Evaluation of Triple Therapy Using Magnetic Resonance Imaging in Asthma
Phase: PHASE3
Conditions: Asthma
Sponsor: Dr. Grace Parraga

Study Number ROB0046 
Drug Substance FF/UMEC/VI (200/62.5/25ug QD) 
 
 
 
 
 
 
 
Version 11 Date 08/07/2022 
 
 
 
 
Evaluation of Triple Therapy using Magnetic Resonance Imaging in Asthma 
ETHA 
 
 
 
 
 
 
Sponsor:  
Robarts Research Institute,  
Schulich School of Medicine & Dentistry 
Western University London CANADA 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property of 
Western University (or under its control), and is therefore provided to you in confidence as an 
investigator, potential investigator, collaborator, trainee, staff or consultant, for review by you, 
your staff and an applicable Institutional Review Committee/Research Ethics Board.  It is 
understood that this information will not be disclosed to others without written authorization, 
except to the extent necessary to obtain informed consent from those participants for whom the 
study may be implemented. 
NCT04651777

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VERSION HISTORY 
Version 01, August 27, 2020 
Version 02, September 8, 2020 
Version 03, September 9, 2020 
Version 04, September 28, 2020 
Version 05, November 18, 2020 
Version 06, November 19, 2020 
Version 07, January 14, 2021 
Version 08, February 24, 2022 
Version 09, May 3, 2022 
Version 10, June 20, 2022 
Version 11, July 8, 2022 
   
 
 

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Principal Investigator 
Grace Parraga, PhD, FCAHS 
Room 2234, Robarts Research Institute 
Western University 
1151 Richmond Street North 
London, Ontario, Canada N6A 5B7 
 
Co-Investigator and Qualified Investigator 
Cory Yamashita, MD, FRCPC 
St. Joseph’s Health Care 
268 Grosvenor Street 
London, Ontario, Canada N6A 4V2 
 
Collaborators (alphabetical listing) 
Lisa Cameron, PhD 
Western University 
1151 Richmond Street North 
London, Ontario, Canada N6A 5B7 
 
Christopher Licskai, MD, FRCPC 
London Health Sciences – Victoria Hospital  
800 Commissioners Road East 
London, Ontario, Canada N6A 5W9 
 
Constance Mackenzie, MD, FRCPC 
St. Joseph’s Health Care 
268 Grosvenor Street 
London, Ontario, Canada N6A 4V2 
 
David G McCormack, MD, FRCPC 
London Health Sciences Centre – Victoria Hospital 
800 Commissioners Road East 
London, Ontario, Canada N6A 5W9 
 
Narinder Paul, MD, FRCPC 
London Health Sciences Centre- University Hospital 
339 Windermere Rd, London, ON N6A 5A5 
 
Staff 
Angela Wilson RRT 
Ivailo Petrov PhD 
 
Study site(s) and number of participants planned 
1 site: 30 participants 
 
Name/address of Institutional Review Board/Ethics Review Committee 
Office of Research Ethics 
Room 5150 Support Services Building 
University of Western Ontario 
London, ON  N6A 3K7 
Telephone:  (519) 661-3036 

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PROTOCOL SYNOPSIS 
Achieving and maintaining asthma control is a primary goal of asthma treatment. Despite 
inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) therapy, some participants with 
asthma remain with poorly controlled symptoms.1  
A recent study in asthma participants of triple therapy [ICS/LABA and a long-acting muscarinic 
antagonist (LAMA)] demonstrated a statistically significant improvement in the forced 
expiratory volume in 1 second (FEV1) after 24 weeks of treatment as compared to dual therapy.2 
In the same study, the annualised rate of moderate/severe exacerbations also improved, but this 
improvement was not significantly different as compared to dual therapy.2  
The objective of this proof-of-principle, investigator-initiated project is to measure the 
effect of six weeks of triple therapy with fluticasone furoate, an ICS; umeclidinium (UMEC), a 
LAMA; and vilanterol (VI), a LABA, delivered in a single daily inhalation via an Ellipta inhaler 
on 129Xe magnetic resonance imaging (MRI) ventilation defect percent (VDP), oscillometry and 
multiple breath nitrogen washout (MBNW) measurements in asthma participants with poor 
disease control while prescribed low or medium dose ICS/LABA inhaled therapy. 
By measuring 129Xe MRI VDP, the function of small and large asthma airways can be directly 
evaluated which may help uncover the mechanism of action by which triple therapy may 
improve FEV1 and asthma control. Our overarching hypothesis is that six weeks of once daily 
therapy with FF/UMEC/VI (200/62.5/25 µg) will result in significantly improved and clinically-
relevant changes in 129Xe MRI VDP as well as MBNW and oscillometry measurements of 
airway function in participants with uncontrolled asthma while prescribed low or medium dose 
ICS/LABA inhaled therapy. 
TITLE 
ETHA: Evaluation of Triple Therapy using 
Magnetic Resonance Imaging in Asthma 
SPONSOR 
Robarts Research Institute, Western University, 
1151 Richmond St. N. London, ON, N6A 5B7 
INDICATION 
Uncontrolled asthma 
OBJECTIVE 
To measure the effect of six weeks of triple therapy 
with fluticasone furoate - an inhaled corticosteroid 
(ICS); umeclidinium (UMEC), a long-acting 
muscarinic antagonist (LAMA); and vilanterol 
(VI), a long-acting β2-adrenergic agonist (LABA), 
delivered in a single daily inhalation via Ellipta 
inhaler on 129Xe MRI ventilation defect percent 
(VDP), oscillometry and multiple breath nitrogen 
washout measurements in asthma participants with 
poor disease control while prescribed low or 
medium dose ICS/LABA inhaled therapy. 
STUDY DESIGN 
Six-week treatment study with no washout from 
ICS/LABA, open label, no control arm 
PLANNED TOTAL SAMPLE SIZE 
30 participants 
PARTICIPANT 
SELECTION 
CRITERIA 
Thirty participants between 18-75 years of age with 
a diagnosis of uncontrolled GINA 2-4 asthma, 
while prescribed low or medium dose ICS/LABA 
inhaled therapy under the care of a respirologist; 
ACQ-6≥1.5 

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TREATMENTS 
1) hyperpolarized 
129Xe gas for MRI, 2) 
FF/UMEC/VI (200/62.5/25 µg QD) via Ellipta 
inhaler 
DOSES 
1) 400 ml inhaled from Tedlar bag, 2) 
FF/UMEC/VI (200/62.5/25 µg QD) 
ROUTE OF ADMINISTRATION 
Ellipta inhaler for FF/UMEC/VI 
MAIN PARAMETERS OF: 
- SAFETY                 
 
-   EFFICACY 
 
 
 
Heart rate, respiration and oxygen saturation during 
imaging.  Adverse events throughout study 
MRI VDP 
Pulmonary function tests 
 Spirometry 
 Plethysmography 
 Oscillometry 
 Multiple breath nitrogen washout 
CBC for blood eosinophils 
FeNO 
ACQ-6/AQLQ/SGRQ questionnaires 
FIRST PARTICIPANT FIRST VISIT 
Q2 2022 
LAST PARTICIPANT LAST VISIT 
Q2 2023 
Study design 
This is an open-label, single arm pilot study in participants prescribed low or medium dose 
ICS/LABA inhaled therapy and uncontrolled asthma to quantify hyperpolarized 129Xe MRI 
VDP before and after six weeks of therapy with FF/UMEC/VI 200/62.5/25 µg QD.  Male and 
females between 18 and 75 years of age will provide written informed consent to two visits 
including screening and baseline (Visit 1 week 0), and study end (Visit 2 week +6). The general 
study procedures are the same for Visit 1/Day 0 and Visit 2/Day 42.  
For Visits 1 and 2, participants are to withhold their medication as previously described.3  Vital 
signs will be recorded at the beginning of the visit.  FeNO, spirometry, plethysmography, forced 
oscillation technique (FOT), MBNW, 1H and 129Xe MRI will be performed pre-bronchodilator.  
FeNO will be performed before all other pulmonary function testing.  Following 129Xe MRI, all 
participants will inhale 4 puffs (100 mcg each) of a bronchodilator and quietly rest for 15 
minutes.  After 15 minutes, participants will undergo post-bronchodilator 1H and 129Xe MRI, 
and once MRI is complete, participants will undergo post-bronchodilator spirometry, 
plethysmography, FOT and MBNW.  St. George’s respiratory questionnaire (SGRQ), asthma 
control questionnaire (ACQ-6) and asthma quality of life questionnaire (AQLQ) will be 
administered after post-bronchodilator assessments are completed. Adverse events will be 
recorded at Visit 2. Computed tomography (CT) imaging will be acquired at Visit 1 with 
optional CT imaging at Visit 2, whilst MRI will be acquired on Visits 1 and 2.  
Objectives 
Primary Objective: 
Outcome Measure: 
To measure the effect of FF/UMEC/VI 
200/62.5/25 µg QD on 129Xe MRI VDP 
after 6 weeks of therapy  
129Xe VDP 
 
Secondary Objectives: 
Outcome Measures: 

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SO1: To measure the effect of 
FF/UMEC/VI 200/62.5/25 µg QD on 
biomarkers of pulmonary function and 
inflammation 
FEV1, FVC, FEV1/FVC, FEF25-75, lung volumes, 
Raw, FOT (R5, R19, R5-19, X5, AX), LCI, Scon, Sacin, 
blood eosinophils, FeNO 
SO2: To measure the effect of 
FF/UMEC/VI 200/62.5/25 µg on asthma 
control and quality-of-life  
ACQ-6, AQLQ, SGRQ 
 
Safety Objectives: 
Outcome Measures: 
SO3: To assess the safety and tolerability 
of FF/UMEC/VI 200/62.5/25 µg 
AE/SAE 
Vital signs 
Exploratory Objectives: 
Outcome Measures: 
To evaluate the relationships between MRI 
VDP and asthma control and quality-of-life 
VDP 
ACQ-6, AQLQ, SGRQ 
To evaluate the relationships between MRI 
VDP and lung function  
VDP 
FEV1, FVC, FEV1/FVC, FEF25-75, lung volumes, 
Raw, FOT (R5, R19, R5-19, X5, AX), LCI, Scon, 
Sacin 
To evaluate the relationships between MRI 
VDP, airway and blood eosinophilia  
VDP 
FeNO, Blood eosinophils 
Target participants 
Thirty participants between 18-75 years of age with a diagnosis of uncontrolled (ACQ-6≥1.5)4 
Global Initiative for Asthma (GINA) 2-4 asthma, according to the treatment step criteria5 and 
under the care of a respirologist and prescribed low or medium dose ICS/LABA inhaled therapy. 
Duration of treatment 
There are no washout or run-in periods for this study. The treatment period will be 6 weeks and 
the maximum total study time will be 6-8 weeks. 
Investigational product, dosage, mode of administration and drug formulation 
400mL of hyperpolarized 129Xe is administered via inhalation up to four times per study visit 
(up to two times pre-bronchodilator and up to two times post-bronchodilator) on Visit 1/Day 0 
and Visit 2/Day 42. 129Xe gas polarization will be performed at Robarts Research Institute using 
a mixture of 129Xe, nitrogen and helium, purified to ≥99.99% purity. 400mL of hyperpolarized 
129Xe gas will be mixed with medical grade 4He to a 1L volume and will be used immediately.  
Treatment, dosage and mode of administration 
FF/UMEC/VI 200/62.5/25 µg used daily at the same time in the morning (±2 hours), starting 
on Visit 1/Day 0 and completing on Visit 2/Day 42/week 6, at which time a treatment decision 
will be made in consultation with the respirologist.  
Statistical methods 
Data will be tested for normality using the Shapiro-Wilk test and when data are not normally 
distributed, non-parametric tests will be performed.  Unpaired t-tests and Mann-Whitney U-
tests will be performed to compare participant characteristics, pulmonary function and MRI 
measurements in participants with eosinophilic asthma. To correct for multiple comparisons, a 
Holm-Bonferroni correction will be applied. Paired t-tests will be used to analyze the 
differences between the pre-treatment and post-treatment measurements in each participant.  
Univariate relationships will be evaluated using Pearson (r) and Spearman () correlation 

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coefficients. Statistical analyses will be performed using SPSS (SPSS Statistics 25.0; IBM, 
Armonk, NJ, USA) and all results will be considered statistically significant when the 
probability of making a Type I error was less than 5% (p < 0.05). 

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TABLE OF CONTENTS 
PAGE 
 
VERSION HISTORY .............................................................................................. 2 
PROTOCOL SYNOPSIS ......................................................................................... 4 
TABLE OF CONTENTS ......................................................................................... 8 
1. 
INTRODUCTION ................................................................................................. 12 
1.1 
Background and rationale for conducting this study ............................................. 12 
1.2 
Rationale for study design, doses and control groups ............................................ 12 
1.2.1 
Goal and Hypothesis .............................................................................................. 12 
1.2.2 
Study design ........................................................................................................... 12 
1.2.3 
Primary and secondary outcome measures ............................................................ 13 
1.2.4 
Dosing and study duration ..................................................................................... 13 
1.2.5 
Biological samples ................................................................................................. 13 
1.3 
Benefit/risk and ethical assessment........................................................................ 13 
1.4 
Study objectives ..................................................................................................... 14 
2. 
PARTICIPANT SELECTION, ENROLLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 14 
2.1 
Inclusion criteria .................................................................................................... 15 
2.2 
Exclusion criteria ................................................................................................... 15 
2.3 
Participant enrollment ............................................................................................ 16 
2.4 
Procedures for handling incorrectly enrolled participants ..................................... 17 
2.5 
Restrictions ............................................................................................................ 17 
2.6 
Discontinuation of treatment or investigational product........................................ 17 
2.6.1 
Procedures for discontinuation of a participant from treatment or 
investigational product ........................................................................................... 17 
2.7 
Criteria for withdrawal ........................................................................................... 17 
2.7.1 
Screen failures ........................................................................................................ 17 
2.7.2 
Withdrawal of the informed consent ...................................................................... 18 
2.8 
Discontinuation of the study .................................................................................. 18 
3. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 18 
3.1 
Enrollment/screening period .................................................................................. 19 
3.2 
Treatment period .................................................................................................... 19 
4. 
STUDY ASSESSMENTS ..................................................................................... 20 
4.1 
Efficacy assessments .............................................................................................. 20 
4.1.1 
Clinical and Laboratory Measurements for Efficacy ............................................. 20 

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4.2 
Safety assessments ................................................................................................. 21 
4.2.1 
Laboratory safety assessments ............................................................................... 21 
4.2.2 
Urine Pregnancy Test ............................................................................................. 21 
4.2.3 
Physical examination ............................................................................................. 21 
4.2.4 
Vital signs .............................................................................................................. 22 
4.2.4.1 
Body temperature ................................................................................................... 22 
4.2.4.2 
Safety Monitoring and Risk Management of Investigational Product ................... 22 
4.3 
Other assessments .................................................................................................. 22 
4.3.1 
Participant reported outcomes ................................................................................ 22 
4.3.1.1 
Asthma Control Questionnaire .............................................................................. 22 
4.3.1.2 
Asthma Quality of Life Questionnaire ................................................................... 22 
4.3.1.3 
St. George’s Respiratory Questionnaire ................................................................ 22 
5. 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 22 
5.1 
Definition of adverse events .................................................................................. 22 
5.2 
Definitions of serious adverse event (SAE) ........................................................... 22 
5.2.1 
Management of Acute Adverse Events .................................................................. 23 
5.2.2 
Time period for collection of adverse events ......................................................... 23 
5.2.3 
Follow-up of unresolved adverse events ................................................................ 23 
5.2.4 
Variables ................................................................................................................ 23 
5.2.5 
Causality collection ................................................................................................ 24 
5.2.6 
Adverse events based on signs and symptoms....................................................... 25 
5.2.7 
Adverse events based on examinations and tests ................................................... 25 
5.3 
Reporting of serious adverse events to WSREB, Health Canada, GSK 
Collaborator ........................................................................................................... 25 
5.4 
Overdose ................................................................................................................ 25 
5.5 
Pregnancy ............................................................................................................... 25 
5.5.1 
Maternal exposure .................................................................................................. 25 
5.5.2 
Paternal exposure ................................................................................................... 26 
6. 
TREATMENT, INVESTIGATIONAL PRODUCT AND OTHER 
TREATMENTS ..................................................................................................... 26 
6.1 
Identity of treatment and investigational product(s) .............................................. 26 
6.2 
Dose and treatment regimens ................................................................................. 26 
6.3 
Labelling ................................................................................................................ 26 
6.4 
Storage ................................................................................................................... 27 
6.5 
Compliance ............................................................................................................ 27 
6.6 
Accountability ........................................................................................................ 27 
6.7 
Concomitant and other treatments ......................................................................... 27 
6.7.1 
Other concomitant treatment .................................................................................. 27 
6.8 
Device Malfunction ............................................................................................... 27 

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7. 
STATISTICAL ANALYSES ................................................................................ 27 
7.1 
Statistical considerations ........................................................................................ 27 
7.2 
Sample size estimate .............................................................................................. 27 
7.3 
Definitions of analysis sets .................................................................................... 28 
7.3.1 
Efficacy analysis set ............................................................................................... 28 
7.3.2 
Safety analysis set .................................................................................................. 28 
7.4 
Outcome measures for analyses ............................................................................. 28 
7.5 
Methods for statistical analyses ............................................................................. 28 
8. 
STUDY AND DATA MANAGEMENT ............................................................... 29 
8.1 
Training of study site personnel ............................................................................. 29 
8.2 
Study timetable and end of study ........................................................................... 29 
8.3 
Data management ................................................................................................... 29 
8.3.1 
Database Setup ....................................................................................................... 29 
8.3.2 
Data Access ............................................................................................................ 29 
8.3.3 
Data Security .......................................................................................................... 29 
8.3.4 
Data Lock ............................................................................................................... 29 
8.3.5 
Data Archiving ....................................................................................................... 29 
9. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 30 
9.1 
Ethical conduct of the study ................................................................................... 30 
9.2 
Participant data protection ..................................................................................... 30 
9.3 
Informed consent ................................................................................................... 30 
9.4 
Changes to the protocol and informed consent form ............................................. 31 
9.5 
Audits and inspections ........................................................................................... 31 
10. 
LIST OF REFERENCES ....................................................................................... 32 
 
LIST OF TABLES 
Table 1 
Laboratory Safety Variables ..................................................................... 21 
 
LIST OF FIGURES 
Figure 1. Study Schematic ...................................................................................................... 13 
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information .................................................................. 35 
Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document ................................................................................. 36 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or special term 
Explanation 
129Xe 
Xenon-129 
ACQ-6 
Asthma control questionnaire 
AE 
Adverse event 
AQLQ 
Asthma Quality of Life questionnaire 
CRF 
Case report form (electronic/paper) 
CT 
Computed tomography 
AX 
Area of Reactance which is defined as the area under the curve 
of reactance between 5Hz and resonant frequency, reflecting a 
composite index for reactance measured using oscillometry  
FeNO 
Fractional exhaled nitric oxide 
FOT 
Forced oscillation technique; oscillometry 
GINA 
Global Initiative for Asthma 
ICH 
International Conference on Harmonisation 
IP 
Investigational product  
LCI 
Lung clearance index 
MBNW 
Multiple breath nitrogen washout 
MRI 
Magnetic resonance imaging 
Raw 
Airways resistance 
R5 
Resistance measured at 5Hz using oscillometry 
R19 
Resistance measured at 19Hz using oscillometry 
R5-19 
Resistance difference (5Hz-19Hz) measured using oscillometry 
SAE 
Serious adverse event 
Scon 
Conducting airways ventilation heterogeneity measured using 
multiple breath nitrogen washout 
Sacin 
Acinar airways ventilation heterogeneity measured using 
multiple breath nitrogen washout 
VDP 
Ventilation defect percent measured using 129Xe MRI 
X5 
Reactance measured at 5Hz using oscillometry 

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1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
Achieving and maintaining asthma control is a primary goal of asthma treatment. Despite 
inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) therapy, some participants with 
asthma remain with poorly controlled symptoms.1  
A recent treatment study in asthma participants of triple therapy [ICS/LABA and a long-acting 
muscarinic antagonist (LAMA)], demonstrated a statistically significant improvement in the 
forced expiratory volume in 1 second (FEV1) after 24 weeks of treatment as compared to dual 
therapy.6 Hence, in asthma participants, objective evidence is required to guide personalized 
treatment decisions directed at the inflammatory and non-inflammatory smooth muscle-
mediated components of airways disease.   
Biomarkers provided by inhaled 3He and 129Xe magnetic resonance imaging (MRI) have been 
developed and validated as a way to measure the structural and functional determinants of 
obstructive lung disease, including in participants with asthma.7  For example, focal ventilation 
defects measured using MRI are commonly observed in patients with asthma8,9 and these were 
shown to be spatially related to airway abnormalities10,11 and they also respond to 
bronchoconstriction10,12-15 and bronchodilation.12,16  MRI ventilation defects were shown to be 
correlated with disease severity17,18 and to independently predict asthma control in severe 
asthma.19   
1.2 
Rationale for study design, doses and control groups 
1.2.1 Goal and Hypothesis 
The goal of this proof-of-principle, investigator-initiated project is to measure the effect of 
six weeks of triple therapy with fluticasone furoate - an ICS; umeclidinium (UMEC), a LAMA; 
and vilanterol (VI), a LABA, delivered in a single daily inhalation via an Ellipta inhaler on 
129Xe MRI ventilation defect percent (VDP), forced oscillation technique (FOT) and multiple 
breath nitrogen washout (MBNW) measurements in asthma participants with poor disease 
control while prescribed low or medium dose ICS/LABA inhaled therapy. 
By measuring 129Xe MRI VDP, the function of small and large asthmatic airways can be directly 
evaluated which may help uncover the mechanism of action by which triple therapy may 
improve FEV1 and asthma control.  
Our overarching hypothesis is that six weeks of daily therapy with FF/UMEC/VI (200/62.5/25 
µg) will result in significantly improved and clinically-relevant changes in 129Xe MRI VDP, as 
well as MBNW and FOT measurements of airway function in participants with asthma and 
uncontrolled disease while prescribed low or medium dose ICS/LABA inhaled therapy. 
1.2.2 Study design 
This is a single-arm open-label study, so no blinding or randomization will be performed. For 
the evaluation of imaging biomarkers, trained observers will be blinded to time point in order 
to minimize the potential for bias in image analysis or interpretation. Figure 1 provides a 
summary of the study which includes two visits.  
 
 
 

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Figure 1. Study Schematic 
 
 
 
Visit 1 
Week 0 
Treatment 
Visit 2 
Week 6 ± 1   
Bloodwork 


PFT 


MRI 


CT 


ACQ-6/AQLQ/SGRQ 


PFT = pulmonary function test; MRI = magnetic resonance imaging; CT = computed 
tomography; ACQ-6 = asthma control questionnaire; AQLQ = asthma quality of life 
questionnaire; SGRQ = St. George’s respiratory questionnaire  
1.2.3 Primary and secondary outcome measures 
Participants with uncontrolled asthma measured using ACQ-6≥1.5 at Visit 1 will be enrolled 
and receive FF/UMEC/VI 200/62.5/25 µg daily for 6 weeks.  The primary outcome 
measurement is 129Xe MRI VDP at week 6/Day 42. Secondary outcome measurements include: 
biomarkers of inflammation (FeNO and blood eosinophils), pulmonary function [FEV1, forced 
vital capacity (FVC), lung volumes, airway resistance (Raw), FOT, ventilation hetereogeneity of 
the conducting (Scon) and acinar (Sacin) airways, lung clearance index (LCI)], asthma control and 
quality-of-life (ACQ-6, AQLQ, SGRQ). 
1.2.4 Dosing and study duration 
FF/UMEC/VI 200/62.5/25 µg will be administered via Ellipta inhaler QD for 6 weeks at the 
same time in the morning (±2 hours). Study visits will be planned for mornings.  
1.2.5 Biological samples 
Leftover biological samples will be destroyed appropriately. There is no intent to collect 
additional biological samples or use any leftover samples. 
1.3 
Benefit/risk and ethical assessment 
Study participants with poorly controlled disease may benefit from treatment with 
FF/UMEC/VI 200/62.5/25 µg, including reduced asthma exacerbations, reduced use of OCS 
and improved lung function. The safety of FF/UMEC/VI 200/62.5/25 µg has been previously 
demonstrated20 and the most common side effects were nasopharyngitis, headache and back 
pain.21  
129Xe MRI has well-demonstrated safety and tolerability.22,23 At our site,23 we previously 
observed two mild adverse events after administration of 136 doses of 500 mL Xe gas mixed 
with ultrapure 4He or N2 gas (2/136=1%). One of these adverse events was light-headedness 
that resolved within two minutes without treatment while the other adverse event was 
determined unrelated to 129Xe gas. Another study in the US, employed a 1L 129Xe gas breathhold 
inhalation (double the dose used at Robarts) and reported dizziness (59%), paresthesia (34%), 
euphoria (30%) and hypoesthesia (30%). All these symptoms resolved within three minutes 
without clinical intervention.22   
For MRI in general, adverse events do not arise from the MRI scan itself, but from a failure to 
disclose or detect MRI incompatible objects in or around the body of the participant or in the 
scanner room.  The published reported risk of injury is less than 1 in 100,000 and the risk of 
Study Duration 

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death is less than 1 in 10 million.24 Other remote risks involve temporary hearing loss from the 
noise (<95DB) produced by the scanner which can be completely prevented by ensuring the use 
of ear plug protection that also allows for continuous communication between the participant 
and research staff during the scan.  
There is a possibility that incidental findings may be observed on MRI. If this occurs, 
participants will be notified by the principal investigator and the qualified clinical investigator 
will arrange for referral to University Hospital, London Health Sciences Centre, Department of 
Medical Imaging for follow-up clinical imaging and diagnosis.  
1.4 
Study objectives 
Primary Objective: 
Outcome Measure: 
To measure the effect of FF/UMEC/VI 
200/62.5/25 µg QD on 129Xe MRI VDP 
after 6 weeks of therapy  
129Xe VDP 
 
Secondary Objectives: 
Outcome Measures: 
SO1: To measure the effect of 
FF/UMEC/VI 200/62.5/25 µg QD on 
biomarkers of pulmonary function and 
inflammation 
FEV1, FVC, FEV1/FVC, FEF25-75, lung volumes, 
Raw, FOT, (R5, R19, R5-19, X5, X19, AX), LCI, Scon, 
Sacin, blood eosinophils, FeNO 
SO2: To measure the effect of 
FF/UMEC/VI 200/62.5/25 µg on asthma 
control and quality-of-life  
ACQ-6, AQLQ, SGRQ 
 
Safety Objectives: 
Outcome Measures: 
SO3: To assess the safety and tolerability 
of FF/UMEC/VI 200/62.5/25 µg 
AE/SAE 
Vital signs 
Exploratory Objectives: 
Outcome Measures: 
To evaluate the relationships between MRI 
VDP and asthma control and quality-of-life 
VDP 
ACQ-6, AQLQ, SGRQ 
To evaluate the relationships between MRI 
VDP and lung function  
VDP 
FEV1, FVC, FEV1/FVC, FEF25-75, lung volumes, 
Raw, FOT, (R5, R19, R5-19, X5, X19, AX), LCI, 
Scon, Sacin 
To evaluate the relationships between MRI 
VDP, airway and blood eosinophilia  
VDP 
FeNO, blood eosinophils 
2. 
PARTICIPANT SELECTION, ENROLLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL  
Participants between 18 and 75 years of age with a diagnosis of asthma, according to the Global 
Initiative of Asthma (GINA) treatment step criteria5 and under the care of a respirologist, will 
be recruited.  All participants will provide written informed consent to a protocol approved by 
local research ethics boards at Western University and registered at https://clinicaltrials.gov.  
Each participant should meet all of the inclusion criteria and none of the exclusion criteria for 
this study.  Under no circumstances will exceptions to this be allowed. 

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2.1 
Inclusion criteria 
 Participant understands study procedures and is willing to participate in the study as 
indicated by the participant’s signature 
 Provision of written, informed consent prior to any study specific procedures  
 Males and females aged 18 to 75 years, inclusively, at the time of Visit 1 (enrollment), 
under the care of a respirologist 
 FEV1 ≥35 and ≤80% predicted 
 Participant is a current non-smoker and non-vaper, having not smoked tobacco or 
cannabis, pipe or cigar or vaped any product for at least 12 months prior to the study 
with a tobacco smoking history of no more than 10 pack-years (i.e. 1 pack per day for 
10 years) 
 Women of childbearing potential (after menarche) must use a highly effective form of 
birth control (confirmed by the investigator or designee) 
 A highly effective form of birth control includes true sexual abstinence, a vasectomized 
sexual partner, Implanon®, female sterilization by tubal occlusion, any effective 
intrauterine device/levonorgestrel intrauterine system, Depo-ProveraTM injections, oral 
contraceptive and Erva PatchTM or NuvaringTM 
 Women of childbearing potential (after menarche) must agree to use a highly effective 
form of birth control, as defined above, from enrollment, throughout the study duration, 
and 8 weeks after last dose of study drug, with negative urine pregnancy test result at 
Visit 1 and Visit 2 
 Male participants who are sexually active must agree to use a double barrier method of 
contraception (male condom with diaphragm or male condom with cervical cap) from 
the first dose of the study drug until 8 weeks after last dose 
 Participant has documented treatment with a stable dose of low to medium dose inhaled 
corticosteroids (defined as >250 and ≤500 mcg fluticasone proprionate/day or 
equivalent or, >400 to ≤800 mcg Budesonide/day for at least 6 months prior to 
enrollment 
 LABA for at least 6 months prior to enrollment 
 Participant has ACQ-6 ≥1.5 at Visit 1  
 All participants must have received 2 doses of a Health Canada approved COVID-19 
vaccine at least 14 days prior to their first visit 
2.2 
Exclusion criteria 
 Participant is, in the opinion of the investigator, mentally or legally incapacitated, 
preventing informed consent from being obtained, or cannot read or understand written 
material 
 Participant has clinically important pulmonary disease other than asthma (e.g. active 
lung infection, chronic obstructive pulmonary disease, bronchiectasis, pulmonary 
fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, 
alpha-1 antitrypsin deficiency and primary ciliary dyskinesia) 
 Participant has a medical condition such as narrow-angle glaucoma, urinary retention, 
prostatic hypertrophy, bladder neck obstruction or any other disorder that may be 
negatively impacted by antimuscarinic effects and/or could affect the safety of the 
participant throughout the study, influence the findings of the study or their 
interpretations, or impede the participant’s ability to complete the entire duration of the 
study, as assessed by the qualified investigator 
 Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, 
psychiatric, or major physical impairment that is not stable in the opinion of the 
Qualified Investigator and/or could affect the safety of the participant throughout the 
study, influence the findings of the study or their interpretations, or impede the 

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participant’s ability to complete the entire duration of the study, as assessed by the 
qualified investigator 
 Known history of allergy or reaction to the study drug formulation 
 Acute upper or lower respiratory infections requiring antibiotics or antiviral medication 
within 30 days prior to the date of informed consent 
 Confirmed positive COVID-19 test within the last 30 days (either PCR or rapid antigen 
test) 
 Participant has been prescribed LAMA within the last 6 months 
 Clinically significant asthma exacerbation, defined as a change from baseline deemed 
clinically relevant in the opinion of the qualified investigator, including those requiring 
the use of OCS, or an increase in maintenance dosage of OCS within 30 days prior to 
the date of informed consent. Participants with an exacerbation after providing informed 
consent but prior to treatment start will be excluded from the study 
 Receipt of immunoglobulin or blood products within 30 days prior to the date of 
informed consent 
 Receipt of live attenuated vaccines 30 days prior to the date of enrollment 
 Previously randomized in any FF/UMEC/VI 200/62.5/25 µg study 
 Planned surgical procedure during the conduct of the study 
 Concurrent enrollment in another clinical trial 
 Participant has history of alcohol or drug abuse within 12 months prior to the date of 
informed consent 
 Participant is a female who is ≤8 weeks post-partum or breast feeding an infant 
 Participant is pregnant, or intends to become pregnant during the time course of the 
study 
 Participant is unable to perform MRI breath-hold maneuver 
 Participant is unable to perform spirometry maneuver 
 Participant is hospitalized or has had a major surgical procedure, major trauma requiring 
medical attention, or significant illness requiring medical attention within 4 weeks of 
Visit 1 
 Participant has a blood pressure of >150 mmHg systolic or >95 mmHg diastolic on more 
than 2 measurements done >5 minutes apart at Visit 1 
 In the opinion of the investigator, participant suffers from any physical, psychological 
or other condition(s) that might prevent performance of the MRI, such as severe 
claustrophobia 
 Participant has implanted mechanically, electrically or magnetically activated device or 
any metal in their body, which cannot be removed, including but not limited to 
pacemakers, neurostimulators, biostimulators,  implanted insulin pumps, aneurysm 
clips, bioprosthesis, artificial limb, metallic fragment or foreign body, shunt, surgical 
staples (including clips or metallic sutures and/or ear implants) – at the discretion of the 
MRI Technologist 
2.3 
Participant enrollment  
Upon study enrollment, all participants will be allocated to receive FF/UMEC/VI 200/62.5/25 
µg treatment.  This is a single-arm study design therefore there is no randomization or blinding.  
Participants who discontinue from the study will not be replaced. We expect a 90% retention 
rate. The principal investigator will keep a record, the participant screening log, of participants 
who entered pre-study screening and will: 
 Obtain signed written informed consent from the potential participant before any study 
specific procedures are performed 
 Assign potential participant a unique enrollment number 
 Determine participant eligibility 

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If a participant withdraws from participation in the study, then his/her enrollment code cannot 
be reused. Enrollment codes will be assigned strictly sequentially as participants become 
eligible for the study.  
2.4 
Procedures for handling incorrectly enrolled participants 
Without exception, participants who fail to meet the eligibility criteria should not, under any 
circumstances, be enrolled or receive study medication.  Participants who are enrolled, but 
subsequently found not to meet all the eligibility criteria must not be initiated on treatment and 
will be withdrawn from the study. 
Where a participant does not meet all the eligibility criteria but is incorrectly started on 
treatment, the participant will discontinue the treatment. Study personnel at Robarts Research 
Institute must ensure all decisions are appropriately documented. 
2.5 
Restrictions 
The following restrictions apply once the participant has started the treatment: 
 Participants must withhold short-acting beta-agonist (SABA) use 6 hours prior to all study 
visits 
 Participants must withhold ICS/LABA or study drug use 24 hours prior to all study visits 
 Participants must withhold leukotriene receptor antagonists (LTRA, i.e. Singulair) use 24 
hours prior to all study visits 
 Use of immunosuppressive medication (other than prior, stable OCS for the maintenance 
treatment of asthma) is not permitted 
2.6 
Discontinuation of treatment or investigational product 
Participants may be discontinued from treatment or investigational product (IP) in the following 
situations: 
 
Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment 
 
Adverse event (AE) 
 
Severe non-compliance with the study protocol  
 
Participant becomes pregnant 
 
Any medical condition or personal circumstance which, in the opinion of the investigator, 
exposes the participant to risk by continuing in the study or does not allow the participant 
to adhere to the requirements of the protocol 
2.6.1 Procedures for discontinuation of a participant from treatment or 
investigational product  
A participant who discontinues the treatment or IP will always be asked about the reason(s) for 
discontinuation and the presence of any adverse events.  The principal investigator will perform 
the best possible observation(s), test(s) and evaluation(s) as well as give appropriate medication 
and all possible measures for the safety of the participant. Follow up will be performed for 
adverse events until resolved or at least 28 days after the end of treatment.  
2.7 
Criteria for withdrawal  
2.7.1 Screen failures  
Screening failures are participants who do not fulfil the eligibility criteria for the study, and 
therefore must not be enrolled. These participants should have the reason for study withdrawal 
recorded as ‘Incorrect Enrollment’ (i.e. participant does not meet the required 
inclusion/exclusion criteria).   

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2.7.2 Withdrawal of the informed consent 
Participants are free to withdraw from the study at any time (treatment, investigational product 
and assessments), without prejudice to further treatment. 
A participant who withdraws consent will always be asked about the reason(s) and the presence 
of any AE. The Investigator will follow up AEs outside of the clinical study.  
If a participant withdraws from participation in the study, then his/her enrollment code cannot 
be reused. Withdrawn participants will not be replaced.  
2.8 
Discontinuation of the study 
The study may be stopped if, in the judgment of the investigator(s), trial participants are placed 
at undue risk because of clinically significant findings that: 
 
meet individual stopping criteria or are otherwise considered significant  
 
are assessed as causally related to study drug 
 
are not considered to be consistent with continuation of the study 
Regardless of the reason for discontinuation all data available for the participant at the time of 
discontinuation of follow-up must be recorded in the Case Report Form (CRF). All reasons for 
discontinuation of treatment must be documented. In discontinuing the study, for an individual 
participant, and for all participants, the investigator(s) will ensure that adequate consideration 
is given to the protection of the participants’ interests.  
 
3. 
STUDY PLAN AND TIMING OF PROCEDURES 
Visit 
Visit 1 = Day 0 
Visit 2 = Day 42 ± 5 days 
1 
2 
Week 
0 
6 
Day 
0 
42 
Month 
 
 
Written informed consent  
X 
 
Demographics  
X 
 
Physical examination/ height/ weight 
X 
 
Medical/surgical history 
X 
 
Inclusion/exclusion criteria 
X 
 
Vital signs 
X 
X 
Treatment dispensed/returned 
X 
X 
Concomitant medication  
X 
 
Adverse event review 
X 
X 
Blood samples 
X 
X 
Spirometry 
X 
X 
Plethysmography 
X 
X 
FeNO 
X 
X 
FOT 
X 
X 
MBNW 
X 
X 
ACQ 
X 
X 
AQLQ 
X 
X 
SGRQ 
X 
X 
CT 
X 
X 
MRI 
X 
X 

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3.1 
Enrollment/screening period 
Procedures will be performed according to the Study Plan. Participants will be recruited by 
respirologist referral. Potential participants will be evaluated to determine whether they fulfil 
the entry requirements. In addition, the Investigator shall discuss and provide in writing the 
nature of the study, its requirements and restrictions in the form of a letter of information. 
Written informed consent will be obtained from participants who elect to participate, prior to 
any study procedures.  
Adherence to the scheduling of study visits and study procedures is of paramount importance; 
this must be emphasized to participants. Procedures in all treatment visits must be scheduled so 
that all study procedures are performed at the same time during the day.  
Participants will be screened for MR safety using the MRI screening form. This form will be 
reviewed by the MR technologist, who will compare the identity of the participant to the identity 
recorded on the form to verify participant safety. The form will then be filed as a part of the 
study records, separately from the de-identified data associated with that participant. 
Participants are instructed to restrict their medications prior to study visits.  
At the screening/enrollment visit, the participant will provide informed consent, be assigned a 
baseline number, and review inclusion and exclusion criteria, study procedures, clinical history, 
medication restrictions, prior therapy, concomitant therapy, adverse experiences, vital signs and 
temperature. Female participants of childbearing potential will be administered a urine 
pregnancy test.  Participants will undergo pre- and post-bronchodilator spirometry and complete 
ACQ-6. A blood sample will be acquired pre-bronchodilator. 
During the enrollment visit, the participant should demonstrate ACQ-6 ≥1.5 to continue in the 
study.  Participants will only be enrolled if all study assessment results during the enrollment 
visit satisfy inclusion and exclusion criteria.  Spirometry and ACQ-6 results may be confirmed 
immediately during the enrollment visit 
The study staff will call the participant prior to each visit to remind the participant of the 
medication restrictions and the next visit. Study staff will also complete COVID-19 screening 
by telephone prior to each visit. 
3.2 
Treatment period 
The general study procedures are the same for Visit 1/Day 0 and Visit 2/Day 42.  
Any adverse events from the previous visit should be reviewed and assessed at the beginning of 
each visit.  
For Visits 1 and 2, participants are to withhold their medication as previously described.3  Vital 
signs will be recorded at the beginning of the visit.  FeNO, spirometry, plethysmography, FOT, 
MBNW, 1H and 129Xe MRI will be performed pre-bronchodilator.  FeNO will be performed 
before all other pulmonary function testing.  Following 129Xe MRI, all participants will inhale 
4 puffs (100mcg each) of a bronchodilator and quietly rest for 15 minutes. After 15 minutes, 
participants will undergo post-bronchodilator 1H and 129Xe MRI, and once MRI is complete, 
participants will undergo post-bronchodilator spirometry, plethysmography, FOT and MBNW.  
In total, participants will be in the MRI for up to a total of 20 minutes for image acquisition.  
ACQ-6, AQLQ and SGRQ will be administered after post-bronchodilator assessments are 
completed.  Patients will undergo low dose chest CT after post-bronchodilator MRI. Participants 
will be accompanied to the CT scanner at Robarts Research Institute. For Visits 1 and 2, 
bloodwork will be drawn either at University Hospital or Robarts.  For blood draws at 
University Hospital, the patient will be accompanied to the phlebotomy lab, which is connected 
to Robarts.   

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4. 
STUDY ASSESSMENTS 
The investigator will ensure that data are recorded on Case Report Forms generated by the local 
team.  The investigator ensures the accuracy, completeness, and timeliness of the data recorded.   
4.1 
Efficacy assessments 
4.1.1 Clinical and Laboratory Measurements for Efficacy 
Spirometry, Plethysmography, FOT and Bronchodilator Response  
Spirometry and plethysmography will be performed according to American Thoracic Society 
Guidelines3 using a MedGraphics Elite Series plethysmograph (MedGraphics; St. Paul, MN, 
USA) pre- and post-bronchodilator. FOT will be performed pre- and post-bronchodilator 
according to European Respiratory Society Guidelines25 using a tremoFlo® C-100 airwave 
oscillometry system (Thorasys Thoracic Medical Systems Inc.; Montreal, QC, Canada) to 
measure resistance and reactance at 5 Hz (R5, X5), 19 Hz (R19) and the difference between 5 and 
19 Hz (R5-19).  For post-bronchodilator measurements, four 100 mcg doses of Novo-Salbutamol® 
HFA (Teva Novopharm Ltd.; Toronto, ON, Canada) will be delivered through a pressurized 
metered dose inhaler using an AeroChamber Plus spacer (Trudell Medical International; 
London, ON, Canada).  
FeNO 
FeNO will be measured pre-bronchodilator according the American Thoracic Society/European 
Respiratory Society Guidelines26 using the NIOX VERO® (Circassia Pharmaceuticals Inc, 
Morrisville, NC, USA). Participants will be seated upright and given the mouthpiece of the 
NIOX VERO®. Participants will be instructed to breathe out fully, then bring the mouthpiece 
to their lips to create a seal around the mouthpiece. Participants are then asked to inhale deeply 
to total lung capacity, then exhale slowly and completely into the mouthpiece.   
MBNW 
MBNW will be performed for measurement of LCI pre- and post-bronchodilator using 100% 
oxygen for nitrogen washout and the ndd EasyOne Pro LAB system (ndd Medical Technologies, 
Zurich, Switzerland) equipped with an ultrasonic flow and molar mass sensor. Participants will 
be seated upright with the washout phase initiated by switching from room air to 100% oxygen 
at end expiration. Tidal breathing of 100% oxygen will be performed until the expired nitrogen 
concentration is <2.5% of the concentration at the start of the test. LCI is the number of 
functional residual capacity (FRC) lung turnovers and will be calculated as the cumulative 
expired volume or air during the washout divided by FRC. MBNW will be performed in 
duplicate and reported as the mean of two maneuvers. Scon and Sacin will also be estimated.  
Image Acquisition and Analysis 
Anatomical proton (1H) and hyperpolarized 129Xe MR images will be acquired within 5 minutes 
of one another using a 3T MR system with broadband imaging capabilities (General Electric 
Health Care; Milwaukee, WI, USA), as previously described.16   MRI scanning will take place 
with the use of a 129Xe Lung coil, which is approved for research use only.  Participants will 
be instructed to inhale 1.0 L of gas (100% N2 for 1H MRI and a 129Xe/4He mixture for 129Xe 
MRI) from FRC, and 15 coronal slices will be acquired under breath-hold conditions.  129Xe gas 
will be polarized to 40-60% (Polarean; XeniSpin, Durham, NC, USA), and diluted with 600 mL 
of medical grade 4He gas.  Quantitative MRI evaluation will be performed by a single trained 
observer with at least two years’ experience using semi-automated segmentation software as 
previously described.27  129Xe MRI VDP will be generated as the ventilation defect volume 
normalized to the thoracic cavity volume.28 CT images will be acquired with an Aquilion ONE 
CT Scanner (Canon Medical Systems USA, INC., Tustin, CA, USA) at Robarts Research 
Institute. Participants will be scanned in the supine position and during inspiration breath-hold 
from FRC after inhaling 1.0 L of N2 gas in order to match the CT and MRI breath-hold volumes 

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and anatomy. CT images will be acquired with the following parameters: beam collimation of 
80 x 0.5 mm, tube voltage of 120 kVp, effective current of 210 mAs, 260 mAs and 390 mAs 
based on patient body mass index (BMI), 500 ms gantry rotation time and 0.95 pitch. The 
ImPACT CT patient dosimetry calculator (based on Health Protection Agency [UK] NRBP-
SR250) was used to estimate the mean total effective dose as 1.3 mSv or approximately equal 
to the total of background radiation experienced in one year in London, Ontario. CT images will 
be quantitatively analyzed using the VIDAvision software (VIDA Diagnostics, Coralville, IA, 
USA).  
Blood 
Blood samples will be acquired and analyzed either at Robarts in the phlebotomy lab and 
analyzed at a commercial lab or at the clinical biochemistry laboratory at University Hospital, 
London Health Sciences Centre, to measure blood eosinophils. Blood eosinophils will be 
determined using a complete blood count (CBC) analysis. 
4.2 
Safety assessments 
4.2.1 Laboratory safety assessments 
Participants that have provided written informed consent will undergo laboratory testing at Visit 
1.   
Blood samples for determination of clinical chemistry and haematology will be taken during 
Visit 1 only; these samples will also be analyzed for blood eosinophils.  Blood samples during 
Visit 2 will be analyzed for blood eosinophils only.  
The following laboratory variables will be measured: 
Table 1 
Laboratory Safety Variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Haemoglobin (Hb) 
S/P-Creatinine 
B-Leukocyte count 
S/P-Bilirubin, total 
B-Leukocyte differential count (absolute 
count) 
S/P-Alkaline phosphatise (ALP) 
B-Platelet count 
S/P-Aspartate transaminase (AST) 
 
S/P-Alanine transaminase (ALT) 
The principal and qualified investigators will evaluate results regarding clinically relevant 
abnormalities. The laboratory results will be signed and dated and retained as source data for 
laboratory variables.   
4.2.2 Urine Pregnancy Test 
On Visits 1 and 2, a urine pregnancy test will be administered to screen female participants for 
pregnancy. 
4.2.3 Physical examination 
A complete physical examination will be performed at Visit 1 and include an assessment of : 
height, weight, general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, abdomen, musculo-skeletal 
(including spine and extremities) and neurological systems.   

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4.2.4 Vital signs 
Vital signs will be taken at all visits prior to all other tests including: sitting blood pressure, 
respiratory rate, pulse, oxygen saturation and temperature. Blood pressure will be performed on 
the right arm, pulse, oxygen saturation and blood pressure will be measured using an automated 
blood pressure cuff and pulse oximeter. 
4.2.4.1 
Body temperature 
Body temperature will be taken at all visits using a laser thermometer. 
4.2.4.2 
Safety Monitoring and Risk Management of Investigational Product 
During the gas administration and breath hold, all participants will be monitored using pulse 
oximetry for blood oxygenation and heart rate.   
Supplemental oxygen will be administered via nasal cannula at a flow rate of 2L/min during the 
MRI procedure until immediately prior to administration of hyperpolarized 
129Xe.  
Supplemental oxygen will continue after the breath hold is complete. If a participant becomes 
uncomfortable during the breath hold, they can breathe out the gas and subsequently breathe in 
room air and/or supplemental oxygen.  Furthermore, in the event that oxygen saturation, as 
measured by pulse oximetry, decreases to less than 88% for a period of >10 seconds, the 
participant will be administered supplemental oxygen and this will be recorded as an adverse 
event.  
4.3 
Other assessments 
4.3.1  
Participant reported outcomes 
All participants will complete the ACQ-6, AQLQ, and SGRQ at Visits 1 and 2.  
4.3.1.1 
Asthma Control Questionnaire  
The ACQ measures the adequacy of asthma control and change in asthma control that may 
occur as a result of treatment.29 This study will employ the ACQ-6.30  
4.3.1.2 
Asthma Quality of Life Questionnaire 
The AQLQ was developed to evaluate the quality of life in participants suffering from 
asthma.31,32 Study personnel will administer AQLQ to participants on paper.  
 
4.3.1.3 
St. George’s Respiratory Questionnaire 
The SGRQ measures impact on overall health, daily life and perceived well-being in patients 
with obstructive airways disease.33 Study personnel will administer SGRQ to patients on paper 
during Visits 1 and 2. 
5. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.  
5.1 
Definition of adverse events 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition can 
be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, electrocardiogram). In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered. 
5.2 
Definitions of serious adverse event (SAE) 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
 
Results in death 

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 
Is immediately life-threatening 
 
Requires in-participant hospitalisation or prolongation of existing hospitalisation  
 
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
 
Is a congenital abnormality or birth defect 
 
Is an important medical event that may jeopardise the participant or may require 
medical intervention to prevent one of the outcomes listed above 
The causality of SAE (their relationship to all study treatment/procedures) will be assessed by 
the investigator-sponsor. The investigator-sponsor will be responsible for forwarding all serious 
adverse events regardless of causality to the collaborator, GSK plc within 24 hours of awareness 
and to the Western Research Ethics Board.  
Appendix A: Additional Safety Information provides further guidance on the definition of an 
SAE. 
5.2.1 Management of Acute Adverse Events 
The 2nd floor 3T MRI facility, 1st floor 3T/7T MRI facility and room 2252 in Robarts Research 
Institute are covered by the University Hospital Code Blue Team in case of a Code Blue 
emergency (cardiac or respiratory arrest). All other areas of Robarts Research Institute utilize 
paramedic services in case of a medical emergency.   
 
If any life-threatening adverse event occurs at any time during a study visit, the appropriate 
emergency service (Code Blue team or paramedics) will be mobilized to respond to the event.   
A Code Blue is initiated by calling 55555 to reach the University Hospital switchboard and 
reporting the type of emergency and its location, along with directions to the location. Code 
Blue instructions, including a script of what to say to switchboard, are posted in areas with Code 
Blue coverage. Each area has a button to unlock the doors between Robarts Research Institute 
and University Hospital during a Code Blue, which also alerts Robarts Research security and 
the facility manager of the emergency to activate their support.   
 
There is a Code Blue cart and AED located outside of the MR suite for use during an emergency.  
This equipment is kept up to date by LHSC staff. All staff involved in study visits are trained 
in CPR. Mock Code Blues are done periodically with University Hospital staff to ensure all 
parties are aware of procedures and responsibilities in the event of a Code Blue emergency.   
 
In any event that an acute adverse event does not require immediate response by the Code Blue 
team or paramedics but requires timely medical intervention, participants will be taken to 
University Hospital Emergency Department via wheelchair. Robarts Research Institute is 
connected to University Hospital, providing a direct indoor route to the Emergency Department.   
The principal investigator and qualified investigator will be alerted of any medical emergency 
as soon as possible without jeopardizing the immediate care required by the participant.   
5.2.2 Time period for collection of adverse events 
Adverse Events will be collected from the time of signature of informed consent on Visit 1 
throughout the treatment period up to and including Visit 2 and recorded in the CRF. 
5.2.3 Follow-up of unresolved adverse events 
Any AEs that are unresolved at the participant’s last AE assessment or other assessment/visit 
as appropriate in the study are followed up by the Investigator for as long as medically indicated, 
but without further recording in the CRF. 
5.2.4 Variables  
The following variables will be collected for each AE; 

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 
AE (verbatim) 
 
The date and time when the AE started and stopped 
 
Maximum intensity and changes in intensity 
 
Whether the AE is serious or not 
 
Investigator causality rating against the treatment or investigational product (yes or 
no) 
 
Action taken with regard to treatment or investigational product 
 
AE caused participant’s withdrawal from study (yes or no) 
 
Outcome 
In addition, the following variables will be collected for SAEs: 
 
Date AE met criteria for serious AE 
 
Date Investigator became aware of serious AE 
 
AE serious rationale 
 
Date of hospitalisation 
 
Date of discharge 
 
Probable cause of death 
 
Date of death 
 
Autopsy performed 
 
Causality assessment in relation to Study procedure(s)  
 
Causality assessment in relation to other medication 
 
Causality assessment in relation to Additional Study Drug 
 
Description of SAE.  
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 5.2. An AE of severe intensity need not 
necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea, but not an SAE unless it meets the criteria shown in Section 5.2. On 
the other hand, a stroke that results in only a limited degree of disability may be considered a 
mild stroke but would be an SAE when it satisfies the criteria shown in Section 5.2. 
5.2.5 Causality collection 
The investigator will assess causal relationship between treatment or investigational product 
and each Adverse Event, and answer ‘yes’ or ‘no’ to the questions ‘Do you consider that there 
is a reasonable possibility that the event may have been caused by the treatment?’ and ‘Do you 
consider that there is a reasonable possibility that the event may have been caused by the 
investigational product?’ 
For SAE, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A (Additional Safety 
Information). 

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5.2.6 Adverse events based on signs and symptoms 
All AEs spontaneously reported by the participant or care provider or reported in response to 
the open question from the study personnel: ‘Have you had any health problems since the 
previous visit/you were last asked?’, or revealed by observation will be collected and recorded 
in the CRF.  When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately. 
5.2.7 Adverse events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report. Deterioration as compared to baseline in protocol-mandated laboratory 
values and vital signs should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the study drug or investigational 
product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator uses 
the clinical, rather than the laboratory term (e.g. anaemia versus low haemoglobin value).  In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.  
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
5.3 
Reporting of serious adverse events to WSREB, Health Canada, 
GSK Collaborator 
All SAEs MUST be reported, whether or not considered causally related to the treatment or 
investigational product. The investigator is responsible for informing the WSREB and/or the 
Health Canada as per local requirements.  Notification is required within 15 days after becoming 
aware of the occurrence of the SAE if it is neither fatal nor life threatening, and within seven 
days of becoming aware of the occurrence of the SAE if it is fatal or life threatening. Within 
eight days of having informed the SAE, the sponsor will submit a complete report in respect of 
the information that includes an assessment of the importance and implication of any findings.  
The investigator-sponsor is also responsible for forwarding all serious adverse events regardless 
of causality to the collaborator GSK plc immediately and under no circumstances should this 
exceed 24 hours.  The investigator will submit any updated SAE data to GSK Collaborator 
within 24 hours of it being available. 
5.4 
Overdose 
For overdoses associated with an SAE, the standard reporting timelines apply as above. For 
other overdoses, reporting must occur within 30 days. 
5.5 
Pregnancy 
All pregnancies and outcomes of pregnancy should be documented appropriately in the CRF. 
5.5.1 Maternal exposure 
If a participant becomes pregnant during the course of the study, the treatment and 
investigational product should be discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the treatment 
or investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital abnormalities/birth defects and spontaneous miscarriages 

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should be reported and handled as SAEs.  Elective abortions without complications should not 
be handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital abnormality) should be followed up 
and documented even if the participant was discontinued from the study. 
5.5.2 Paternal exposure  
Male participants should refrain from fathering a child or donating sperm during the study and 
for 8 weeks following the last dose.  
6. 
TREATMENT, 
INVESTIGATIONAL 
PRODUCT 
AND 
OTHER 
TREATMENTS 
 
6.1 
Identity of treatment and investigational product(s)  
Treatment  
Dosage form and strength 
Manufacturer 
FF/UMEC/VI  
200/62.5/25 µg 
GlaxoSmithKline plc 
 
Investigational product 
Dosage form and strength 
Manufacturer 
Hyperpolarized 129Xe 
400mL per dose, up to four 
doses per visit administered 
15 minutes apart minimum 
on Visit 1 and 2 
Robarts Research Institute 
6.2 
Dose and treatment regimens 
Participants will take the first dose of FF/UMEC/VI 200/62.5/25 µg directly after Visit 1/Day 
0 assessments are completed 
Participants will receive hyperpolarized 129Xe in doses of 400mL, with up to four doses 
administered per visit on Visit 1/Day 0 and Visit 2/Day 42.  Doses will be administered at least 
15 minutes apart.   
6.3 
Labelling 
The FF/UMEC/VI 200/62.5/25 µg label includes the following information: 
 Packaging Control #/ Lot Trace ID # 
 Allocation # 
 Fill Count & Dosage Form 
 Interval ID (Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) 
 Re-evaluation Date 
 Dosing Instructions 
 Storage conditions 
 Compound ID – Protocol # 
In addition, the label will indicate ‘for clinical study use only’ and ‘keep out of reach of 
children’. 

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6.4 
Storage 
All study drug is kept in a secure place under appropriate storage conditions. A description of 
the appropriate storage conditions is specified on the label of the product(s).   
6.5 
Compliance 
Participants will be given instructions on the administration of FF/UMEC/VI 200/62.5/25 µg 
during Visit 1/Day 0.  The administration of all study drugs (including investigational products) 
will be recorded in the appropriate sections of the CRF. 
6.6 
Accountability 
The study drug provided for this study will be used only as directed in the study protocol.  
The study personnel will account for all study drugs dispensed and administered to participants.  
The study drugs remaining after study completion will be destroyed. 
6.7 
Concomitant and other treatments  
Restricted Medication/Class of drug: 
Usage: 
SABA 
Withhold use 6 hours before all visits 
LTRA 
Withhold use 24 hours before all visits 
6.7.1 Other concomitant treatment 
All medications considered necessary for the participant’s safety and well-being, will be 
recorded in the appropriate sections of the CRF. 
The medication described above may be used within the withholding period if medically 
necessary.  In the event that a medication described above is used within the withholding period 
before a study visit, the study visit may continue as scheduled or be rescheduled at the discretion 
of the Investigator.  
6.8 
Device Malfunction 
Participants will receive the first dose of study medication under the direction and supervision 
of study staff. Should the inhaler device malfunction during initial use, it will be replaced with 
a new one and be set aside. The malfunctioning device will be labelled as such and the study 
collaborator will be notified within 24 hours. The device will then either be returned to the 
collaborator or destroyed, according to the collaborator’s instructions. 
Participants will be instructed to contact research staff if the device malfunctions after they 
leave. They would be advised to return to Robarts to pick up a replacement device as soon as 
possible. Details will be documented in the CRF. 
Should a device malfunction cause an adverse event, it will be documented as such and 
replaced as soon as possible. The collaborator will be notified of such an event as soon as 
possible and within 24 hours. Details will be documented in the CRF. 
7. 
STATISTICAL ANALYSES  
7.1 
Statistical considerations 
Study personnel performing image analysis will be blinded to study visit number. 
7.2 
Sample size estimate 
Our primary hypothesis is that 129Xe VDP in participants with uncontrolled asthma will 
significantly change after FF/UMEC/VI 200/62.5/25 µg treatment as measured 6 weeks after 
the first treatment. We expect that the mean change in VDP will be both clinically relevant (> 
minimal clinically important difference) and statistically significant in a sample size of 30 

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participants. However, this is a pilot study and we did not power the study to show a statistically 
significant effect. The study sample size we have in place was chosen for pragmatic reasons and 
the study results will be used to estimate effect size so that a sample size for a larger multicentre 
study may be prospectively determined. 
7.3 
Definitions of analysis sets 
7.3.1 Efficacy analysis set 
All participants who completed Visits 1 and 2 will be included for the efficacy analysis. 
7.3.2 Safety analysis set 
All participants who completed Visit 1 will be used for the safety analysis. 
7.4 
Outcome measures for analyses 
Primary Objective: 
Outcome Measure: 
To measure the effect of FF/UMEC/VI 
200/62.5/25 µg QD on 129Xe MRI VDP 
after 6 weeks of therapy  
129Xe VDP 
 
Secondary Objectives: 
Outcome Measures: 
SO1: To measure the effect of 
FF/UMEC/VI 200/62.5/25 µg QD on 
biomarkers of pulmonary function and 
inflammation 
FEV1, FVC, FEV1/FVC, FEF25-75, lung volumes, 
Raw, FOT, (R5, R19, R5-19, X5, X19, AX), LCI, Scon, 
Sacin, blood eosinophils, FeNO 
SO2: To measure the effect of 
FF/UMEC/VI 200/62.5/25 µg on asthma 
control and quality-of-life  
ACQ-6, AQLQ, SGRQ 
 
Safety Objectives: 
Outcome Measures: 
SO3: To assess the safety and tolerability 
of FF/UMEC/VI 200/62.5/25 µg 
AE/SAE 
Vital signs 
Exploratory Objectives: 
Outcome Measures: 
To evaluate the relationships between MRI 
VDP and asthma control and quality-of-life 
VDP 
ACQ-6, AQLQ, SGRQ 
To evaluate the relationships between MRI 
VDP and lung function  
VDP 
FEV1, FVC, FEV1/FVC, FEF25-75, lung volumes, 
Raw, FOT, (R5, R19, R5-19, X5, AX), LCI, Scon, 
Sacin, 
To evaluate the relationships between MRI 
VDP, airway and blood eosinophilia  
VDP 
FeNO, blood eosinophils 
7.5 
Methods for statistical analyses 
Data will be tested for normality using the Shapiro-Wilk tests and when data are not normally 
distributed, non-parametric tests will be performed.  Unpaired t-tests and Mann-Whitney U-
tests will be performed to compare participant characteristics, pulmonary function and MRI 
measurements in participants with eosinophilic asthma. To correct for multiple comparisons, a 
Holm-Bonferroni correction will be applied. Paired t-tests will be used to analyze the 
differences between the pre-treatment and post-treatment measurements in each participant.  

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Univariate relationships will be evaluated using Pearson (r) and Spearman () correlation 
coefficients. Statistical analyses will be performed using SPSS (SPSS Statistics 25.0; IBM, 
Armonk, NJ, USA) and all results will be considered statistically significant when the 
probability of making a Type I error was less than 5% (p < 0.05). 
8. 
STUDY AND DATA MANAGEMENT  
8.1 
Training of study site personnel 
The principal investigator will ensure that appropriate training relevant to the study is provided 
to all of study staff, and as well she will insure that staff are appropriately qualified for their 
role and that any new information relevant to the performance of this study is forwarded to the 
staff involved. 
The principal investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
8.2 
Study timetable and end of study 
Planned duration of the study: 12 months 
Study period: June 1 2022 – April 30 2023 
8.3 
Data management  
Data management will be performed by study personnel at Robarts Research Institute. Adverse 
events and medical/surgical history will be classified according to the terminology of the latest 
version the Medical Dictionary for Regulatory Activities (MedDRA). Data reporting will be 
provided annually by the sponsor investigator to all collaborators and stakeholders. There will 
be no interim analysis.  
8.3.1 Database Setup 
A password protected Microsoft Access database will be created for this study. De-identified 
data will be stored in this database and a unique database ID will be assigned to each participant. 
In a second database the unique database ID will link each participant to personal identifiers 
such as address, phone number, email address, full date of birth and family physician. The two 
databases will be stored separately to minimize the breach of identity.  
8.3.2 Data Access 
Only the clinical research coordinator and delegated personnel with proper privacy and 
confidentiality training will have access to the databases described in section 10.3.1. This will 
ensure that personal information is kept secure. The clinical coordinator will ensure that 
individuals with access to research data maintain competence in proper data handling by 
ensuring that privacy training and recertification is kept up to date.  
8.3.3 Data Security 
Paper copies will be stored in a locked filing cabinet, in a locked office in a security monitored 
building at Robarts Research Institute. Electronic records will be stored on an internal firewall 
protected server that is located in a secured server room at Robarts Research Institute. 
Furthermore, only de-identified data may also be saved on local hard drives at Robarts Research 
Institute for data analysis purposes. Robarts Research Institute is a controlled access building 
with security on site. 
8.3.4 Data Lock 
Only the clinical research coordinator and individuals delegated to perform data entry with 
proper training will have write access to the databases described in section 10.3.1. Read only 
access will be granted to other trained personnel involved in data analysis.  
8.3.5 Data Archiving 
All records pertaining to this study will be retained for a period of 25 years, at which time all 
such records will be destroyed. Paper documents with collected study participant information 
will be stored in a locked file cabinet in the clinical coordinator's secured office. Electronic 

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records will be stored on an internal firewall protected server that is located in a secured server 
room at Robarts Research Institute. Password protection will be used on any document 
containing participant information. De-identified data may be saved on local hard drives at 
Robarts Research Institute for data analysis purposes. Robarts Research Institute is a controlled 
access building with security on site.  
9. 
ETHICAL AND REGULATORY REQUIREMENTS 
9.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
/Good Clinical Practice, applicable local regulatory requirement, for example ‘Good Clinical 
Practice for Trials on Drugs (MHLW Ordinance No. 28, 27 March 1997, partially revised by 
MHLW Ordinance and their related notifications). 
9.2 
Participant data protection 
The Master Informed Consent Form will explain that:  
 
Study data will be stored in a computer database, maintaining confidentiality 
 
Participant data will be stored confidentially 
 
For data verification purposes, the Western Research Ethics Board may require direct 
access to the records relevant to the study, including participants’ medical history 
The Western Research Ethics Board (WREB) will be required to approve the final study 
protocol, including the final version of the Informed Consent Form and any other written 
information and/or materials to be provided to the participants.   
The opinion of the WREB should be given in writing.  The WREB should approve all 
advertising used to recruit participants for the study. 
9.3 
Informed consent 
The principal investigator will: 
 
Ensure each participant is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study 
 
Ensure each participant is notified that they are free to discontinue from the study at 
any time 
 
Ensure that each participant is given the opportunity to ask questions and allowed 
time to consider the information provided 
 
Ensure each participant provides signed and dated informed consent before 
conducting any procedure specifically for the study 
 
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 
 
Ensure a copy of the signed Informed Consent Form is given to the participant 
 
Ensure that any incentives for participants who participate in the study as well as any 
provisions for participants harmed as a consequence of study participation are 
described in the informed consent form that is approved by WREB 
If any new information on the study medication becomes available which may influence the 
decision of the participant to continue the study, the Investigator(s) MUST inform the 
participant of such information immediately, record this in a written form, and confirm with the 
participant if he or she wishes to continue the participation in the study.  In addition, if the 
Investigator(s) deem it necessary to revise the Informed Consent Form, they should revise it 

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immediately (Refer to Section 9.4).  The investigator(s) should re-explain the participants using 
updated Informed Consent Form even if the participants have already been informed of the new 
information verbally.  Written informed consent to continue participation in the study should be 
provided separately. 
9.4 
Changes to the protocol and informed consent form 
In principal, study procedures will not be changed. If it is necessary for the study protocol to be 
amended, the amendment will first be approved by Western’s REB. Approval of the revised 
Informed Consent Form by WREB is required before the revised form is used. If an 
administrative change is required, such a change should be notified to or approved by each IRB 
according to local requirements. 
9.5 
Audits and inspections 
The WSREB or Health Canada may perform audits or inspections at the centre, including source 
data verification.   
 
 
 

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10. 
LIST OF REFERENCES 
 
1 
Dreher, M. & Muller, T. Add-on Therapy for Symptomatic Asthma despite Long-Acting 
Beta-Agonists/Inhaled 
Corticosteroid. 
Tuberc 
Respir 
Dis 
(Seoul) 
81, 
1-5, 
doi:10.4046/trd.2017.0102 (2018). 
2 
Lee, L. A. et al. Efficacy and safety of once-daily single-inhaler triple therapy 
(FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma 
(CAPTAIN): a double-blind, randomised, phase 3A trial. Lancet Respir Med 9, 69-84, 
doi:10.1016/S2213-2600(20)30389-1 (2021). 
3 
Miller, M. R. et al. Standardisation of spirometry. Eur Respir J 26, 319-338, 
doi:10.1183/09031936.05.00034805 (2005). 
4 
Juniper, E. F., Bousquet, J., Abetz, L., Bateman, E. D. & Goal Committee. Identifying 
'well-controlled' and 'not well-controlled' asthma using the Asthma Control 
Questionnaire. Respir Med 100, 616-621, doi:10.1016/j.rmed.2005.08.012 (2006). 
5 
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention. (2022). 
6 
Kerwin, E. et al. A phase IIb, randomised, parallel-group study: the efficacy, safety and 
tolerability of once-daily umeclidinium in patients with asthma receiving inhaled 
corticosteroids. Respiratory research 21, 148, doi:10.1186/s12931-020-01400-5 (2020). 
7 
Fain, S., Schiebler, M. L., McCormack, D. G. & Parraga, G. Imaging of lung function 
using hyperpolarized helium-3 magnetic resonance imaging: Review of current and 
emerging translational methods and applications. J Magn Reson Imaging 32, 1398-1408, 
doi:10.1002/jmri.22375 (2010). 
8 
Altes, T. A. et al. Hyperpolarized 3He MR lung ventilation imaging in asthmatics: 
preliminary findings. J Magn Reson Imaging 13, 378-384, doi:10.1002/jmri.1054 
(2001). 
9 
Aysola, R., de Lange, E. E., Castro, M. & Altes, T. A. Demonstration of the 
heterogeneous distribution of asthma in the lungs using CT and hyperpolarized helium-
3 MRI. J Magn Reson Imaging 32, 1379-1387, doi:10.1002/jmri.22388 (2010). 
10 
Campana, L. et al. Probing airway conditions governing ventilation defects in asthma 
via hyperpolarized MRI image functional modeling. J Appl Physiol (1985) 106, 1293-
1300, doi:10.1152/japplphysiol.91428.2008 (2009). 
11 
Svenningsen, S. et al. What are ventilation defects in asthma? Thorax 69, 63-71, 
doi:10.1136/thoraxjnl-2013-203711 (2014). 
12 
Costella, S. et al. Regional pulmonary response to a methacholine challenge using 
hyperpolarized (3)He magnetic resonance imaging. Respirology 17, 1237-1246, 
doi:10.1111/j.1440-1843.2012.02250.x (2012). 
13 
Kruger, S. J. et al. Hyperpolarized Helium-3 MRI of exercise-induced 
bronchoconstriction during challenge and therapy. J Magn Reson Imaging 39, 1230-
1237, doi:10.1002/jmri.24272 (2014). 
14 
Samee, S. et al. Imaging the lungs in asthmatic patients by using hyperpolarized helium-
3 magnetic resonance: assessment of response to methacholine and exercise challenge. 
J Allergy Clin Immunol 111, 1205-1211, doi:10.1067/mai.2003.1544 (2003). 
15 
Tzeng, Y. S., Lutchen, K. & Albert, M. The difference in ventilation heterogeneity 
between asthmatic and healthy subjects quantified using hyperpolarized 3He MRI. J 
Appl Physiol (1985) 106, 813-822, doi:10.1152/japplphysiol.01133.2007 (2009). 

Study Number ROB0046 
 
 
 
 
 
 
 
 
 
 
Drug Substance FF/UMEC/VI (200/62.5/25ug) 
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Page 33 of 36 
 
16 
Svenningsen, S. et al. Hyperpolarized (3) He and (129) Xe MRI: differences in asthma 
before bronchodilation. J Magn Reson Imaging 38, 1521-1530, doi:10.1002/jmri.24111 
(2013). 
17 
de Lange, E. E. et al. Evaluation of asthma with hyperpolarized helium-3 MRI: 
correlation with clinical severity and spirometry. Chest 130, 1055-1062, 
doi:10.1378/chest.130.4.1055 (2006). 
18 
Hahn, A. D. et al. Redistribution of inhaled hyperpolarized 3He gas during breath-hold 
differs 
by 
asthma 
severity. 
J 
Appl 
Physiol 
(1985) 
120, 
526-536, 
doi:10.1152/japplphysiol.00197.2015 (2016). 
19 
Svenningsen, S., Nair, P., Guo, F., McCormack, D. G. & Parraga, G. Is ventilation 
heterogeneity 
related 
to 
asthma 
control? 
Eur 
Respir 
J 
48, 
370-379, 
doi:10.1183/13993003.00393-2016 (2016). 
20 
Brealey, N. et al. Pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol 
as a triple therapy in healthy volunteers. Int J Clin Pharmacol Ther 53, 753-764, 
doi:10.5414/CP202390 (2015). 
21 
Lal, C. & Strange, C. Spotlight on fluticasone furoate/umeclidinium/vilanterol in 
COPD: design, development, and potential place in therapy. Int J Chron Obstruct 
Pulmon Dis 12, 135-140, doi:10.2147/COPD.S114273 (2017). 
22 
Driehuys, B. et al. Chronic obstructive pulmonary disease: safety and tolerability of 
hyperpolarized 129Xe MR imaging in healthy volunteers and patients. Radiology 262, 
279-289, doi:10.1148/radiol.11102172 (2012). 
23 
Shukla, Y. et al. Hyperpolarized 129Xe magnetic resonance imaging: tolerability in 
healthy volunteers and subjects with pulmonary disease. Acad Radiol 19, 941-951, 
doi:10.1016/j.acra.2012.03.018 (2012). 
24 
Schmidt, M. H., Marshall, J., Downie, J. & Hadskis, M. R. Pediatric magnetic resonance 
research and the minimal-risk standard. IRB 33, 1-6 (2011). 
25 
King, G. G. et al. Technical standards for respiratory oscillometry. Eur Respir J 55, 
doi:10.1183/13993003.00753-2019 (2020). 
26 
American 
Thoracic 
Society 
& 
European 
Respiratory 
Society. 
ATS/ERS 
recommendations for standardized procedures for the online and offline measurement 
of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit 
Care Med 171, 912-930, doi:10.1164/rccm.200406-710ST (2005). 
27 
Kirby, M. et al. Hyperpolarized 3He magnetic resonance functional imaging 
semiautomated segmentation. Acad Radiol 19, 141-152, doi:10.1016/j.acra.2011.10.007 
(2012). 
28 
Kirby, M., Wheatley, A., McCormack, D. G. & Parraga, G. Development and 
application of methods to quantify spatial and temporal hyperpolarized He-3 MRI 
ventilation dynamics: Preliminary results in chronic obstructive pulmonary disease. 
Proc. SPIE 7626, 762605, doi:Artn 762605 
10.1117/12.843821 (2010). 
29 
Juniper, E. F., O'Byrne, P. M., Guyatt, G. H., Ferrie, P. J. & King, D. R. Development 
and validation of a questionnaire to measure asthma control. Eur Respir J 14, 902-907, 
doi:10.1034/j.1399-3003.1999.14d29.x (1999). 

Study Number ROB0046 
 
 
 
 
 
 
 
 
 
 
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30 
Juniper, E. F., Svensson, K., Mork, A. C. & Stahl, E. Measurement properties and 
interpretation of three shortened versions of the asthma control questionnaire. Respir 
Med 99, 553-558, doi:10.1016/j.rmed.2004.10.008 (2005). 
31 
Juniper, E. F., Buist, A. S., Cox, F. M., Ferrie, P. J. & King, D. R. Validation of a 
standardized version of the Asthma Quality of Life Questionnaire. Chest 115, 1265-
1270, doi:10.1378/chest.115.5.1265 (1999). 
32 
Juniper, E. F. et al. Evaluation of impairment of health related quality of life in asthma: 
development of a questionnaire for use in clinical trials. Thorax 47, 76-83, 
doi:10.1136/thx.47.2.76 (1992). 
33 
Jones, P. W., Quirk, F. H., Baveystock, C. M. & Littlejohns, P. A self-complete measure 
of health status for chronic airflow limitation. The St. George's Respiratory 
Questionnaire. Am Rev Respir Dis 145, 1321-1327, doi:10.1164/ajrccm/145.6.1321 
(1992). 

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Appendix A 
Additional Safety Information 
Further Guidance on the Definition of a Serious Adverse Event (SAE) 
Life threatening 
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (e.g. hepatitis that resolved without hepatic failure). 
Hospitalisation 
Treatment in an emergency room is not a serious AE, although the reasons for it may be (e.g. 
bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations planned 
before or during a study are not considered AE if the illness or disease existed before the 
participant was enrolled in the study, provided that it did not deteriorate in an unexpected way 
on study. 
Important medical event or medical intervention 
Medical judgement will be exercised in deciding whether a case is serious in situations where 
important medical events may not be immediately life threatening or result in death, 
hospitalisation, disability or incapacity but may jeopardize the participant or may require 
intervention to prevent one or more outcomes listed in the definition of serious. These should 
usually be considered as serious. 
A Guide to Interpreting the Causality Question 
The following factors will be considered: 
 
Time Course 
 
Consistency with known drug profile 
 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
 
No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors 
 
Re-challenge experience 
 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship 
In difficult cases, other factors could be considered such as: 
 
Is this a recognized feature of overdose of the drug? 
 
Is there a known mechanism? 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility. 

Study Number ROB0046 
 
 
 
 
 
 
 
 
 
 
Drug Substance FF/UMEC/VI (200/62.5/25ug) 
Version 10 Date 20/06/2022 
 
 
 
 
 
 
Page 36 of 36 
 
Appendix B 
International Airline Transportation Association (IATA) 6.2 Guidance 
Document 
Labelling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B or Exempt.  There is 
no direct relationship between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, can cause permanent disability, life-threatening or fatal disease in otherwise healthy 
humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus: 
 
are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name: 
 
UN 3373 – Biological Substance, Category B 
 
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
 
Clinical trial samples will fall into Category B or exempt under IATA regulations 
 
Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging  
 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 
 
Samples routinely transported by road or rail are participant to local regulations which 
require that they are always packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and packaging 
/ containment materials.  The IATA 650 biological sample containment standards are 
encouraged wherever possible when road or rail transport is used