that treatment (period). 
 
• Rationale for estimand:  
The test formulation is developed to have comparable PK characteristics and 
treatment effects. Interest lies in the PK values obtained while the participant is 
exposed to correct dose as prescribed, prior to the discontinuation of the 
randomized sequence and prior to the occurrence of emesis or coughing on 
dosing. 
• Population-level summary:  
PK data of tmax and t1/2 will be summarized using descriptive statistics 
(arithmetic mean, geometric mean, median, 95% CI [arithmetic and geometric], 
standard deviation [arithmetic and on ln-scale], minimum, maximum, and 
geometric CV), and will be listed and summarized in tabular and/or graphical 
form. 
Secondary Estimand (2): 
The clinical question of interest is for the secondary objective: What is the geometric 
mean ratio (GMR) of the PD parameters of Salbutamol HFA-152a MDI vs Salbutamol 
HFA‑134a MDI after administration of single doses of salbutamol in healthy participants.  
• Population:  
Healthy male or female participants aged 18 to 55 years 
• Endpoints: 
o Minimum and 0-4h weighted mean serum potassium  
o Maximum and 0-4h weighted mean heart rate  
o Maximum and 0-4h weighted mean QTc interval 


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Protocol (Final 2.0) 
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• Treatment conditions: 
Salbutamol will be administered as a single 800 µg dose, given as 8 actuations 
each separated by a 20-second interval, each delivering 100 µg as the ex‑valve 
dose for the test treatment and a reference treatment. 
The comparison of interest is: The ratio of Salbutamol HFA-152a MDI vs 
Salbutamol HFA‑134a MDI.  
• Intercurrent events: 
Treatment discontinuation due to any reasons - hypothetical strategy  
o Interest lies in the comparisons of ratio of formulations in a hypothetical 
scenario where no participant discontinued from the study. The individual PD 
concentrations affected by occurrence of the intercurrent event would be 
treated as missing from the occurrence of the intercurrent event until the end 
of the study and consequently affected individual PD parameters will be 
missing. 
 
Occurrence of emesis or coughing on dosing - Hypothetical strategy  
o Interest lies in the comparisons of ratio of formulations in a hypothetical 
scenario where no participant experiences an episode of coughing or emesis 
within a treatment that is judged by the investigator to have impacted inhaled 
drug delivery to the airways or swallowed drug absorption from the 
gastrointestinal tract. The individual PD concentrations affected by 
occurrence of the intercurrent event would be treated as missing from the 
occurrence of the intercurrent event until the end of the treatment (period) and 
consequently affected individual PD parameters will be missing for that 
treatment (period). 
 
Dosing error: Considered less than or more than prescribed dose and wrong 
treatment - Hypothetical strategy 
o Where the investigator is interested in the treatment effects in a hypothetical 
scenario where all participants have taken dose correctly as prescribed. The 
individual PD concentrations affected by occurrence of the intercurrent event 
would be treated as missing from the occurrence of the intercurrent event 
until the end of the treatment (period) and consequently affected individual 
PD parameters will be missing for that treatment (period). 
 
• Rationale for estimand: 
Interest lies in the PD values obtained while the participant is exposed to correct 
dose as prescribed, prior to the discontinuation of the randomized sequence and 
prior to the occurrence of emesis or coughing on dosing. 


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Protocol (Final 2.0) 
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24 
• Population-level summary:  
Ratio of geometric mean (for logarithmic transformed values) and 90% CI for the 
ratio of the geometric means for serum potassium, heart rate and QTc interval 
(weighted means and minimum or maximum). 
Secondary Estimand (3): 
The clinical question of interest is for the secondary objective: What is the safety and 
tolerability profile of single doses of salbutamol in healthy participants delivered via 
MDI. 
• Population:  
Healthy male or female participants aged 18 to 55 years 
• Endpoints: 
o Incidence of AEs and SAEs  
o Pre- and post–dose 12-lead ECGs recording of HR, PR, QRS, QT and QTc 
intervals (absolute and change from baseline values). 
o Clinical laboratory (absolute values) 
o Vital signs (systolic and diastolic blood pressure and pulse rate) (absolute 
values) 
 
• Treatment conditions:  
Salbutamol will be administered as a single 800 µg dose, given as 8 actuations 
each separated by a 20-second interval, each delivering 100 µg as the ex‑valve 
dose for the test treatment and a reference treatment. Descriptive summary by 
treatment groups are: 
o Salbutamol HFA-152a MDI  
o Salbutamol HFA‑134a MDI 
 
• Remaining intercurrent events: 
Treatment discontinuation due to any reason - Treatment policy strategy. 
• Rationale for estimand: 
Safety data will be monitored throughout the study after the start of treatment. 
There is interest in evaluating and reporting safety events regardless of whether 
participants discontinued treatment. 


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Protocol (Final 2.0) 
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• Population-level summary:  
Frequency and percentages for incidence of AEs and SAEs. Absolute and changes 
from baseline values for pre-dose and post-dose 12-lead ECGs recording of HR, 
PR, QRS, QT and QTc intervals, absolute values for clinical laboratory values, 
and vital signs (systolic and diastolic blood pressure and pulse rate) parameters 
will be listed and will be summarized descriptively (arithmetic mean, SD, median, 
minimum, and maximum). 
Overall Design:  
This is a randomized, double-blind, single dose, 2-way cross-over study in healthy male 
and female participants with salbutamol. On each dosing day, salbutamol will be 
administered as a single 800 µg dose, given as 8 actuations each separated by a 
20-second interval, each delivering 100 µg as the ex-valve dose for the test treatment and 
a reference treatment. There will be a minimum washout period of 72 hours between each 
treatment period. 
Number of Participants:  
Thirty (30) participants will be included in the trial. 
Intervention Groups and Duration: 
While HFA-152a alone has been well-tolerated in humans, this is the first administration 
of salbutamol + HFA-152a. Therefore, a sentinel dosing approach will be utilized, so that 
any emergent safety signals from the combination can be identified prior to dosing of the 
broader cohort.  
 
For the first dose of the treatment sequence, sentinel dosing will be implemented in the 
first 2 participants. Two participants will be dosed (one to currently approved Ventolin 
Evohaler [HFA-134a] and one to Salbutamol HFA-152a MDI). Following review of a 
minimum of 24 hours safety data, all remaining 28 participants will be dosed. 
 
Remaining participants will be randomized only after review of at least 24 hours safety 
and tolerability data (i.e. AE/SAEs, clinical laboratory values, vital signs and 12-lead 
ECGs) from the sentinel participants by the Investigator or appropriately qualified 
delegate, in consultation with the Medical Monitor or delegate if unavailable, and it has 
been deemed safe to do so. 
 
The remaining 28 participants will be dosed in various groups in accordance with CRO 
bed space and clinical resourcing (e.g., 4 groups of seven or 2 groups of fourteen etc). 
The participant population will be assigned equally to the total number of treatment 
sequences. The site will have no visibility of the order in which the treatment arms are to 
be assigned as this will be managed by the RAMOS IRT system. 
 
 
 


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1.2. 
Schema 
Figure 1 
Study design overview 
 
 
 
 
 
 
 
 
 
Treatment A: 
Salbutamol HFA-152a MDI 
Treatment B: 
Salbutamol HFA-134a MDI 
HFA-152a=hydrofluoroalkane 1,1-difluoroethane; HFA-134a=hydrofluoroalkane 1,1,1,2-tetrafluoroethane; 
MDI=metered dose inhaler  
 
1.3. 
Schedule of activities (SoA) 
The Schedule of Activities (SoA) can be found in Table 1 on the next page. 
 
 
 
SCREENING 
DISCHARGE 
72 hours 
washout 
Sequence 
1 
 A-B 
Sequence 
2: 
 B-A 


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Table 1 
Schedule of Activities 
Procedure 
 
Screening  
 
Intervention perioda 
 
Discharge or early discontinuation 
 
Study day 
-28 to -1 
-1 
1 (pre-dose) 
1 
2 
3 
4 
5 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
Admission 
 
X 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
X 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Physical examinationb 
X 
 
 
 
 
 
 
Xb 
Body weight 
X 
X 
 
 
 
 
 
 
Height and BMI calculation 
X 
 
 
 
 
 
 
 
Medical history (includes substance usage) 
X 
 
 
 
 
 
 
 
Serum pregnancy test (females only) 
X 
X 
 
 
 
 
 
X 
FSH (females only) 
X 
 
 
 
 
 
 
 
Serology (HBsAg, anti-HCV, anti-HIV 1 and 2) 
X 
 
 
 
 
 
 
 
SARS-CoV-2 PCR testc 
 
X 
 
 
X 
 
 
 
Drug and alcohol screen 
X 
X 
 
 
 
 
 
 
Clinical laboratory assessmentsd 
X 
X 
 
 
 
 
 
X 
Blood sampling for serum potassium (PD) and 
glucose (safety)e 
 
 
Xe 
Xe 
 
 
Xe 
 
Vital signsf 
X 
X 
X 
X 
 
 
X 
X 
12-lead ECGg 
X 
X 
X 
X 
 
 
X 
X 
MDI teachingh 
 
X 
X 
 
 
 
X 
 
Randomization 
 
 
X 
 
 
 
 
 
Administration of study interventioni 
 
 
 
X 
 
 
X 
 
Blood sampling for PKj 
 
 
X 
X 
X 
 
X 
X 
AE reviewk 
 
 
 
Xi 
X 
X 
X 
X 
SAE reviewk 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 


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AE=adverse event; HCV=hepatitis C virus; HIV=human immunodeficiency virus; BMI=body mass index; ECG=electrocardiogram; FSH=follicle stimulating hormone; HBsAg=hepatitis B 
surface antigen; HR=heart rate; IMP=investigational medicinal product; MDI=metered dose inhaler; PCR= polymerase chain reaction; PD=pharmacodynamic(s); 
PK=pharmacokinetic(s); QTcF=QT interval corrected using Fridericia’s formula; SARS-CoV-2= severe acute respiratory syndrome-corona virus type 2; SAE=serious adverse event;  
a. 
Participants will be in the clinic for 1 period, from Day -1 until Day 5 (24 hours after the last dose on Day 4). 
b. 
Complete physical examinations will be conducted at screening. Symptom driven physical examinations may be conducted at discharge or any other time, per the 
investigator’s discretion. 
c. 
Sampling of nasal and throat mucosal cells for PCR testing for SARS-CoV-2. If deemed necessary, additional tests may be conducted during the study per site specific 
requirements. 
d. 
Clinical laboratory assessments (including clinical chemistry [includes liver chemistries], hematology, and urinalysis): at screening, on Day -1 (admission), and at discharge;  
e. 
Blood sampling for serum potassium (PD) and glucose (safety): on each dosing day (Day 1 and 4), blood samples will be taken pre-dose and at the following time points 
post-dose: 15 and 30 minutes and 1, 1.5, 2 and 4 hours post-dose. 
f. 
Vital signs (systolic and diastolic blood pressure, and pulse rate): vital signs will be recorded at screening, admission, on each dosing day (Day 1 and 4) at pre-dose and at 
the following time points post-dose: 15 and 30 minutes and 1, 1.5, 2 and 4 hours post-dose, and at discharge. 
g. 
12-lead ECG: 12-lead ECG will be recorded at screening, admission, on each dosing day (Day 1 and 4) at pre-dose and at the following time points post-dose: 15 and 
30 minutes and 1, 1.5, 2 and 4 hours post-dose, and at discharge. As the ECG parameters QTc and HR will be PD parameters, ECG will be measured in triplicate at 
pre-dose on Days 1 and 4. The 3 pre-dose measures will be averaged for QTc interval and HR to derive one baseline value. Each individual capture of the triplicate 12-lead 
ECG set will be separated by 1 to 5 minutes between the first and the third ECG. Post-dose 12-lead ECG measurements will be single measurements on both dosing days. 
Note: if an ECG meets potential stopping criteria, then the ECG measurement should be repeated in triplicate, with the averaged QT and QTcF used to determine stopping. 
h. 
Participants will be trained by using the
device on Day -1 and prior to each dosing on Days 1 and 4. Additional training instructions are provided using the
device which provides auditory feedback when the participant generates an adequate breath in: 
Day -1: using the 
 device, review the instructions, with particular focus on Steps 4-7. Once the participant is comfortable with using the training device, practice 
completing a sequence of 8 puffs.  
Dosing days: using the 
 device, review the instructions, and observe the patient performing a single puff using the training device. Provide feedback as necessary 
until proper technique is observed before conducting the full dose using the investigational inhaler. 
Additional training using the
 (eg, on Day 3) may be performed at the discretion of the clinic. 
i. 
Administration of study intervention: start of the 8 inhalations study intervention, with the inhalations administered at 20-second intervals. Note: All post-dose time points will 
be from start of dosing (first inhalation).  
j. 
PK blood sampling: on each dosing day (Day 1 and 4), PK blood samples will be taken at pre-dose, at 3, 5, 10, 15, 20, 30, and 45 minutes post-dose; and at 1, 1.5, 2, 3, 4, 5, 
6, 8, 10, 12, 16 and 24 hours post-dose for plasma salbutamol determination. PK collection will be from start of study intervention (i.e. first inhalation). When assessments are 
scheduled at the same time, ECG and vital signs will be taken first followed by the blood samples, with PK blood sampling on time. 
k. 
All SAEs will be collected from the signing of the ICF until discharge.  
All AEs will be collected from the start of study intervention until discharge. 
 
 
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2. 
INTRODUCTION 
2.1. 
Study rationale 
In the currently marketed Ventolin MDI, micronized particles of salbutamol are 
suspended in a propellant, currently HFA-134a. However, this propellant has significant 
GWP and hence its use in medicine and other applications is being phased out under 
mounting environmental pressure to replace it with a low carbon footprint alternative 
such as HFA-152a. 
GSK is seeking to develop a sustainable version of Ventolin Evohaler (salbutamol sulfate 
suspension in propellant hydrofluoroalkane, HFA-134a) to address global climate 
change.  
Salbutamol sulfate is a selective β2–adrenergic receptor agonist that acts on bronchial 
smooth muscle providing short acting (4 to 6 hour) bronchodilation with a fast onset 
(within 5 minutes) and is suitable for the relief and prevention of asthma symptoms and 
reversible airway obstruction. 
Inhaled salbutamol has been approved for human use since 1968 initially as an MDI 
containing CFC propellants. These were later replaced with propellant HFA-134a due to 
international treaties phasing out CFC production arising from environmental concern. 
The current product, Ventolin Evohaler, is approved in over 130 countries. 
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, had minimal impact on taste, 
and was rapidly cleared from the blood. HFA-152a has similar PK properties to the 
current HFA-134a propellant and has also been shown to have no toxic effect at vapor 
concentrations far in excess of those likely to be experienced by patients.  
The maximum recommended total daily dose of salbutamol for chronic use delivered via 
the Ventolin MDI is 800 µg. This dose requires 8 inhalations (800 µg salbutamol). The 
exposure to HFA-152a (8 x 63 µL) is estimated to be 454 µg/day (6.87 µmol/day). This 
is well below the exposures of HFA-152 shown to have no adverse effects in humans 
(Section 2.2.5.1). 
2.2. 
Background 
The current propellant used in Ventolin Evohaler MDI is a potent greenhouse gas, which 
urgently needs to be addressed to reduce our climate impact. GSK is developing a 
sustainable version of its Ventolin Evohaler product using an alternative new propellant 
(HFA-152a) with a much lower GWP compared to the current propellant HFA-134a. 
 
 
  
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2.2.1. 
Background information on the disease to be treated 
Salbutamol sulfate is used in the management of bronchospasm and reversible airway 
obstruction. These symptoms arise in patients with a variety of airway diseases including 
asthma, chronic bronchitis, and emphysema. The predominant use of salbutamol is in 
asthma, which is a heterogeneous disease usually characterized by chronic airway 
inflammation. It is defined by a history of respiratory symptoms such as wheeze, 
shortness of breath, chest tightness and cough that vary over time and in intensity, 
together with variable expiratory airflow limitation [GINA, 2022].  
Asthma is also usually associated with airway hyperresponsiveness to direct or indirect 
stimuli and with chronic airway inflammation. These features usually persist, even when 
symptoms are absent or lung function is normal but may normalize with treatment 
[GINA, 2022]. 
Approximately 339 million people currently suffer from asthma, and it is the most 
common noncommunicable disease among children [WHO, 2020]. Asthma requires 
medical assessment and care when it occurs on either a persistent, or intermittent but 
frequently recurring basis. Exacerbations of asthma are episodes characterized by a 
progressive increase in symptoms of shortness of breath, cough, wheezing, or chest 
tightness and a progressive decrease in lung function, such that they represent a change 
from the patient’s usual status that is sufficient to require a change in treatment [GINA, 
2022]. Severe exacerbations are potentially life threatening and their treatment requires 
close medical supervision [GINA, 2022]. 
Pharmacotherapy for asthma follows a stepwise process determined by symptoms and 
disease severity. The most common treatment options are short- and long-acting 
bronchodilators, corticosteroid anti-inflammatory agents, and combination products 
containing both bronchodilators and corticosteroids. Biological agents are also available 
for more severe disease in patients with eosinophilic asthma. Short-acting reliever 
medications such as salbutamol sulfate are a cornerstone of asthma therapy for as-needed 
relief of breakthrough symptoms, including worsening asthma or exacerbations [GINA, 
2022]. 
2.2.2. 
Background information on the product 
Salbutamol sulfate, the active ingredient in Ventolin Evohaler (HFA-134a), is approved 
in over 130 countries globally.  
Salbutamol sulfate is available in a variety of formulations suitable for inhalation by 
adults and children including solutions for nebulization, dry powder inhalers, and MDIs 
with or without spacers. Salbutamol sulfate is widely used in all severities of asthma to 
relieve and/or prevent symptoms. Salbutamol sulfate is a selective β2-adrenoceptor 
agonist that acts on the β2-adrenoceptors in bronchial smooth muscle providing short 
acting (4 to 6 hour) bronchodilation with a fast onset (within 5 minutes if salbutamol is 
inhaled) and is suitable for the relief and prevention of asthma symptoms and reversible 
airway obstruction. It is used to relieve symptoms when they occur and to prevent them 


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in those circumstances recognized by the patient to precipitate an asthma attack (e.g., 
before exercise or unavoidable allergen exposure). 
Information on the chemical structure of salbutamol sulfate is provided in Table 2. 
Table 2 
Structural information for salbutamol sulfate  
Structural formula: 
 
Molecular formula: 
(C13H21NO3)2×H2SO4 
ATC=Anatomical Therapeutic Chemical code 
Pharmacotherapeutic group: adrenergic, inhalants. Selective β2-adrenoreceptor agonists. ATC code: R03AC02 
The sustainable new version of Ventolin will use propellant HFA-152a which is being 
investigated to replace propellant HFA-134a. The chemical structures of these 
2 propellants are presented in Figure 2. 
Figure 2 
Chemical structures of HFA-134a and HFA-152a  
Propellant HFA-134a   
 
 
Propellant HFA-152a 
1,1,1,2–tetrafluoroethane 
 
 
1,1–difluoroethane 
 
 
Ventolin HFA-152a will be developed as a replacement product for the current Ventolin 
Evohaler (HFA-134a) with the same indications and posology. Ventolin HFA-152a is an 
MDI delivering 100 µg of salbutamol (as salbutamol sulfate) per dose; 200 doses per 
device. Salbutamol has a duration of action of 4 to 6 hours with administration of up to 
2 inhalations (200 µg total) not exceeding 4 times daily. 


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In this study, one formulation of salbutamol HFA-152a MDI will be compared to the 
current Ventolin Evohaler (HFA-134a).  
2.2.3. 
Quality development 
GSK’s Ventolin brand of salbutamol sulfate or salbutamol has existed as an MDI 
medicinal product and has been available to patients for over 50 years. The Ventolin MDI 
product was originally introduced containing CFC-based propellants (P11 and P12) with 
the drug substance salbutamol and oleic acid as a surfactant-type excipient. The product 
was later reformulated to remove CFC propellants and switched to a 2-component 
formulation comprising HFA propellant (HFA-134a), with the drug substance salbutamol 
sulfate, to address concerns about depletion of the ozone in the stratosphere over 20 years 
ago. This product is referred to as Ventolin Evohaler (HFA-134a). 
2.2.4. 
Nonclinical development 
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 current ICH guidelines for the technical requirements of nonclinical 
testing of pharmaceuticals for human use. 
 
 
 
 
 
 
  
 
 
 
 
 
 
2.2.5. 
Clinical development 
Inhaled salbutamol sulfate marketed as Ventolin has been approved for human use since 
1968 initially as an MDI containing CFC propellants and later replaced with propellant 
HFA-134a with continued positive risk-benefit profile. GSK is now planning to replace 
the HFA-134a propellant with the HFA-152a propellant to reduce its global warming 
potential as stated above. 
2.2.5.1. 
Background information on propellant HFA-152a 
In humans, a study was performed to determine the uptake, distribution, and elimination 
of HFA-152a during and after short-term inhalation exposure [Ernstgård, 2012]. Healthy 
participants were exposed to 0 ppm, 200 ppm or 1000 ppm HFA-152a for 2 hours at light 
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exercise in an exposure chamber. Capillary blood, urine, and exhaled air were sampled up 
to 22 hours post-exposure and analyzed for HFA-152a. Fluoride and other potential 
metabolites were analyzed in urine. Symptoms of irritation and central nervous system 
effects were rated, and inflammatory markers were analyzed in blood. Within a few 
minutes of exposure to 200 and 1000 ppm, HFA-152a increased rapidly in blood and 
reached average levels of 7.4 and 34.3 μM, respectively. The post-exposure decreases in 
blood were fast and parallel to those in exhaled air. The estimated net uptake during 
exposure to 1000 ppm of 6.6 mmol (6.7%) equates to the amount exhaled post-exposure. 
About 20 μmol excess fluoride (0.013% of inhaled HFA-152a on a molar basis) was 
excreted in urine after exposure to 1000 ppm, compared to control. No 
fluorine-containing metabolites were detected in urine. Symptom ratings and changes in 
inflammatory markers revealed no exposure-related effects. 
2.2.5.2. 
Salbutamol sulfate and propellant HFA-152a MDI 
At the maximum recommended daily dose of 8 inhalations of salbutamol sulfate, the 
exposure to HFA-152a (8 x 63 µL) is estimated to be 454 µg/day (6.87 µmol/day). This 
is well below the exposures shown to have no adverse effects in humans. The human 
peak blood exposure (Cmax) of HFA-152a from the salbutamol HFA-152a propellant 
MDI for 8 actuations of 63 µL (delivering a total dose of 800 µg of salbutamol) is 
estimated to be 1.739 mg/L (26.2 µmol/L). This represents acute and transient exposure 
to HFA-152a, whereas, following extended exposure 1000 ppm of HFA-152a for 2 hours 
in an exposure chamber resulted in average concentrations of 34.3 μmol/L, which was 
well tolerated, had minimal impact on taste, and was rapidly cleared from the blood. 
Therefore, HFA-152a is expected to have similar characteristics to the HFA-134a 
propellant used in the currently marketed Ventolin Evohaler (HFA-134a), in that it has 
been shown to have no toxic effect at vapor concentrations in excess of those likely to be 
experienced by patients. 
CCI


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2.3. 
Benefit/risk assessment 
This study will be conducted to assess the PK and safety of salbutamol delivered via MDI 
containing propellant HFA-152a, and to compare to MDI containing propellant 
HFA-134a. There is no added benefit expected for the healthy participants. A risk 
assessment has been presented in Section 2.3.1. 
 


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2.3.1. 
Risk assessment 
Potential risk of clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study interventions 
Based on nonclinical and clinical studies conducted with 
HFA-152a, and information from the SmPC of Ventolin 
Evohaler (salbutamol sulfate containing propellant 
HFA-134a), the safety concerns following salbutamol 
dosing at the levels employed in this study include 
hypokalemia, hyperglycemia, and cardiovascular effects 
(including tachycardia and, in rare cases, cardiac 
arrythmias).  
Hypokalemia: β-adrenergic agonist medicines may 
produce significant hypokalemia in some patients, 
possibly through intracellular shunting, which has the 
potential to produce adverse cardiovascular effects. The 
decrease in serum potassium is usually transient, not 
requiring supplementation. 
Hyperglycemia: β-adrenergic agonist medicines may 
produce a transient rise in serum glucose which is not 
expected to be clinically significant with inhalational 
administration. However, large doses of intravenous 
salbuterol have been reported to aggravate preexisting 
diabetes mellitus and ketoacidosis. 
Cardiovascular effects: β-adrenergic agonist medicines 
may produce clinically significant cardiovascular effects in 
some patients such as changes in pulse rate or blood 
pressure. In addition, β-agonists have been reported to 
produce ECG changes, such as flattening of the T wave, 
prolongation of the QTc interval, and ST segment 
depression. The clinical relevance of these findings is 
unknown. 
  
Healthy participants are included who will be carefully 
screened against the defined inclusion and exclusion 
criteria (including overall cardiac health, vital signs, ECG 
interval values, and lab safety values [including serum 
potassium and glucose levels) and by ECG monitoring 
and lab PD/safety assessments (including serum 
potassium and glucose levels) as per the SoA. 
A sentinel dosing approach will be implemented for the 
first dosing period such that post-dose safety data in a 
limited number of participants will be reviewed prior to 
further dosing. 
 
Study procedures 
There are no specific risks associated with the study 
design.  
 
 


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Potential risk of clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
Other 
COVID-19 infection 
The risk-benefit assessment for the participants receiving 
the study intervention remains unchanged in relation to 
the COVID-19 pandemic as available clinical data do not 
suggest that administration of salbutamol will lead to 
suppression or modulation of the immune system. In 
addition, the mode of action does not appear to have any 
clinically significant adverse effects on the respiratory or 
cardiovascular system, which are the systems most 
affected by a SARS-CoV-2 infection. 
As the participants to be included in this study are in 
general young to middle aged without major 
comorbidities, the study population is not considered to 
be a high-risk population for serious COVID-19. Only 
persons with a negative SARS-CoV-2 test at admission to 
the clinical research centre will be allowed to participate in 
the study. In addition, all appropriate measures to prevent 
SARS-CoV-2 infection during the study will be taken as 
detailed in Section 4.2.2. 
COVID-19=coronavirus disease 2019; ECG=electrocardiogram; HFA-134a=1,1,1,2-tetrafluoroethane ; HFA-152a=1,1-difluoroethane; SARS-CoV-2=severe acute respiratory 
syndrome-corona virus type 2; SmPC=summary of product characteristics; SoA=schedule of activities


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2.3.2. 
Benefit assessment 
The study data will provide generally applicable information to support understanding of 
the PK and PD for all MDI-based therapies with salbutamol and based on HFA-152a as a 
propellant. 
2.3.3. 
Overall benefit-risk conclusion 
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with salbutamol sulfate suspension in propellant 
HFA-152a (Test) or HFA-134a (Reference) are justified by the anticipated benefits to all 
ongoing and future programs with HFA-152a as a propellant.  
 
 
 


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3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
Table 3 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
To characterise the PK of single doses of 
salbutamol in healthy participants delivered via 
an MDI containing propellant HFA-152a, and to 
compare to an MDI containing propellant 
HFA-134a 
• 
AUC(0-30min) 
• 
AUC(0-∞) 
• 
AUC(0-t) 
• 
Cmax 
Secondary 
Pharmacokinetics: To characterise the PK of 
single doses of salbutamol in healthy 
participants delivered via an MDI containing 
propellant HFA-152a, and to compare to an 
MDI containing propellant HFA-134a 
• 
Tmax 
• 
t1/2 
Pharmacodynamics: To characterise the PD 
of single doses of salbutamol in healthy 
participants delivered via an MDI containing 
propellant HFA-152a, and to compare to an 
MDI containing propellant HFA-134a 
 
• 
Minimum and 0-4h weighted mean serum 
potassium  
• 
Maximum and 0-4h weighted mean heart 
rate  
• 
Maximum and 0-4h weighted mean QTc 
interval  
Safety: To characterise the safety and 
tolerability of single doses of salbutamol in 
healthy participants delivered via an MDI 
containing propellant HFA-152a, and to 
compare to an MDI containing propellant 
HFA-134a 
 
• 
Incidence of AEs and SAEs 
• 
Pre- and post-dose 12-lead ECGs 
recording of HR, PR, QRS, QT and QTc 
intervals (absolute and change from 
baseline values) 
• 
Clinical laboratory assessment (absolute 
values) 
• 
Vital signs (systolic and diastolic blood 
pressure and pulse rate) (absolute 
values) 
 
AUC=area under the curve; ECG=electrocardiogram; HFA-134a=1,1,1,2-tetrafluoroethane ; HFA-152a=1,1-
difluoroethane ; HR=heart rate; MDI=metered dose inhaler; PD=pharmacodynamic(s); PK=pharmacokinetic(s) 


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3.1. 
Primary Estimand: 
The primary clinical question of interest is: What is the geometric mean ratio (GMR) of 
the PK parameters of Salbutamol HFA-152a MDI vs Salbutamol HFA‑134a MDI after 
administration of single doses of salbutamol in healthy participants. 
 
The estimand is described by the following attributes: 
  
• Population:  
Healthy male or female participants aged 18 to 55 years 
• Endpoints:  
AUC (0-∞), AUC (0-30min), AUC (0-t) and Cmax 
• Treatment Conditions:  
• Salbutamol will be administered as a single 800 µg dose, given as 8 actuations 
each separated by a 20-second interval, each delivering 100 µg as the ex‑valve 
dose for the test treatment and a reference treatment. 
The comparison of interest is: The ratio of Salbutamol HFA-152a MDI vs 
Salbutamol HFA‑134a MDI.   
• Intercurrent events: 
 
Treatment discontinuation due to any reasons - Hypothetical Strategy  
o Interest lies in the comparisons of ratio of two formulations in a hypothetical 
scenario where no participant discontinued from the study. The individual PK 
concentrations affected by occurrence of the intercurrent event would be 
treated as missing from the occurrence of the intercurrent event until the end 
of the study and consequently affected individual PK parameters will be 
missing. 
 
Occurrence of emesis or coughing on dosing - Hypothetical strategy  
o Interest lies in the comparisons of ratio of two formulations in a hypothetical 
scenario where no participant experiences an episode of coughing or emesis 
within a treatment that is judged by the investigator to have impacted inhaled 
drug delivery to the airways or swallowed drug absorption from the 
gastrointestinal tract. The individual PK concentrations affected by 
occurrence of the intercurrent event would be treated as missing from the 
occurrence of the intercurrent event until the end of the treatment (period) and 
consequently affected individual PK parameters will be missing for that 
treatment (period). 
 


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Dosing error: Considered less than or more than prescribed dose and wrong 
treatment - Hypothetical strategy 
o Where the investigator is interested in the treatment effects in a hypothetical 
scenario where all participants have taken dose correctly as prescribed. The 
individual PK data affected by occurrence of the intercurrent event would be 
treated as missing from the occurrence of the intercurrent event until the end 
of the treatment (period) and consequently affected individual PK parameters 
will be missing for that treatment (period). 
 
• Rationale for estimand: The test formulation is developed to have comparable 
PK characteristics and treatment effects. Interest lies in the PK values obtained 
while the participant is exposed to correct dose as prescribed, prior to the 
discontinuation of the randomized sequence and prior to the occurrence of emesis 
or coughing on dosing. 
• Population-level summary: Ratio of geometric mean (for logarithmic 
transformed values) and 90% CI for the ratio of the geometric means for 
AUC(0-∞), AUC (0-t), AUC(0-30min), and Cmax. 
 
3.2. 
Secondary Estimand (1): 
The clinical question of interest for the secondary objective is: What is the summarized 
PK profile using descriptive statistics for tmax and t1/2 after administration of single doses 
of salbutamol in healthy participants. 
The estimand is described by the following attributes: 
• Population:  
Healthy male or female participants aged 18 to 55 years 
•  Endpoints: 
tmax and t1/2 
• Treatment conditions:  
Salbutamol will be administered as a single 800 µg dose, given as 8 actuations 
each separated by a 20-second interval, each delivering 100 µg as the ex‑valve 
dose for the test treatment and a reference treatment. Descriptive summary by 
treatment groups are:  
o Salbutamol HFA-152a MDI 
o Salbutamol HFA‑134a MDI  
 


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• Intercurrent events: 
Treatment discontinuation due to any reasons - Hypothetical strategy  
o Interest lies in the descriptive summary by treatment groups in a hypothetical 
scenario where no participant discontinued from the study. The individual PK 
concentrations affected by occurrence of the intercurrent event would be 
treated as missing from the occurrence of the intercurrent event until the end 
of the study and consequently affected individual PK parameters will be 
missing. 
 
Occurrence of emesis or coughing on dosing - Hypothetical strategy  
o Interest lies in the descriptive summary by treatment groups in a hypothetical 
scenario where no participant experiences an episode of coughing or emesis 
within a treatment that is judged by the investigator to have impacted inhaled 
drug delivery to the airways or swallowed drug absorption from the 
gastrointestinal tract. The individual PK concentrations affected by 
occurrence of the intercurrent event would be treated as missing from the 
occurrence of the intercurrent event until the end of the treatment (period) and 
consequently affected individual PK parameters will be missing for that 
treatment (period). 
 
Dosing error: Considered less than or more than prescribed dose and wrong 
treatment - Hypothetical strategy 
o Where the investigator is interested in the treatment effects in a hypothetical 
scenario where all participants have taken dose correctly as prescribed. The 
individual PK data affected by occurrence of the intercurrent event would be 
treated as missing from the occurrence of the intercurrent event until the end 
of the treatment (period) and consequently affected individual PK parameters 
will be missing for that treatment (period). 
 
• Rationale for estimand:  
The test formulation is developed to have comparable PK characteristics and 
treatment effects. Interest lies in the PK values obtained while the participant is 
exposed to correct dose as prescribed, prior to the discontinuation of the 
randomized sequence and prior to the occurrence of emesis or coughing on 
dosing. 
• Population-level summary:  
PK data of tmax and t1/2 will be summarized using descriptive statistics 
(arithmetic mean, geometric mean, median, 95% CI [arithmetic and geometric], 
standard deviation [arithmetic and on ln-scale], minimum, maximum, and 


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geometric CV), and will be listed and summarized in tabular and/or graphical 
form. 
3.3. 
Secondary Estimand (2): 
The clinical question of interest is for the secondary objective: What is the geometric 
mean ratio (GMR) of the PD parameters of Salbutamol HFA-152a MDI vs Salbutamol 
HFA‑134a MDI after administration of single doses of salbutamol in healthy participants. 
• Population:  
Healthy male or female participants aged 18 to 55 years 
• Endpoints: 
o Minimum and 0-4h weighted mean serum potassium  
o Maximum and 0-4h weighted mean heart rate  
o Maximum and 0-4h weighted mean QTc interval 
 
• Treatment conditions: 
Salbutamol will be administered as a single 800 µg dose, given as 8 actuations 
each separated by a 20-second interval, each delivering 100 µg as the ex‑valve 
dose for the test treatment and a reference treatment. 
The comparison of interest is: The ratio of Salbutamol HFA-152a MDI vs 
Salbutamol HFA‑134a MDI. 
• Intercurrent events: 
Treatment discontinuation due to any reasons - hypothetical strategy  
o Interest lies in the comparisons of ratio of formulations in a hypothetical 
scenario where no participant discontinued from the study. The individual PD 
concentrations affected by occurrence of the intercurrent event would be 
treated as missing from the occurrence of the intercurrent event until the end 
of the study and consequently affected individual PD parameters will be 
missing. 
 
Occurrence of emesis or coughing on dosing - Hypothetical strategy  
o Interest lies in the comparisons of the ratio of formulations in a hypothetical 
scenario where no participant experiences an episode of coughing or emesis 
within a treatment that is judged by the investigator to have impacted inhaled 
drug delivery to the airways or swallowed drug absorption from the 
gastrointestinal tract. The individual PD concentrations affected by 
occurrence of the intercurrent event would be treated as missing from the 
occurrence of the intercurrent event until the end of the treatment (period) and 
consequently affected individual PD parameters will be missing for that 
treatment (period). 


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Dosing error: Considered less than or more than prescribed dose and wrong 
treatment - Hypothetical strategy 
o Where the investigator is interested in the treatment effects in a hypothetical 
scenario where all participants have taken dose correctly as prescribed. The 
individual PD data affected by occurrence of the intercurrent event would be 
treated as missing from the occurrence of the intercurrent event until the end 
of the treatment (period) and consequently affected individual PD parameters 
will be missing for that treatment (period). 
 
• Rationale for estimand: 
Interest lies in the PD values obtained while the participant is exposed to correct 
dose as prescribed, prior to the discontinuation of the randomized sequence and 
prior to the occurrence of emesis or coughing on dosing. 
• Population-level summary:  
Ratio of geometric mean (for logarithmic transformed values) and 90% CI for the 
ratio of the geometric means for serum potassium, heart rate and QTc interval 
(weighted means and minimum or maximum). 
3.4. 
Secondary Estimand (3): 
The clinical question of interest is for the secondary objective: What is the safety and 
tolerability profile of single doses of salbutamol in healthy participants delivered via 
MDIs. 
• Population:  
Healthy male or female participants aged 18 to 55 years 
• Endpoints: 
o Incidence of AEs and SAEs  
o Pre- and post-dose 12-lead ECGs recording of HR, PR, QRS, QT and QTc 
intervals (absolute and change from baseline values). 
o Clinical laboratory (absolute values) 
o Vital signs (systolic and diastolic blood pressure and pulse rate) (absolute 
values) 
 
• Treatment conditions:  
Salbutamol will be administered as a single 800 µg dose, given as 8 actuations 
each separated by a 20-second interval, each delivering 100 µg as the ex‑valve 
dose for the test treatment and a reference treatment.  
o Salbutamol HFA-152a MDI 


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o Salbutamol HFA‑134a MDI 
 
• Remaining intercurrent events: 
Treatment discontinuation due to any reason - Treatment policy strategy. 
• Rationale for estimand: 
Safety data will be monitored throughout the study after the start of treatment. 
There is interest in evaluating and reporting safety events regardless of whether 
participants discontinued treatment. 
• Population-level summary:  
Frequency and percentages for incidence of AEs and SAEs. Absolute and changes 
from baseline values for pre-dose and post-dose 12-lead ECG recording of HR, 
PR, QRS, QT and QTc intervals, absolute values for clinical laboratory values, 
and vital signs (systolic and diastolic blood pressure and pulse rate) parameters 
will be listed and will be summarized descriptively (arithmetic mean, SD, median, 
minimum, and maximum). 
 
4. 
STUDY DESIGN 
4.1. 
Overall design 
This is a randomized, double-blind, single dose, 2-way cross-over study in healthy male 
and female participants with salbutamol. Salbutamol will be administered as a single 
800 µg dose, given as 8 actuations at 20-second intervals, each delivering 100 µg as the 
ex-valve dose for the test treatment and a reference treatment. There will be a minimum 
washout period of 72 hours between each treatment period. 
Participants will be randomly assigned to one of 2 treatment sequences in 2 treatment 
periods using a cross-over design. The following treatment sequences will be tested: 
Treatment Sequence 1: AB 
Treatment Sequence 2: BA 
For the first dose of the treatment sequence, the first 2 participants will be randomized to 
one of the following: currently approved Ventolin or Salbutamol HFA-152a MDI.  
Remaining participants will be randomized only after review of at least 24 hours safety 
and tolerability data (i.e. AE/SAEs, clinical laboratory values, vital signs and 12-lead 
ECGs) from the sentinel participants by the Investigator or appropriately qualified 
delegate, in consultation with the Medical Monitor or delegate if unavailable, and it has 
been deemed safe to do so. 


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The remaining 28 participants will be dosed in various groups in accordance with CRO 
bed space and clinical resourcing 
 
. The participant population will be assigned equally to the total number of treatment 
sequences. The site will have no visibility of the order in which the treatment arms are to 
be assigned as this will be managed by the RAMOS IRT system. 
4.2. 
Scientific rationale for study design 
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. 
Additionally, the duration of exposure is sufficiently short to not be able to provide clear 
therapeutic benefit and justify patients discontinuing current therapies. Moreover, use of 
healthy participants as opposed to patients will allow a clearer interpretation of the study 
results, as there will be no confounding factors resulting from changes in disease state 
and/or concomitant medications. 
A cross-over design to compare the different treatments was chosen to reduce the 
influence of confounding covariates as each participant serves as their own control. The 
cross-over design requires a small number of participants compared to a parallel group 
design. Carryover effects are expected to be eliminated by introducing a washout phase 
of a minimum of 72 hours between study drug administrations (expected to be equivalent 
to at least 5 half-lives of salbutamol). 
4.2.1. 
Participant input into design 
Not applicable.  
4.2.2. 
COVID-19 risk mitigation 
This study will be conducted in accordance with guidance from the Central Committee 
on Research Involving Human Subjects CCMO Dutch CA on conducting Phase 1 trials in 
clinical research centres in the Netherlands during the COVID-19 pandemic. 
During the entire study, the clinical research centre will implement all recommendations 
issued by the Dutch government, including specific guidelines related to clinical research 
executed in clinical research centres with respect to minimizing the risk of disease 
spreading (e.g., social distancing, disinfection, hygiene, and wearing of personal 
protection equipment by study staff). Details on specific procedures are described in the 
site-specific manual.  
In cases where participants are not able to attend study visits due to an infection with 
SARS-CoV-2, the investigator will discuss with the sponsor potential mitigation 
approaches (including, but not limited to, extending the visit window, conducting 
evaluations via video link or phone call, allowing for safety procedures to be conducted 
at a local facility). The rationale (e.g., the specific limitation imposed by the 
SARS-CoV-2 infection that led to the inability to perform the protocol specified 
assessment) and outcome of the discussion will be documented in the eCRF. 
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In addition, the following containment measures will be taken during the study: 
• PCR testing for SARS-CoV-2 will be performed at the time points indicated in the 
SoA. 
• A participant should not be admitted if there was any close contact with a person who 
tested positive for SARS-CoV-2 or a COVID-19 patient within the last 2 weeks prior 
to admission to the clinical research centre. 
• If a participant is tested to be SARS-CoV-2 positive on Day -1, the participant will be 
excluded from participation with reference to Exclusion Criterion 26, and referred for 
treatment. 
• Physical examinations will be limited. 
• If a participant becomes ill and/or is tested to be SARS-CoV-2 positive after the first 
administration of study intervention, dosing will be stopped. 
Furthermore, it is not anticipated that there will be any interaction between the study 
intervention and any of the currently approved vaccines against SARS-CoV-2 that would 
lead to increased risk to the participant above that of receiving such a vaccination without 
participating in this study. Therefore, both vaccinated and unvaccinated participants are 
allowed. However, to mitigate against any interruptions to study-related procedures and 
assessments, vaccination against SARS-CoV-2 is not allowed from 2 weeks prior to 
admission until discharge (i.e., up to Day 11) (see Exclusion Criterion 8). 
These COVID-19 risk mitigation measures will be kept in place for as long as the 
pandemic is ongoing, as defined by country and site-specific regulations. Once the 
pandemic has ended, SARS-CoV-2 testing may be omitted at the discretion of the 
investigator. 
4.3. 
Justification for dose 
The dose of 800 µg was chosen to ensure adequate plasma concentration-time profile to 
estimate the AUC(0-∞) with minimal extrapolation (assuming a LLOQ of 50 pg/mL) and 
minimize within- and between-participant variability in inhaled drug dosing. In addition, 
the 800 µg dose (8 inhalations) is the maximum recommended daily dose for salbutamol 
which has been approved in the EU. Any differences in systemic exposure between the 
(2) test and (single) reference formulations at this dose level are not expected to increase 
the risk of known safety concerns with salbutamol, which (as per Section 2.3.1) are being 
mitigated in any case via careful participant screening and safety assessments.  
Three previous studies (Study 200921 SALB1002 and SALB1003) used a single dose of 
600, 1200 and 1200 µg. Study 200921 only collected PK samples for 12 hours, 
SALB1002 and SALB1003 collected PK samples for 24 hours. Based on these data, 
800 µg would give lowest quantifiable concentrations of 100 pg/mL assuming the HFA-
152a MDI produces similar concentrations. Where reported in these studies, treatments 
were generally well tolerated with no clinically significant laboratory safety 


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abnormalities and no serious adverse events. Adverse events were those expected with 
high dose beta2- agonists but reported in low numbers, these included: tremor, 
palpitations, tachycardia, flushing and headache which was usually the most frequently 
reported event. 
At the proposed dose of 8 inhalations of salbutamol sulfate, the exposure to HFA-152a 
(8 x 63 µL) is estimated to be 454 µg/day (6.87 µmol/day). This is well below the 
exposures shown to have no adverse effects in humans (see Section 2.2.5.2). 
4.4. 
End-of-study definition 
A participant is considered to have completed the study if the participant has completed 
the 2 treatments of the study including the last visit or the last scheduled procedure 
shown in the SoA. 
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.  
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
It is aimed to enrol up to 30 healthy male and female participants. 
5.1. 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply:
1. 
Sex 
: 
male or female; females may be of childbearing potential, of  
 
 
nonchildbearing potential, or postmenopausal 
2. 
Age 
: 
18 to 55 years, inclusive, at screening 
3. 
BMI 
: 
18.0 to 30.0 kg/m2, inclusive, at screening 
4. 
Weight 
: 
≥50 kg 
5. 
Status 
: 
healthy participants 
6. 
At screening, females must not be pregnant or lactating, or of nonchildbearing 
potential (see for definition Section 10.4.1.2). 
7. 
Female participants of childbearing potential (see for definition Section 10.4.1.1) 
who have a fertile male sexual partner must agree to use adequate contraception as 
described in Section 10.4.2. 
8. 
Male participants, if not surgically sterilized, must agree to use adequate 
contraception as described in Section 10.4.2.  


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9. 
All prescribed medication must have been stopped at least 30 days prior to admission 
to the clinical research centre based on investigator judgment. An exception is made 
for hormonal contraceptives, which may be used throughout the study. 
10. All over-the-counter medication, vitamin preparations and other food supplements, 
or herbal medications (e.g., St. John’s wort) must have been stopped at least 14 days 
prior to admission to the clinical research centre based on investigator judgment. An 
exception is made for acetaminophen, which is allowed up to admission to the 
clinical research centre. 
11. Ability and willingness to abstain from alcohol from 48 hours (2 days) prior to 
screening, and from 48 hours (2 days) prior to admission until discharge from the 
clinical research centre. 
12. Ability and willingness to abstain from methylxanthine-containing beverages or food 
(coffee, tea, cola, chocolate, energy drinks) from 48 hours (2 days) prior to 
admission to the clinical research centre.  
13. Good physical and mental health on the basis of medical history, physical 
examination, clinical laboratory, ECG, and vital signs, as judged by the investigator.  
14. Serum potassium and serum glucose levels within reference ranges of the clinical 
research centre.  
15. Willing and able to sign the ICF. 
5.2. 
Exclusion criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. 
History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematologic, or neurological disorders capable of significantly altering 
the absorption, metabolism, or elimination of drugs; constituting a risk when taking 
the study intervention or interfering with the interpretation of data. 
2. 
History or presence of any form of asthma, including childhood asthma and exercise 
induced asthma. 
3. 
Systolic blood pressure <90 mmHg or >140 mmHg, or diastolic blood pressure 
<50 mmHg or >90 mmHg. 
4. 
History of pathological tachycardia, or a pulse rate > 85 bpm at screening or Day -1. 
5. 
Lymphoma, leukemia, or any malignancy within the past 5 years except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years. 
6. 
Breast cancer within the past 10 years. 
7. 
A QTcF value of >450 msec at screening based on a single measurement. 
8. 
Vaccine(s) within 2 weeks prior to admission, or plans to receive such vaccines 
during the study. 
9. Donation or loss of more than 450 mL of blood within 60 days prior to (the first) drug 
administration. Donation or loss of more than 1.5 L of blood (for male participants) or 


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more than 1.0 L of blood (for female participants) in the 10 months prior to (the first) 
drug administration in the current study. 
10. Participation in a drug study within 30 days prior to (the first) drug administration in 
the current study. Participation in 4 or more other drug studies in the 12 months prior 
to (the first) drug administration in the current study. 
11. Current enrollment or past participation in this clinical study. 
12. ALT >1.5x ULN.  
13. Total bilirubin >1.5xULN (isolated total bilirubin >1.5xULN is acceptable if total 
bilirubin is fractionated and direct bilirubin <35%). 
14. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
15. Presence of HBsAg at screening or within 3 months prior to first dose of study 
intervention. 
16. Positive hepatitis C antibody test result at screening or within 3 months prior to first 
dose of study intervention. NOTE: Participants with positive hepatitis C antibody 
test result due to prior resolved disease can be enrolled if a confirmatory negative 
hepatitis C RNA test is obtained. 
17. Positive pre-study drug/alcohol screen, including THC. 
18. Positive HIV antibody test. 
19. Cotinine levels indicative of smoking or history or use of tobacco- or 
nicotine-containing products within 6 months prior to screening 
20. Average intake of more than 24 units of alcohol per week (clinical site standard: 
1 unit of alcohol equals approximately 250 mL of beer, 100 mL of wine, or 35 mL of 
spirits). 
21. Regular use of known drugs of abuse, including tetrahydrocannabinol. 
22. Use of combustible tobacco products, and non-combustible nicotine delivery 
systems, inclusive of cigarettes, cigars, pipes, and materials used to “vape” within 
6 months prior to screening. 
23. Hypersensitivity to heparin or heparin-induced thrombocytopenia. 
24. 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. 
25. Use of any products intended to treat medical conditions that are not approved by the 
governing health authority in a given country or region (for example, herbal 
medicine, health supplements, traditional medicine, homeopathic remedies, etc.). 
26. Positive nasopharyngeal PCR test for SARS-CoV-2 on Day -1 or any known close 
contact with a person who tested positive for SARS-CoV-2 or with a COVID-19 
patient within 2 weeks prior to admission. 


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27. Impairment which would prevent the correct and consistent use of an MDI, as 
determined by the investigator. 
5.3. 
Lifestyle considerations 
5.3.1. 
Meals and dietary restrictions 
• A fasting period of at least 4 hours is required before obtaining clinical laboratory 
blood samples at all time points. 
• Participants will be advised not to consume any foods containing poppy seeds within 
48 hours (2 days) prior to admission to the clinical research centre as this could cause 
a false positive drug screen result. 
• Meals and snacks (such as decaffeinated coffee, herbal tea, fruit, biscuits) will be 
provided according to the standard operating procedures of the clinical research 
centre. A light supper will be provided on the evening before dosing days. 
• Study drug will be administered to participants after a light breakfast. Participants 
will fast for a period of 4 hours after drug administration on all dosing days, i.e., until 
scheduled lunch. During fasting, no fluids other than water are allowed; water is 
allowed ad libitum throughout. 
5.3.2. 
Caffeine, alcohol, and tobacco 
• 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 admission until after collection of the final PK sample. 
• During the study, participants will abstain from alcohol from 48 hours prior to 
admission until after collection of the final PK sample. 
• Use of tobacco products will not be allowed from 6 months prior to screening until 
after discharge. 
5.3.3. 
Activity 
• 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). 
5.3.4. 
Other restrictions 
• Participants must not donate blood during the study until discharge (other than the 
blood sampling planned for this study). 
5.4. 
Screen failures 
A screen failure occurs when a participant who has consented to participate in the clinical 
study is not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 


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CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes (but not limited to) demography, screen failure 
details, eligibility criteria, 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.  
5.5. 
Criteria for temporarily delaying administration of study 
intervention 
Not applicable for this study. 
6. 
STUDY INTERVENTIONS AND CONCOMITANT 
THERAPY 
The definition of study intervention is defined as a set of investigational product(s) or 
marketed products or placebo intended to be administered to a participant.  
Note: “Study intervention” and “study treatment” are used interchangeably unless 
otherwise specified. 
6.1. 
Study intervention(s) administered 
Table 4 
Study Intervention(s) Administered 
Intervention Label 
 
Treatment A 
Treatment B 
Intervention Name 
Salbutamol HFA-152a MDI 
Salbutamol HFA-134a MDI 
Intervention 
Description 
 
A single 800 µg dose, given as 8 x 
100 µg (ex-valve) at 20-second 
intervals 
A single 800 µg dose, given as 8 x 100 µg 
(ex-valve) at 20-second intervals 
Type  
 
Test 
Reference 
Dose Formulation 
Salbutamol sulfate HFA-152a 
suspension 
Salbutamol sulfate HFA-134a suspension 
Unit Dose Strength(s) 
100 µg (ex-valve)  
100 µg (ex-valve)  
Dosage Level(s) 
800 µg 
800 µg 
Route of 
Administration 
Inhalation 
Inhalation 
Use 
 
Experimental 
Active comparator 
IMP and NIMP/AxMP. 
IMP  
IMP  
Sourcing 
GSK 
GSK 
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. 


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AxMP=auxiliary medicinal product; HFA-134a=1,1,1,2-tetrafluoroethane; HFA-152a=1,1-difluoroethane; 
IMP=investigational medicinal product; MDI=metered dose inhaler; NIMP=noninvestigational medicinal product 
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 
(± 1 hour) on each dosing day.  
The start and end-time of the dosing will be recorded (clock time and as precise as in 
seconds). 
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. 
• 
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 8.4.6 and 10.6) and appropriately managed by GSK. 
Of note, MDIs need to be primed before use. The priming of the MDIs should not be 
done in the vicinity of the participants, as unintended inhalation of micronized particles 
of salbutamol may affect the salbutamol plasma concentrations of the participants. 
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, or authorized site staff is responsible for study intervention 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records). 
• Further guidance and information for the final disposition of unused study 
interventions are provided in the pharmacy manual. 
• Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, medical monitor and/or GSK 
study contact. 


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• A MSDS or 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 IRT 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.  
6.4. 
Blinding 
Participants will be randomly assigned to 1 of 2 treatment sequences in 2 treatment 
periods using a cross-over design as indicated in Section 4.1 (Overall design).  
Investigators will remain blinded to each participant’s assigned study intervention 
throughout the course of the study. Each participant will be dispensed blinded study 
intervention, labelled with the participant’s unique randomization number, throughout the 
study. 
Participants will be instructed to avoid discussing the taste, dosing frequency, or 
packaging of the study intervention with the investigator. 
In the event of a quality assurance audit, the auditor(s) will be allowed access to 
unblinded study intervention records at the site to verify that randomization/dispensing 
has been conducted accurately. 
A participant will be withdrawn if the participant’s intervention code is unblinded by the 
investigator or treating physician. 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 


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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. 
This is a double-blind study in which participants and investigators are blinded to study 
intervention. The RAMOS NG will be programmed with blind-breaking instructions. In 
case of an emergency, the investigator has the sole responsibility for determining if 
unblinding of a participant’s 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. 
If the investigator is unable to access RAMOS NG, they can contact the GSK helpdesk 
(available 24/24 hours and 7/7 days) based on the information provided in the study 
specific manuals.  
6.5. 
Study intervention compliance 
When participants are dosed at the site, they will receive study intervention directly from 
the investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents.  
In order 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 
 which provide flow 
and co-ordination coaching. 
6.6. 
Dose modification 
In this study a fixed dose level will be administered. Dose modifications will not be 
applicable.  
6.7. 
Continued access to study intervention after the end of the 
study 
Participants will not receive any additional treatment from GSK after completion of the 
study because only healthy participants are eligible for study participation. 
6.8. 
Treatment of overdose 
An overdose is any dose of study intervention given to a participant that exceeds the 
planned, randomized dose for an individual within a given dose group.  
GSK does not recommend specific treatment for an overdose. 
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6.9. 
Prior and concomitant therapy 
The use of all prescribed medication is not allowed from 30 days prior to admission to the 
clinical research centre until discharge (i.e., up to Day 5 or early discontinuation). An 
exception is made for hormonal contraceptives, which are allowed throughout the study.  
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 14 days 
prior to admission to the clinical research centre until discharge.  
Vaccination (including vaccination against SARS-CoV-2) is not allowed from 2 weeks 
prior to admission until discharge. 
Acetaminophen (paracetamol), at doses of 2 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. 
The reason is that acetaminophen may decrease the excretion rate of salbutamol, which 
could result in a higher serum level (drugbank online). Other concomitant medications 
may be considered on a case-by-case basis by the investigator in consultation with the 
GSK Medical Monitor. 
Other medication to treat AEs may only be prescribed if deemed necessary by the 
investigator. If medication is used, the name of the drug, the dose, and dosage regimen 
will be recorded in the eCRF. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study intervention 
‘Discontinuation’ of study intervention refers to any participant who has not received all 
planned 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: 
Reasons 
Additional items/Sub-reasons 
AE 
Unsolicited AE 
Solicited AE 


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Reasons 
Additional items/Sub-reasons 
Lost to follow-up 
Subject Relocated  
Subject was Incarcerated  
Other, specify 
Unknown 
Participant Reached Protocol-Defined 
Stopping Criteria 
Liver chemistry stopping criteria  
QTc Stopping criteria  
Physician Decision 
Specify 
Pregnancy 
  
Protocol Deviation 
Specify 
Site Terminated by Sponsor 
  
Study Terminated by Sponsor 
  
Withdrawal by Participant 
Burden of Procedure  
Participant Relocated  
COVID-19 Pandemic  
Other 
Other 
Specify 
Death 
  
AE=adverse event; COVID-19=coronavirus disease-19; QTc=corrected QT interval 
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 3 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. 
 


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Figure 3 
Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; ULN = 
upper limit of normal 
Refer to Section 10.5 (Appendix 5) for required liver safety actions and follow-up 
Assessments. 
7.1.2. 
QTc stopping criteria 
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline [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 potential stopping criteria, then the ECG measurement 
should be repeated in triplicate, with the averaged QT and QTcF values used to determine 
stopping. 


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− 
QTcF > 500 msec 
− 
QT uncorrected > 600 msec 
− 
Change from baseline: QTcF > 60 msec 
 
7.2. 
Participant discontinuation/withdrawal from the study 
A participant may withdraw from the study at any time at the participant’s own request 
for any reason (or without providing any reason). 
A participant may be withdrawn at any time at the discretion of the investigator for 
safety, behavioural, or compliance reasons. 
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. The participant will be followed up in quarantine in the clinical 
research centre until complete elimination of the study compound or will be asked to 
quarantine at home according to guidelines of the Dutch government. 
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 early discontinuation 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. 
All data and samples collected up to and including the date of withdrawal of/last contact 
with the participant will be included in the study analyses. If the participant withdraws 
consent for disclosure of future information, the sponsor may retain and continue to use 
any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, the participant may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 
The primary reason for participant discontinuation/withdrawal from the study will be 
documented in the eCRF based on the list below: 
Reasons 
Additional items/Sub-reasons 
AE 
Unsolicited AE 
Solicited AE 


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Reasons 
Additional items/Sub-reasons 
Lost to follow-up 
Subject Relocated  
Subject was Incarcerated  
Other, specify 
Unknown 
Participant Reached Protocol-Defined 
Stopping Criteria 
 
Liver chemistry stopping criteria  
QTc Stopping criteria  
Physician Decision 
Specify 
Pregnancy 
  
Protocol Deviation 
Specify 
Site Terminated by Sponsor 
  
Study Terminated by Sponsor 
  
Withdrawal by Participant 
Burden of Procedure  
Participant Relocated  
COVID-19 Pandemic  
Other 
Other 
Specify 
Death 
  
AE=adverse event; COVID-19=coronavirus disease-19 
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 10.3.6.5). 
7.3. 
Lost to follow-up 
A participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 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. 


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• 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 Schedule of activities 
(SoA). 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. Participants who have signed informed 
consent but are not eligible to proceed should be recorded in the eCRF with a status 
of ‘screen failure’. 
• 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. 
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 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 and vaccination history by interviewing the participants 
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 
Efficacy and/or immunogenicity will not be evaluated in this study. 


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8.3. 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA (see Section 1.3). 
8.3.1. 
Physical examination 
• A complete physical examination will include, at a minimum, assessments of the 
(cardiovascular, respiratory, gastrointestinal, and neurological) systems. Height and 
weight 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 
supine position. Manual techniques will be used only if an automated device is not 
available. 
8.3.3. 
Electrocardiograms 
• A standard 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) 
using an ECG machine that automatically calculates the HR and measures PR, QRS, 
QT, and QTcF 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. 
• Pre-dose 12-lead ECG will be measured in triplicate. The 3 pre-dose measures will be 
averaged for QTc interval and HR to derive one baseline value. Each individual 
capture of the triplicate 12-lead ECG set will be separated by 1 to 5 minutes between 
the first and the third ECG. Screening and post-dose 12-lead ECG measurements will 
be single measurements.  
8.3.4. 
Clinical safety laboratory tests 
• See Section 10.2 for the list of clinical laboratory tests to be performed in accordance 
with 
 and the SoA (Section 1.3). 
• The investigator must review the laboratory results, document this review, and record 
any clinically significant changes occurring during the study as an AE. The laboratory 
results must be retained with source documents.  
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 1 day after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. 
o 
In the absence of a diagnosis, abnormal laboratory findings assessments or 
other abnormal results the investigator considers clinically significant will 
be recorded as an AE or SAE, if they meet the definition of an AE or SAE 
(refer to Sections 10.3.1 and 10.3.2).  
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o 
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. 
o 
If laboratory values from non-protocol-specified laboratory tests performed 
at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g, 
SAE or AE), then the results must be recorded. 
The addresses of clinical laboratories performing the laboratory assessments are 
documented in the Protocol Supporting Documentation.  
8.3.5. 
Pregnancy testing 
• Female participants of childbearing potential must perform a blood pregnancy test 
before the administration of any dose of study intervention. Pregnancy testing must 
be done even if the participant is menstruating at the time of the study visit. The study 
intervention may only be administered if the pregnancy test is negative. 
• Refer to Section 8.4.5 for the information on study continuation for participants who 
become pregnant during 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 7). This 
includes events reported by the participant. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.4.1. 
Time period and frequency for collecting AE, SAE, and other 
safety information 
All SAEs will be collected from the signing of the ICF until discharge at the time points 
specified in the SoA.  
All AEs will be collected from the start of study intervention until discharge at the 
timepoints specified in the SoA. 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded as medical history, 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 


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investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
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, at any time after a participant has been discharged from the study, and 
the investigator considers the event to be reasonably related to the study intervention or 
study participation, the investigator must promptly notify the sponsor. 
8.4.2. 
Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.3.6.5. 
8.4.4. 
Regulatory reporting requirements for SAEs  
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of 
a study intervention under clinical investigation are met. See Section 8.4.1 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 10.3.6.3. 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB, IFU, or package insert (as applicable) and will 
notify the IRB/IEC, if appropriate according to local requirements. 


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Table 5 
Timeframes for submitting SAE and pregnancy 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 Adverse Events 
Report 
24 hours* 
paper Adverse Events Report 
Pregnancies  
24 hours* 
paper pregnancy 
notification report  
24 hours * 
paper pregnancy follow-up 
report 
SAE(s)=serious adverse events 
* Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
‡ Paper Adverse Events 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. 
8.4.5. 
Pregnancy 
Female participants who become pregnant after the first study intervention dose must not 
receive subsequent doses of the study intervention but may continue other study 
procedures at the discretion of the investigator. 
• Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study intervention and 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 participant or 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, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• The participant/pregnant female partner will be followed to determine the outcome of 
the pregnancy. The investigator will collect follow-up information on the 
participant/pregnant female partner and the neonate and the information will be 
forwarded to the sponsor. See Table 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 8.4.4. While the investigator is not obligated to actively seek this information 
in former study participants/pregnant female partners, he or she may learn of an SAE 
through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 


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8.4.6. 
Contact information for reporting SAEs and pregnancies 
Table 6 
Contact information for reporting SAEs and pregnancies  
Study contact for questions regarding 
SAEs and pregnancies  
 
Study contact for reporting of stopping 
rules  
Contact GSK’s local and/or medical contacts 
If a stopping rule is met, the investigator must 
immediately inform GSKs Local and/or Medical 
contacts. 
Contacts for reporting SAEs and 
pregnancies  
 
Available 24/24 hours and 7/7 days 
OAX37649@gsk.com  
Back-up study contact for escalation of 
stopping rules  
 
OAX37649@gsk.com OR facsimile number 
+44-20-8754 7822. 
 
8.4.7. 
Medical device Deficiencies 
Medical devices are being provided for use in this study as the study intervention. To 
fulfil 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 10.6. 
NOTE: Deficiencies fulfilling the definition of an AE/SAE will follow the processes 
outlined in Section 10.6 of the protocol.  
8.4.11.1. 
Time Period for Detecting Medical Device Deficiencies 
• Medical device deficiencies that result in an incident will be detected, documented, 
and reported during all periods of the study in which the medical device is used. 
• If the investigator learns of any device deficiency at any time after a participant has 
been discharged from the study, and such a deficiency is considered reasonably 
related to a medical device provided for the study, the investigator will promptly 
notify the sponsor. 
The method of documenting medical device deficiencies is provided in Section 10.6. 
8.4.11.2. 
Follow-up of Medical Device Deficiencies 
• Follow-up applies to all participants, including those who discontinue study 
intervention. 
• The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
• New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator. 


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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 via 
email/facsimile equipment. If email/facsimile equipment is unavailable, then 
notification by telephone is acceptable with a copy of the data collection tool sent by 
overnight mail or courier service. 
• The sponsor will be the contact for the receipt of device deficiency reports. 
 
8.4.11.4. 
Regulatory Reporting Requirements for Device Deficiencies 
• The investigator will promptly report all device deficiencies occurring with any 
medical device provided for use in the study in order for the sponsor to fulfill the 
legal responsibility to notify appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices being used in clinical 
studies. 
• 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 
Blood samples of approximately 6 mL will be collected for measurement of plasma 
concentrations of salbutamol as specified in the SoA (Section 1.3). 
Plasma salbutamol will be analyzed by solid phase extraction in combination with 
LC-MS-MS with a lower limit of quantification of 50 pg/mL. 
Instructions for the collection and handling of plasma samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
Details of PK blood sampling collection, processing, storage and shipping procedures are 
provided in the Lab Manual to be prepared by GSK. 
8.6. 
Pharmacodynamics 
The following PD parameters will be evaluated and compared: serum potassium 
weighted means and minimum serum potassium.  
Blood samples of approximately 3.5 mL will be collected for measurement of potassium 
concentrations in serum as specified in the SoA (Section 1.3).  
Serum potassium concentrations will be assessed by the 
 
 
CCI


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8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Immunogenicity assessments 
Immunogenicity is not evaluated in this study.  
8.10. 
Health economics or medical resource utilization and health 
economics 
Health economics OR medical resource utilization and health economics parameters are 
not evaluated in this study. 
8.11. 
Timing of assessments 
8.11.1. 
Timing of dosing 
The study intervention will be administered between 08:00 and 10:00 hours in the 
morning. Dosing for each individual participant will be at around the same time (±1 hour) 
on each dosing day. 
8.11.2. 
PK blood sampling 
For PK blood samples, pre-dose samples will be obtained between waking up and dosing. 
Post-dose samples up to 30 minutes post-dose will be obtained with a time window of ±1 
minute. Thereafter, post-dose samples will be obtained with time margins of ±5% of the 
time that has passed since (last) dosing.  
8.11.3. 
PD blood sampling 
For PD blood samples, pre-dose samples will be obtained between waking up and dosing. 
Post-dose samples up to 30 minutes post-dose will be obtained with a time window of 
±2 minutes. Thereafter, post-dose samples will be obtained with time margins of ±5% of 
the time that has passed since (last) dosing. 
8.11.4. 
Safety assessments 
For safety assessments, pre-dose assessments will be performed between waking up and 
dosing. For safety assessments up to 2.5 hours post-dose, a time window of ±15 minutes 
is allowed. Thereafter, serial post-dose assessments (e.g., multiple assessments within 


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any given day) will be performed with time margins of ±10% of the time that has passed 
since (last) dosing. 
When assessments are planned for the same scheme time, the order of the assessments 
should be arranged in such a way that ECG and vital signs will be done first followed by 
the PK (then PD) blood sampling, with PK blood sampling exactly on time. 
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. The statistical analysis plan will be finalized prior to database lock. 
Any deviation from the statistical analysis plan will be reported in the Section “Changes 
in Planned Analysis” in the CSR. 
9.1. 
Statistical hypotheses 
This study is designed to compare the PK profile of salbutamol HFA-152a MDI and 
salbutamol HFA-134a MDI (currently marketed Ventolin product). For each primary PK 
endpoint (AUC[0-30], AUC[0-∞], AUC[0-t] and Cmax), point estimates and 
corresponding 90% CIs will be constructed for the ratio of the geometric mean of the test 
treatment to the geometric mean of the reference treatment, μ(test)/μ(reference). 
 
The comparison of interest is: The ratio of Salbutamol HFA-152a MDI vs Salbutamol 
HFA-134a MDI (A vs B). 
 
Refer to Section 9.3.1 for the statistical analysis.  
 
9.2. 
Analysis sets 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Enrolled  
• 
All participants who entered the study (who were 
randomized or received study intervention or underwent a 
post screening study procedure). 
• 
Note screening failures (who never passed screening even 
if rescreened) and participants screened but never enrolled 
into the study (met eligibility but not needed) are excluded 
from the Enrolled analysis set as they did not enter the 
study. 
• 
Study Population 
Screened 
• 
All Participants who were screened for eligibility 
• 
Study Population 
Safety 
• 
All participants who received at least one dose of study 
intervention. 
• 
Safety 


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Analysis Set 
Definition / Criteria 
Analyses Evaluated 
PK 
• 
All participants in the Safety analysis set who had at least 1 
non-missing PK assessment (Non-quantifiable values will 
be considered as non-missing values). 
• 
Data will be reported according to the actual study 
intervention. 
• 
PK 
PD 
• 
All participants who received at least one dose of study 
intervention and have at least 1 non-missing potassium 
concentration result. 
• 
PD 
9.3. 
Statistical analyses 
9.3.1. 
Pharmacokinetic analysis 
PK analysis will be the responsibility of the 
 
 Plasma concentration-time data will be analysed by 
noncompartmental methods with WinNonlin 8.3. Calculations will be based on the actual 
sampling times recorded during the study. From the plasma concentration-time data, the 
PK parameters will be determined as indicated in Table 7, as data permit. 
Table 7 
Pharmacokinetic parameters 
Parameter 
Description 
AUC(0-30min) 
Area under the plasma concentration-time curve up to 30 minutes post-dose 
AUC(0-∞) 
Area under the plasma concentration-time curve from time 0 to infinity 
calculated as: AUC0-inf=AUC0-t+Clast/kel, 
where Clast is the last measurable plasma concentration and Kel is the 
elimination rate constant 
AUC(0-t) 
Area under the plasma concentration-time curve up to time t, where t is the 
last point with concentrations above the LLOQ 
Cmax 
Maximum observed plasma concentration 
tmax 
Time to Cmax 
t1/2 
Apparent terminal phase half-life 
 
The primary PK parameters are AUC(0-30min), AUC(0-t), AUC(0-∞) and Cmax. 
PK data will be summarized, listed and may be presented in graphical form and will be 
summarised descriptively. 
The PK parameters AUC(0-30min), AUC(0-∞), AUC(0-t) (where it is the last point with 
concentrations above the LLOQ), and Cmax will be statistically analysed. The 
comparison of interest is described in Section 9.1. 
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Following log(e)-transformation, AUC parameters and Cmax will be separately analysed 
using a mixed effects model with fixed effect terms for period and treatment. Participant 
will be treated as a random effect in the model. Point estimates and their associated 90% 
CI will be constructed for the comparisons stated in Section 9.1. The point estimates and 
their associated 90% CI will then be back-transformed to provide point estimates and 
90% CI for the ratios, as described in Section 9.1. 
9.3.2. 
Safety analysis 
Safety and tolerability will be assessed through AEs, clinical laboratory, vital signs, and 
ECGs, and any other parameter that is relevant for safety assessment. Safety analysis is 
described in further detail below. 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively.  
9.3.2.1. 
Adverse events 
Frequency and percentages for incidence of AEs and SAEs will be provided. Absolute 
and changes from baseline values for 12-lead ECG, and absolute values for clinical 
laboratory values, vital signs (systolic and diastolic blood pressure and pulse rate) 
parameters will be listed and will be summarized descriptively (arithmetic mean, SD, 
median, minimum, and maximum). A listing of all individual AEs and SAEs will be 
provided. Summary tables of TEAEs (eg. including tremor, palpitations, tachycardia, 
flushing and headache) and SAEs will be presented by system organ class based on the 
MedDRA terminology list (preferred terms): 1 containing the number of TEAEs 
(frequency and percentage for incidence by treatment and 1 containing the number of 
drug-related TEAEs (frequency of occurrence, number of participants experiencing the 
event) per treatment. Additional tables of total counts by treatment and relationship and 
by treatment and severity will be given. 
9.3.2.2. 
Clinical laboratory 
Clinical laboratory data (absolute values) will be listed accompanied by an indication of 
whether the parameter is outside the reference range. A summary of all data outside the 
reference range of the clinical laboratory will be provided. Clinical laboratory data will 
be presented descriptively, where applicable. If a clinical laboratory value is clinically 
significant as judged by the investigator, then the clinical laboratory value will be 
recorded as an AE.   
9.3.2.3. 
Vital signs and electrocardiograms 
Absolute values for vital signs (systolic and diastolic blood pressure and pulse rate) will 
be listed and will be presented descriptively (arithmetic mean, SD, median, minimum, 
and maximum). 


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Absolute and changes from baseline values for ECG parameters detailed in Section 8.3.3 
will be listed and will be presented descriptively (arithmetic mean, SD, median, 
minimum, and maximum), where applicable. 
In addition, the following ECG parameters will be summarised by treatment groups: QTc 
interval and HR (change from baseline and absolute values), and peak HR and peak QTc 
interval (absolute values). Three pre-dose measures will be averaged for QTc interval and 
HR to derive one baseline value. 
If an absolute value for vital signs or ECG parameters is clinically significant as judged 
by the investigator, then the value will be recorded as an AE. 
9.3.3. 
Pharmacodynamic analysis 
The following PD parameters will be evaluated and compared: serum potassium HR and 
QTcF, as weighted means and minimum or maximum. 
All PD data will be summarized using descriptive statistics (arithmetic mean, geometric 
mean, %CV, SD, median, minimum, and maximum) and will be listed and summarized 
in tabular and/or graphical form. 
PD parameters (serum potassium, HR and QTcF as weighted means and minimum or 
maximum) will be separately analysed using a mixed effects model with fixed effect 
terms for period and treatment. Participant will be treated as a random effect in the 
model. Point estimates and their associated 90% CI will be constructed for the 
comparisons stated above. If necessary, additional analysis will be performed in 
accordance with current regulatory guidelines. 
9.4. 
Interim analyses 
Not applicable.  
9.5. 
Sample size determination 
The target number of participants is chosen to achieve sufficient half width of the 90% 
CI, in the estimate of the geometric mean ratios for the primary endpoints. Assuming a 
within-participant CVw of 25.4% for Cmax and 22% for AUC parameters (from 
previously conducted studies (Study 200921, Study SALB1003)), the sample size of 
30 participants is expected to result in a half-width of the 90% CI for Test/Reference ratio 
of 11.61% for Cmax and 10.02% for the AUC parameters. 
Presented in Table 8 below are the half width of the 90% CI for observed treatment 
ratios, based on varying sample size and by fixing CVw% of 25.4% for Cmax and 22% 
for AUC. 


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Table 8 
Sample size sensitivity table 
Parameter 
Sample 
size 
Within Subject SD 
Half width of the 90% CI for 
Observed Treatment Ratio 
AUC(0-inf) 
18 
0.22 (CVw=22%) 
13.49% 
24 
0.22 (CVw=22%) 
11.38% 
Cmax 
18 
0.25 (CVw=25.4%) 
15.66% 
24 
0.25 (CVw=25.4%) 
13.20% 
CI=confidence interval; CVw=coefficient of variation within 
It is assumed that all AUC parameters will follow a similar level of variability as 
AUC(0-∞). 
Note: A sample size of 18, and a CVw of 22%, the half width of the 90% CI for observed 
treatment ratio of AUC between two treatment arms is estimated to be within 13.49% of 
the point estimate. (As an example, if the observed treatment ratio is 0.95, the upper 
bound of the 90% CI for observed treatment ratio will be 0.95*(1+0.1349) = 1.08 and the 
lower bound will be 0.95/(1+0.1349) = 0.84). 
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: 
o 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS international ethical guidelines 
o 
Applicable ICH GCP guidelines 
o 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.  
• Any 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.  


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• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following, as applicable: 
o 
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 
o 
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
o 
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), and all other applicable local 
regulations 
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 
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 local regulations, ICH guidelines, privacy, and data protection requirements, 
where applicable, and the IRB/IEC or study centre. 
• The medical record must include a statement that 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. 
Participants who are rescreened are required to sign a new ICF and will be assigned a 
new participant number. 
In case of unexpected pregnancy, participant must be informed that personal information 
such as date of birth and sex of the baby will be collected as part of safety follow-up. 


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Consent for the baby may be obtained from the participant and/or their partner as per 
local regulations. 
If partners of male participants become pregnant during the study, consent will be needed 
to be obtained or notification given as per local regulation to the partner before collecting 
their personal information such as last menstrual period and year of birth, or personal 
information such as date of birth as sex of their baby as part of safety follow-up. 
10.1.4. 
Recruitment strategy 
Participants will be identified for potential recruitment using clinical database, and 
IEC/IRB-approved newspaper/radio/social media advertisements, prior to consenting to 
take part in this study. 
10.1.5. 
Data protection 
• Participants will be assigned a unique identifier by the investigator. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
• GSK will ensure protection of the personal data of the investigator and site staff 
which is collected within the framework of and for the purpose of the study. 
• The participant must be informed that their personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant that 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 to data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect 
such data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. 
10.1.6. 
Committees structure 
Not Applicable. 


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10.1.7. 
Dissemination of Clinical Study Data 
• The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study Register in compliance with 
applicable regulations/GSK policy. GSK will aim to register protocols summaries 
prior to study start and target results summaries submission within 12 months of 
primary/ study completion date. Where external regulations require earlier disclosure, 
GSK will follow those timelines.  
• Where required by regulation, summaries will also be posted on applicable national 
or regional clinical study registers. 
• Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the study report, and provided reasonable access to 
statistical tables, figures, and relevant reports. GSK will also provide the investigator 
with the full summary of the study results, including a summary of trial results 
understandable to laypersons. The investigator is encouraged to share the plain 
language summary with the study participants, as appropriate. The full study report 
will be made available upon request, after decision on marketing authorization by 
regulatory authorities.  
• GSK will provide the investigator with the randomization codes and participant-level 
line listings for their site only after completion of the full statistical analysis. 
• GSK intends to make anonymized participant-level data from this study available to 
external researchers for scientific analyses or to conduct further research that can help 
advance medical science or improve patient care. This helps ensure the data provided 
by study participants are used to maximum effect in the creation of knowledge and 
understanding. 
10.1.8. 
Data quality assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 
• Guidance on completion of eCRFs will be provided in eCRF completion guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
• QTLs will be predefined in the Action Item Key Decision Log to identify 
systematic issues that can impact participant safety and/or reliability of study 
results. These predefined parameters will be monitored during the study, and 
important deviations from the QTLs and remedial actions taken will be 
summarized in the CSR. 
• Monitoring details describing strategy, including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), 
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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.  
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 is 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. 


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The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or temporarily suspended, the sponsor shall 
promptly inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
temporary suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up. 
10.1.11. 
Publication policy 
The results of this study may be published in peer reviewed scientific literature and/or 
presented at scientific meetings. The sponsor will comply with the requirements for 
publication of study results in accordance with standard editorial and ethical practice and 
as per the sponsor’s internal policy. Authorship will be determined by mutual agreement 
and in line with ICMJE authorship requirements. 
10.2. 
Appendix 2: Clinical laboratory tests 
• The tests detailed in Table 9 will be performed at the 
 
 
• Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 
Table 9 
Protocol-required safety laboratory tests  
Laboratory Tests 
Parameters 
 Hematology 
• 
Platelet count 
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Laboratory Tests 
Parameters 
• 
Red blood cell (RBC) count 
• 
RBC indices 
o 
Mean corpuscular volume (MCV) 
o 
Mean corpuscular hemoglobin (MCH) 
o 
%Reticulocytes 
• Absolute white 
blood cell (WBC) 
count with 
differential: 
o Neutrophils 
o Lymphocytes 
o Monocytes 
o Eosinophils 
o Basophils 
• Hemoglobin 
• Hematocrit 
 Clinical chemistry 
• Blood urea nitrogen 
(BUN)/urea 
• Potassium** 
• Creatinine* 
• Sodium 
• Calcium 
• Glucose (fasting)** 
• Creatine 
phosphokinase 
(CPK) 
• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic 
transaminase (SGOT) 
• Alanine aminotransferase (ALT)/serum glutamic-pyruvic 
transaminase (SGPT) 
• Alkaline phosphatase 
• Total bilirubin 
• Direct bilirubin 
• Total protein 
 Routine urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones by dipstick 
• Microscopic examination (urine sediment examinations will only be performed if there is 
an abnormality in urinalysis in accordance with 
 
 Pregnancy test 
• Highly sensitive serum human chorionic gonadotropin (hCG) pregnancy test (as needed 
for WOCBP) 
CCI


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Laboratory Tests 
Parameters 
 Other screening tests • Follicle stimulating hormone (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)] 
• PCR testing for SARS-CoV-2 
* To assess the kidney function, use the estimated glomerular filtration rate (eGFR) 2021 calculator (CKD-Epi 
creatinine equation). eGFR (based on CKD-Epi) will be measured at all time points when creatinine is measured.  
** Blood sampling for serum potassium and glucose on each dosing day (Day 1 and 4) and at the following time 
points: pre-dose and 15 and 30 minutes, 1, 1.5, 2 and 4 hours post dose 
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. 


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• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• Events that occur as a result of protocol-mandated procedures (i.e. invasive 
procedures, modification of participant’s previous therapeutic regimen). 
Events NOT meeting the AE definition  
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
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 that 
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. 


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d. Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study participant 
f. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) 
g. Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
h. Other situations: 
• 
Possible Hy’s Law case: ALT ≥ 3x ULN AND total bilirubin ≥ 2x ULN (>35% 
direct bilirubin) or international normalized ratio (INR) >1.5 must be reported as 
SAE 
• 
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
o 
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. 
Solicited events 
• 
Definition of solicited event 
• 
Solicited AEs are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participant in their diary.  
10.3.4. 
Unsolicited AE 
• 
Definition of unsolicited AE 
• 
An unsolicited AE is an AE that was not solicited using a participant diary and that 
is communicated by a participant who has signed the informed consent. 
Unsolicited AEs include serious and nonserious AEs. 
• 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, emergency room visit, or visit to/by a healthcare 
provider). The participant will be instructed to contact the site as soon as possible 
to report medically attended event(s), as well as any events that, though not 
medically attended, are of participant concern. Detailed information about reported 


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unsolicited AEs will be collected by qualified site personnel and documented in 
the participant’s records. 
• 
Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant will be collected during an interview with the participant and by review 
of available medical records at the next visit. 
10.3.5. 
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. 
10.3.6. 
Recording, assessment and follow-up of AE, SAE, and 
pregnancies 
10.3.6.1. 
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 GSK, AE/SAE required form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
10.3.6.2. 
Assessment of intensity 
The investigator will make an assessment of intensity for each AE and SAE 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 


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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.  
10.3.6.3. 
Assessment of causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• 
For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
• 
The investigator must review and provide an assessment of causality for each 
AE/SAE and document this in the medical notes There may be situations in which an 
SAE has occurred and the investigator has minimal information to include in the 
initial report to GSK. However, it is very important that the investigator always 
make an assessment of causality for every event before the initial transmission 
of the SAE data to GSK. 
• 
The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
10.3.6.4. 
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). 


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10.3.6.5. 
Follow-up of AEs, SAEs, pregnancies or any other events of interest  
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any postmortem 
findings including histopathology. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
After the initial AE/SAE/pregnancy or any other event of interest, the investigator is 
required to proactively follow each participant at subsequent visits/contacts. All SAEs, 
will be followed until the event is resolved, stabilized, otherwise explained, or the 
participant is lost to follow-up. 
Other nonserious AEs must be followed until follow-up or until the participant is lost to 
follow-up. 
Follow-up during the study 
AEs documented at a previous visit/contact and defined as not recovered/not resolved or 
recovering/resolving will be reviewed at subsequent visits/contacts until follow-up or 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 post-mortem findings, 
including histopathology. 
Follow-up of pregnancies 
Pregnant participants will be followed to determine the outcome of the pregnancy. At the 
end of the pregnancy, whether full-term or premature, information on the status of the 
mother and child will be forwarded to GSK using the paper pregnancy report and the 
Adverse Events 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 10.3.7. 


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10.3.6.6. 
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 8.4.6). 
10.3.7. 
Reporting of SAEs and pregnancies 
SAE reporting to GSK via an electronic data collection tool 
• 
The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor by telephone. 
• 
If the site during the course of the study 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 via the national spontaneous 
reporting system. These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in Section 8.4.6. 
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 8.4.6. 


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10.4. 
Appendix 4: Contraceptive and barrier guidance 
10.4.1. 
Definitions 
10.4.1.1. 
Woman of childbearing potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
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 
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 one 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. 


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10.4.2. 
Contraception guidance 
Female participants of childbearing potential with fertile male partners must use one of 
the following contraceptive methods from at least 4 weeks prior to first study intervention 
until 90 days post-dose of last study intervention. 
• 
Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception. 
• 
Use of a highly effective contraceptive (see list below) plus partner use of a condom. 
 
Male participants with female partners of childbearing potential must use one of the 
following contraceptive methods for 48 hours post-dose of last study intervention. 
Investigators are responsible for consulting with participants on selection of contraceptive 
methods. 
• 
Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception. 
• 
Condom plus partner use of a highly effective contraceptive (see list below). 
 
Highly effective contraceptive methods with a failure rate of < 1% 
• Oral contraceptive, either combined or progestogen alone 
• Injectable progestogen 
• Implants of etonogestrel or levonorgestrel 
• Percutaneous contraceptive patches 
• Intra-urine devices (hormonal or copper) 
10.5. 
Appendix 5: Liver safety: suggested actions and follow-up 
assessments 
Phase 1 liver chemistry increased monitoring criteria have been designed to assure 
participant safety and to evaluate liver event aetiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
 
 


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Phase 1 liver chemistry increased monitoring criteria and required follow-up 
assessments 
Liver Chemistry Increased Monitoring Criteria 
ALT-absolute 
ALT≥3xULN 
If ALT≥3xULN AND bilirubin1,2  2xULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE. 
See additional Actions and Follow-Up Assessments listed below 
Required Actions and Follow-up Assessments following Liver Event 
Actions 
Follow-Up Assessments 
• Report the event to GSK within 24 hours 
• Complete the liver event CRF, and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2 
• Perform liver event follow-up assessments 
• Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below) 
• Viral hepatitis serology3 
• Blood sample for PK analysis, 
obtained within 72 hrs of identified 
liver event.4 
• Serum CPK and LDH. 
• Fractionated bilirubin (i.e., 
direct and indirect 
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 AE report form 
• Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, 
other over-the-counter medications. 
• Record alcohol use on the liver event 
alcohol intake case report form 


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MONITORING: 
If ALT≥3xULN AND bilirubin  2xULN or INR 
>1.5: 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow-up assessments within 24 hrs 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to within 
baseline 
• A specialist or hepatology consultation is 
recommended 
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5: 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow-up assessments within 24-72 hrs 
• Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
If ALT≥3xULN AND bilirubin  2xULN 
or INR >1.5: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total IgG (or gamma 
globulins). 
• Assess history of acetaminophen 
usage in the past week. 
• Liver imaging (ultrasound, magnetic 
resonance, or computerized 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms. 
 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury. 
2. All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, 
if INR measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an 
SAE INR measurement is not required and the threshold value stated will not apply to participants 
receiving anticoagulants 
3. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
Hepatitis cRNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody; Hepatitis 
E IgM antibody 
4. Record the date/time of the PK blood sample draw and the date/time of the dose of study intervention prior 
to blood sample draw on the CRF. Instructions for sample handling and shipping are in the Lab Manual. 
10.6. 
Appendix 6: Medical device AEs, ADEs, SAEs, SADEs, 
USADEs and device deficiencies: Definitions and 
procedures for recording, evaluating, follow-up, and 
reporting in medical device studies 
• 
The definitions and procedures detailed in this appendix are in accordance with ISO 
14155 and the European Medical Device Regulation (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. 


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• 
The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 6.1.1 for the list 
of sponsor medical devices. 
10.6.1. 
Definition of medical device AE and ADE 
Medical device AE and ADE definition  
• 
A medical device AE is any untoward medical occurrence, in a clinical study 
participant, users, or other persons, temporally associated with the use of study 
intervention whether or not considered related to the investigational medical 
device. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of an investigational medical device. This 
definition includes events related to the investigational medical device or 
comparator and events related to the procedures involved except for events in 
users or other persons, which only include events related to investigational 
devices. 
• 
An ADE is defined as an AE related to the use of an investigational medical 
device. This definition includes any AE resulting from insufficient or inadequate 
instructions for use, or any malfunction of the investigational medical device as 
well as any event resulting from use error or from intentional misuse of the 
investigational medical device. 
10.6.2. 
Definition of medical device SAE, SADE and USADE 
A medical device SAE is any serious adverse event 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 that 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 


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• 
A SADE is defined as an adverse device effect 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 adverse device effect that by its nature, incidence, severity or 
outcome has not been identified in the current version of the risk analysis report 
(see Section 2.3). 
10.6.3. 
Definition of device deficiency 
Device deficiency definition 
• 
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequacy of the information supplied by 
the manufacturer. 
10.6.4. 
Recording and follow-up of medical device AE and/or SAE and 
device deficiencies 
10.6.4.1. 
Medical device AE, SAE, and device deficiency recording 
• 
When an AE/SAE/device deficiency occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE/device deficiency information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice and on the appropriate form. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the AE/SAE/device deficiency 
form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
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. 


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o 
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 CA via the 
national spontaneous reporting system. These will be classified as spontaneous 
ICSRs. 
10.6.4.2. 
Assessment of intensity 
Refer to Section 10.3.6.2. 
10.6.4.3. 
Assessment of causality 
Refer to Section 10.3.6.3. 
10.6.4.4. 
Follow-up of medical device AE/SAE and device deficiency 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE/SAE/device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 
• 
New or updated information will be recorded in the originally completed form. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
10.6.5. 
Reporting of medical device SAEs 
Medical device SAE reporting to GSK via an electronic data collection tool 
• 
The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool 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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10 Feb 2023 
93 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on a paper SAE form or to the 
medical monitor by telephone. 
• 
Contacts for SAE reporting can be found in Section 8.4.6. 
Medical Device SAE Reporting to GSK via Paper Data Collection Tool 
• 
Email/Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor. 
• 
In rare circumstances and in the absence of email/facsimile equipment, notification 
by telephone is acceptable with a copy of the SAE paper data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE paper data collection tool within the designated reporting 
time frames. 
Contacts for SAE reporting can be found in Section 8.4.6. 
10.6.6. 
Reporting of SADEs 
SADE reporting to GSK 
NOTE: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs that must fulfill the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to 
medical devices being used in clinical studies. 
• 
Any device deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the 
definition of a device deficiency. 
• 
The sponsor will review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These device deficiencies will be 
reported to the regulatory authorities and IRBs/IECs as required by national 
regulations. 
• 
Contacts for SAE reporting can be found in Section 8.4.6. 
10.6.7. 
Reporting of medical device deficiencies for associated person 
• 
Reporting to GSK  
If an Associated Person (i.e. e.g., spouse, caregiver, site staff) experiences a device 
deficiency, the medical device deficiency information, and any associated AE/SAE 
information will be reported to GSK. The associated person will be provided with the 
authorization to contact physician letter. 


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10 Feb 2023 
94 
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. 
• 
If the device incident is linked to an SAE, please email the medical device 
deficiency report form, within 24 hours. Refer to Section 8.4.6 for reporting.  
• 
GSK will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported 
to the regulatory authorities and IRBs/IECs as required by national regulations. 
10.7. 
Appendix 7: Country-specific requirements 
Not applicable.  
10.8. 
Appendix 8: Protocol amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents. 
11. 
REFERENCES 
Directive 2001/20/EC of the European Parliament and of the Council of 4 Apr 2001 on 
the approximation of the laws, regulations and administrative provisions of the Member 
States relating to the implementation of good clinical practice in the conduct of clinical 
trials on medicinal products for human use. 
Ernstgård L, Sjögren B, Dekant W, Schmidt T, Johanson G, Uptake and disposition of 
1,1-difluoroethane (HFC-152a) in humans. Toxicology Letters, 2012; 209(1):21-9. 
https://doi.org/10.1016/j.toxlet.2011.11. 
GINA 2020 Appendix: https://ginasthma.org › wp-content › uploads › 2020 › 0. 
GINA 2022: https://ginasthma.org/wp-content/uploads/2022/07/GINA-Main-Report-
2022-FINAL-22-07-01-WMS.pdf. 
Guideline on the investigation of bioequivalence. European Medicines Agency (EMA), 
Committee for Medicinal Products for Human Use (CHMP). Document Reference 
CPMP/EWP/QWP/1401/98 Rev. 1/ Corr.**, Aug 2010. 
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline, E6(R2): 


CONFIDENTIAL 
  
 
Protocol (Final 2.0) 
10 Feb 2023 
95 
Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice. Adopted by 
the European Medicines Agency (EMA), Committee for Human Medicinal Products, 
Document Reference EMA/CHMP/ICH/135/1995), 14 Jun 2017. 
Medical Research Involving Human Subjects Act (WMO, Wet Medisch 
Wetenschappelijk Onderzoek met Mensen), revision Dec 2015. 
Package leaflet for Ventolin Evohaler 100 micrograms: Information for the User, 2021 
Protocol: Mex‐HFA‐152a: Clinical Study Report Mex-HFA-152a - A Phase 1 Dose 
HFA-152a Exposure Clinical Study in Healthy Male Volunteers**. 
WHO Asthma Fact Sheet. No. 307. Date last updated, 15 May 2020. Available from 
https://www.who.int/news-room/facts-in-pictures/detail/asthma. Accessed on 31-Aug-
2021. 
World Medical Association (WMA) Declaration of Helsinki – Ethical Principles for 
Medical Research Involving Human Subjects (18th WMA General Assembly 1964), 
revised at 64th WMA General Assembly, Fortaleza, Brazil, Oct 2013. 
Drugbank online: https://go.drugbank.com/drugs/DB01001. 

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  219430 
Official Title of Study: A single dose two-way cross-over study in 
healthy participants to compare the pharmacokinetics (PK) of salbutamol 
administered via metered dose inhalers containing propellants HFA-152a 
and HFA-134a
NCT ID: NCT05791565
Date of Document: 15-June-2023


Statistical Analysis Plan 
 
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EDSREP 009 T 01 G 
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Statistical Analysis Plan 
 
Sponsor: 
GlaxoSmithKline Research & Development Limited 
Protocol No: 
219430 
Protocol Title: 
A single dose two-way cross-over study in healthy participants to 
compare the pharmacokinetics (PK) of salbutamol administered via 
metered dose inhalers containing propellants HFA-152a and HFA 134a 
Version Date: 
13-Jun-2023 
1.0 Approvals 
The undersigned have approved this Statistical Analysis Plan for use in this study. 
Name of Sponsor 
Representative/Title 
for SAP: 
 Project Statistician 
 
Signature of 
Sponsor 
Representative 
/Date: 
 
 
 
 
Name of Sponsor 
Representative/Title 
for Shells: 
 Project Programmer 
Signature of 
Sponsor 
Representative 
/Date: 
 
 
 
 
Name of Author 
/Title: 
, Biostatistician 
Signature of Author 
/Date: 
 
 
 
 
 
 
 
 
15-Jun-2023
15-Jun-2023
PPD
PPD
PPD
PPD
PPD
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2.0 Table of Contents 
1.0 Approvals ................................................................................................................................................ 1 
2.0 Table of Contents .................................................................................................................................... 2 
3.0 Introduction ............................................................................................................................................. 4 
4.0 Changes from Previous Version of Approved SAP ................................................................................ 4 
5.0 Study Objectives ..................................................................................................................................... 4 
5.1 Primary Objectives and Endpoints ...................................................................................................... 4 
5.2 Secondary Objectives and Endpoints ................................................................................................. 5 
5.3 Primary Estimand ................................................................................................................................ 5 
5.4 Secondary Estimand (1) ...................................................................................................................... 6 
5.5 Secondary Estimand (2) ...................................................................................................................... 7 
5.6 Secondary Estimand (3) ...................................................................................................................... 8 
6.0 Study Design ........................................................................................................................................... 9 
6.1 Sample Size Considerations ............................................................................................................. 10 
6.2 Randomization and Unblinding ......................................................................................................... 10 
7.0 Overview of Planned Analysis .............................................................................................................. 11 
7.1 Changes from Protocol ..................................................................................................................... 11 
7.2 Key Results and Final Analysis ......................................................................................................... 11 
8.0 Data Review .......................................................................................................................................... 11 
8.1 Data Management ............................................................................................................................. 11 
8.2 Acceptance of Data for Summarization ............................................................................................ 11 
9.0 Definitions and General Analysis Methods ........................................................................................... 12 
9.1 Analysis Data Presentation ............................................................................................................... 12 
9.1.1 Rounding .................................................................................................................................... 12 
9.1.2 Imputation .................................................................................................................................. 12 
9.1.3 Descriptive Statistics .................................................................................................................. 12 
9.1.4 Pooling ....................................................................................................................................... 12 
9.1.5 Unscheduled Measurements ..................................................................................................... 13 
9.2 Analysis Data Definitions .................................................................................................................. 13 
9.2.1 Baseline Definition ..................................................................................................................... 13 
9.2.2 Treatment/Participant Grouping ................................................................................................. 14 
9.2.3 Common Variable Derivations ................................................................................................... 14 
9.2.4 QC .............................................................................................................................................. 14 
9.2.5 ADaM Datasets and Metadata ................................................................................................... 14 
9.3 Software ............................................................................................................................................ 15 
9.4 Statistical Methods ............................................................................................................................ 15 
9.4.1 Statistical Outlier Determination ................................................................................................. 15 
9.4.2 Predetermined Covariates and Prognostic Factors ................................................................... 15 
9.4.3 Hypothesis Testing ..................................................................................................................... 15 
9.5 TFL Layout ........................................................................................................................................ 15 
10.0 Analysis Sets ....................................................................................................................................... 16 
10.1 Screened Set .................................................................................................................................. 16 
10.2 Enrolled Set ..................................................................................................................................... 16 
10.3 Safety Set ........................................................................................................................................ 17 
10.4 PK Set ............................................................................................................................................. 17 
10.5 PD Set ............................................................................................................................................. 17 
11.0 Participant Disposition ......................................................................................................................... 17 
12.0 Protocol Deviations ............................................................................................................................. 17 
13.0 Demographic and Baseline Characteristics ........................................................................................ 17 
13.1 Medical History ................................................................................................................................ 17 
13.2 Other Baseline Characteristics ....................................................................................................... 17 
14.0 Concomitant Medications .................................................................................................................... 18 
15.0 Treatment Compliance and Exposure ................................................................................................ 18 
16.0 Pharmacokinetic Analyses .................................................................................................................. 18 
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16.1 Pharmacokinetic Variables.............................................................................................................. 18 
16.1.1 Plasma Variables ..................................................................................................................... 18 
16.2 Pharmacokinetic Summaries .......................................................................................................... 21 
16.2.1 Pharmacokinetic Concentrations ............................................................................................. 21 
16.2.2 Pharmacokinetic Parameters ................................................................................................... 21 
17.0 Pharmacodynamic Analysis ................................................................................................................ 23 
17.1 Pharmacodynamic Variables .......................................................................................................... 23 
17.1.1 Variables .................................................................................................................................. 23 
17.2 Pharmacodynamic Summaries ....................................................................................................... 24 
17.2.1 Pharmacodynamic Levels ........................................................................................................ 24 
17.2.2 Pharmacodynamic Parameters ................................................................................................ 25 
18.0 Safety Analyses .................................................................................................................................. 26 
18.1 Safety Variables .............................................................................................................................. 26 
18.1.1 Adverse Events ........................................................................................................................ 26 
18.1.2 Deaths and Serious Adverse Events ....................................................................................... 28 
18.1.3 Laboratory Data ....................................................................................................................... 28 
18.1.4 Vital Signs ................................................................................................................................ 28 
18.1.5 Electrocardiograms .................................................................................................................. 28 
18.1.6 Other Observations Related to Safety ..................................................................................... 29 
19.0 Result Summary Public Disclosure Information .................................................................................. 29 
20.0 References .......................................................................................................................................... 29 
Appendix 1: Glossary of Abbreviations ....................................................................................................... 30 
Appendix 2: Schedule of Assessments ....................................................................................................... 32 
Appendix 3: List of In-Text Outputs ............................................................................................................. 34 
Appendix 4: List of End of Text Outputs ..................................................................................................... 34 
Appendix 5: List of Public Disclosure Tables .............................................................................................. 38 
19.0 Document History ................................................................................................................................ 38 
 
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3.0 Introduction 
This Statistical Analysis Plan (SAP) describes the statistical methods that will be used during the analysis 
and reporting of data collected under GlaxoSmithKline Research & Development Limited (GSK) 
Protocol 219430. 
This SAP should be read in conjunction with the study protocol and electronic case report form (eCRF). 
This version of the plan has been developed using the protocol dated 10-Feb-2022 and the final eCRF(s) 
dated 05-Apr-2023. 
An approved and signed SAP is a requirement for database lock. An approved SAP is also required for 
unblinding of the study treatments. 
This SAP only covers the results that will be processed by the 
 
 for pharmacokinetic (PK) parameter calculation. 
 will perform the PK, Pharmacodynamic (PD) and safety and tolerability evaluation.  
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be so identified. Any post-hoc or unplanned analyses, or significant changes 
from the planned analysis in this SAP performed to provide results for inclusion in the clinical study report 
(CSR) but not included in this SAP, will be clearly identified in Section 9.8.2 of the CSR. Changes to planned 
analyses do not require an updated SAP but should be included in the CSR if significant. 
4.0 Changes from Previous Version of Approved SAP 
This is the second version of the SAP. Changes from the first SAP version: 
- 
Public disclosure tables have been added. 
- 
Additional imputation rules for partial dates have been added for AEs. 
- 
Sections of statistical analysis on PK and PD parameters have been changed slightly to allow for 
data driven model modifications. In addition, participants with parameter results for only one 
treatment will no longer be excluded from the statistical analyses.   
- 
Descriptive statistics for routine urinalysis has been added. 
- 
Headline summary PK TFLs as a separate deliverable and dry-run delivery have been removed. 
5.0 Study Objectives 
5.1 Primary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To characterise the PK of single doses of 
salbutamol in healthy participants delivered via an 
MDI containing propellant HFA-152a, and to 
compare 
to 
an 
MDI 
containing 
propellant 
HFA-134a 
• 
AUC(0-30min) 
• 
AUC(0-∞) 
• 
AUC(0-t) 
• 
Cmax 
AUC=area 
under 
the 
curve; 
HFA-134a=1,1,1,2-tetrafluoroethane; 
HFA-152a=1,1-difluoroethane; 
MDI=metered dose inhaler. 
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5.2 Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Pharmacokinetics: To characterise the PK of 
single doses of salbutamol in healthy participants 
delivered via an MDI containing propellant 
HFA-152a, and to compare to an MDI containing 
propellant HFA-134a 
• 
Tmax 
• 
t1/2 
Pharmacodynamics: To characterise the PD of 
single doses of salbutamol in healthy participants 
delivered via an MDI containing propellant 
HFA-152a, and to compare to an MDI containing 
propellant HFA-134a 
 
• 
Minimum and 0-4h weighted mean serum 
potassium  
• 
Maximum and 0-4h weighted mean heart rate  
• 
Maximum and 0-4h weighted mean QTc 
interval  
Safety: To characterise the safety and tolerability 
of single doses of salbutamol in healthy 
participants delivered via an MDI containing 
propellant HFA 152a, and to compare to an MDI 
containing propellant HFA-134a 
 
• 
Incidence of AEs and SAEs 
• 
Pre- and post-dose 12-lead ECGs recording 
of HR, PR, QRS, QT and QTc intervals 
(absolute and change from baseline values) 
• 
Clinical laboratory assessment (absolute 
values) 
• 
Vital signs (systolic and diastolic blood 
pressure and pulse rate) (absolute values) 
AE=adverse 
event; 
ECG=electrocardiogram; 
HFA-134a=1,1,1,2-tetrafluoroethane; HFA-152a=1,1-
difluoroethane; HR=heart rate; MDI=metered dose inhaler; SAE=serious. 
 
5.3 Primary Estimand 
The primary clinical question of interest is: What is the geometric mean ratio (GMR) of the PK parameters 
of Salbutamol HFA-152a MDI vs Salbutamol HFA‑134a MDI after administration of single doses of 
salbutamol in healthy participants. 
 
The estimand is described by the following attributes: 
  
• 
Population:  
Healthy male or female participants aged 18 to 55 years 
• 
Endpoints:  
AUC (0-∞), AUC (0-30min), AUC (0-t) and Cmax 
• 
Treatment Conditions:  
• 
Salbutamol will be administered as a single 800 µg dose, given as 8 actuations each separated by a 
20-second interval, each delivering 100 µg as the ex‑valve dose for the test treatment and a 
reference treatment. 
The comparison of interest is: The ratio of Salbutamol HFA-152a MDI vs Salbutamol HFA‑134a MDI .   
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• 
Intercurrent events: 
 
Treatment discontinuation due to any reasons - Hypothetical Strategy  
o 
Interest lies in the comparisons of ratio of two formulations in a hypothetical scenario where no 
participant discontinued from the study. The individual PK concentrations affected by occurrence 
of the intercurrent event would be treated as missing from the occurrence of the intercurrent 
event until the end of the study and consequently affected individual PK parameters will be 
missing. 
 
Occurrence of emesis or coughing on dosing - Hypothetical strategy  
o 
Interest lies in the comparisons of ratio of two formulations in a hypothetical scenario where no 
participant experiences an episode of coughing or emesis within a treatment that is judged by the 
investigator to have impacted inhaled drug delivery to the airways or swallowed drug absorption 
from the gastrointestinal tract. The individual PK concentrations affected by occurrence of the 
intercurrent event would be treated as missing from the occurrence of the intercurrent event until 
the end of the treatment (period) and consequently affected individual PK parameters will be 
missing for that treatment (period). 
 
Dosing error: Considered less than or more than prescribed dose - Hypothetical strategy 
o 
Where the investigator is interested in the treatment effects in a hypothetical scenario where all 
participants have taken dose correctly as prescribed. The individual PK data affected by 
occurrence of the intercurrent event would be treated as missing from the occurrence of the 
intercurrent event until the end of the treatment (period) and consequently affected individual PK 
parameters will be missing for that treatment (period). 
 
• 
Rationale for estimand: The test formulation is developed to have comparable PK characteristics 
and treatment effects. Interest lies in the PK values obtained while the participant is exposed to 
correct dose as prescribed, prior to the discontinuation of the randomized sequence and prior to the 
occurrence of emesis or coughing on dosing. 
• 
Population-level summary: Ratio of geometric mean (for logarithmic transformed values) and 90% 
CI for the ratio of the geometric means for AUC(0-∞), AUC (0-t), AUC(0-30min), and Cmax. 
 
5.4 Secondary Estimand (1) 
The clinical question of interest for the secondary objective is: What is the summarized PK profile using 
descriptive statistics for tmax and t1/2 after administration of single doses of salbutamol in healthy 
participants. 
The estimand is described by the following attributes: 
• 
Population:  
Healthy male or female participants aged 18 to 55 years 
• 
 Endpoints: 
tmax and t1/2 
• 
Treatment conditions:  
Salbutamol will be administered as a single 800 µg dose, given as 8 actuations each separated by a 
20-second interval, each delivering 100 µg as the ex‑valve dose for the test treatment and a 
reference treatment. Descriptive summary by treatment groups are:  
o 
Salbutamol HFA-152a MDI 
o 
Salbutamol HFA‑134a MDI  
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• 
Intercurrent events: 
Treatment discontinuation due to any reasons - Hypothetical strategy  
o 
Interest lies in the descriptive summary by treatment groups in a hypothetical scenario where no 
participant discontinued from the study. The individual PK concentrations affected by occurrence 
of the intercurrent event would be treated as missing from the occurrence of the intercurrent 
event until the end of the study and consequently affected individual PK parameters will be 
missing. 
 
Occurrence of emesis or coughing on dosing - Hypothetical strategy  
o 
Interest lies in the descriptive summary by treatment groups in a hypothetical scenario where no 
participant experiences an episode of coughing or emesis within a treatment that is judged by the 
investigator to have impacted inhaled drug delivery to the airways or swallowed drug absorption 
from the gastrointestinal tract. The individual PK concentrations affected by occurrence of the 
intercurrent event would be treated as missing from the occurrence of the intercurrent event until 
the end of the treatment (period) and consequently affected individual PK parameters will be 
missing for that treatment (period). 
 
Dosing error: Considered less than or more than prescribed dose - Hypothetical strategy 
o 
Where the investigator is interested in the treatment effects in a hypothetical scenario where all 
participants have taken dose correctly as prescribed. The individual PK data affected by 
occurrence of the intercurrent event would be treated as missing from the occurrence of the 
intercurrent event until the end of the treatment (period) and consequently affected individual PK 
parameters will be missing for that treatment (period). 
 
• 
Rationale for estimand:  
The test formulation is developed to have comparable PK characteristics and treatment effects. 
Interest lies in the PK values obtained while the participant is exposed to correct dose as prescribed, 
prior to the discontinuation of the randomized sequence and prior to the occurrence of emesis or 
coughing on dosing. 
• 
Population-level summary:  
PK data of tmax and t1/2 will be summarized using descriptive statistics (arithmetic mean, geometric 
mean, median, 95% CI [arithmetic and geometric], standard deviation [arithmetic and on ln-scale], 
minimum, maximum, and geometric CV), and will be listed and summarized in tabular and/or 
graphical form. 
5.5 Secondary Estimand (2) 
The clinical question of interest is for the secondary objective: What is the geometric mean ratio (GMR) of 
the PD parameters of Salbutamol HFA-152a MDI vs Salbutamol HFA‑134a MDI after administration of 
single doses of salbutamol in healthy participants. 
• 
Population:  
Healthy male or female participants aged 18 to 55 years 
• 
Endpoints: 
o 
Minimum and 0-4h weighted mean serum potassium  
o 
Maximum and 0-4h weighted mean heart rate  
o 
Maximum and 0-4h weighted mean QTc interval 
 
• 
Treatment conditions: 
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Salbutamol will be administered as a single 800 µg dose, given as 8 actuations each separated by a 
20-second interval, each delivering 100 µg as the ex‑valve dose for the test treatment and a 
reference treatment. 
The comparison of interest is: The ratio of Salbutamol HFA-152a MDI vs Salbutamol HFA‑134a MDI . 
• 
Intercurrent events: 
Treatment discontinuation due to any reasons - hypothetical strategy  
o 
Interest lies in the comparisons of ratio of formulations in a hypothetical scenario where no 
participant discontinued from the study. The individual PD concentrations affected by occurrence 
of the intercurrent event would be treated as missing from the occurrence of the intercurrent 
event until the end of the study and consequently affected individual PD parameters will be 
missing. 
 
Occurrence of emesis or coughing on dosing - Hypothetical strategy  
o 
Interest lies in the comparisons of the ratio of formulations in a hypothetical scenario where no 
participant experiences an episode of coughing or emesis within a treatment that is judged by the 
investigator to have impacted inhaled drug delivery to the airways or swallowed drug absorption 
from the gastrointestinal tract. The individual PD concentrations affected by occurrence of the 
intercurrent event would be treated as missing from the occurrence of the intercurrent event until 
the end of the treatment (period) and consequently affected individual PD parameters will be 
missing for that treatment (period). 
 
Dosing error: Considered less than or more than prescribed dose - Hypothetical strategy 
o 
Where the investigator is interested in the treatment effects in a hypothetical scenario where all 
participants have taken dose correctly as prescribed. The individual PD data affected by 
occurrence of the intercurrent event would be treated as missing from the occurrence of the 
intercurrent event until the end of the treatment (period) and consequently affected individual PD 
parameters will be missing for that treatment (period). 
 
• 
Rationale for estimand: 
Interest lies in the PD values obtained while the participant is exposed to correct dose as prescribed, 
prior to the discontinuation of the randomized sequence and prior to the occurrence of emesis or 
coughing on dosing. 
• 
Population-level summary:  
Ratio of geometric mean (for logarithmic transformed values) and 90% CI for the ratio of the 
geometric means for serum potassium, heart rate and QTc interval (weighted means and minimum or 
maximum). 
5.6 Secondary Estimand (3) 
The clinical question of interest is for the secondary objective: What is the safety and tolerability profile of 
single doses of salbutamol in healthy participants delivered via MDIs. 
• 
Population:  
Healthy male or female participants aged 18 to 55 years 
• 
Endpoints: 
o 
Incidence of AEs and SAEs  
o 
Pre- and post-dose 12-lead ECGs recording of HR, PR, QRS, QT and QTc intervals (absolute 
and change from baseline values). 
o 
Clinical laboratory (absolute values) 
o 
Vital signs (systolic and diastolic blood pressure and pulse rate) (absolute values) 
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• 
Treatment conditions:  
Salbutamol will be administered as a single 800 µg dose, given as 8 actuations each separated by a 
20-second interval, each delivering 100 µg as the ex‑valve dose for the test treatment and a 
reference treatment.  
o 
Salbutamol HFA-152a MDI 
o 
Salbutamol HFA‑134 a MDI 
 
• 
Remaining intercurrent events: 
Treatment discontinuation due to any reason - Treatment policy strategy. 
• 
Rationale for estimand: 
Safety data will be monitored throughout the study after the start of treatment. There is interest in 
evaluating and reporting safety events regardless of whether participants discontinued treatment. 
• 
Population-level summary:  
Frequency and percentages for incidence of AEs and SAEs. Absolute and changes from baseline 
values for pre-dose and post-dose 12-lead ECG recording of HR, PR, QRS, QT and QTc intervals, 
absolute values for clinical laboratory values, and vital signs (systolic and diastolic blood pressure 
and pulse rate) parameters will be listed and will be summarized descriptively (arithmetic mean, SD, 
median, minimum, and maximum). 
 
6.0 Study Design 
This is a randomized, double-blind, single dose, 2-way cross-over study in healthy male and female 
participants with salbutamol. Salbutamol will be administered as a single 800 µg dose, given as 8 actuations 
at 20-second intervals, each delivering 100 µg as the ex-valve dose for a test treatment and a reference 
treatment. There will be a minimum washout period of 72 hours between treatment (dosing) periods. 
Following a screening period of up to 28 days, eligible participants will be confined to the clinical research 
unit (CRU) from Day -1 until Day 5, (24 hours after the last dose on Day 4), when all study assessments 
are completed. 
Thirty participants will be randomly assigned to one of 2 treatment sequences in 2 treatment interventions 
using a cross-over design: 
Table 1: Treatment Sequences 
Sequence 
AB (n=15) 
BA (n=15) 
 
The following treatments will be administered as single 800 µg inhalation doses, given as 8 x 100 µg 
(ex-valve) at 20-second intervals: 
• 
Treatment A: Salbutamol HFA-152a MDI (Test formulation).  
• 
Treatment B: Salbutamol HFA-134a MDI (Reference formulation, currently approved Ventolin). 
For the first dose of the treatment sequence, the first 2 participants will be randomized to one of the 
following: currently approved Ventolin, or Salbutamol HFA-152a MDI. 
Remaining participants will be randomized only after review of at least 24 hours safety and tolerability data 
(i.e. adverse events (AEs) / serious AEs (SAEs), clinical laboratory values, vital signs and 12-lead ECGs) 
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from the sentinel participants by the Investigator or appropriately qualified delegate, in consultation with the 
Medical Monitor or delegate if unavailable, and it has been deemed safe to do so.  
The remaining 28 participants will be dosed in various groups in accordance with CRO bed space and 
clinical resourcing 
 The participant population will be 
assigned equally to the total number of treatment sequences. 
6.1 Sample Size Considerations 
No formal sample size calculation has been performed. 
The target number of participants is chosen to achieve sufficient half width of the 90% CI, in the estimate 
of the geometric mean ratios for the primary endpoints. Assuming a within-participant CVw of 25.4% for 
Cmax and 22% for AUC parameters (from previously conducted studies (Study 200921, Study SALB1003)), 
the sample size of 30 participants is expected to result in a half-width of the 90% CI for Test/Reference 
ratio of 11.61% for Cmax and 10.02% for the AUC parameters.  
Presented  in Table 2 are the half width of the 90% CI for observed treatment ratios, based on varying 
sample size and by fixing CVw% of 25.4% for Cmax and 22% for AUC. 
Table 2: Sample size sensitivity table 
Parameter 
 
Sample 
size 
Within Subject SD 
Half width of the 90% CI for 
Observed Treatment Ratio 
AUC(0-inf) 
 
18 
0.22 (CVw=22%) 
13.49% 
 
24 
0.22 (CVw=22%) 
11.38% 
Cmax 
 
18 
0.25 (CVw=25.4%) 
15.66% 
 
24 
0.25 (CVw=25.4%) 
13.20% 
CI=confidence interval; CVw=coefficient of variation within 
 
It is assumed that all AUC parameters will follow a similar level of variability as AUC(0-inf). 
Note: A sample size of 18, and a CVw of 22%, the half width of the 90% CI for observed treatment ratio of 
AUC between two treatment arms is estimated to be within 13.49% of the point estimate. (As an example, 
if the observed treatment ratio is 0.95, the upper bound of the 90% CI for observed treatment ratio will be 
0.95*(1+0.1349) = 1.08 and the lower bound will be 0.95/(1+0.1349) = 0.84). 
Participants who drop out during the study will not be replaced. 
6.2 Randomization and Unblinding 
After obtaining informed consent, participants will receive a screening number and will be screened 
according to the inclusion and exclusion criteria.  
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 technology 
(IRT) through the central Randomization and Medication Ordering System Next Generation (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 
(randomization numbers 
) (designating the participant’s randomization code and treatment 
sequence assignment) for each participant in the study. Participant numbers will be within 
 
range. 
At study Day 1 participants will be assigned a unique randomization number in ascending numerical order. 
The randomization number encodes the participant’s assignment to one of the 2 treatment sequences of 
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the study, according to the randomization schedule generated prior to the study by the statistics department 
at GSK. 
The randomization code will be kept at GSK (by the randomization officer and is not accessible for blinded 
study team members. The
 and GSK study team are blinded throughout the study and will 
receive the actual randomization code from GSK randomization officer only after database lock and after 
approval from GSK.  
The RAMOS NG will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 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. 
7.0 Overview of Planned Analysis 
7.1 Changes from Protocol 
PD evaluation is not only related to serum potassium results, but also related to heart rate and QTcF results. 
Therefore, the PD set has been changed from “The PD set consists of all participants who received at least 
one dose of study intervention and have at least 1 non-missing potassium concentration result” to “The PD 
set consists of all participants who received at least one dose of study intervention and have at least 1 non-
missing potassium concentration result, or having at least 1 non –missing heart rate or QTc result. 
Modified an intercurrent event since “wrong treatment scenario in the dosing error event” is not applicable. 
7.2 Key Results and Final Analysis 
Draft TFLs will be provided after database lock.  
The finalization of TFLs will be done after the incorporation of sponsor comments, and before GSK's 
Statistical Analysis Complete (SAC), which will be included in the first draft CSR.   
8.0 Data Review 
8.1 Data Management 
Data handling and transfer will take place under the 
Data Management Plan for the study. 
8.2 Acceptance of Data for Summarization 
Programming of analysis datasets and TFLs may be ongoing during the data management of the study. 
However, programming of analysis datasets and TFLs will be completed and quality controlled (QC’d) after 
database lock 
Analysis datasets and TFLs will be QC’d for each deliverable per the 
 QC plan. 
Only quality assured (QA’d) results released by the Safety Laboratory, Bioanalytical Laboratory, or other 
external data source will be used for the programming of analysis datasets and TFLs for the final report. 
Any data values requiring investigation or corrections that are identified while programming the analysis 
datasets and TFLs will be sent to the project Data Manager. If the issue affects the TFLs the Programmer 
or Statistician who identified the issue will follow it to resolution. 
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9.0 Definitions and General Analysis Methods 
9.1 Analysis Data Presentation 
9.1.1 Rounding 
In listings, data will be presented with the same precision as the original data. Derived data will be rounded 
for presentation purposes, derived data will be unrounded in the dataset.  
Values of PK parameters, except tmax, will generally be presented with 3 significant figures. Values greater 
than 999 will be presented as integers. 
Tmax will be rounded to 2 decimals. Coefficient of variation (CV%) will be presented with one decimal.  
Percentages will be presented with 1 decimal, except for 0 and 100%, these are rounded to integers. 
For all summaries, descriptive statistics for mean and median will be presented with 1 additional decimal, 
Standard deviation will be presented with 2 additional decimals. Minimum and maximum will be presented 
with the same precision (number of decimals) as the data they are calculated from. Median Tmax will be 
presented with 2 decimals.  
P-values will be reported to four decimal places; p-value less than 0.0001 will be reported as p <0.0001. 
9.1.2 Imputation 
Data will not be imputed, except for the following data:  
• 
PK concentrations below the quantifiable limit (BQL) (see Section 16.2.1). 
• 
If the actual time or dose time is missing, the scheduled time may be substituted in order to calculate 
the PK parameters (see Section 16.2.2). 
• 
Missing start or end date/times of AEs for the calculation of onset and duration (see Section 18.1.1). 
Partial dates will be displayed as captured in the participant listing displays. 
• 
Missing AE severity, relationship and seriousness of AEs see Section 18.1.1). 
• 
Safety laboratory data that are <x or >x (e.g. “<1.03”, “>1000”): the analysis value or normal limit value 
will be the value of the detection limit itself plus or minus one precision unit for the parameter concerned 
(respectively 1.02 and 1001 in the example). The values before imputation (“<1.03”, “>1000”) will only 
be shown in listings. Listings will present the values before imputation. 
9.1.3 Descriptive Statistics 
Unless otherwise indicated, continuous variables will be summarized with the following descriptive 
statistics: n (number of observations), (arithmetic) mean, standard deviation (SD), minimum (min) value, 
median, and maximum (max) value. For PK data, n, arithmetic mean. SD, min, median, max, CV%, 95% 
CI, geometric mean, geometric SD, CV% of the geometric mean (geoCV%), and geometric 95% CI, will be 
presented. For PD data, n, (arithmetic) mean, SD, min, median, max, CV% and geometric mean will be 
presented. 
Categorical data will be summarized with frequencies and percentages. Percentages by categories will be 
based on the number of participants exposed within a treatment.  
For categorical data the categories will be presented in the tables exactly as they appear in the eCRF / 
Database. 
9.1.4 Pooling 
For summaries on demographic data (data summarized in tables of Appendix 4: List of End of Text Outputs, 
Section 15.1 – Disposition and Demographic Data), an overall summary (i.e. on all participants) will be 
provided for table 15.1.1. Summary of Participant Disposition, and table 15.1.3 Summary of Demographics. 
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Table 15.1.2 Summary of Participant Treatment Status and Reasons for Discontinuation of Study Treatment 
will be summarized by treatment, and table 15.1.4 Summary of Major Protocol Deviations will be 
summarized by treatment sequence and overall.  TEAE summaries will be provided by treatment and 
overall. Other summary statistics (data summarized in tables of Appendix 4: List of End of Text Outputs, 
Section 15.2 – Pharmacokinetic Data, Section 15.3– Pharmacodynamic Data, Section 15.4.3 Laboratory 
Data , and Section 15.4.4 Other Safety Parameters) will be displayed by treatment (and time point, if 
applicable). 
The treatments used for summaries are presented in Section 9.2.2.  
9.1.5 Unscheduled Measurements 
Unscheduled measurements will be included in the listings. With the exception of unscheduled 
measurements used for baseline, unscheduled measurements will be excluded from the descriptive 
statistics and statistical analysis. In case an unscheduled measurement was performed immediately after 
the scheduled measurement because of a previous measurement error (e.g. equipment failure), this 
repeated measurement will be used, and the original erroneous measurement will be excluded from the 
analysis. Listings will provide any scheduled and unscheduled measurements, and measurements used as 
baseline.  
9.2 Analysis Data Definitions 
9.2.1 Baseline Definition 
Unless otherwise stated, baseline for post-dose evaluations within each (dosing) period is defined as the 
last observation recorded before the first study drug administration in each dosing period. The last 
observation can be an unscheduled / repeated measurement. If a pre-treatment observation is missing in 
a given period then the screening value may be used. 
For electrocardiogram (ECG) measurements, the average of the triplicate measurements taken at pre-dose 
on Days 1 and 4 for heart rate and QTcF (as provided in the database) are taken as baseline. For other 
triplicate ECG measurements taken at pre-dose on Days 1 and 4, but not provide as an average in the 
database (PRS duration, QRS duration, QT interval), the triplicate measurements will be averaged and 
taken as baseline.  
If no triplicate is available before the first study drug administration, the mean of the last recorded duplicate 
closest to the first study drug administration will be considered as baseline. If no duplicate is available, the 
last single ECG recorded before the first study drug administration will be considered as baseline. 
 
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9.2.2 Treatment/Participant Grouping 
Label 
Grouping 
Study Drug 
Salbutamol 
Treatment 
Treatment A: Salbutamol HFA-152a MDI (Test formulation) 
Treatment B: Salbutamol HFA-134a MDI (Reference formulation, currently 
approved Ventolin). 
Overall 
Treatment Labels for 
TFLs 
HFA-152a MDI  
HFA-134a MDI  
Overall  
 
A footnote will provide details on the treatments: 
HFA-152a MDI: 800 ug Salbutamol HFA-152a MDI (Test formulation) 
HFA-134a MDI: 800 ug Salbutamol HFA-134a MDI (Reference formulation) 
  
9.2.3 Common Variable Derivations 
Variable 
Data Type 
Definition/Calculation 
Change from Baseline 
All 
Post-dose Observation minus Baseline 
Observation in each dosing period 
If either the baseline or post-randomization value 
is missing, the change from baseline is set to 
missing as well. 
Analysis Study Day 
(Prior to First Dose) 
All 
Date of Measurement minus Dose Date 
Analysis Study Day 
(Post Dose) 
All 
For intervention period: Date of Measurement 
minus Dose Date +1 in each dosing period 
(timepoint 0-24h all set to 1) 
Actual Dose 
Exposure 
Value given after 8 actuations at 20-second 
intervals, each delivering 100 µg as the ex-valve 
dose (800 ug) 
9.2.4 QC 
Clinical Data Interchange Standard Consortium (CDISC) compliant analysis datasets and TFLs will be QC’d 
according to the 
 QC plan. 
All datasets will be double programmed per the 
 QC plan.  
9.2.5 ADaM Datasets and Metadata 
The analysis datasets will be generated in accordance with CDISC Analysis Data Model (ADaM) 
Version 2.1, and CDISC ADaM Implementation Guide 1.2. The following ADaM datasets will be prepared: 
ADaM Dataset Name 
Description 
ADSL 
Subject-Level Analysis Dataset 
ADAE 
Adverse Events Analysis Dataset 
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ADEG 
ECG Analysis Dataset 
ADLB 
Laboratory Test Results Analysis Dataset 
ADPC 
Pharmacokinetic Concentrations Analysis Dataset 
ADPDP 
Pharmacodynamic Parameters Analysis Dataset 
ADPP 
Pharmacokinetic Parameters Analysis Dataset 
ADVS 
Vital Signs Analysis Dataset 
 
ADaM compliant datasets will be delivered to the Sponsor. A define.xml file Version 2 with the 
corresponding metadata will be included. Analysis results (analysis displays or program details) metadata 
are excluded. 
9.3 Software 
The statistical analysis and reporting will be done using SAS® for WindowsTM version 9.4 or higher (SAS 
Institute, Inc.). 
PK parameter calculations will primarily be done using Phoenix® WinNonlin® version 8.3 or higher (Certara 
USA Inc.). Additional PK computations may be performed in SAS®. 
9.4 Statistical Methods 
9.4.1 Statistical Outlier Determination 
No statistical outlier analysis is planned. 
9.4.2 Predetermined Covariates and Prognostic Factors 
There are no predetermined covariates or prognostic factors. 
9.4.3 Hypothesis Testing 
No formal hypothesis testing will be done. 
No formal hypothesis will be tested. For each primary PK endpoint, point estimates and corresponding 90% 
CIs will be constructed for the ratio of the geometric mean of the test treatment to the geometric mean of 
the reference treatment, μ(test)/μ(reference) 
9.5 TFL Layout 
Report layout will be according to the
 – ICH E3 compliant – CSR Template. The layout 
TFLs will be according to the 
 standards. 
Table shells will be provided as separate document to this SAP. The TFLs will be provided in Adobe PDF 
format (in A4 format), one for the Participant Data Listings, and one for the Table and Figures, referred to, 
but not included in text. Separate files will be created for in-text tables (RTF) and in-text figures (PNG) 
planned for this study. 
In addition, tables shells will be provided for the public disclosure tables.   
Format: 
• 
Page size: A4 
• 
Data in listings will be sorted by participant number, and time point (if applicable).  
• 
Data in tables will be sorted by analyte/parameter, treatment and time point (if applicable). 
Laboratory data will be sorted by laboratory category, parameter, treatment and time point. 
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AE tables will be sorted by SOC and PT, by descending (total) number of participants per system 
organ class and within the system organ class per preferred term.  
• 
Column titles will be in title case letters. 
• 
All end-of-text tables and listings and participant data listings will be in landscape format. In-text 
tables will be in portrait format. Layout can be adapted to landscape at the discretion of the medical 
writer to enhance overview and readability. 
• 
The treatment labels will be as outlined in Section 9.2.2. 
10.0 Analysis Sets 
Analyses 
Screened Set 
Enrolled 
Set 
Safety Set 
PK Set 
PD Set 
Disposition 
Summaries 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
Baseline 
Characteristics 
 
 
 
 
 
Primary Analysis 
 
 
 
 
 
PK Concentrations 
 
 
 
 
 
PK Parameters 
 
 
 
 
 
PD Concentrations 
 
 
 
 
 
PD Parameters 
 
 
 
 
 
10.1 Screened Set 
The screened set will consist of all participants who were screened for eligibility. 
In this study, a limited amount of information of screen failures will be included in study data tabulation 
model (SDTM), like information on demographics, results on eligibility criteria, screen failure details, and 
any SAEs.  
All participants who have a signed informed consent whether screen failure or met eligibility criteria will be 
summarized in the disposition table. 
10.2 Enrolled Set 
The enrolled set will consist of all participants who entered the study (who were randomized or received 
study intervention or underwent a post screening study procedure).  
This set will be used for disposition summaries. 
Screening failures (who never passed screening even if rescreened) and participants screened but never 
enrolled into the study (met eligibility but not needed) are excluded from the enrolled analysis set as they 
did not enter the study. 
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10.3 Safety Set 
The safety set will consist of all participants who received at least one dose of study intervention. This set 
will be used for the safety data summaries and baseline characteristic summaries. 
10.4 PK Set 
The PK set will consist of all participants in the safety analysis set who had at least 1 non-missing PK 
assessment (non-quantifiable values will be considered as non-missing values). The PK set will be 
determined by a blinded data review meeting of the data prior to database lock, based on collected protocol 
deviations and available data at DB freeze.  
This set will be used for PK concentration and PK parameter summaries.  
10.5 PD Set 
The PD set consists of all participants who received at least one dose of study intervention and have at 
least 1 non-missing potassium concentration result, or having at least 1 non –missing heart rate or QTc 
result. 
This set will be used for PD value summaries and PD parameter summaries. 
11.0 Participant Disposition 
The number of participants enrolled, and the number and percentage of participants randomized, dosed, 
members of each analysis set will be presented by treatment sequence and overall. The number and 
percentage of participants who withdrew from the study after dosing prematurely and a breakdown of the 
corresponding reasons for withdrawal will also be presented. The number of screen failures and reason for 
screen failure will be presented for overall (all subjects).   
 A listing information on early study intervention/treatment unblinding will be provided. 
12.0 Protocol Deviations 
Protocol deviations will be listed, based on the available information of the SDTM.PD dataset. Any major 
deviations will be summarized by treatment sequence. 
13.0 Demographic and Baseline Characteristics 
All demographic data as collected during the screenings visit will be listed by participant.  
Only year of birth is collected on eCRF. Age (in years) is derived using the year of the screening visit. Birth 
date will be presented in listings as ‘YYYY’. 
Participant demographics will be summarized for the enrolled set. Participant demographics will be 
summarized descriptively for all participants (overall). The summary will include the participants’ age (in 
years), sex, race, ethnicity, weight (in kg), height (in cm), and body mass index (BMI) [in kg/m2]. 
13.1 Medical History 
Medical history will be listed. Medical history will be coded according to Medical Dictionary for Regulatory 
Activities (MedDRA), version 25.0 or higher. 
13.2 Other Baseline Characteristics 
Substance use will be listed.  
The results of drug and alcohol screen will be listed. 
The results of serology at screening will be listed. 
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The results of pregnancy tests (beta-human chorionic gonadotropin [β-HCG]) and follicle stimulating 
hormone (FSH) test results will be listed. 
The results of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests will be listed. 
Non-compliance to inclusion- or exclusion criteria (if any) will be listed. 
14.0 Concomitant Medications 
Concomitant medications, categorized by medication group and subgroup according to World Health 
Organization (WHO) Drug Dictionary (Version WHO Drug Global B3 September 2022 or later), will be listed 
by participant. The reported name of the drug and standardized medication name will be reported.  
Medications with an end date prior to the first dose of study drug will be considered prior medications and 
will be noted as ‘prior’ in the listing. Concomitant medications are defined as those taken by the participant 
at any time between the date of first study drug administration and study completion/discontinuation. 
Any ongoing medications with a start date before study drug administration will be reported as concomitant 
medication. 
15.0 Treatment Compliance and Exposure 
Exposure data (date, time, dose form, fasting and other requirements met, etc.) will be listed by participant.  
A listing of study dates (Date of informed consent signature, date of medication, and follow-up) will be 
provided. 
16.0 Pharmacokinetic Analyses  
The concentrations of salbutamol in plasma will be determined using a validated liquid chromatography 
tandem mass spectrometry assay by GSK. LLOQ is 50 pg/mL. 
16.1 Pharmacokinetic Variables 
PK concentrations will be measured in plasma.  
16.1.1 Plasma Variables 
16.1.1.1 Concentrations 
Plasma concentration of salbutamol.  
16.1.1.2 Parameters 
PK Parameters for salbutamol will be calculated as defined in Table 3, as data permit.  
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Table 3 PK Parameters for Salbutamol in Plasma 
Parameter 
Description 
SAS Programming Notes 
Primary PK parameters 
AUC(0-30) 
Area under the plasma concentration-time curve calculated from time 0 
(pre-dose measurement)  to 30 minutes post-dose 
AUC0_30 from WNL 
The partial AUC is calculated according to 
the WinNonlin rules for partial areas. 
AUC(0-t) 
Area under the plasma concentration-time curve calculated from time 0 
(pre-dose measurement)   to time t of last  quantifiable concentration  
AUClast from WNL 
AUC(0-inf) 
Area under the plasma concentration-time curve from time 0 (pre-dose 
measurement) to extrapolated to infinity, 
calculated as 
AUC(0-inf) =AUC(0-t) + Clast/kel 
Where Clast is the observed concentration at the last timepoint with a 
quantifiable concentration and kel is the terminal elimination rate 
constant. 
AUCINF_obs from WNL 
If AUC_%Extrap_obs>20% and/or 
Rsq_adjusted ≤ 0.80 then parameter is 
flagged, and maybe excluded. 
Cmax 
Maximum observed plasma concentration. Observed peak analyte 
concentration obtained directly from the concentration-time data 
without interpolation, expressed in concentration units. If multiple 
maxima occur at equal concentrations, the first temporal value will be 
taken. 
CMAX from WNL 
PK parameters related to secondary endpoints: 
tmax 
Time to reach Cmax, expressed in time units. 
TMAX from WNL 
t1/2 
Terminal elimination half-life expressed in time units.  
t1/2= 
ln  (2)
𝜆𝜆𝑍𝑍 
HL_Lambda_z from WNL 
If Rsq_adjusted ≤ 0.80 then parameter is 
flagged, and maybe excluded. 
Other PK parameters (listed only): 
kel (λz )  
Reported 
as kel 
Terminal elimination rate constant calculated by linear regression of 
the terminal log-linear portion of the concentration vs. time curve. 
Linear regression of at least three datapoints, excluding Cmax are 
required to obtain a reliable kel. 
Lambda_z from WNL 
If Rsq_adjusted ≤ 0.80 then parameter is 
flagged, and maybe excluded.  
AUCextra 
Percentage of AUC0-inf obtained by extrapolation, calculated as: 
AUC_%Extrap_obs from WNL 
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Note: AUCs will be calculated using linear up / log down trapezoidal rule, expressed in units of concentration x time. 
𝐴𝐴𝐴𝐴𝐴𝐴(𝑡𝑡−𝑖𝑖𝑖𝑖𝑖𝑖)
𝐴𝐴𝐴𝐴𝐴𝐴(0 −𝑖𝑖𝑖𝑖𝑖𝑖)
 𝑥𝑥 100% 
 
Adj r2 
Goodness of fit statistic for the log-linear terminal 
elimination phase of the concentration time profile identified by least 
squares linear regression and adjusted for the number of points 
(minimum of 3, not including Cmax) used in the estimation of Kel 
Rsq_adjusted from WNL.  
If adjusted Rsq ≤ .80 then a flag will be 
added   
Listed only 
kel_Start 
The start time used in the regression for the determination of kel 
Lambda_z_lower from WNL 
Listed only 
kel_End 
The end time used in the regression for the determination of kel 
Lambda_z_upper from WNL 
Listed only 
kel_N 
The number of points used in the regression for the determination of kel 
No_points_lambda_z  from WNL 
Listed only 
tlast 
Time of last measurable observed concentration. 
Tlast from WNL 
Listed only 
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16.2 Pharmacokinetic Summaries 
16.2.1 Pharmacokinetic Concentrations 
Individual plasma concentrations for salbutamol before the first quantifiable concentration will be set to 
zero. If a single value below the lower limit of quantification (LLOQ) occurs between measurable 
concentrations in a profile, the LLOQ will be set to missing. If two or more LLOQ values occur in succession 
between measurable concentrations, the LLOQ will be set to zero, and the profile will be deemed to have 
terminated at the last measurable concentration prior to these LLOQs; for the purpose of individual plots, 
these non quantifiable results (NQ) will be set to O and the subsequent measurable concentrations will be 
retained. The LLOQ value which are after the last measurable concentration will be set to missing in the 
individual subject plots. 
If there is physiological or operational plausibility for erratic absorption - NQ in the middle of a concentration 
profile may be set to missing while subsequent valid concentrations are retained. 
Descriptive statistics (n, arithmetic mean, SD, CV, 95% CI of arithmetic mean, median, min, and max) will 
be used to summarize the plasma concentrations by treatment at each scheduled time point. In the 
calculation of descriptive statistics, all LLOQ values will be set to zero except when an individual LLOQ falls 
between two quantifiable values in which case it will be omitted (set to missing) from the calculation. 
Descriptive statistics at a time point where one or more samples have LLOQ values will be reported (as per 
listings), irrespective of the number of LLOQ results.  
 
Participants excluded from the PK analysis set will be flagged in the listing and excluded from descriptive 
statistics.  
All individual participant PK concentrations, time deviations and comments will be listed. 
Linear and semi-logarithmic plots of the arithmetic mean plasma concentration by scheduled sampling time 
will be provided for each treatment (treatments in one plot).  Linear plots will show the zero concentrations 
before the first measurable concentration. These plots will show nominal (scheduled) time in hours. The 
plots will match the summary table results.  
Linear and semi-logarithmic plots of the median plasma concentration by scheduled sampling time will be 
provided for each treatment (treatments in one plot). Linear plots will show the zero concentrations before 
the first measurable concentration. These plots will show nominal (scheduled) time in hours. The plots will 
match the summary table results.  
Linear and semi-logarithmic plots of the individual plasma concentration by actual sampling time will be 
provided by participant (two PK profiles per participant in one plot). These plots will show actual time in 
hours.  Linear plots will show the zero concentrations before the first measurable concentration. Individual 
plots will match the individual PK concentration results (and imputations).  
Linear and semi-logarithmic spaghetti plots of the (combined) individual plasma concentrations by actual 
sampling times will be provided by treatment. These plots will show actual time in hours. Spaghetti plots 
will match the individual PK concentration results (and imputations) for each participant. 
16.2.2 Pharmacokinetic Parameters 
PK parameters for salbutamol will be estimated using non-compartmental methods with WinNonlin® (WNL). 
The plasma PK parameters will be estimated from the concentration-time profiles. In estimating the PK 
parameters, below LLOQ (BQL) values prior to the first quantifiable concentration will be set to zero. BQL 
values that occur after the first quantifiable point will be considered missing. Values that are embedded 
between BQLs, or quantifiable values occurring after two or more BQLs, will be set to missing at the 
discretion of the pharmacokineticist. LLOQ value which are after the last measurable concentration will be 
set to missing. Actual sampling times, rather than scheduled sample collection times, will be used in all 
computations involving sample collection times. If the actual sample collection time or dose time is missing, 
the scheduled time will be substituted in order to calculate the PK parameter.  
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Descriptive statistics (n, arithmetic mean, geometric mean, SD, CV, geoSD, geoCV%, 95% CI of geometric 
and arithmetic mean, median, min, and max) will be used to summarize the calculated PK parameters by 
treatment. For tmax only median, min, max and 95% CI will be presented.  
Participants excluded from the PK analysis set will be flagged in the listing and excluded from descriptive 
statistics.  
All individual participant PK parameters will be listed. 
The points to be included in the λz range will be determined after inspection of the semi-log 
concentration-time profiles. At least 3 points will be required to be used, the Cmax data point will not be 
included. Parameters based on adjusted r2 equal or below 0.85 will be flagged but not excluded from 
descriptive statistics. 
If AUCextra value is above 20%, it will be flagged but not excluded from descriptive statistics if the 
proportion of AUC extrapolated that exceed 20% does not exceed 20% of the values.  If more than 20% of 
the values exceed 20% or if an individual value is >40% then this will be discussed with the Sponsor. 
The individual values and geometric mean of salbutamol AUCs and Cmax will be presented graphically 
versus treatment with a line connecting the geometric means of the treatments. 
16.2.2.1 Statistical Analyses 
Analysis will be performed to compare the PK profile of salbutamol HFA-152a MDI and salbutamol 
HFA-134a MDI (currently marketed Ventolin product). Analysis will be performed on the natural logarithm 
of AUC(0-30), AUC(0-t), AUC(0-inf) and Cmax using a linear mixed model with the treatment and period 
(dosing day) as fixed effects and subjects as random effects. A one model will be used, grouped by 
parameter.  
Point estimates and 90% CIs for treatment differences on the log scale derived from the model will be 
exponentiated to obtain estimates for geometric mean (GM) ratios and CIs on the original scale. The within-
subject coefficients of variation (CVw) for AUC and Cmax will be calculated based on the loge-normal 
distribution. The within-subject coefficients of variation (CVw) for AUC and Cmax will be calculated based 
on the loge-normal distribution.  
Model Checking & Diagnostics: 
• 
Model assumptions will be checked before analysis. 
• 
The underlying distributional assumptions involved in the statistical analyses will be assessed by 
visual inspection of residual plots. Normality will be examined by normal probability plots while 
homogeneity of variance will be assessed by plotting the residuals against the predicted values for 
the model.  
• 
If the assumptions are seriously violated, then alternative data transformations will be explored. If 
no suitable transformation can be found, equivalent nonparametric analyses (ex. Wilcoxon signed-
rank test) will be performed. 
The following kernel code of SAS PROC MIXED will be used:  
proc mixed;  
by parameter;  
class subject treatment period;  
model log(value)= treatment period / ddfm=kenwardroger cl;  
random subject type=un; 
lsmeans treatment period /alpha=0.1;  
/*estimates for treatment order Test1-Ref*/  
estimate “T vs R” treatment 1  -1 /alpha=0.1;  
run;  
 
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SAS code might be updated depending on the data. An unstructured type of the covariance matrices R 
(accounting for the within subject variability) and G (accounting for the between subject variability) will be 
used. If this model fails to converge, alternative covariance structures may be considered based on a lower 
AIC values (for example variance component, etc.). For the described linear mixed model analyses, the 
Kenward and Roger method for approximating the denominator degrees of freedom and correcting for bias 
in the estimated variance-covariance of the fixed effects will be used.  Statistical analysis model table will 
present N, n, least squares GM values and associated 90% CI, GM ratios and associated 90% confidence 
intervals and within-subject CV. 
Intercurrent events and handling of missing data: 
• 
Participant level missing PK concentration considered as missing at random, will not be imputed. 
• 
The PK concentration will be affected by occurrence of the intercurrent event (Treatment 
discontinuation of the study) would be treated as missing at random from the occurrence of the 
intercurrent event until the end of the study and only reliable available data will be used in the 
primary analysis and summary descriptive. 
17.0 Pharmacodynamic Analysis 
Based on nonclinical and clinical studies conducted with HFA-152a, and information from the Summary of 
product characteristics (SmPC) of Ventolin Evohaler (salbutamol sulfate containing propellant HFA-134a), 
the safety concerns following salbutamol dosing at the levels employed in this study include hypokalemia, 
hyperglycemia, and cardiovascular effects (including tachycardia and, in rare cases, cardiac arrhythmias). 
The analysis of potassium in serum samples will be performed at 
 
 
Heart rate and QTcF data used for PD parameters will result from the 12-Lead ECG measurements as part 
of the safety measurements. 
17.1 Pharmacodynamic Variables 
17.1.1 Variables 
17.1.1.1 Serum Potassium, Heart Rate and QTcF   
• 
Serum potassium. 
 
Heart rate and QTcF results will be reported as safety assessments, see Section 18.1.5. Additional 
parameters will be part of the PD assessments, see section 17.1.1.2.  
17.1.1.2 Parameters 
PD parameters for serum potassium, heart rate and QTcF will be calculated as defined in Table 4, as 
data permit.  
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Table 4 PD Parameters for Serum Potassium, Heart Rate and QTcF 
Parameter 
Description 
SAS Programming Notes 
Emin, K 
Minimum observed serum 
potassium  
Minimum observed concentration after dose (pre-
dose not included)  
AUEC, K 
Weighted mean serum 
potassium (0-4 hr).  
Summation of each interval, each interval calculated 
as: 
(C2-C1)/2 * (t2-t1), where C2 and t2 are 
concentration and timepoint at the end of each 
interval, and C1 and t1 are concentration and 
timepoint at the start of each interval.  
Emax, HR 
Maximum observed heart rate  
Maximum observed heart rate after dose (pre-dose 
not included)  
AUEC, HR 
Weighted mean heart rate 
(0-4 hr).  
Summation of each interval, each interval calculated 
as: 
(C2-C1)/2 * (t2-t1), where C2 and t2 are heart rate 
and timepoint at the end of each interval, and C1 
and t1 are heart rate and timepoint at the start of 
each interval.  
Emax, QTcF 
Maximum observed QTcF  
Maximum observed QTcF after dose (pre-dose not 
included)  
AUEC, QTcF 
Weighted mean QTcF (0-4 hr).  
Summation of each interval, each interval calculated 
as: 
(C2-C1)/2 * (t2-t1), where C2 and t2 are QTcF and 
timepoint at the end of each interval, and C1 and t1 
are QTcF and timepoint at the start of each interval.  
17.2 Pharmacodynamic Summaries 
17.2.1 Pharmacodynamic Levels 
Serum Potassium 
BLQ serum potassium concentrations will be set to ½  lower limit of quantification (LLOQ) in the computation 
of mean concentration values. Descriptive statistics (n, arithmetic mean, SD, CV%, median, min, and max,) 
will be used to summarize serum potassium concentrations and changes from baseline by treatment at 
each scheduled time point.  
Participants excluded from the PD analysis set will be flagged in the listing and excluded from descriptive 
statistics.  
All individual participant serum potassium concentrations, time deviations and comments will be listed. 
Linear plots of the arithmetic mean serum potassium concentrations by scheduled sampling time will be 
provided by treatment (2 treatments in one plot). These plots will show time in hours. The plots will match 
the summary table results.  
Linear spaghetti plots of serum potassium concentrations by actual sampling times will be provided by 
treatment.  
Heart rate and QTcF 
Refer to Section 18.1.5 for reporting of the heart rate and QTcF values. 
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17.2.2 Pharmacodynamic Parameters 
PD parameters will be calculated in SAS. 
Actual times, rather than scheduled sampling times, will be used in all computations involving timepoints, 
except for pre-dose timepoint. Pre-dose timepoints will be set to zero. 
Descriptive statistics (number of participants, arithmetic mean, SD, CV, geometric mean, median, min, and 
max) will be used to summarize the calculated PD parameters by treatment. For Emax and Emin, only 
median, min and max will be presented. 
Participants excluded from the PD analysis set will be flagged in the listing and excluded from descriptive 
statistics.  
All individual participant serum potassium parameters, heart rate and QTcF parameters will be listed.  
17.2.2.1 Statistical Analysis of Pharmacodynamic Parameters 
Analysis will be performed to compare the PD parameters after dosing of salbutamol HFA-152a MDI and 
salbutamol HFA-134a MDI (currently marketed Ventolin product). Analysis will be performed on the natural 
logarithm of Emin and AUEC of serum potassium, and EMax and AUEC of heart rate and QTcF, using a 
linear mixed model with the treatment and period (dosing day) as fixed effects and subjects as random 
effects. A one model will be used, grouped by parameter.  
Point estimates and 90% CIs for treatment differences on the log scale derived from the model will be 
exponentiated to obtain estimates for geometric mean (GM) ratios and CIs on the original scale. The within-
subject coefficients of variation (CVw) for AUEC, Emin and Emax will be calculated based on the loge-
normal distribution.  
Model Checking & Diagnostics: 
• 
Model assumptions will be checked before analysis. 
• 
The underlying distributional assumptions involved in the statistical analyses will be assessed by 
visual inspection of residual plots. Normality will be examined by normal probability plots while 
homogeneity of variance will be assessed by plotting the residuals against the predicted values for 
the model.  
• 
If the assumptions are seriously violated, then alternative data transformations will be explored. If 
no suitable transformation can be found, equivalent nonparametric analyses (ex. Wilcoxon signed-
rank test) will be performed. 
The following kernel code of SAS PROC MIXED will be used:  
proc mixed;  
by parameter;  
class subject treatment period;  
model log(value)= treatment period / ddfm=kenwardroger cl;  
random subject /type=un; 
lsmeans treatment period /alpha=0.1;  
/*estimates for treatment order Test1-Ref*/  
estimate “T vs R” treatment 1  -1 /alpha=0.1;  
run;  
 
SAS code might be updated depending on the data. An unstructured type of the covariance matrices R 
(accounting for the within subject variability) and G (accounting for the between subject variability) will be 
used. If this model fails to converge, alternative covariance structures may be considered based on a lower 
AIC values (for example variance component, etc.). For the described linear mixed model analyses, the 
Kenward and Roger method for approximating the denominator degrees of freedom and correcting for bias 
in the estimated variance-covariance of the fixed effects will be used.  
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Statistical analysis model table will present N, n, least squares GM values and associated 90% CI, GM 
ratios and associated 90% confidence intervals and within-subject CV.  
Intercurrent events and handling of missing data: 
• 
Participant level missing PD measurements considered as missing at random, will not be imputed. 
• 
The PD measurements will be affected by occurrence of the intercurrent event (Treatment 
discontinuation of the study) would be treated as missing at random from the occurrence of the 
intercurrent event until the end of the study and only reliable available data will be used in the 
primary analysis and summary descriptive. 
 
18.0 Safety Analyses 
18.1 Safety Variables 
The following safety variables will be summarized: 
• Adverse Events (AEs)  
• Vital Signs  
o 
Supine Blood Pressure  
• 
Systolic Blood Pressure (SBP)  
• 
Diastolic Blood Pressure (DBP)  
o 
Pulse rate  
• Electrocardiograms (ECG)  
o Heart Rate  
o 
PR Interval  
o 
QRS-Duration  
o 
QT Interval  
o 
QTc (Fridericia’s) Interval  
• Clinical Laboratory Evaluations 
o 
Clinical Chemistry (including glucose measurements)  
o 
Hematology 
o 
Urinalysis  
Impact of COVID-19 Pandemic on Safety Results 
Available safety results of participants with COVID-19 will not be excluded from any safety analysis. 
No specific analyses on safety endpoints will be performed on subjects without and with COVID-19.  
18.1.1 Adverse Events 
All AE summaries will include only treatment emergent adverse events (TEAEs). TEAE are those which 
occur (or worsen) after the first dose of study drug.  
TEAEs occurring following dosing in a specific period but before dosing in the next period will be attributed 
to that specific period. If the time is missing for an AE on a dosing day then the AE will be attributed to the 
treatment given on that day.  
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A summary overview of the number of events, and number and percentage of participants reporting TEAEs, 
TEAEs by severity, TEAEs by relationship, SAEs, and participants who discontinued study drug due to an 
AE will be provided. 
A breakdown of the number of TEAEs, number and percentage of participants reporting each TEAE, 
categorized by body system and preferred term coded according to MedDRA (Version 25.0 or higher), will 
be presented by treatment and overall. One such table will be presented for all TEAEs and one such table 
will be presented for TEAEs considered to be related to the study medication. 
Participants will only be counted once within each body system or preferred term.  
The system organ class and preferred terms in these tables will be ordered by descending (total) number 
of participants per system organ class and within the system organ class per preferred term. 
A summary of events reported, categorized by relationship not related vs related, will be provided by 
treatment and overall.  
A summary of events reported, categorized by severity (categories as recorded in the eCRF: mild, 
moderate, severe) will be provided by treatment and overall. If AEs are judged as severe, the additional 
indication life-threatening or results in death will be combined in the summary, resulting in the following 
severities: 
mild  
moderate 
severe (no indication of life-threatening or fatal AE) 
life-threatening (severe AE with indication life-threatening) 
fatal (severe AE with indication results in death). 
These tables will present the number of events, and number and percentage of participants per given 
category.  
A listing of adverse events (AEs) leading to study discontinuation will be provided.  
All AEs (including non-treatment-emergent events in a separate listing) recorded on the eCRF will be listed. 
The following missing data will be imputed as defined (for calculations only / will not be presented):  
o 
Missing AE start and / or end times for the calculation of onset and duration will be assumed to be 
at 00:01 for a start time and 23:59 for end times 
o 
Missing AE severity or relationship will be assumed to be severe or related, respectively 
o 
Missing AE start times for the determination of treatment emergence will be assumed to occur 
after treatment unless partial date documents the AE as happening prior to treatment 
o 
Missing AE start times for the determination of treatment assignment will be assumed to occur 
after treatment on the recorded date one minute after dosing 
o 
Missing AE start date: First of the month will be used unless this is before the date of first study 
treatment of the cohort (i.e. clinic group); in this case the date of first study treatment date will be 
used. 
o 
Missing AE end date: Last day of the month will be used, unless this is after the date of last visit 
of the cohort (i.e. clinic group); in this case the last visit date of the cohort will be used.   
o 
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing. 
Onset of AEs related to treatment and duration of AEs will be calculated as follows: 
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Onset  (time since last dosing in days, hours, minutes 
[dd hh:mm]) 
AE start date/time - treatment start 
date/time. 
Duration  (in dd hh:mm) 
AE end date/time – AE start date/time. 
 
18.1.2 Deaths and Serious Adverse Events 
A listing of deaths and other SAEs will be provided by participant. 
If applicable, narratives of deaths, other SAEs, and other significant AEs will be described in the CSR. 
18.1.3 Laboratory Data 
Clinical laboratory data will be presented using units from the study data tabulation model (SDTM) 
Controlled Terminology. 
All laboratory data will be listed, including laboratory variables not listed in the protocol. A separate listing, 
of out-of-normal-range values will also be provided. Normal ranges will be used directly from the clinical 
laboratory. An overview of clinical laboratory normal ranges is provided in separate document 
RefSet21001_21Jun21_4.pdf.  
Clinical laboratory results outside the reference normal range will be flagged. In case the out of reference 
normal range values were considered clinically significant by the investigator, this will also be indicated in 
the listings. Comments with regard to the laboratory test results will be shown in a separate listing, and will 
cover reasons for not done measurements, specimen conditions, any comment available in the database 
related to laboratory measurements. 
Descriptive statistics summarizing continuous laboratory results of clinical chemistry, hematology and 
routine urine analysis (observed values) by treatment and scheduled time will be provided. 
Glucose 
Linear plots of the arithmetic mean glucose concentrations by scheduled sampling time will be provided by 
treatment (2 treatments in one plot). These plots will show time in hours. The plots will match the summary 
table results.  
Linear spaghetti plots of glucose concentrations by actual sampling times will be provided by treatment. 
18.1.4 Vital Signs 
Vital signs data (observed values) will be listed by participants and summarized descriptively by treatment 
per scheduled time point. 
If SBP, DBP and/or pulse rate is out of the normal range, the physician’s evaluation for that vital signs 
measurement will be listed. Normal ranges are as follows: 
• 
SBP: 90 – 140 mmHg 
• 
DBP: 50 – 90 mmHg 
• 
Pulse Rate: 50 – 100 beats/min 
If pulse rate is >85 beats/min at screening or day -1, the participant is not eligible for the study. 
18.1.5 Electrocardiograms 
The observed measurements for all ECG parameters (HR, PR, QRS, QT and QTc) and the corresponding 
abnormalities and physicians’ conclusions will be listed by participant. The means of triplicate 
measurements for continuous parameters and the change from baseline of the mean triplicate 
measurements at each scheduled timepoint will be listed by participant. 
Descriptive statistics will be provided to summarize mean ECG parameters (observed and changes from 
baseline) by treatment and scheduled time. 
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For heart rate and QTcF, linear plots of the arithmetic mean values (absolute values) by scheduled time 
will be provided by treatment (2 treatments in one plot). These plots will show time in hours. The plots will 
match the summary table results.  
Linear spaghetti plots of the heart rate and QTcF values by actual times will be provided by treatment.  
18.1.6 Other Observations Related to Safety 
Bodyweight results will be listed. 
19.0 Result Summary Public Disclosure Information 
The following public study disclosure information will be provided: 
- Summary of Subject Disposition at Each Study Period 
- Summary Demographics 
- Summary of Site Related Information 
- Summary of Adverse Events Overview – Any AEs 
- Summary of Adverse Events Overview – Any SAEs 
- Summary of Adverse Events Overview – Any Drug Related SAEs 
- Summary of Adverse Events Overview – Any Fatal SAEs 
- Summary of Adverse Events Overview – Any Drug Related Fatal SAEs 
- Summary of Common Non-serious AEs (>=5%) by System Organ Class and Preferred Term  
- Summary of All-cause Mortality - Occurrence of Death Due to Any Cause 
- Summary of Urinary Dipstick Results  
 
The complete list of result summary public disclosure tables will be provided in Appendix 5: List of Public 
Disclosure Tables.  
20.0 References 
 
SAS Institute, Inc., SAS® Version 9.4 software, Cary, NC.  
Clinical Study Protocol. A single dose two-way cross-over study in healthy participants to compare the 
pharmacokinetics (PK) of salbutamol administered via metered dose inhalers containing propellants 
HFA-152a and HFA 134a. Version 2.0, Final, 10 Feb 2022.  
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Appendix 1: Glossary of Abbreviations 
Glossary of Abbreviations: 
ADAE 
Adverse event analysis dataset 
ADaM 
Analysis data model 
ADEG  
ECG analysis dataset  
ADLB  
Laboratory analysis dataset  
ADPC  
Pharmacokinetic concentrations analysis dataset  
ADPP  
Pharmacokinetic parameters analysis dataset  
ADSL  
Subject-level analysis dataset  
ADVS  
Vital signs analysis dataset  
AE 
Adverse event 
β-HCG 
Beta-human chorionic gonadotropin 
BMI 
Body mass index 
BQL 
Below the quantifiable limit 
CDISC 
Clinical data interchange standard consortium 
CI 
Confidence interval 
CRU  
Clinical research unit 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CV% 
Coefficient of variation 
CVw 
Within participant coefficient of variation  
DBP 
Diastolic blood pressure  
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDS 
Early development services 
FSH 
Follicle stimulating hormone 
geoCV% 
CV% of the geometric mean 
GSK 
GlaxoSmithKline Research & Development Limited 
ICH 
The International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IRT 
Interactive response technology 
LLOQ 
Lower Limit of Quantification 
LSM 
Least Square Means 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
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MDI 
Metered dose inhaler 
Min 
Minimum 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
RAMOS NG 
Randomization and Medication Ordering System Next Generation 
QA’d 
Quality assured 
QC’d 
Quality controlled 
SAP 
Statistical analysis plan 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SBP 
Systolic blood pressure  
SD 
Standard deviation  
SDTM 
Study data tabulation model 
SmPC 
Summary of product characteristics 
TEAE 
Treatment-emergent adverse event 
TFL(s) 
Tables, Figures and Listings 
ULOQ 
Upper Limit of Quantification 
WHO 
World Health Organization  
WNL 
WinNonlin 
For PK and PD parameters please refer to Section 16 and 17 
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Appendix 2: Schedule of Assessments 
Procedure 
 
Screening  
 
Intervention perioda 
 
Discharge or early discontinuation 
 
Study day 
-28 to -1 
-1 
1 (pre-dose) 
1 
2 
3 
4 
5 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
Admission 
 
X 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
X 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Physical examinationb 
X 
 
 
 
 
 
 
Xb 
Body weight 
X 
X 
 
 
 
 
 
 
Height and BMI calculation 
X 
 
 
 
 
 
 
 
Medical history (includes substance usage) 
X 
 
 
 
 
 
 
 
Serum pregnancy test (females only) 
X 
X 
 
 
 
 
 
X 
FSH (females only) 
X 
 
 
 
 
 
 
 
Serology (HBsAg, anti-HCV, anti-HIV 1 and 
2) 
X 
 
 
 
 
 
 
 
SARS-CoV-2 PCR testc 
 
X 
 
 
X 
 
 
 
Drug and alcohol screen 
X 
X 
 
 
 
 
 
 
Clinical laboratory assessmentsd 
X 
X 
 
 
 
 
 
X 
Blood sampling for serum potassium (PD) 
and glucose (safety)e 
 
 
Xe 
Xe 
 
 
Xe 
 
Vital signsf 
X 
X 
X 
X 
 
 
X 
X 
12-lead ECGg 
X 
X 
X 
X 
 
 
X 
X 
MDI teachingh 
 
X 
X 
 
 
 
X 
 
Randomization 
 
 
X 
 
 
 
 
 
Administration of study interventioni 
 
 
 
X 
 
 
X 
 
Blood sampling for PKj 
 
 
X 
X 
X 
 
X 
X 
AE reviewk 
 
 
 
Xi 
X 
X 
X 
X 
SAE reviewk 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
 
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AE=adverse event; HCV=hepatitis C virus; HIV=human immunodeficiency virus; BMI=body mass index; ECG=electrocardiogram; FSH=follicle stimulating hormone; 
HBsAg=hepatitis B surface antigen; HR=heart rate; IMP=investigational medicinal product; MDI=metered dose inhaler; PCR= polymerase chain reaction; 
PD=pharmacodynamic(s); PK=pharmacokinetic(s); QTcF=QT interval corrected using Fridericia’s formula; SARS-CoV-2= severe acute respiratory syndrome-corona virus type 2; 
SAE=serious adverse event;  
a. 
Participants will be in the clinic for 1 period, from Day -1 until Day 5 (24 hours after the last dose on Day 4). 
b. 
Complete physical examinations will be conducted at screening. Symptom driven physical examinations may be conducted at discharge or any other time, per the 
investigator’s discretion. 
c. 
Sampling of nasal and throat mucosal cells for PCR testing for SARS-CoV-2. If deemed necessary, additional tests may be conducted during the study per site specific 
requirements. 
d. 
Clinical laboratory assessments (including clinical chemistry [includes liver chemistries], hematology, and urinalysis): at screening, on Day -1 (admission), and at 
discharge;  
e. 
Blood sampling for serum potassium (PD) and glucose (safety): on each dosing day (Day 1 and 4), blood samples will be taken pre-dose and at the following time points 
post-dose: 15 and 30 minutes and 1, 1.5, 2 and 4 hours post-dose. 
f. 
Vital signs (systolic and diastolic blood pressure, and pulse rate): vital signs will be recorded at screening, admission, on each dosing day (Day 1 and 4) at pre-dose and 
at the following time points post-dose: 15 and 30 minutes and 1, 1.5, 2 and 4 hours post-dose, and at discharge. 
g. 
12-lead ECG: 12-lead ECG will be recorded at screening, admission, on each dosing day (Day 1 and 4) at pre-dose and at the following time points post-dose: 15 and 
30 minutes and 1, 1.5, 2 and 4 hours post-dose, and at discharge. As the ECG parameters QTc and HR will be PD parameters, ECG will be measured in triplicate at 
pre-dose on Days 1 and 4. The 3 pre-dose measures will be averaged for QTc interval and HR to derive one baseline value. Each individual capture of the triplicate 
12-lead ECG set will be separated by 1 to 5 minutes between the first and the third ECG. Post-dose 12-lead ECG measurements will be single measurements on both 
dosing days. Note: if an ECG meets potential stopping criteria, then the ECG measurement should be repeated in triplicate, with the averaged QT and QTcF used to 
determine stopping. 
h. 
Participants will be trained by using the
device on Day -1 and prior to each dosing on Days 1 and 4. Additional training instructions are provided using the 
 device which provides auditory feedback when the participant generates an adequate breath in: 
Day -1: using the
device, review the instructions, with particular focus on Steps 4-7. Once the participant is comfortable with using the training device, practice 
completing a sequence of 8 puffs.  
Dosing days: using the
device, review the instructions, and observe the patient performing a single puff using the training device. Provide feedback as 
necessary until proper technique is observed before conducting the full dose using the investigational inhaler. 
Additional training using the
(eg, on Day 3) may be performed at the discretion of the clinic. 
i. 
Administration of study intervention: start of the 8 inhalations study intervention, with the inhalations administered at 20-second intervals. Note: All post-dose time points 
will be from start of dosing (first inhalation).  
j. 
PK blood sampling: on each dosing day (Day 1 and 4), PK blood samples will be taken at pre-dose, at 3, 5, 10, 15, 20, 30, and 45 minutes post-dose; and at 1, 1.5, 2, 3, 
4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose for plasma salbutamol determination. PK collection will be from start of study intervention (i.e. first inhalation). When 
assessments are scheduled at the same time, ECG and vital signs will be taken first followed by the blood samples, with PK blood sampling on time. 
k. 
All SAEs will be collected from the signing of the ICF until discharge.  
All AEs will be collected from the start of study intervention until discharge. 
 
 
 
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Appendix 3: List of In-Text Outputs 
 
List of CSR In-Text Tables and Figures: 
Output 
Title  
Analysis Set 
Table 
Summary of Participant Disposition  
Screened (all 
participants), 
and enrolled 
Table  
Summary of Demographics for Safety Set  
Enrolled 
Figure  
Geometric Mean Plasma Salbutamol Concentrations versus Time 
Profile (Linear and Semi-Logarithmic Scale) 
PK 
Table  
Summary Statistics of Salbutamol Plasma PK Parameters  
PK 
Figure  
Scatterplot of Individual Values and Geometric Mean Salbutamol 
Plasma PK Parameters 
PK 
Table  
Statistical Analysis on PK Parameters 
PK 
Figure  
Arithmetic Mean PD Potassium versus Time Profile (Linear and 
Semi-Logarithmic Scale) 
PD 
Table  
Summary Statistics of PD Potassium Parameters  
PD 
Table  
Statistical Analysis on PD Potassium Parameters 
PD 
Figure  
Arithmetic Mean Heart Rate and QTcF Values versus Time Profile 
by Parameter (Linear and Semi-Logarithmic Scale) 
PD 
Table  
Summary Statistics of PD Heart Rate and QTcF Parameters  
PD 
Table  
Statistical Analysis on PD Heart Rate and QTcF Parameters 
PD 
Table  
Summary of all TEAEs by System Organ Class and Preferred Term 
Safety 
Table 
Summary of Related TEAEs by System Organ Class and Preferred 
Term 
Safety 
Table 
Summary of all TEAEs by Treatment by Relationship to Study Drug 
Safety 
Table 
Summary of all TEAEs by Treatment by Severity 
Safety 
 
Appendix 4: List of End of Text Outputs 
List of End of Text Tables and Figures:  
Output 
Title  
Analysis Set 
Section 15.1 – Disposition and Demographic Data 
Table 15.1.1 
Summary of Participant Disposition 
Screened (all 
participants), 
and enrolled 
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Table 15.1.2 
Summary of Participant Treatment Status and Reasons for 
Discontinuation of Study Treatment 
Enrolled 
Table 15.1.3 
Summary of Demographics 
Enrolled 
Table 15.1.4 
Summary of Major Protocol Deviations 
Safety 
Section 15.2 – Pharmacokinetic Data 
 
Table 15.2.1 
Descriptive Statistics of Salbutamol Plasma Concentrations by 
Treatment 
PK 
Table 15.2.2 
Descriptive Statistics of Salbutamol Plasma PK Parameters by 
Treatment 
PK 
Table 15.2.3 
Statistical Analysis on Salbutamol PK Parameters 
PK 
Figure 15.2.4 
Plot of Arithmetic Mean Salbutamol Plasma Concentrations 
versus Time (Linear and Semi-Logarithmic Scale) 
PK 
Figure 15.2.5 
Plot of Median Salbutamol Plasma Concentrations versus Time 
(Linear and Semi-Logarithmic Scale) 
PK 
Figure 15.2.6 
Combined Individual Salbutamol Plasma Concentrations versus 
Time Profile Linear and Semi-Logarithmic Scale) 
PK 
Figure 15.2.7 
Individual Salbutamol Plasma Concentrations versus Time Profile 
(Linear and Semi-Logarithmic Scale) 
PK 
Figure 15.2.8 
Individual Salbutamol PK parameters and Geometric Mean versus 
Treatment   
PK 
Section 15.3 – Pharmacodynamic Data 
 
Table 15.3.1 
Descriptive Statistics of Serum Potassium Concentrations by 
Treatment 
PD 
Table 15.3.2 
Descriptive Statistics of PD Serum Potassium Parameters by 
Treatment 
PD 
Table 15.3.3 
Statistical Analysis on PD Serum Potassium Parameters by 
Treatment 
PD 
Figure 15.3.4 
Plot of Arithmetic Mean PD Serum Potassium Concentrations 
versus Time (Linear Scale) 
PD 
Figure 15.3.5 
Combined Individual PD Serum Potassium Concentrations versus 
Time Profile (Linear Scale) 
PD 
Table 15.3.6 
Descriptive Statistics of PD Heart Rate and QTcF Parameters by 
Treatment 
PD 
Table 15.3.7 
Statistical Analysis on PD Heart Rate and QTcF Parameters 
PD 
Figure 15.3.8 
Plot of Arithmetic Mean PD Heart Rate and QTcF Values versus 
Time by Parameter (Linear Scale) 
PD 
Figure 15.3.9 
Combined Individual PD Heart Rate and QTcF Values versus 
Time Profile by Parameter (Linear Scale) 
PD 
Section 15.4 Safety  Data 
 
15.4.1 Adverse Events 
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Table 15.4.1.1   
Overview of Treatment-emergent Adverse Events  
Safety 
Table 15.4.1.2   
Summary of Treatment emergent Adverse Events by System 
Organ Class and Preferred Term  
Safety 
Table 15.4.1.3 
Summary of Treatment-emergent Adverse Events by Severity and 
by System Organ Class and Preferred  Term 
Safety 
Table 15.4.1.4 
Summary of Treatment-emergent Adverse Events Leading to 
Study Discontinuation by System Organ Class and Preferred 
Term 
Safety 
Table 15.4.1.5 
Summary of Related Treatment-emergent Adverse Events by 
System Organ Class and Preferred Term  
Safety 
Table 15.4.1.6 
Summary of Treatment-emergent Serious Adverse Events by 
System Organ Class and Preferred Term 
Safety 
Table 15.4.1.7 
Summary of Related Treatment-emergent Serious Adverse 
Events by System Organ Class and Preferred Term 
Safety 
Table 15.4.1.8 
Summary of Treatment-emergent Serious Adverse Events 
Leading to Discontinuation from the Study by System Organ Class 
and Preferred Term 
Safety 
15.4.2 Lists of Deaths, Other Serious and Significant Adverse Events 
Table 15.4.2.1 
Listing of Deaths and Other Serious Adverse Events  
Screened 
15.4.3 Laboratory Data 
Table 15.4.3.1 
Listing of Abnormal Laboratory Values 
Safety 
Table 15.4.3.2 
Summary of Hematology Parameters 
Safety 
Table 15.4.3.3 
Summary of Blood Chemistry Parameters 
Safety 
Table 15.4.3.4 
Summary of Routine Urinalysis Parameters 
Safety 
Figure 15.4.3.5 
Plot of Arithmetic Mean Glucose Concentrations versus Time 
(Linear Scale) 
Safety 
Figure 15.4.3.6 
Combined Individual Glucose Concentrations versus Time Profile 
(Linear Scale) 
Safety 
Section 15.4.4 Other Safety Parameters 
Table 15.4.4.1 
Summary of Vital Signs (Absolute Values) 
Safety 
Table 15.4.4.2 
Summary of 12-Lead Electrocardiogram (Absolute Values and 
Changes from Baseline) 
Safety 
 
List of Subject Data Listings:  
Output 
Title  
Section 16.2.1 – Disposition 
Listing 16.2.1 
Participant Disposition 
Section 16.2.2 – Protocol Deviations 
Listing 16.2.2 
Protocol Deviations 
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Section 16.2.3 – Excluded Participants 
Listing 16.2.3 
Analysis Sets 
Section 16.2.4 – Demographics and Baseline Characteristics 
Listing 16.2.4.1 
Participant Demographics 
Listing 16.2.4.2 
Medical History 
Listing 16.2.4.3 
Drug and Alcohol Screen Results 
Listing 16.2.4.4 
Serology Test Results 
Listing 16.2.4.5 
Pregnancy Test and FSH Test Results 
Listing 16.2.4.6 
SARS-CoV-2 Results 
Listing 16.2.4.7 
Substance Use 
Listing 16.2.4.8 
Non-compliance to Inclusion or Exclusion Criteria 
Listing 16.2.4.9 
Early Study Intervention /Treatment Unblinding  
Section 16.2.5 - Compliance 
Listing 16.2.5.1  
Study Dates 
Listing 16.2.5.2 
Study Drug Administration 
Section 16.2.6 – Response Data PK and PD 
Listing 16.2.6.1 
Salbutamol Plasma Concentrations, Sampling Time Deviations and Comments 
Listing 16.2.6.2 
Salbutamol Plasma PK Parameters 
Listing 16.2.6.3 
Serum Potassium Concentrations,  Sampling Time Deviations and Comments 
Listing 16.2.6.4 
Serum Potassium Parameters 
Listing 16.2.6.5 
Heart Rate and QTcF Parameters 
Section 16.2.7 – Adverse Events Data 
Listing 16.2.7.1 
Adverse Events 
Listing 16.2.7.2 
Adverse Events Leading to Study Discontinuation 
Listing 16.2.7.3 
Prior and Concomitant Medications 
Section 16.2.8 – Laboratory Data 
Listing 16.2.8.1 
Clinical Laboratory Results – Hematology 
Listing 16.2.8.2 
Clinical Laboratory Results – Chemistry 
Listing 16.2.8.3 
Clinical Laboratory Results – Urinalysis 
Listing 16.2.8.4 
Clinical Laboratory Results – Comments 
Section 16.2.9 – Other Safety Data 
Listing 16.2.9.1 
Vital Signs 
Listing 16.2.9.2 
12-Lead Electrocardiogram Results 
Listing 16.2.9.3 
Body Weight 
 
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Other Appendix Outputs: 
Output 
Title  
Appendix 16.1.9.2 
Statistical Appendices 
Appendix 5: List of Public Disclosure Tables 
All outputs related to primary and secondary endpoints will be taken from the main list of outputs in 
Appendix 4: List of End of Text Outputs. 
 
Public Disclosure Tables: 
Table 1 
Summary of Subject Disposition at Each Study Period 
Table 2 
Summary Demographics 
Table 3 
Summary of Site Related Information 
Table 4 
Summary of Adverse Events Overview – Any AEs 
Table 5 
Summary of Adverse Events Overview – Any SAEs 
Table 6 
Summary of Adverse Events Overview – Any Drug Related SAEs 
Table 7 
Summary of Adverse Events Overview – Any Fatal SAEs 
Table 8 
Summary of Adverse Events Overview – Any Drug Related Fatal SAEs 
Table 9 
Summary of Common Non-serious AEs (>=5%) by System Organ Class and Preferred Term 
Table 10 
Summary of All-cause Mortality - Occurrence of Death Due to Any Cause 
Table 11 
Summary of Urinary Dipstick Results 
19.0 Document History 
Version Date 
Modified/Reviewed 
By 
Brief Summary of Changes (if created from a 
template, include template code) 
17-Jan-2023 
Internal review version 
24-Jan-2023 
First draft version – CSP version 1.0 (09Dec22) 
13-Feb-2023 
Second draft version – CSP version 2.0 (10Feb23)- 
internal review version 
17-Feb-2023 
Second draft version – CSP version 2.0 (10Feb23) 
21-Mar-2023 
Third draft version – CSP version 2.0 (10Feb23) 
04-Apr-2023 
Fourth draft version – CSP version 2.0 (10Feb23) 
13-Apr-2023 
Prefinal – CSP version 2.0 (10Feb23) 
18-Apr-2023 
Final – CSP version 2.0 (10Feb23) 
20-Apr-2023 
Final – CSP version 2.0 (10Feb23) 
02-Jun-2023 
Draft v2.0 (see SAP version 4.0 for an overview of the 
updates).  
13-Jun-2023 
Final version for signatures 
PPD
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