Clinical trial NCT03162055
Conditions: Chronic Obstructive Pulmonary Disease COPD
Keywords: COPD
Sponsor: AstraZeneca
Start date: 2017-05-25; Completion date: 2018-05-04
Enrollment: 1119 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase IIIb randomised, double-blind, double-dummy, multicentre, parallel group, 24 week study to assess the efficacy and safety of Glycopyrronium/Formoterol Fumarate (GFF) fixed-dose combination 7.2/4.8 μg 2 inhalations twice daily compared to Umeclidinium/Vilanterol (UV) 62.5/25 μg fixed-dose combination 1 inhalation once daily in Patients with moderate to very severe COPD.

Detailed description:

Arms: arm 1: glycopyrronium/formoterol fumarate 7.2/4.8 μg per actuation, twice daily arm 2: umeclidinium/vilanterol 62.5/ 25μg per inhalation, once daily
Interventions: intervention 1: Glycopyrronium/Formoterol Fumarate intervention 2: umeclidinium/vilanterol
Intervention descriptions: intervention 1: Metered dose inhaler (MDI), contains glycopyrronium/formoterol fumarate fixed-dose combination 7.2/4.8 μg per actuation intervention 2: Dry powder inhaler (DPI), Each metered dose contains umeclidinium/vilanterol 62.5/ 25μg fixed-dose combination per inhalation

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol (CSP) - ANGEL
Version 18.0
Template Form Doc ID: LDMS_001_00026737
Parent Doc ID: SOP AZDoc0018580
Clinical Study Protocol 
Drug Substance
Glycopyrronium/Formoterol 
Fumarate 
Study Code
D5970C00002
Version
2
Date
14 July 2017
A Randomised, Double-Blind, Double-Dummy, Multicentre, Parallel Group 
Study to Assess the Efficacy and Safety of Glycopyrronium/Formoterol 
Fumarate fixed-dose combination relative to Umeclidinium/Vilanterol fixed-
dose combination over 24 Weeks in Patients with Moderate to Very Severe
Chronic Obstructive Pulmonary Disease (AERISTO)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
2 (129)
VERSION HISTORY
Version 1, 1 February 2017
Initial version.
Version 2, 14 July 2017
Descriptive summary of changes:
Clinical Study Protocol Synopsis:
!
Primary and Secondary Objective tables updated by moving the Peak change 
from baseline in FEV1 within 2 hours post-dosing over 24 weeks from the 
secondary one to become a co-primary endpoint.
!
Exploratory table updated with additional Time to the first moderate or 
severe COPD exacerbation endpoint.
!
Statistical methods section updated to reflect the above
Section 1.2 updated to reflect the above.
Section 1.3 updated to add a clarification on the chest x-ray.
Section 2.1, 2.2 and 2.3 updated with the below:
!
Primary and Secondary Objective tables updated by moving the Peak change 
from baseline in FEV1 within 2 hours post-dosing over 24 weeks from the 
secondary one to become a co-primary endpoint.
!
Exploratory table updated with additional Time to the first moderate or 
severe COPD exacerbation endpoint.
Section 3.1, inclusion criterion on chest x-ray 9 clarified
Section 3.2, exclusion criteria:
!
2, last item on hypertension clarified
!
3 clarified and corrected with “/1.73 m2“ that was missing
!
10 clarified
Section 3.8, inconsistency corrected in the ipratropium bromide restrictions


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
3 (129)
Table 2 on Timed Assessments updated to be consistent with the descriptive parts of the 
protocol
Section 4.1, screening period length clarified
Section 4.1.1, Visit 1 requirements clarified for IWRS use, ECG, laboratory testing, chest 
image or CT, and inhalation technique training
Section 4.1.2, Visit 2 requirements clarified for inhalation technique training, IWRS use and 
possible albuterol/salbutamol dispensing, and forced spirometry manoeuvres number made 
consistent within the protocol
Section 4.2.1, Visit 3 requirements clarified for inhalation technique training, spirometry 
pre-dose assessments, IWRS use, spirometry time windows, and ePRO reminders
Section 4.2.2, Visit 4-6 requirements clarified for inhalation technique training, spirometry 
time windows, and ePRO reminders
Section 4.2.3, Visit 7 corrected with removing of a wrong suggestion to dispense new kits; 
requirements clarified for spirometry time windows, and ePRO reminder
Section 4.2.4, Early Discontiuation/Withdrawal Visit requirements clarified for spirometry 
time windows, and ePRO reminder
Section 5.1.1.2 clarified with the priority of spirometry relation to the IP intake
Section 5.1.1.3 acceptable manoeuvers explained
Section 5.1.1.5 corrected to cover the inspiratory capacity assessments at all visits 3-7 and 
with detailed guidance on what manoeuvers should be performed
Section 5.1.2.1 updated with an illogical sentence removed and clarification on when the 
assessment is not done
Section 5.1.2.2 updated with a clarification on when the assessment is not done
Section 5.2.1 clarified
Section 6.7 on medication error added to correct its erroneous removal from the original 
protocol
Section 6.8 numbering updated due to addition of the above
Table 8 on Prohibited COPD Medications: use of the ICS/LABA combination clarified, and 
triple therapy removed
Section 7.7.1.1 updated to remove a sentence on the local purchase of albuterol/salbutamol 


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
4 (129)
inconsistent within the protocol
Table 10 on Allowed Medications to treat a COPD exacerbation updated for the Systemic 
corticosteroids (oral or injections) to refer to the spirometry restriction rather than to the 
visit restriction
Section 8 on the Statistical Analyses update throughout to cover for the endpoint changes 
described above, more extensive details on the analyses, updated subsections and figures
Section 11 updated with a new reference (Burman et al 2009) resulting from the above 
statistical changes
Additionally, minor spelling corrections and updated style formatting 


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
5 (129)
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


Clinical Study Protocol Synopsis
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
6 (129)
CLINICAL STUDY PROTOCOL SYNOPSIS 
A Randomised, Double-Blind, Double-Dummy, Multicentre, Parallel Group 
Study to Assess the Efficacy and Safety of Glycopyrronium/Formoterol 
Fumarate fixed-dose combination relative to Umeclidinium/Vilanterol 
fixed-dose combination over 24 Weeks in Patients with Moderate to Very 
Severe Chronic Obstructive Pulmonary Disease (AERISTO)
International Co-ordinating Investigator:
Study site(s) and number of patients planned
The study will be conducted at approximately 150 sites in about 7 countries in North America 
and Europe. Across these sites, it is planned that approximately 1400 patients will be screened 
and 1000 patients will be randomised into the study.
Phase of development 
IIIb
Study design
This is a phase IIIb randomised, double-blind, double-dummy, multicentre, parallel group, 24 
week study to assess the efficacy and safety of Glycopyrronium/Formoterol Fumarate (GFF) 
fixed-dose combination 7.2/4.8 μg 2 inhalations twice daily compared to 
Umeclidinium/Vilanterol (UV) 62.5/25 μg fixed-dose combination 1 inhalation once daily in 
patients with moderate to very severe COPD.
Objectives
Primary Objective:
Outcome Measure:
To assess the effects of GFF relative to UV on 
lung function as measured by trough FEV1 and 
peak FEV1 in patients with moderate to very 
severe COPD
Co-primary endpoints:
∀
Change from baseline in morning pre-dose trough 
FEV1 over 24 weeks
∀
Peak change from baseline in FEV1 within 2 hours 
post-dosing over 24 weeks
REDACTED


Clinical Study Protocol Synopsis
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
7 (129)
Secondary Objective:
Outcome Measure:
To further assess the effects of GFF relative to 
UV on lung function.
Secondary endpoints:
∀
Onset of action on day 1; proportion of patients 
with increase of FEV1 of ≥100 ml from baseline at 
5 minutes
∀
Peak change from baseline in Inspiratory Capacity 
(IC) within 2 hours post-dosing over 24 weeks
To assess the effects of GFF relative to UV on 
dyspnea
Secondary endpoint:
Transition Dyspnea Index (TDI) focal score over 24 
weeks
To assess the effects of GFF relative to UV on 
symptoms of COPD
Secondary endpoint:
Change from baseline in Early Morning Symptoms 
COPD Instrument (EMSCI) over 24 weeks
Other endpoints:
∀
Change from baseline in Night Time Symptoms 
COPD Instrument (NiSCI) over 24 weeks
∀
Change from baseline in daily rescue 
(albuterol/salbutamol MDI) use over 24 weeks
To assess the effects of GFF relative to UV on 
health-related quality of life
Other endpoint:
Change from baseline in COPD Assessment Test 
(CAT) score over 24 weeks


Clinical Study Protocol Synopsis
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
8 (129)
Safety Objective:
Outcome Measure:
To assess the safety of GFF
Adverse events (AEs), serious adverse events (SAEs), 
adverse events leading to treatment discontinuation 
(DAEs)
Exploratory Objective:
Outcome Measure:
To assess health status for COPD patients 
treated with GFF
Change from baseline in EuroQol 5 Dimensions 
Questionnaire (EQ-5D-5L) over 24 weeks
To assess overall and COPD-specific 
Healthcare Resource Utilization and work 
productivity loss for GFF
Health Economics Questionnaire for healthcare 
resource utilization. 
Time to the first moderate or severe COPD 
exacerbation
Work Productivity and Activity Impairment - General 
Health (WPAI-GH)
Target patient population
Patients, 40-95 years of age, with moderate to very severe COPD.
Duration of treatment
Patients will be treated for 24 weeks.
Investigational product, dosage and mode of administration
Each patient will undergo a screening period of 1 to 4 weeks (-28 to -9 days).  During the 
screening period, patients will be provided with ipratropium bromide MDI 2 inhalations QDS 
as COPD maintenance therapy. Albuterol/salbutamol MDI will be provided as rescue 
medication during the screening period and throughout the study. 
Patients will be randomised in a 1:1 scheme. Approximately 500 patients will be randomised 
to the GFF and UV treatment groups, respectively. Patients will be stratified based on 
incoming COPD treatment at screening; rescue/maintenance monotherapy (LAMA, LABA or 
ICS only) vs. double maintenance therapy (LABA/LAMA or ICS/LABA). 
The first dose of IP will be taken at Visit 3 (Day 1). During the 24 week double-blind 
treatment period, patients will take two inhalations in the morning and in the evening from the 
GFF inhaler (active or placebo) and one inhalation in the morning from the UV inhaler (active 
or placebo). 
Statistical methods
The co-primary non-inferiority analyses will be conducted using the Per Protocol analysis set. 
Data following important protocol deviations which may affect efficacy or from visits where 
patients do not comply with required restrictions will be excluded from this analysis. 


Clinical Study Protocol Synopsis
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
9 (129)
Supportive analyses and superiority testing will be conducted in the full analysis set of all 
patients randomised and dosed, using all data obtained while on treatment.
The co-primary endpoints of change from baseline in morning pre-dose trough FEV1 and peak 
change from baseline in FEV1 within 2 hours post-dosing will be analysed separately using a 
linear mixed effects repeated measures approach. The models will include baseline FEV1 and 
bronchodilator responsiveness as continuous covariates and stratification factors (prior 
treatment - rescue/maintenance monotherapy vs double maintenance therapy), region, visit, 
treatment, and treatment by visit, as categorical covariates. Patient will be considered a 
random effect. 
The co-primary analyses will be based upon an estimate of the treatment difference over the 
entire 24-week treatment period, along with two-sided 95% and 97.5% confidence intervals. 
For both endpoints, non-inferiority will be concluded using a 1-sided hypothesis test 
according to a significance level of either 1.25% or 2.5% based upon the hierarchical testing 
and recycling procedure. This is equivalent to the lower bound of the 95% or 97.5% 2-sided 
confidence interval being greater than the pre-specified margin of -50 mL. For peak FEV1, a 
similar model will then be used for the formal assessment of the superiority hypothesis in the 
full analysis set. 1-sided p-values will be produced accordingly for all non-inferiority and 
superiority hypothesis testing.
The secondary endpoints of peak change from baseline in IC within 2 hours post-dosing, TDI 
focal score and EMSCI symptom severity score will be analysed using a similar repeated 
measures model to the co-primary endpoints, including appropriate baselines in the model. 
Peak IC will be referred to a non-inferiority margin of -50mL, while TDI and EMSCI will be 
referred to non-inferiority margins of -1.0 units and -0.1 units respectively.
In order to strongly control the 1-sided type I error rate at 2.5% across all co-primary endpoint 
hypothesis tests and the non-inferiority hypothesis tests of the secondary endpoints, a 
hierarchical testing procedure with recycling will be defined. 
To account for the multiplicity of the two co-primary endpoints, the test mass (1 sided alpha 
of 2.5%) will initially be split equally between the tests of the non-inferiority null hypothesis 
for each of trough FEV1 and peak FEV1 (1-sided alpha of 1.25% each). Should either of these 
null hypotheses be rejected, the test mass will be recycled. As such, respective hypothesis tests 
will be conducted at either a 1-sided 1.25% or 2.5% significance level depending upon this 
recycling. The superiority of peak FEV1 is only tested once non-inferiority of peak FEV1 is 
achieved. Should all three null hypotheses relating to the co-primary endpoints be rejected 
then testing will proceed to the secondary endpoints using a 1-sided 2.5% significance level.
If non-inferiority is demonstrated for a secondary endpoint in the per protocol analysis set, 
then testing may proceed to the next endpoint in the hierarchy, and a superiority test of the 
endpoint will also be conducted in the full analysis set where relevant. 
An exception to this sequential non-inferiority/superiority testing procedure is the secondary 
endpoint of onset of action (proportion of patients with increase in FEV1 of ≥100 ml from 


Clinical Study Protocol Synopsis
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
10 (129)
baseline at 5 minutes on day 1). For this endpoint superiority testing will immediately be 
carried out using logistic regression without any prior non-inferiority testing.
Rescue medication use, CAT, NiSCI and other spirometry and symptom sub-scale endpoints 
will also be analysed using mixed effects repeated measures models.
Adverse events (AEs) and exploratory endpoints will be reported descriptively.
Approximately 500 patients per arm are to be randomised and it is expected that around 440 
patients per arm will be included in the Per Protocol Analysis Set for the co-primary analyses. 
This sample size will provide around 94% power to demonstrate that the difference between 
GFF and UV in change from baseline in morning pre-dose trough FEV1 over 24 weeks is 
greater than the non-inferiority margin of -50 mL, using a one-sided significance level of 
2.5% and assuming an effective standard deviation of 167mL and a true difference of -10 mL. 
Should testing be conducted at a one-sided significance level of 1.25% then the power would 
be 90%. 
For the co-primary endpoint of peak FEV1 over 24 weeks the power to show non-inferiority is 
expected to be at least that of trough FEV1. Assuming an effective SD of 188mL for peak 
FEV1, and a true difference of 50mL then 500 patients would provide at least 97% power to 
demonstrate superiority of GFF to UV in peak FEV1 with a one-sided significance level of 
1.25%.


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
11 (129)
TABLE OF CONTENTS
PAGE
VERSION HISTORY..............................................................................................2
CLINICAL STUDY PROTOCOL SYNOPSIS.......................................................6
TABLE OF CONTENTS.......................................................................................11
1.
INTRODUCTION .................................................................................................20
1.1
Background and rationale for conducting this study .............................................20
1.2
Rationale for study design, doses and control groups............................................21
1.3
Benefit/risk and ethical assessment........................................................................23
1.4
Study Design..........................................................................................................24
1.5
Study governance and oversight – Not Applicable................................................26
2.
STUDY OBJECTIVES..........................................................................................26
2.1
Primary objective...................................................................................................26
2.2
Secondary objectives .............................................................................................26
2.3
Safety objectives ....................................................................................................27
2.4
Exploratory objectives ...........................................................................................27
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................27
3.1
Inclusion criteria ....................................................................................................27
3.2
Exclusion criteria ...................................................................................................28
3.3
Patient enrolment and randomisation.....................................................................32
3.4
Procedures for handling incorrectly enrolled or randomised patients ...................33
3.5
Methods for assigning treatment groups................................................................33
3.6
Methods for ensuring blinding...............................................................................33
3.7
Methods for unblinding..........................................................................................33
3.8
Restrictions ............................................................................................................34
3.9
Discontinuation of IP .............................................................................................34
3.9.1
Procedures for discontinuation of a patient from investigational product.............35
3.10
Criteria for withdrawal...........................................................................................35
3.10.1
Screen failures........................................................................................................35
3.10.2
Discontinuation of investigational product............................................................36
3.10.3
Withdrawal of the informed consent......................................................................36


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
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3.11
Discontinuation of the study..................................................................................36
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................36
4.1
Screening/Enrolment period ..................................................................................43
4.1.1
Visit 1 (day -28 to -9).............................................................................................43
4.1.2
Visit 2 (Day -11 to -8)............................................................................................45
4.2
Treatment period....................................................................................................46
4.2.1
Visit 3, Randomisation Visit (Day 1) ....................................................................46
4.2.2
Visit 4 – Visit 6 (Week 4, Week 12, Week 18 ±3 days)........................................50
4.2.3
Visit 7 (Week 24 ±3days) ......................................................................................54
4.2.4
Early Discontinuation/Withdrawal Visit................................................................56
4.3
Follow-up period....................................................................................................59
4.3.1
Follow-up call ........................................................................................................59
4.4
Rescreening and rescheduling of visits..................................................................59
4.4.1
Rescreening............................................................................................................59
4.4.2
Rescheduling of visits............................................................................................59
5.
STUDY ASSESSMENTS .....................................................................................60
5.1
Efficacy assessments..............................................................................................60
5.1.1
Spirometry Assessments at Clinic Visits ...............................................................60
5.1.1.1
General requirements.............................................................................................60
5.1.1.2
Time of day for scheduled site visit spirometry.....................................................61
5.1.1.3
Spirometry technique.............................................................................................61
5.1.1.4
Post-bronchodilator spirometry..............................................................................62
5.1.1.5
Inspiratory Capacity...............................................................................................62
5.1.1.6
Record keeping ......................................................................................................62
5.1.1.7
Spirometry references ............................................................................................62
5.1.2
Patient Reported Outcomes....................................................................................63
5.1.2.1
Baseline/Transitional Dyspnea Index (BDI/TDI)..................................................64
5.1.2.2
COPD Assessment Test (CAT) .............................................................................65
5.1.2.3
Night-time and Early morning symptoms of COPD instrument (NiSCI and 
EMSCI)..................................................................................................................65
5.1.3
Investigational Product Use ...................................................................................66
5.1.4
Rescue Medication Use..........................................................................................66
5.2
Safety assessments.................................................................................................66
5.2.1
Laboratory safety assessments...............................................................................66
5.2.1.1
Pregnancy Test.......................................................................................................67
5.2.2
Physical examination .............................................................................................67
5.3
Other assessments ..................................................................................................68
5.3.1
Clinical Outcome Assessments/Patient Reported Outcomes.................................68
5.3.1.1
EQ-5D-5L EuroQol 5 Dimensions Questionnaire.................................................68
5.3.1.2
Work Productivity and Activity Impairment Questionnaire - General 
Health (WPAI - GH)..............................................................................................68
5.3.1.3
Healthcare Resource Utilization ............................................................................68


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
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5.4
Pharmacokinetics – Not Applicable.......................................................................69
5.5
Pharmacodynamics – Not Applicable....................................................................69
5.6
Genetics – Not Applicable.....................................................................................69
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................69
6.1
Definition of adverse events ..................................................................................69
6.2
Definitions of serious adverse event......................................................................69
6.3
Recording of adverse events ..................................................................................70
6.3.1
Time period for collection of adverse events.........................................................70
6.3.2
Follow-up of unresolved adverse events................................................................70
6.3.3
Variables ................................................................................................................70
6.3.4
Causality collection................................................................................................71
6.3.5
Adverse events based on signs and symptoms.......................................................72
6.3.6
Adverse events based on examinations and tests...................................................72
6.3.7
Hy’s Law................................................................................................................72
6.3.8
Disease under Study (DUS)...................................................................................72
6.4
Reporting of serious adverse events.......................................................................73
6.5
Overdose ................................................................................................................73
6.6
Pregnancy...............................................................................................................74
6.6.1
Maternal exposure..................................................................................................74
6.7
Medication error.....................................................................................................74
6.8
Management of IP related toxicities - Not Applicable ..........................................76
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................76
7.1
Identity of investigational product(s).....................................................................76
7.2
Dose and treatment regimens.................................................................................76
7.3
Labelling ................................................................................................................77
7.4
Storage ...................................................................................................................78
7.5
Compliance ............................................................................................................78
7.6
Accountability........................................................................................................79
7.7
Concomitant and other treatments .........................................................................79
7.7.1
COPD Medication restrictions...............................................................................82
7.7.1.1
Use of short-acting anticholinergics and short-acting β2-agonists........................82
7.7.1.2
COPD medication restrictions on the days of scheduled spirometry visits...........82
7.7.1.3
Allowed Medications to treat a COPD exacerbation.............................................83
7.7.2
Other concomitant treatment..................................................................................84
7.8
Post Study Access to Study Treatment ..................................................................84
8.
STATISTICAL ANALYSES ................................................................................84


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
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8.1
Statistical considerations........................................................................................84
8.2
Sample size estimate..............................................................................................85
8.3
Definitions of analysis sets ....................................................................................86
8.3.1
Efficacy analysis sets .............................................................................................87
8.3.2
Safety analysis sets ................................................................................................87
8.3.3
Other analysis sets..................................................................................................88
8.4
Outcome measures for analyses.............................................................................88
8.4.1
Definition of baseline.............................................................................................88
8.4.2
Visit windows ........................................................................................................88
8.4.3
Pulmonary Function Outcomes..............................................................................88
8.4.3.1
Morning pre-dose trough FEV1..............................................................................89
8.4.3.2
Peak FEV1 and Inspiratory Capacity post-dosing.................................................89
8.4.3.3
Increase in FEV1 at 5 minutes post-dosing ............................................................89
8.4.4
Patient Reported Outcomes....................................................................................89
8.4.4.1
Transition Dyspnea Index (TDI) focal score .........................................................89
8.4.4.2
Early Morning Symptoms COPD Instrument (EMSCI) and Night Time 
Symptoms COPD Instrument (NiSCI)...................................................................90
8.4.4.3
COPD Assessment Test (CAT) score....................................................................90
8.4.4.4
Daily rescue medication use ..................................................................................90
8.4.4.5
EuroQol 5 Dimensions Questionnaire (EQ-5D-5L) ..............................................91
8.4.4.6
Healthcare Resource Utilisation (HCRU)..............................................................91
8.4.4.7
Work Productivity and Activity Impairment – General Health (WPAI-GH)........91
8.4.5
Safety and tolerability............................................................................................91
8.5
Methods for statistical analyses .............................................................................92
8.5.1
Analysis of the primary variable (s).......................................................................92
8.5.1.1
Trough FEV1..........................................................................................................92
8.5.1.2
Peak FEV1..............................................................................................................92
8.5.1.3
Hierarchical testing strategy – primary endpoints .................................................93
8.5.2
Analysis of the secondary variable(s)....................................................................94
8.5.2.1
Hierarchical testing strategy – secondary endpoints..............................................94
8.5.2.2
Pulmonary Function over 24 weeks.......................................................................95
8.5.2.3
Pulmonary Function at Day 1 ................................................................................96
8.5.2.4
Transition Dyspnea Index Focal Score..................................................................96
8.5.2.5
Early Morning Symptoms COPD Instrument (EMSCI) and Night Time 
Symptoms COPD Instrument (NiSCI)...................................................................97
8.5.2.6
COPD Assessment Test (CAT) score....................................................................97
8.5.2.7
Daily Rescue Medication Use................................................................................97
8.5.3
Subgroup analysis ..................................................................................................98
8.5.4
Interim analysis - Not applicable ...........................................................................98
8.5.5
Sensitivity analysis.................................................................................................98
8.5.6
Safety and tolerability............................................................................................98
8.5.7
Exploratory analysis...............................................................................................99
9.
STUDY AND DATA MANAGEMENT...............................................................99


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
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9.1
Training of study site personnel.............................................................................99
9.2
Monitoring of the study .........................................................................................99
9.2.1
Risk based quality management...........................................................................100
9.2.2
Source data...........................................................................................................100
9.2.3
Study agreements.................................................................................................100
9.2.4
Archiving of study documents.............................................................................101
9.3
Study timetable and end of study.........................................................................101
9.4
Data management by AstraZeneca ......................................................................101
10.
ETHICAL AND REGULATORY REQUIREMENTS.......................................102
10.1
Ethical conduct of the study.................................................................................102
10.2
Patient data protection..........................................................................................102
10.3
Ethics and regulatory review................................................................................102
10.4
Informed consent .................................................................................................103
10.5
Changes to the Clinical Study Protocol and Informed Consent Form.................103
10.6
Audits and inspections .........................................................................................104
11.
LIST OF REFERENCES.....................................................................................104
LIST OF TABLES
Table 1 
Study plan detailing the procedures .........................................................37
Table 2
Timed Assessments at Each Treatment Visit (Visit 3 to Visit 7).............41
Table 3
Laboratory Safety Variables.....................................................................67
Table 4
Identification of investigational product(s) ..............................................76
Table 5
Permitted medications ..............................................................................79
Table 6
Restricted Medications .............................................................................80
Table 7
Screening period Medication and Rescue medication..............................81
Table 8
Prohibited COPD Medications.................................................................81
Table 9
Other prohibited Medications...................................................................82
Table 10
Allowed Medications to treat a COPD exacerbation................................84
LIST OF FIGURES
Figure 1
Study flow chart .......................................................................................25


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Figure 2
Testing hierarchy for primary endpoints ..................................................93
Figure 3
Sequential testing hierarchy for secondary endpoints..............................95
LIST OF APPENDICES
Appendix A
Additional Safety Information................................................................108
Appendix B
COPD Assessment Test (CAT)..............................................................110
Appendix C
EuroQol 5 Dimensions Questionnaire (EQ-5D-5L)...............................111
Appendix D
Work Productivity and Activity Impairment Questionnaire -
General Health (WPAI-GH)...................................................................114
Appendix E 
Nighttime Symptoms of COPD Instrument and Early Morning 
Symptoms of COPD Instrument (NiSCI and EMSCI)...........................116
Appendix F
Baseline/Transitional Dyspnea Index (BDI/TDI) ..................................121


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse Event
ATS
American Thoracic Society
AZRand 
AstraZeneca Global Randomisation system
BDI 
Baseline Dyspnea Index 
BD
Twice daily
BMI
Body Mass Index
CAT
COPD Assessment Test
COPD 
Chronic Obstructive Pulmonary Disease
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CT
Computed Tomography
DAE
Adverse event leading to discontinuation of investigational product
DPI 
Dry Powder Inhaler
DUS 
Disease under study
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG 
Electrocardiogram
eCRF
Case Report Form (electronic)
EQ-5D-5L 
EuroQol 5 Dimensions Questionnaire
EMSCI 
Early Morning Symptoms of COPD Instrument
ERS 
European Respiratory Society
ePRO
Electronic Patient Reported Outcomes
FDA 
U.S. Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FF 
Formoterol Fumarate
FVC 
Forced vital capacity
GCP
Good Clinical Practice
GFF
Glycopyrronium and Formoterol Fumarate


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Abbreviation or 
special term
Explanation
GLI
Global Lung Function Initiative
GMP 
Good Manufacturing Practice
GOLD 
Global Initiative for Chronic Obstructive Lung Disease
GP
Glycopyrronium
HCRU 
Healthcare resource utilization
ICF 
Informed Consent Form
ICH
International Conference on Harmonisation
ICS 
Inhaled corticosteroids
IC
Inspiratory capacity
IP
Investigational Product 
IWRS/IVRS
Interactive Web Response System/Interactive Voice Response System
LABA 
Long-acting beta2-adrenergic agonist
LAMA
Long-acting muscarinic antagonist/inhaled anticholinergic
LPLV
Last Patient Last Visit
MedDRA 
Medical Dictionary for Regulatory Activities
MDI 
Metered dose inhaler
NiSCI 
Nighttime Symptoms of COPD Instrument
OAE
Other Significant Adverse Event
OD
Once daily
QDS 
Four times daily
PI
Principal Investigator 
PP 
Per Protocol
Pre-BD 
Pre-bronchodilator
PRN
As needed
Post-BD 
Post-bronchodilator
SAE
Serious Adverse Event 
SAMA 
Short-acting muscarinic antagonist/ inhaled anticholinergics
SAP
Statistical Analysis Plan
SD 
Standard Deviation
TDI
Transitional Dyspnea Index 
UV
Umeclidinium/Vilanterol
VAS 
Visual Analogue Scale


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Abbreviation or 
special term
Explanation
WBDC
Web Based Data Capture
WPAI-GH
Work Productivity and Activity Impairment Questionnaire - General Health


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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Long-acting bronchodilators are central to the pharmacological management of chronic 
obstructive pulmonary disease (COPD) (GOLD 2017). However, many patients remain 
symptomatic despite the availability of effective long-acting monotherapies. In a real-world 
study (Dransfield et al 2011), patients receiving tiotropium, formoterol, or salmeterol as long-
acting bronchodilator maintenance therapy continued to report dyspnea and high levels of 
supplemental rescue medication use, irrespective of the level of airflow limitation.
Glycopyrronium (GP) is a long-acting muscarinic antagonist (LAMA) which exerts its 
bronchodilatory effect via muscarinic receptors located on smooth muscle cells within the 
trachea and bronchi. GP is approved in many countries in multiple formulations for different 
indications, including for the treatment of COPD.
Formoterol fumarate (FF) is a selective long-acting β2-agonist (LABA) approved worldwide 
for use in COPD. In addition, FF is also approved worldwide in combination with inhaled 
corticosteroids (ICS) such as budesonide (e.g., Symbicort® MDI, Symbicort® Turbuhaler®
(TBH [AstraZeneca, LP]) for use in patients with asthma and COPD. When inhaled, FF acts 
locally in the lung as a bronchodilator. FF stimulates β2-adrenoreceptors in the airways, 
inducing airway smooth muscle relaxation and reducing or preventing bronchoconstriction. 
Dual long-acting bronchodilator therapy represents an alternative to long-acting 
bronchodilator monotherapy (Cazzola et al 2010). Glycopyrronium/Formoterol Fumarate 
(GFF) is a fixed-dose combination of GP and FF in a metered dose inhaler (MDI). It is 
approved in the USA for maintenance treatment of COPD (at a dose of 7.2/4.8μg two 
inhalations twice daily (Bevespi Aerosphere™ prescribing information, 2016.). Dual 
bronchodilation with GFF has been shown to provide greater improvements in lung function 
than GP or FF alone, with similar or greater improvements in measures of dyspnea, rescue 
medication use, and health-related quality of life (Martinez et al 2016). However, a direct 
comparison between GFF and other inhaled LAMA/LABA combinations has not been 
performed 
Umeclidinium/Vilanterol (UV) is a fixed-dose combination of the LAMA umeclidinium and 
the LABA vilanterol, which is approved in many countries for the treatment of COPD. UV is 
a dry powder inhaler (DPI) prescribed at a dose of 62.5 μg/25 μg once daily (Anoro™ 
Ellipta™ prescribing information, 2016.).
The rationale for a direct comparison between LAMA/LABA combinations is multi-fold. 
There are several LAMA/LABA combinations available, approved at once-daily or twice-
daily dosing regimens (Duaklir® Genuair® Summary of Product Characteristics 2015; 
Anoro™ Ellipta™ prescribing information, 2016.;Utibron™ Neohaler® prescribing 
information 2016.;Stiolto® Respimat® prescribing information 2016). The mono-components 
of the LAMA/LABA combinations have different pharmacological properties which may 


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have an impact clinically on both lung function and symptoms. The symptomatic impact of 
COPD can vary over the course of the day and night, whereby different dosing regimens and 
differences in treatment effects may be important. It is a well-known fact that many COPD 
patients find the morning hours particularly burdensome, as they get up and start their day. 
Therefore, effective bronchodilation during the night and fast onset of effect in the morning 
have relevance for this patient group (Roche et al 2013). A direct comparison between two 
LAMA/LABAs will help elucidate the influence of their different dosing regimens and 
pharmacological properties on the treatment effects and evaluate the importance of these 
differences for patients’ lung function, symptoms and health-related quality of life.
This study will compare the efficacy of GFF to UV in patients with moderate to very severe 
COPD.
1.2
Rationale for study design, doses and control groups
This is a randomised, double-blind, active controlled, parallel group study of 24 weeks 
duration in patients with moderate to very severe COPD. The study design is commonly used 
in COPD and is consistent with regulatory guidelines. 24 weeks is sufficient duration to be 
able to observe improvements in airflow obstruction and symptom relief.
As described in Section 1.1, both GFF and UV are approved therapies for COPD in the USA, 
and while UV is already approved in several other major markets, GFF is expected to gain 
similar approvals by the time of completion of this study. Both treatments will be given in 
accordance with their labelled dosing regimens. A direct comparison of these two treatments 
will support the evidence base for the prescribing of GFF.
This study will recruit patients with moderate to very severe COPD; therefore, spirometry 
entry requirements are set according to the thresholds defined by GOLD grade 2 or above 
(GOLD 2017). These requirements are in line with the inclusion criteria used in the pivotal 
study programmes of both GFF and UV. In addition, patients are required to be symptomatic 
at baseline with a COPD Assessment Test (CAT) score of 10 or above. This threshold is 
specified in the current guidelines (GOLD 2017) as determining those in need of treatment for 
symptoms of COPD. In patients meeting these criteria, with severe or persistent 
breathlessness, treatment with dual bronchodilator therapy is recommended (GOLD 2017).
Randomisation and blinding minimise any potential for selection bias, or for bias in the 
assessment of study endpoints or the management of patients. This is especially important 
given the patient-reported endpoints collected in this study. As GFF is delivered in a metered 
dose inhaler (MDI) and UV in a dry powder inhaler (DPI), it is not possible to provide a single 
matched inhaler that could deliver either investigational treatment. Therefore, a double-
dummy design will be used whereby matched placebo versions of each of the MDI and DPI 
will be used and patients will be randomised to receive one of the active inhalers to be taken 
alongside one of the placebo inhalers. Patients will also continue to use short-acting rescue 
medication when necessary (albuterol/salbutamol MDI inhaler). As the aim of this study is to 
directly assess the differences in lung function and symptoms attributable to the two 
LAMA/LABA combinations, patients should discontinue from inhaled corticosteroid (ICS) 


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treatment before being randomised. Given that multiple inhalers are involved in study 
treatment, there would also be concerns about treatment complexity and compliance if a 
fourth inhaler were used. Patients who are receiving a stable ICS/LABA combination at 
screening may enter the study if ICS treatment is withdrawn. The switch to LAMA/LABA 
treatment for these patients, particularly those with lower blood eosinophil counts, is justified 
since recent studies (Wedzicha et al 2016) have demonstrated the benefits of LAMA/LABA 
dual bronchodilation over ICS/LABA combination treatment in terms of reduction in 
exacerbation risk and improvements in lung function and symptoms. 
Patients at high exacerbation risk who experience further exacerbations may need their 
treatment to be escalated (for example to triple therapy including ICS). Patients who 
experience ≥2 moderate exacerbations (requiring antibiotics or ≥3 days of systemic steroids) 
or ≥1 severe exacerbation (leading to hospitalisation) while on study will be withdrawn.
The co-primary endpoints in this study are morning pre-dose trough FEV1 and peak FEV1
within 2 hours post-dosing. These are recognised measures of pulmonary function and airflow 
obstruction and have been used as primary or secondary endpoints in many regulatory studies 
in COPD. Trough FEV1 was the primary endpoint in the pivotal studies of both GFF and UV 
(Martinez et al 2016; Donohue et al 2013). Since trough FEV1 measures lung function at the 
nadir of the effect of the randomised therapies and it is important to consider the entire dosing 
interval, peak FEV1 is included as a co-primary endpoint at the zenith of the effect. Secondary 
endpoints include recognised and validated measures of dyspnea, COPD symptoms and 
health-related quality of life. These are important factors to patients experiencing COPD in 
addition to measures of airflow obstruction.
As the comparator is an approved active therapy, the primary aim of the study will initially 
involve establishing the non-inferiority of GFF to UV in improving lung function and 
symptoms. The potential for superiority over UV in maximum bronchodilation, inspiratory 
capacity (IC), early onset of effects and morning symptom control will then also be assessed. 
No placebo arm is included, but as there is extensive experience of these therapies in terms of 
the endpoints used (in particular the co-primary endpoints and other spirometry assessments), 
there are no concerns about assay sensitivity in this study. Similar two-arm non-inferiority 
studies have been conducted with other products in COPD, including between dual 
bronchodilator combinations (Kalberg et al 2016; Buhl et al 2015).
The proposed non-inferiority margin of 50mL for trough FEV1 is well established and based 
upon considerable experience in reproducible effects of long acting bronchodilators over 
placebo. It relates to half of the commonly recognised clinically important difference of 
100mL (Donohue 2005) and has been used in several non-inferiority studies, both of dual and 
single long acting bronchodilators (Kalberg et al 2016; Chapman et al 2014; Volgelmeier et al 
2010). The same margin will be applied to Peak FEV1 and IC. As the magnitude of changes in 
peak FEV1 with therapy are typically larger than for trough FEV1, this represents a relatively 
more stringent non-inferiority margin for peak FEV1.
The non-inferiority margin for TDI is based upon the Minimum Clinically Important 
Difference (MCID) of 1 unit (Mahler et al 2005). Although there is less precedent for formal 


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non-inferiority testing of TDI, a similar approach to using the MCID as a pre-specified margin 
has been used previously for SGRQ (Buhl et al 2015). There is less clinical experience with 
the use of EMSCI, but a non-inferiority margin of 0.1 units is proposed based upon the 
difference observed between LAMA/LABA and LAMA only treated patients (D’Urzo et al 
2014). 
1.3
Benefit/risk and ethical assessment
GFF was approved by the US FDA for patients with COPD in April 2016 and launched in the 
US January 2017. Its two mono-components, GP and FF, are used as single therapy or in 
combination with other inhaled drugs in patients with COPD in many countries worldwide. 
The clinical development program for GFF included 4,602 patients with COPD. Overall, the 
program demonstrated that GFF was effective for long-term maintenance therapy in patients 
with COPD and provided additional efficacy benefits compared to its mono-components (as 
assessed by measures of lung function, COPD symptoms and disease-specific health status). 
GFF was well tolerated, with a safety profile comparable to the mono-components, and with 
no unexpected safety observations. Adverse drug reactions with ≥1% incidence were anxiety, 
headache, tremor, dry mouth, nausea, muscle spasms and chest pain. Less common adverse 
drug reactions were hyperglycaemia, agitation, restlessness, sleep disturbance, tachycardia, 
palpitations, atrial fibrillation, supraventricular tachycardia, extrasystoles, dizziness and 
hypersensitivity. In conclusion, these findings support a favourable benefit-risk profile for 
GFF in the treatment of patients with COPD. 
UV was approved by the US FDA in 2013 and has since then been launched worldwide for 
patients with COPD. Adverse drug reactions with ≥1% incidence reported with UV are 
pharyngitis, sinusitis, lower respiratory tract infection, constipation, diarrhea, pain in 
extremity, muscle spasms, neck pain and chest pain. Less common adverse drug reactions are 
productive cough, dry mouth, dyspepsia, abdominal pain, gastroesophageal reflux disease, 
vomiting, musculoskeletal chest pain, chest discomfort, asthenia, atrial fibrillation, ventricular 
extrasystoles, supraventricular extrasystoles, myocardial infarction, pruritus, rash, and 
conjunctivitis. 
During screening, all patients will switch their COPD therapy to ipratropium bromide MDI 
four times daily (QDS) and albuterol/salbutamol MDI as needed (PRN). Although this 
regimen is expected to give adequate symptom relief for most patients, some of them (mainly 
those with previous LAMA/LABA combination treatment) may experience an increase in 
symptoms.  Patients will be have a faster follow up than what they would experience in 
regular clinical settings and will be reminded to contact their physicians if they have 
significantly worsening symptoms.   During the 24-week treatment period, all patients will be 
treated with a LAMA/LABA combination, and since patients on incoming triple therapy will 
not be eligible, no patients will be subjected to a step-down in therapy after randomisation 
compared to their regular maintenance therapy. Patients on incoming rescue treatment only or 
maintenance monotherapy will be eligible only if they are symptomatic (CAT score ≥10) at 
screening, i.e. a step-up in treatment for these patients will be based on clinical judgement and 
will offer a potential for improvement. Both arms will use approved doses and the study 
population represents the population for which these medications were approved.


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Based on the safety profile of the investigational products (IPs), no new or specific risks 
beyond what has been described are anticipated with the doses and the dose regimens being 
used in this trial. Investigators will ensure adequate medical care of the study participants at 
all times throughout the course of the study, and patients will be followed by clinic visits 
every 4-8 weeks.
The study requires documentation of a standard chest x-ray as per local practice (postero-
anterior and lateral projections strongly recommended), or computed tomography (CT) scan 
of the chest/lungs, within 6 months of enrolment to rule out clinically significant 
abnormalities not associated with COPD. The requirement for chest x-ray introduces minimal 
radiation exposure and is a standard diagnostic test for COPD symptom worsening and 
pneumonia.
1.4
Study Design 
This is a phase IIIb randomised, double-blind, double-dummy, multicentre, parallel group, 24 
week study to assess the efficacy and safety of GFF  7.2/4.8 μg 2 inhalations twice daily (BD) 
compared to UV 62.5/25 μg 1 inhalation once daily (OD) in patients with moderate to very 
severe COPD.
The study will be conducted in approximately 150 sites. Across these sites, it is planned that 
approximately 1400 patients will be screened and 1000 randomised into the study.
Patients will be randomised in a 1:1 scheme. Approximately 500 patients each will be 
randomised to the GFF and UV treatment groups. Patients will be stratified based on incoming 
COPD treatment at screening: rescue only/maintenance monotherapy (LAMA or LABA or 
ICS only) vs. double maintenance therapy (LABA/LAMA or ICS/LABA). 
The study will evaluate the benefit of GFF compared to UV in patients with moderate to very 
severe COPD. Patients on rescue medication only or maintenance monotherapy will be 
required to be symptomatic (CAT ≥10) at screening (Visit 1), whereas there will be no 
symptom requirement at screening for patients on double maintenance therapy (ICS/LABA or 
LAMA/LABA). All patients will be required to be symptomatic (CAT ≥10) at randomisation 
(Visit 3). Patients on triple maintenance therapy will not be eligible. A history of 
exacerbations in the previous year will be obtained to characterize the population but will not 
be included as an entry criterion. COPD severity, defined as post-bronchodilator forced 
expiratory volume in 1 second (FEV1), must be <80% predicted normal value, calculated 
using the Global Lung Function Initiative (GLI) equations (Quanjer et al 2012), and the 
measured FEV1 must also be ≥750 mL if FEV1 less than 30 % of predicted normal value. 
Post-bronchodilator FEV1 (after inhalation of albuterol/salbutamol MDI) will be tested at 
screening (Visit 1 and Visit 2) to determine eligibility and COPD severity. Bronchodilator 
responsiveness to albuterol/salbutamol MDI will be tested at Visit 2.
Any treatment with ICS, LAMA, LABA and existing rescue medications will be stopped at 
the screening visit. During the screening period, patients will be treated with ipratropium 


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bromide MDI 2 inhalations QDS and albuterol/salbutamol MDI as needed. 
Albuterol/salbutamol MDI will also be used as rescue medication throughout the 24-week 
treatment period.
Baseline assessments: vital signs, 12-lead electrocardiogram (ECG), clinical laboratory testing 
and pregnancy test will be performed to assess patients’ eligibility.
After the Randomisation Visit (Visit 3), patients will be evaluated at Visit 4 (Week 4), Visit 5 
(Week 12), Visit 6 (Week 18) and Visit 7 (Week 24) using spirometry and patient reported 
outcome questionnaires. From Visit 2 onwards, patients will also enter data daily in an 
electronic Patient Reported Outcomes device (ePRO).
For patients who remain on treatment throughout the study (i.e., complete Visit 7), a follow-
up telephone call will be performed approximately 14 days after the last IP dose.  
Patients who discontinue study treatment prior to Week 24 (Visit 7) will complete a Treatment 
Discontinuation/Withdrawal Visit. These patients will be placed on appropriate maintenance 
COPD medications, as per the Investigator’s judgement. Consideration should be given to 
maintaining patients on at least double therapy, while ensuring appropriate follow-up and 
further evaluation of the prescribed treatment. 
A follow-up telephone call will be performed approximately 14 days after the last IP dose. No 
further data will be collected. In the event the Treatment Discontinuation/Withdrawal Visit is 
performed approximately14 days post last IP dosing, a follow-up TC will not be required. 
Figure 1
Study flow chart


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1.5
Study governance and oversight – Not Applicable
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To assess the effects of GFF relative to UV on 
lung function as measured by trough FEV1 and 
peak FEV1 in patients with moderate to very 
severe COPD
Co-primary endpoints:
∀
Change from baseline in morning pre-dose trough 
FEV1 over 24 weeks
∀
Peak change from baseline in FEV1 within 2 hours 
post-dosing over 24 weeks
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To further assess the effects of GFF relative to 
UV on lung function.
Secondary endpoints:
∀
Onset of action on day 1; proportion of patients 
with increase of FEV1 of ≥100 ml from baseline at 
5 minutes 
∀
Peak change from baseline in Inspiratory Capacity 
(IC) within 2 hours post-dosing over 24 weeks
To assess the effects of GFF  relative to UV on 
dyspnea
Secondary endpoint:
Transition Dyspnea Index (TDI) focal score over 24 
weeks
To assess the effects of GFF relative to UV on 
symptoms of COPD
Secondary endpoint:
Change from baseline in Early Morning Symptoms 
COPD Instrument (EMSCI) over 24 weeks
Other endpoints:
∀
Change from baseline in Night Time Symptoms 
COPD Instrument (NiSCI) over 24 weeks
∀
Change from baseline in daily rescue 
(albuterol/salbutamol MDI) use over 24 week
To assess the effects of GFF relative to UV on 
health-related quality of life
Other endpoint:
Change from baseline in COPD Assessment Test 
(CAT) score over 24 weeks


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2.3
Safety objectives
Safety Objective:
Outcome Measure:
To assess the safety of GFF
Adverse events (AEs), serious adverse events (SAEs), 
adverse events leading to treatment discontinuation 
(DAEs)
2.4
Exploratory objectives  
Exploratory Objective:
Outcome Measure:
To assess health status for COPD patients 
treated with GFF
Change from baseline in EuroQol 5 Dimensions 
Questionnaire (EQ-5D-5L) over 24 weeks
To assess overall and COPD-specific 
Healthcare Resource Utilization and work 
productivity loss for GFF
Health Economics Questionnaire for healthcare 
resource utilization. 
Time to the first moderate or severe COPD 
exacerbation
Work Productivity and Activity Impairment - General 
Health (WPAI-GH)
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1.
Provision of informed consent prior to any study specific procedures.
2.
Female or male patients aged 40-95 years inclusive at the time of enrolment at Visit 
1.
3.
Tobacco Use: Current or former smoker with a history of at least 10 pack-years of 
cigarette smoking (1 pack year = 20 cigarettes smoked per day for 1 year).
4.
A current clinical diagnosis of COPD, with COPD symptoms for more than 1 year 
prior to screening, as defined by GOLD criteria or other current guidelines.
5.
COPD Severity defined as:


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!
At Visit 1 and Visit 2, post-bronchodilator FEV1/FVC ratio <0.70, FEV1 <80% 
of predicted normal value, and FEV1 ≥750 mL if FEV1 is <30% of predicted 
normal value.
!
At Visit 3 (randomisation), FEV1/FVC ratio <0.70 and FEV1 <80% of 
predicted normal value in both pre-dose assessments.
6.
COPD treatment with rescue medication only, or stable dose of maintenance 
monotherapy (LAMA, LABA or ICS), or stable dose of double maintenance 
therapy (LAMA/LABA or ICS/LABA), for one month prior to screening (Visit 1). 
Triple maintenance therapy (LAMA/LABA/ICS) is not allowed for one month prior 
to screening. Stepping-down from triple maintenance therapy before the month 
prior to screening must only be based on clinical symptoms in the opinion of the 
Investigator.
7.
COPD symptom severity: CAT ≥10 at screening (Visit 1) for patients on rescue 
medication only or maintenance monotherapy. No symptom requirement at 
screening for patients on double maintenance therapy. CAT ≥10 at randomisation 
(Visit 3) for all patients.
8.
Patient is willing and, in the opinion of the Investigator, able to adjust current 
COPD therapy as required by the protocol.
9.
Documentation of a chest x-ray as per local practice (postero-anterior and lateral 
projections strongly recommended) or computed tomography (CT) within 6 months 
prior to Visit 1, with no clinically significant pulmonary abnormalities other than 
related to COPD. 
!
Specific to countries with restrictive radiology assessment practice: if no 
documentation of chest x-ray or CT of the chest/lungs within 6 months prior to 
Visit 1 is available, an MRI may be used instead, as per local practice 
assessment, or the Investigator may follow local guidelines to have the chest x-
ray or CT approved.
!
If the result is not available at Visit 1, it must be available by Visit 2 at the 
latest
10.
Ability and willingness to comply with all study procedures, including daily 
completion of ePRO.
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Respiratory disease:


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(a)
Asthma: Patients that, in the opinion of the Investigator, have a current diagnosis of 
asthma.
(b)
Alpha-1 Antitrypsin Deficiency: Patients who have alpha-1 antitrypsin deficiency 
as the cause of COPD.
(c)
Other Respiratory Disorders: Patients who have other active pulmonary disease 
such as active tuberculosis, lung cancer, clinically significant bronchiectasis 
disease, sarcoidosis, idiopathic interstitial pulmonary fibrosis (IPF), primary 
pulmonary hypertension, or uncontrolled sleep apnea.
(d)
Lung Volume Reduction: Patients who have undergone lung volume reduction 
surgery, lobectomy or bronchoscopic lung volume reduction within 1 year of Visit 
1.
(e)
A severe COPD exacerbation (resulting in hospitalisation) that has not resolved 
within 8 weeks prior to Visit 1, or a moderate COPD exacerbation (requiring 
antibiotics or ≥3 days of systemic steroids) that has not resolved within 4 weeks 
prior to Visit 1, or a moderate or severe COPD exacerbation that occurs between 
Visit 1 and Visit 3 (randomisation).
(f)
Pneumonia or lower respiratory tract infection: Patients who had pneumonia or 
lower respiratory tract infection that required antibiotics within 8 weeks prior to 
Visit 1 (screening) or during the screening period (Visit 1 to Visit 3).
(g)
Risk factors for pneumonia: immune suppression (HIV), severe neurological 
disorders affecting control of the upper airway or other risk factors that in the 
opinion of the Investigator would put the patients at substantial risk of pneumonia.
(h)
Oxygen: patients receiving long-term-oxygen therapy (LTOT) or nocturnal oxygen 
therapy required for greater than 12 hours per day.
(i)
Patient use of any non-invasive positive pressure ventilation device. Note:  Patients 
using continuous positive airway pressure or bi-level positive airway pressure for 
sleep apnea syndrome are allowed in the study if not used for ventilatory support.
(j)
Pulmonary rehabilitation: Patients who have participated in the acute phase of a 
pulmonary rehabilitation program within 4 weeks prior to Visit 1 (screening) or 
who will enter the acute phase of a pulmonary rehabilitation program during the 
screening period.  Patients who are in the maintenance phase of a pulmonary 
rehabilitation program are not to be excluded.
2.
Cardiac disease:


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!
Unstable angina/acute coronary syndrome, or Coronary Artery Bypass Grafting 
(CABG), Percutaneous Coronary Intervention (PCI) or myocardial infarction 
within the past 6 months.
!
Congestive heart failure New York Heart Association (NYHA) class III/IV.
!
Structural heart disease (hypertrophic cardiomyopathy, significant valvular 
disease).
!
Paroxysmal (within the past 6 months) or symptomatic chronic cardiac 
tachyarrhythmia.
!
Left bundle branch or high-degree AV block (second degree AV block type 2 
and third degree AV block) unless the patient has a pacemaker.
!
Sinus node dysfunction with pauses.
!
Ventricular pre-excitation and/or Wolff-Parkinson-White syndrome.
!
QTcF interval >470 msec (QT interval corrected using Fridericia's formula; 
QTcF=QT/[RR1/3]).
!
Any other ECG abnormality deemed clinically significant by the Investigator.
!
Bradycardia with ventricular rate < 45 bpm. 
!
Uncontrolled hypertension (> 165/95 mmHg), as per investigator’s judgement.
3.
Renal disease: Patients with a calculated eGFR <30 mL/minute /1.73 m2, using 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (Levey, 
2009). On-line calculators can be used.
4.
Cancer: Patients who have cancer that has not been in complete remission for at 
least 5 years. Note:  Patients with squamous cell carcinoma of the skin, basal cell 
carcinoma of the skin, or localized prostate cancer are eligible if, in the opinion of 
the Investigator, the condition has been adequately worked up, is clinically 
controlled and the patient's participation in the study would not represent a safety 
concern.
5.
Glaucoma: Patients with a diagnosis of narrow-angle glaucoma that, in the opinion 
of the Investigator, has not been adequately treated.  All medications approved for 
control of intraocular pressures are allowed including topical ophthalmic non-
selective beta-blockers (such as betaxolol, carteolol, levobunolol, metipranolol, 
timolol) and prostaglandin analogues.


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Study Code D5970C00002
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Date 14 July 2017
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6.
Patients with symptomatic prostatic hypertrophy or bladder neck 
obstruction/urinary retention that is clinically significant in the opinion of the 
Investigator. 
7.
Significant diseases or conditions other than COPD which, in the opinion of the 
Investigator, may put the patient at risk because of participation in the study or may 
influence either the results of the study or the patient's ability to participate in the 
study.
8.
Any clinically relevant abnormal findings in physical examination, clinical 
chemistry, haematology, urinalyses, vital signs or ECG, which in the opinion of the 
Investigator, may put the patient at risk because of his/her participation in the study.
9.
Women who are pregnant or lactating, or are planning to become pregnant during 
the course of the study, or women of childbearing potential who are not using an 
acceptable method of contraception, as judged by the Investigator. Female patients 
who are not post-menopausal or surgically sterile must have a negative pregnancy 
test prior to randomisation and must comply with contraception methods.
10.
Drug allergy: Patients who have a history of hypersensitivity to β2 agonists, GP or 
other muscarinic anticholinergics, or any component of the MDI or DPI, including 
severe milk protein allergy.
11.
Substance abuse: Patients who in the opinion of the Investigator abuse alcohol or 
drugs.
12.
Medication prior to spirometry: Patients who are medically unable to withhold their 
short-acting bronchodilators for the 6-hour period required prior to spirometry 
testing at study visits.
13.
Prohibited medications:  Patients who, in the opinion of the Investigator, would be 
unable to abstain from protocol-defined prohibited medications during the screening 
period and treatment phases of this study (see Table 3). 
14.
Non-compliance: Patients unable to comply with study procedures during 
screening, including non-compliance with ePRO completion (i.e., <70% patient 
completion of ePRO assessments).
15.
Affiliations with Investigator site:  Study Investigators, sub-Investigators, study 
coordinators, employees of a participating Investigator or immediate family 
members of the aforementioned are excluded from participation.
16.
Questionable validity of consent: Patients with a history of psychiatric disease, 
intellectual deficiency, poor motivation, substance abuse (including drug and 
alcohol), or other conditions that will limit the validity of informed consent to 
participate in the study as judged by Investigator.


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Study Code D5970C00002
Version 2
Date 14 July 2017
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17.
Investigational drugs or devices: Treatment with IP or device in another clinical 
study within the last 30 days or 5 half-lives prior to Visit 1 (screening), whichever is 
longer.  Note:  Patient participation in observational studies (i.e., studies that do not 
require change to medication or an additional intervention) is not exclusionary.
18.
Patients who have needed additions or alterations to their usual maintenance 
therapy for COPD due to worsening symptoms within 1 month prior to Visit 1 and 
up to Visit 3.
19.
Treatment with depot corticosteroids within 6 weeks, and other systemic 
corticosteroids within 4 weeks, prior to Visit 1. Exception: Patients who are steroid 
dependent, and maintained on an equivalent of 5 mg prednisone per day, or 10 mg 
every other day, for at least 3 months prior to Visit 1, are eligible for enrolment 
providing the dose of oral steroids remains stable during the screening period.
20.
Any monoclonal or polyclonal antibody therapy taken for any reason within 6 
months prior to Visit 1.
21.
Planned hospitalisation or significant surgical procedure during the study.
22.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).
23.
Previous randomisation in the present study.
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment and randomisation
The Investigator should keep a record, the Patient Screening Log, of patients who entered pre-
study screening.
The Investigator will:
1. Obtain signed informed consent from the patient before any study-specific procedures are 
performed.
2. Assign the patient a unique enrolment number, beginning with ‘E#’ (using the Interactive 
Web Response System [IWRS/IVRS]).
3. Determine patient eligibility (see Section 3.1 and 3.2).
4. Randomise the patient using IWRS/IVRS (randomisation code will be blinded).
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Only the enrolment number will be used for patient identification in 
the eCRF. 


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Study Code D5970C00002
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Date 14 July 2017
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3.4
Procedures for handling incorrectly enrolled or randomised 
patients 
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be randomised 
or initiated on treatment and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the Investigator regarding whether to continue or discontinue the patient from 
treatment. Treatment must be discontinued in all cases where continued treatment is deemed 
to pose a safety risk to the patient. The AstraZeneca study physician must ensure all decisions 
including the rationale for continuing or discontinuing treatment are appropriately 
documented.
3.5
Methods for assigning treatment groups
The randomisation codes will be computer-generated using the AstraZeneca Global 
Randomisation system (AZRand) and loaded into the IWRS/IVRS database. The 
randomisation codes will be generated in blocks to ensure approximate balance (1:1) between 
the two treatment groups. Patients will be stratified based on incoming COPD treatment; 
rescue or maintenance monotherapy (LAMA, LABA or ICS only) at screening vs. double 
maintenance therapy (LABA/LAMA or ICS/LABA).
3.6
Methods for ensuring blinding
Patients, study site personnel, and AZ personnel will not know which medication the patient is 
receiving.
Since there are two different devices, a double-dummy technique will be applied to ensure the 
double-blinding of the study.  Matched placebo to GFF and UV will be present with the same 
external appearance. There will be no differences between active and placebo formulations 
with regards to appearance, odour or colour that could unmask the blinded design.  
3.7
Methods for unblinding
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the Investigator or pharmacists from the IWRS/IVRS. Routines for 
this will be described in the IWRS/IVRS user manual that will be provided to each site.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation. The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient to the AstraZeneca staff.


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Study Code D5970C00002
Version 2
Date 14 July 2017
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AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities. Treatment codes will not be broken for the planned analyses of data 
until all decisions on the evaluability of the data from each individual patient have been made 
and documented.
3.8
Restrictions
The following is restricted during the study:
!
Donation of blood is not allowed throughout the study.
!
Patient should keep regular night/day shifts.
!
The activities that should be avoided in the morning prior to lung function 
testing are :

Smoking within at least 1 hour of testing.

Consuming alcohol within 4 hours of testing.

Performing vigorous exercise within 30 minutes of testing.

Wearing clothing that substantially restricts full chest and abdominal 
expansion.

Eating a large meal within 2 hours of testing.

Using albuterol/salbutamol MDI within approximately 6 hours of 
testing.

Using ipratropium bromide MDI within approximately 6 hours of 
testing at Visit 2 and Visit 3.

Using IP in the morning before visits 4-7.
!
Restrictions regarding concomitant medication are described in Section 7.
Any event likely to interfere with the objectives of the study will be communicated to the 
Investigator and reported without delay to AstraZeneca.
3.9
Discontinuation of IP
Patients may be discontinued from IP in the following situations:
∀
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
35 (129)
∀
AEs that, in the opinion of the Investigator, contraindicates further IP treatment.
∀
Severe non-compliance with the Clinical Study Protocol as judged by the 
Investigator or AstraZeneca. The study physician should be consulted before IP is 
discontinued based on this criterion.
∀
In the opinion of the Investigator, patient requires additional treatment or care 
beyond what is provided by the study, including treatment with prohibited COPD 
medications (see Table 8). 
∀
Eligibility requirement found not to be fulfilled.
∀
A severe COPD exacerbation (requiring hospitalisation) or more than one moderate 
exacerbation (requiring antibiotics or ≥3 days of systemic steroids).
∀
Pregnancy.
3.9.1
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue IP or withdraw from the study (i.e., IP and 
assessments – see Section 3.10), without prejudice to further treatment.  A patient that decides 
to discontinue IP will always be asked about the reason(s) and the presence of any AEs. 
If possible, patients who discontinue IP prematurely will be seen and assessed by the 
Investigator at an Early Discontinuation/Withdrawal Visit which should be performed at the 
earliest possibility. Patients will return to appropriate COPD maintenance medications, per the 
Investigator’s discretion. Consideration should be given to maintaining patients on at least 
double therapy, while ensuring appropriate follow-up and further evaluation of the prescribed 
treatment. AEs will be followed up (see Section 6) and rescue medication, ePRO and all IPs 
should be returned by the patient. The reason and date for premature discontinuation of IP will 
be documented in the source documentation and in the eCRF. 
A follow-up telephone call will be performed approximately 14 days after the last IP dose for 
follow-up of any AEs. After the follow-up telephone call, patients will be withdrawn and no 
further data will be collected. In the event the Early Discontinuation/Withdrawal Visit is 
performed approximately 14 days post last IP dosing, a follow-up contact will not be required. 
If a patient is withdrawn from study (see Section 3.10).
3.10
Criteria for withdrawal 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn patients will not be replaced.
3.10.1
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised.  These patients should have the reason for study withdrawal 


Clinical Study Protocol
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Study Code D5970C00002
Version 2
Date 14 July 2017
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recorded as ‘Screen failure’. (This reason for study withdrawal is only valid for the patients 
who have not been randomised.)
3.10.2
Discontinuation of investigational product
Patients who discontinue IP will be withdrawn from the study (see Section 3.9.1).
3.10.3
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time without prejudice to further treatment 
(IP and assessments).
A patient who withdraws consent should always be asked about the reason(s) and whether any 
AEs are present; to ensure patient safety in such cases, the Investigator should follow up AEs 
outside of the clinical study period based on clinical judgement. The patient will return 
electronic PRO (ePRO) devices to the study site. 
Withdrawal of consent should be documented by the Investigator in the eCRF and medical 
records. If possible, the patient should complete the Early Discontinuation/Withdrawal Visit at 
the time of withdrawal of consent.
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings that:
∀
are assessed as causally related to IP and 
∀
are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the CRF. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests and wellbeing.
4.
STUDY PLAN AND TIMING OF PROCEDURES 


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
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Table 1 
Study plan detailing the procedures 
Visita
1
Scree
ning
2
3
Randomis
ation
4
5
6
7
Early 
Discontinuatio
n/
Withdrawal 
Visit
Follow-Up 
call
For details 
see Section
Week
0
4
12
18
24
Section
Day
-28 
to -9
-11 to 
-8
1
±3 
days
±3 
days
±3 
days
±3
days
-
14 days
Post-Dose
Obtain Informed Consent
X
4
IWRS/IVRS call/record
X
X
X
X
X
X
X
X
X
3.3
4
Review Inclusion /Exclusion 
Criteria
X
X
X
3.1
3.2
4
Bronchodilator responsiveness 
X
4
Demographics & 
Medical/Surgical History
X
4.1.1
Physical Examination
X
4.1.1
5.2.2
Smoking Status
X
4.1.1
Prior/Concomitant Medicationsb
X
X
X
X
X
X
X
X
X
7.7
Vital Signs
X
4.1.1
12-Lead ECG
X
4.1.1


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Study Code D5970C00002
Version 2
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Visita
1
Scree
ning
2
3
Randomis
ation
4
5
6
7
Early 
Discontinuatio
n/
Withdrawal 
Visit
Follow-Up 
call
For details 
see Section
Week
0
4
12
18
24
Section
Day
-28 
to -9
-11 to 
-8
1
±3 
days
±3 
days
±3 
days
±3
days
-
14 days
Post-Dose
Pregnancy Test
X
X
X
X
X
4
Clinical Laboratory Testing
X
5.2.1
Chest Image or CT
X
4.1.1
Inspiratory Capacity
X
X
X
X 
X
Xd
4
Spirometry (FEV1 and FVC)c
X
X
X
X
X
X
X
Xd
4
5.1.1
Adjust COPD Medications
X
X
X
4.1.1
COPD Exacerbation history
X
4.1.1
Adverse Events
X
X
X
X
X
X
X
X
6
HCRU
X
X
X
X
X
X
4
5.3.1.3
ePRO Training 
X
X
4
5.1.2
ePRO Dispense/Collect
Xe
X
X
X
4
BDI/TDI
X
X
X
X
X
Xd
4
5.1.2.1
Appendix F


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
39 (129)
Visita
1
Scree
ning
2
3
Randomis
ation
4
5
6
7
Early 
Discontinuatio
n/
Withdrawal 
Visit
Follow-Up 
call
For details 
see Section
Week
0
4
12
18
24
Section
Day
-28 
to -9
-11 to 
-8
1
±3 
days
±3 
days
±3 
days
±3
days
-
14 days
Post-Dose
CATf
X
X
X
X
X
X
Xd
4
5.1.2.2
Appendix B
EQ-5D-5L 
X
X
X
4
5.3.1.1
Appendix C
WPAI-GH
X
X
X
X
X
X
4
5.3.1.2
Appendix 
D
Review of ePRO
X
X
X
X
X
X
4
Training of inhalation technique 
and device cleaning 
X
X
X
X
X
X
4
Rescue medication 
Dispensing/Collection 
(dispensing via IWRS/IVRS)
X
X
X
X
X
X
X
4
7
Screening period maintenance 
treatment dispensing/collection 
(dispensing via IWRS/IVRS)
X
X
4


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Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
40 (129)
Visita
1
Scree
ning
2
3
Randomis
ation
4
5
6
7
Early 
Discontinuatio
n/
Withdrawal 
Visit
Follow-Up 
call
For details 
see Section
Week
0
4
12
18
24
Section
Day
-28 
to -9
-11 to 
-8
1
±3 
days
±3 
days
±3 
days
±3
days
-
14 days
Post-Dose
IP Dispensing/Collection
X
X
X
X
X
X
4
7
IP Administration g
X
X
X
X
X
4
Telephone contact in the 
morning of the day before a visit 
(recommended)
X
X
X
X
X
X
4
a
Sites should make every effort to maintain patients within the scheduled visit window. Patients who fall outside the visit window will be placed in the 
appropriate visit window at the next scheduled visit.
b
At all visits beyond Visit 1, note time of last dose of short-acting bronchodilator and other COPD medications (if less than approximately 6 hours, the 
visit should be rescheduled).
c
Spirometry to be performed at specific time points as specified in Table 2.
d
Spirometry, TDI, CAT, to be performed at the Early Discontinuation/Withdrawal Visit only if patient is still taking IP (last dose of IP taken on a day 
before visit or at Early Discontinuation/Withdrawal Visit).
e
At Visit 1 patient should only complete CAT questionnaire using ePRO, and leave it at the site. The ePRO device will only be dispensed at Visit 2 for 
the use at home.
f
CAT score will be used as inclusion criterion as well as endpoint.
g
After Visit 3, note time of IP intake the previous day (and consider rescheduling of the visit as outlined in Section 7.7.1.2).


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Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
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Table 2
Timed Assessments at Each Treatment Visit (Visit 3 to Visit 7)
Clinical 
Variable
Pre-dosing
Dosing
Post-dosing
For details 
see Section
Before  -60 
minutes
-60 
minutes
-30 
minutes
0 
minutes
5 
minutes
15 
minutes
30 
minutes
1 
hour
2 
hours
Review of 
ePRO
X
4
BDI/TDI
X
5.1.2.1
Appendix F
CAT
X
5.1.2.2
Appendix 
B
EQ-5D-5La
X
4,
5.3.1.1
Appendix 
C
WPAI-GH
X
5.3.1.2
Appendix 
D
HCRU 
collectionb
X
4
5.3.1.3
IP Collection
X
4
Inspiratory 
Capacity
Xc
Xc
X
X
4
Spirometry 
(FEV1 and 
FVC)
X
X
Xd
X
X
X
X
4
5.1.1


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Study Code D5970C00002
Version 2
Date 14 July 2017
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Clinical 
Variable
Pre-dosing
Dosing
Post-dosing
For details 
see Section
Before  -60 
minutes
-60 
minutes
-30 
minutes
0 
minutes
5 
minutes
15 
minutes
30 
minutes
1 
hour
2 
hours
IP 
Administration
X
4
7
BDI/TDI=Baseline Dyspnea Index/Transition Dyspnea Index; ECG=electrocardiogram; 
FEV1=forced expiratory volume in 1 second; FVC=Forced vital capacity;
Note: When data collection time points are concurrent, it is recommended that variables be collected in the following order:  BDI/TDI, CAT, EQ-5D-5L 
Questionnaire and spirometry.
a
EQ-5D-5L ONLY at Visit 3 and Visit 7 and Early Discontinuation/Withdrawal Visit
b
This is not a timed assessment.  Sites should plan to perform these activities so as not to interfere with collection of timed assessments such as 
spirometry
c
-60 and -30 min pre-dosing IC assessment ONLY at Visit 3
d
5-minute spirometry assessment post-dose ONLY at Visit 3


Clinical Study Protocol
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Study Code D5970C00002
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Date 14 July 2017
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4.1
Screening/Enrolment period
At screening, consenting patients are assessed to ensure that they meet eligibility criteria. 
Patients who do not meet these criteria must not be enrolled in the study.
The screening period will start at Visit 1 with the signature of the ICF, followed by Visit 2, 
and will end at the randomisation visit (Visit 3).
The minimum length of screening period will be 9 days (one day for Visit 2, and a minimum 
of 7 full days of ePRO assessments in the patient’s home to establish baseline data for the 
ePRO instruments); maximum will normally be 4 weeks. In certain cases, screening may be 
extended after it is agreed with the AstraZeneca study physician.
4.1.1
Visit 1 (day -28 to -9) 
The screening visit will be scheduled in the morning, preferably at a time similar to future 
study visits (as outlined in Section 4.2 and 5.1.1.2). The following assessments and processes 
will be performed during Visit 1:
∀
Obtaining signed informed consent before any study-related procedures
∀
Assignment of an E-code in IWRS/IVRS to the patient
!
Any patient signing the ICF should be recorded in IWRS/IVRS and should be 
assigned an E-code. At this point, albuterol/salbutamol MDI which will be later 
used for the post-bronchodilator spirometry assessment will be assigned as well 
as the screening period maintenance treatment.
∀
Review of medical/surgical history, demographic, COPD history (date of COPD 
diagnosis, diagnosis of chronic bronchitis or emphysema, number of COPD 
exacerbations during last year and date of last COPD exacerbation and if 
hospitalization) and smoking information (i.e., date of smoking initiation, current 
smoker or former smoker, date of smoking cessation and total-pack years)
∀
ePRO Training (for CAT questionnaire)
∀
CAT questionnaire 
!
Completed by patient in the ePRO
!
Patient will be trained how to use ePRO and will be asked to complete CAT 
questionnaire in the ePRO (ePRO device will be dispensed at Visit 2)
∀
Prior/Concomitant Medications 
!
All medications the patient is currently taking and has taken during the month 
prior to signing of the ICF should be collected


Clinical Study Protocol
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Study Code D5970C00002
Version 2
Date 14 July 2017
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∀
Physical examination including body weight (in light indoor clothes, without shoes) 
and height measurement
!
BMI will be calculated automatically by eCRF system
∀
Vital signs
!
Body temperature will be measured by an appropriate method according to 
local practice and standards. Systolic and diastolic pressure (in mmHg) and 
pulse will be measured after at least 5 minutes resting and before taking any 
blood sample and conducting any spirometry. Measurements will be carried out 
as per local practice.
∀
12-Lead ECG
!
Standard 12-lead ECG evaluations will be recorded after approximately 5 
minutes resting in supine position before any blood sampling and spirometry 
test. If the result is not available at Visit 1, it must be available by Visit 2 at the 
latest.
∀
Pregnancy Test when appropriate
!
Urine pregnancy test
∀
Clinical Laboratory Test (non-fasting)
!
Blood sampling performed in the local laboratory for haematology and 
biochemistry 
!
Urinalysis
If the result of the blood or urine sampling is not available at Visit 1, it must be 
available by Visit 2 at the latest.
∀
Chest Image or CT
!
New chest x-ray as per local practice (postero-anterior and lateral projections 
strongly recommended), or computed tomography (CT) scan should be 
obtained if chest x-ray or CT performed within the last 6 months prior to Visit 
1 is not available. If the result is not available at Visit 1, it must be available by 
Visit 2 at the latest.
∀
Training of inhalation technique and device cleaning
!
Training devices will be available at each study site for instructional purposes


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
45 (129)
∀
Spirometry
!
Post-bronchodilator forced manoeuvre test (FEV1 and FVC measurement): 
Administer 4 inhalations of inhaled albuterol/salbutamol MDI with or without a 
spacer device. After 20 to 30 minutes perform 1 set of Spirometry Forced 
manoeuvre.
∀
Review of inclusion/exclusion criteria
Only patients who meet all inclusion/exclusion criteria at this point will be allowed to 
continue (patient meets COPD definition following spirometry assessments). See Section 
4.4 for rescreening procedures.  Otherwise, screening failure will be recorded in the 
IWRS/IVRS and eCRF. When patients fulfil inclusion/exclusion criteria, the following 
will occur:
∀
Screening period maintenance treatment (ipratropium bromide MDI) and rescue 
medication (albuterol/salbutamol MDI) dispensing (as allocated earlier using 
IWRS/IVRS):
!
Adjustment of COPD Medications
!
Stop prohibited COPD medications and change COPD medications (i.e., to 
sponsor provided ipratropium bromide MDI 2 inhalations QDS and 
albuterol/salbutamol MDI PRN).
∀
Scheduling of Visit 2. Patient will be reminded to avoid the intake of ipratropium 
bromide MDI and albuterol/salbutamol MDI for at least approximately 6 hours 
before attending Visit 2, and to bring back the rescue and wash-out medications
∀
It is recommended that the time of Visit 2 is scheduled according to instructions 
outlined in Section 4.2 and Section 5.1.1.2.
4.1.2
Visit 2 (Day -11 to -8)
∀
Telephone Contact - (in the morning of day before the visit) - It is recommended 
that sites call the patient in the morning of the day before a scheduled visit to 
remind the patient of the expectations for the upcoming visit:
!
Withhold albuterol/salbutamol MDI and ipratropium bromide MDI for at least 
approximately 6 hours prior to start of the spirometry procedures
!
Follow other restrictions related to spirometry
!
Bring all study medications to the visit 
∀
Review of inclusion/exclusion criteria


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
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∀
Prior/Concomitant Medications review 
!
Confirm that no prohibited medication was taken during the washout period 
and that the appropriate withholds have been made, if required.
∀
AEs
∀
Training of inhalation technique and device cleaning
∀
Using IWRS/IVRS to register the visit. At this point, it is also possible to obtain 
albuterol/salbutamol MDI for bronchodilator responsiveness test if the patient does 
not bring their albuterol/salbutamol dispensed at Visit 1 or has used it up.
∀
Spirometry Forced manoeuvre test (FEV1 and FVC measurement): 2 sets of tests 
will be performed with an interval of approximately 30 minutes in between them.
∀
Bronchodilator responsiveness test 
!
Administer 4 inhalations of inhaled albuterol/salbutamol MDI with or without a 
spacer device 30 ± 15 minutes after previous spirometry test. After waiting 
another 20 to 30 minutes, perform again 1 set of Spirometry Forced manoeuvre.
∀
ePRO will be dispensed
!
Patient should be trained how to use ePRO and reminded to complete it every 
morning and evening until day of Visit 3. Any rescue medication use should 
also be recorded in the ePRO.
∀
Scheduling of Visit 3. Patient will be reminded to avoid the intake of 
albuterol/salbutamol MDI and ipratropium bromide MDI for at least approximately 
6 hours before attending Visit 3, and to bring back the rescue and wash-out 
medications
∀
It is important that the time of Visit 3 is scheduled according to instructions 
outlined in Section 4.2 and Section 5.1.1.2
4.2
Treatment period
4.2.1
Visit 3, Randomisation Visit (Day 1)
The following assessments will be performed pre-randomisation and pre-morning IP dose:
∀
Telephone Contact (in the morning of day before the visit) - It is recommended that 
sites call the patient in the morning of the day before a scheduled visit to remind the 
patient of the expectations for the upcoming visit:


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
47 (129)
!
Withhold albuterol/salbutamol MDI and ipratropium bromide MDI for at least 
approximately 6 hours prior to start of the spirometry procedures
!
Follow other restrictions related to spirometry
!
Bring all study medications and ePRO to the visit 
A
Pre-dose assessments: 
∀
Review of ePRO
!
Review of ePRO should be performed by site personnel before the visit
!
Check compliance with the ePRO (a minimum of 70% of entries of the 
morning questionnaires is required for eligibility, i.e. at least 5 out of the 7 days 
before randomisation) 
∀
Before proceeding with any visit procedures, patient should be asked if pre-visit 
restrictions have been followed
!
Check appropriate medication wash-outs before visit (at least 6h since last 
intake of ipratropium bromide MDI and albuterol/salbutamol MDI).
∀
BDI 
!
BDI interview should be completed in the ePRO by a trained interviewer 
unaware of current status of the patients based on other assessments. . BDI/TDI 
should be collected first, followed immediately by the CAT, EQ-5D-5L and 
WPAI-GH Questionnaire. The BDI, CAT, EQ-5D-5L and WPAI-GH 
Questionnaire should be completed prior to any other visit procedures.
∀
CAT questionnaire 
!
Completed by patient in the ePRO
∀
EQ-5D-5L Questionnaire
!
Completed by patient in the ePRO
∀
WPAI-GH questionnaire
!
Completed by patient in the ePRO
∀
Pregnancy Test when appropriate
!
Urine pregnancy test


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
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∀
AEs
∀
Prior/Concomitant Medications 
∀
HCRU, including exacerbations of COPD
!
Completed by the Investigator 
∀
Confirmation of inclusion/exclusion criteria
∀
Training of inhalation technique and device cleaning
!
The technique for inhalation from an MDI (GFF) is different from the 
technique used with a DPI (UV). It is important to ensure that patients 
apply correct inhalation technique for both types of inhalers. Training 
devices will be available at each study site for instructional purposes.
∀
Spirometry 
!
Spirometry (slow manoeuvre for IC assessment followed by forced manoeuvre 
for FEV1 and FVC): 2 sets will be performed during the hour preceding the 
scheduled morning IP dose (-60 minutes and -30 minutes), allowing 30 min 
between them. 
!
If the average of the -60 and -30 minute FEV1 is >20% or >200 ml different 
from the average of the same pre-dose FEV1 assessments at visit 2, the 
investigator will be alerted to contact the study physician for a discussion about 
patient eligibility.
Only patients who meet all inclusion/exclusion criteria at this point will be 
allowed to continue. See Section 4.4 for re-screening procedures. Otherwise the 
screening failure will be recorded in the IWRS/IVRS and eCRF. Note: it is 
advised to allow enough time for the randomisation call in IWRS to be ready 
with the assigned kit numbers before the IP needs administration, as shown 
below.
When patient fulfils inclusion/exclusion criteria, the following assessments will be 
performed:
B
Randomisation 
∀
Randomise the patient via IWRS/IVRS, and obtain kits number assignment. 
Document the randomisation date on the medical notes. Stratification factors 
entered into IWRS/IVRS should be consistent with prior medications recorded at 
screening.


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
49 (129)
C
Morning IP administration
∀
Dispense the kit numbers assigned by IWRS/IVRS and record the kits numbers 
dispensed on the medical records
∀
IP Administration
!
Dosing of IP in the clinic should be planned to occur at approximately the same 
time the patient prefers to administer IP in the mornings between the visits. The 
patient should then be advised that subsequent morning IP administration 
should happen at approximately this time, and that evening dosing should occur 
as close as possible to 12 hours from this. It is recommended that dosing in the 
clinic occurs before approximately 10:00 AM. If it is unavoidable that IP 
administration in the clinic is at a later time of day than the patient normally 
administers IP at home (for example due to the travelling time to site), then 
patients should be strongly advised that on the day prior to the next clinic visit,
the time of IP administration should be adjusted to be approximately 24 hours 
and 12 hours prior to the planned dosing at the clinic. Sites should make every 
effort to ensure that dosing in the clinic occurs as close as possible to 24 
and 12 hours after the patient’s IP intake the previous day.
!
IP is administered by inhalation of 2 inhalations from the GFF/placebo inhaler 
followed by 1 inhalation from the UV /placebo inhaler. Site personnel should 
check that the patient uses the inhalers correctly.
!
Record the date and time of the IP administration in the medical notes and in 
the spirometry equipment, Masterscope®CT. In clinic dosing time is recorded 
as the time of the second inhalation.
D
Post-dose assessments
∀
Post-dose spirometry:
∀
FEV1 and FVC at +5 min, +15 min, +30 min, +1h and +2h
∀
IC at +1h and +2h. The slow manoeuvre for IC assessment is always 
conducted prior to the forced manoeuvre for FEV1 and FVC.
!
Spirometry assessments need to be conducted within specific time windows 
relative to each of the timed assessments. Details will be available in the 
spirometer software/instructions.
The following procedures will be performed at any time after post-morning IP dose:
∀
Dispense IP kits to the patient


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
50 (129)
∀
Remind the patient to inhale 2 inhalations from the GFF/placebo inhaler and 1 
inhalation from the UV/placebo inhaler every morning and 2 inhalations from the 
GFF/placebo inhaler every evening until the last evening before next visit. Remind 
the patient to use the GFF/placebo device right before the UV/placebo device, and 
to come to next visit with the medication kits to assess the drug accountability. 
∀
Rescue medication (albuterol/salbutamol MDI) will be dispensed, using 
IWRS/IVRS
!
Containers dispensed during the Visit 1 should be collected and new rescue 
medication (albuterol/salbutamol MDI) should be dispensed
∀
The patient will be reminded to record in the ePRO:
∀
IP administration during the visit
∀
NiSCI and EMSCI: every morning, preferably between 7 AM and 11 
AM and approximately 1 hour or later after taking IP. The NiSCI 
and EMSCI will not be recorded on Visit days
∀
IP administration every morning and evening
∀
Rescue medications use every morning and evening
∀
Next protocol visit will be scheduled according to instructions above and in Section 
5.1.1.2. Patient will be reminded to hold the morning IP dose that day, avoid the 
intake of rescue medication for at least approximately 6 hours before attending the 
next visit, and to bring the IP kits, rescue medication inhaler and ePRO to the clinic. 
The patient should be strongly advised to take morning and evening IP doses on the 
day prior to a clinic visit at approximately 24 and 12 hours prior to the anticipated 
time of dosing in the clinic. (For example at 9am and 9pm on the day prior to a 
clinic visit if they are expected to be dosed at 9am in the clinic). 
4.2.2
Visit 4 – Visit 6 (Week 4, Week 12, Week 18 ±3 days)  
The following assessments will be performed:
∀
Telephone Contact (in the morning of day before the visit) - It is recommended that 
sites call the patient in the morning of the day before a scheduled visit to remind the 
patient of the expectations for the upcoming visit:
!
Take morning and evening IP doses approximately 24 and 12 hours prior 
to the anticipated time of dosing in the clinic. (For example at 9am and 9pm 
on the day prior to a clinic visit if they are expected to be dosed at 9am in the 
clinic).
!
Withhold IP dosing the morning of the scheduled visit


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
51 (129)
!
Withhold rescue albuterol/salbutamol MDI  for at least approximately 6 hours 
prior to start of the spirometry procedures
!
Follow other restrictions related to spirometry
!
Bring all study medications and ePRO to the visit 
A
Pre-dose assessments
∀
Before proceeding with any visit procedures, the dosing of IP on the day prior to the 
visit should be reviewed in the patient’s ePRO, and the patient should be asked if 
pre-visit restrictions have been followed.
!
Check IP dosing the previous day as well as time interval since last IP intake 
(within approximately 12±1 hours and approximately 24±1 hours before the 
planned dosing at the visit, and no IP intake the same morning)
!
Check appropriate rescue medication wash-out (at least 6h since last intake)
∀
TDI 
!
TDI interview should be completed in the ePRO by a trained interviewer 
unaware of current status of the patients based on other assessments.  TDI 
should be collected first, followed immediately by the CAT and WPAI-GH 
Questionnaire. The TDI, CAT and WPAI-GH Questionnaire should be 
completed prior to any other visit procedures.
∀
CAT questionnaire 
!
Completed by patient in the ePRO
∀
WPAI-GH questionnaire 
!
Completed by patient in the ePRO
∀
HCRU, including exacerbations of COPD 
!
Completed by the Investigator 
∀
AEs
∀
Concomitant medication review since last visit
∀
Site personnel should collect empty containers 
∀
Site personnel should check IP compliance and retrain patient if required


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
52 (129)
∀
Re-training of inhalation technique and device cleaning 
!
The technique for inhalation from an MDI (GFF) is different from the 
technique used with a DPI (UV). It is important to ensure that patients 
apply correct inhalation technique for both types of inhalers. Training 
devices will be available at each study site for instructional purposes.
∀
Spirometry (forced manoeuvre for FEV1 and FVC): 2 sets will be performed during 
the hour preceding the scheduled morning IP dose (-60 minutes and -30 minutes), 
allowing 30 min between them. While spirometry assessments should be performed 
within approximately ±1 hour of the time of the spirometry assessments on Visit 3 
(randomisation), priority should be given to the dosing of IP approximately 24 and 
12 hours after the patient’s IP intake the previous day.
∀
Urine pregnancy test – only at Visit 5/week 12
B
Morning IP administration
∀
Dispense the kit numbers assigned by IWRS/IVRS and record the kits numbers 
dispensed on the medical records
∀
IP Administration
!
Dispense new IP kits (assigned by IWRS/IVRS) to the patient 
!
Administration of the IPs (new kits assigned) at approximately the same time as 
Visit 3. It is recommended that dosing occurs before approximately 10:00 AM. 
Patients should be strongly advised that on the day prior to the visit, IP should 
be administered approximately 24 hours and 12 hours prior to the planned 
dosing in the clinic. Sites should make every effort to ensure that dosing in 
the clinic occurs as close as possible to 24 and 12 hours after the patient’s 
IP intake the previous day. If it is not possible to keep these time intervals 
within approximately 24 ±1 hours and 12 ±1 hours, it is strongly recommended 
that the visit is rescheduled. If any IP intake the previous day was missed, or if 
IP was not taken as directed, rescheduling of the visit is required (see Section 
7.7.1.2).
!
IP is administered by 2 inhalations from the GFF/placebo inhaler and 1 
inhalation from the UV/placebo inhaler. The site personnel should check that 
the patient uses the inhalers correctly.
!
Record the date and time of the IP administration in the medical notes and in 
the spirometry equipment, Masterscope CT. In clinic dosing time is recorded as 
the time of the second inhalation.
C
Post-dose assessments


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
53 (129)
∀
Post-dose spirometry: 
∀
FEV1 and FVC at +15 min, +30 min, +1h, and +2h.
∀
IC at + 1h and + 2h. The slow manoeuvre for IC assessment is 
always performed prior to the forced manoeuvre for FEV1 and FVC.
!
Spirometry assessments need to be conducted within specific time windows 
relative to each of the timed assessments. Details will be available in the 
spirometer software/instructions.
The following procedures will be performed at any time after post-morning IP dose:
∀
Remind the patient to inhale 2 inhalations from the GFF/placebo inhaler and 1 
inhalation from the UV /placebo inhaler every morning and 2 inhalations from the 
GFF/placebo inhaler every evening until the last evening before next visit. Remind 
the patient to use the GFF/placebo device right before the UV /placebo DPI device, 
and to come to next visit with the medication kits to assess the drug accountability
∀
Rescue medication (albuterol/salbutamol MDI) will be dispensed, using 
IWRS/IVRS
!
Containers dispensed during the previous visit should be collected and new 
rescue medication (albuterol/salbutamol MDI) should be dispensed
∀
The patient will be reminded to record in the ePRO:
∀
IP administration during the visit
∀
NiSCI and EMSCI: every morning, preferably between 7 AM and 11 
AM, and approximately 1 hour or later after taking IP. The NiSCI 
and EMSCI will not be recorded on Visit days
∀
IP administration every morning and evening
∀
Rescue medications use every morning and evening
∀
Next protocol visit will be scheduled. The start of Visits 4-7 should be scheduled 
according to instructions above and in Section 5.1.1.2. Patient will be reminded to 
hold the morning IP dose that day, avoid the intake of rescue medication for at least 
approximately 6 hours before attending the next visit, and to bring the IP kits, 
rescue medication inhaler and ePRO to the clinic. The patient should be strongly 
advised to take morning and evening IP doses on the day prior to a clinic visit 
approximately 24 and 12 hours prior to the anticipated time of dosing in the clinic. 
(For example at 9am and 9pm on the day prior to a clinic visit if they are expected 
to be dosed at 9am in the clinic). 


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
54 (129)
4.2.3
Visit 7 (Week 24 ±3days)  
The following assessments will be performed:
∀
Telephone Contact (in the morning of day before the visit) - It is recommended that 
sites call the patient in the morning of the day before a scheduled visit to remind the 
patient of the expectations for the upcoming visit:
!
Take morning and evening IP doses approximately 24 and 12 hours prior 
to the anticipated time of dosing in the clinic. (For example at 9am and 9pm 
on the day prior to a clinic visit if they are expected to be dosed at 9am in the 
clinic).
!
Withhold IP dosing the morning of the scheduled visit
!
Withhold rescue albuterol/salbutamol MDI  for at least approximately 6 hours 
prior to start of the spirometry procedures
!
Follow other restrictions related to spirometry 
!
Bring all study medications and ePRO to the visit 
A
Pre-dose assessments
∀
Before proceeding with any visit procedures, the dosing of IP on the day prior to the 
visit should be reviewed in the patient’s ePRO, and the patient should be asked if 
pre-visit restrictions have been followed.
!
Check IP dosing the previous day as well as time interval since last IP intake
(within approximately 12±1 hours and approximately 24±1 hours before the 
planned dosing at the visit, and no IP intake the same morning)
!
Check appropriate rescue medication wash-out (at least 6h since last intake)
∀
TDI 
!
TDI interview should be completed in the ePRO by a trained interviewer 
unaware of current status of the patients based on other assessments. TDI 
should be collected first, followed immediately by the CAT, EQ-5D-5L and 
WPAI-GH Questionnaire. The TDI, CAT, EQ-5D-5L and WPAI-GH 
Questionnaire should be completed prior to any other visit procedures.
∀
CAT questionnaire 
!
Completed by patient in the ePRO
∀
EQ-5D-5L Questionnaire 


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
55 (129)
!
Completed by patient in the ePRO
∀
WPAI-GH 
!
Completed by patient in the ePRO
∀
HCRU, including exacerbations of COPD 
!
Completed by the Investigator 
∀
AEs
∀
Concomitant medication review since last visit
∀
Site personnel should check IP compliance 
∀
Spirometry (forced manoeuvre for FEV1 and FVC): 2 sets will be performed during 
the hour preceding the scheduled morning IP dose (-60 minutes and -30 minutes), 
allowing 30 min between them. While spirometry assessments should be performed 
within approximately ±1 hour of the time of the spirometry assessments on Visit 3 
(randomisation), priority should be given to the dosing of IP approximately 24 and 
12 hours after the patient’s IP intake the previous day. 
∀
Urine pregnancy test 
B
Morning IP administration
∀
IP Administration – using kits assigned on the previous visit - Visit 6 Week 18
!
Administration of the IPs at approximately the same time as Visit 3. Sites 
should make every effort to ensure that dosing occurs before approximately 
10:00 AM. It is recommended that dosing occurs before approximately 10:00 
AM. Patients should be strongly advised that on the day prior to the visit, IP 
should be administered approximately 24 hours and 12 hours prior to the 
planned dosing in the clinic. Sites should make every effort to ensure that 
dosing in the clinic occurs as close as possible to 24 and 12 hours after the 
patient’s IP intake the previous day. If it is not possible to keep these time 
intervals within approximately 24 ±1 hours and 12 ±1 hours, it is strongly 
recommended that the visit is rescheduled. If any IP intake the previous day 
was missed, or if IP was not taken as directed, rescheduling of the visit is 
required (see Section 7.7.1.2).
!
IP is administered by 2 inhalations from the GFF/placebo inhaler and 1 
inhalation from the UV/placebo inhaler. The site personnel should check that 
the patient correctly uses the inhalers. 


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
56 (129)
!
Record the date and time of the IP administration in the medical notes and in 
the spirometry equipment, Masterscope CT. In clinic dosing time is recorded as 
the time of the second inhalation.
C
Post-dose assessments
∀
Post-dose spirometry:
∀
FEV1 and FVC at +15 min, +30 min, +1h, and +2h.
∀
IC at + 1h and + 2h. The slow manoeuvre for IC assessment is 
always performed prior to the forced manoeuvre for FEV1 and FVC.
!
Spirometry assessments need to be conducted within specific time windows 
relative to each of the timed assessments. Details will be available in the 
spirometer software/instructions.
The following procedures will be performed at any time after post-morning IP dose:
∀
Site personnel should collect empty containers
∀
Retrieval of rescue medication
∀
Patient will be instructed by study personnel to resume the COPD medication taken 
before study start, or any other appropriate inhaled maintenance for COPD 
according to medical judgement. Consideration should be given to maintaining 
patients on at least double therapy, while ensuring appropriate follow-up and further 
evaluation of the prescribed treatment. 
∀
The ePRO will be collected after the patient has recorded the IP administration at 
the visit.
∀
IWRS/IVRS Completion call should be recorded in the system
4.2.4
Early Discontinuation/Withdrawal Visit  
∀
Before proceeding with any visit procedures, the dosing of IP on the day prior to the 
visit should be reviewed in the patient’s ePRO, and the patient should be asked if 
pre-visit restrictions have been followed.
!
Check IP dosing the previous day as well as time interval since last IP intake 
(within approximately 12±1 hours and approximately 24±1 hours before the 
planned dosing at the visit, and no IP intake the same morning)
!
Check appropriate rescue medication wash-out (at least 6h since last intake)


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
57 (129)
If IP has already been discontinued and was not administered according to protocol on the day 
before the visit, the following assessments will not be performed at the early discontinuation 
visit:
!
TDI
!
CAT Questionnaire
!
Spirometry 
With the above exceptions, the following procedures will be performed:
∀
TDI
!
TDI interview should be completed in the ePRO by a trained interviewer 
unaware of current status of the patients based on other assessments. TDI 
should be collected first, followed immediately by the CAT and EQ-5D-5L 
Questionnaire. The TDI, CAT and EQ-5D-5L Questionnaire and WPAI-GH 
Questionnaire should be completed prior to any other visit procedures.
∀
CAT Questionnaire
∀
EQ-5D-5L Questionnaire
∀
WPAI-GH 
!
Completed by patient in the ePRO
∀
HCRU, including exacerbations of COPD 
!
Completed by the Investigator 
∀
AEs
∀
Concomitant medication review since last visit
∀
Urine pregnancy test (when appropriate)
∀
Spirometry 
If last dose of IP was taken on the day before the Visit (evening dose):
!
Spirometry (forced manoeuvre for FEV1 and FVC): 2 sets will be performed. 
If last dose of IP will be taken at Early Discontinuation/Withdrawal Visit: 


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
58 (129)
!
Spirometry (forced manoeuvre for FEV1 and FVC): 2 sets will be performed 
during the hour preceding the scheduled morning IP dose (-60 minutes and -30 
minutes), allowing 30 min between them. While spirometry assessments should 
be performed within approximately ±1 hour of the time of the spirometry 
assessments on Visit 3 (randomisation), priority should be given to the dosing 
of IP approximately 24 and 12 hours after the patient’s IP intake the previous 
day. 
!
Administration of the IPs (using kits assigned on the previous visit) at 
approximately the same time as Visit 3. It is recommended that dosing occurs 
before approximately 10:00 AM. Patients should be strongly advised that on 
the day prior to the visit, IP should be administered approximately 24 hours and 
12 hours prior to the planned dosing in the clinic. Sites should make every 
effort to ensure that dosing in the clinic occurs as close as possible to 24 
and 12 hours after the patient’s IP intake the previous day.
!
IP is administered by 2 inhalations from the GFF/placebo inhaler and 1 
inhalation from the UV/placebo inhaler. The site personnel should check that 
the patient correctly uses the inhalers. 
!
Record the date and time of the IP administration in the medical notes and in 
the spirometry equipment, Masterscope CT. In clinic dosing time is recorded as 
the time of the second inhalation.
!
Post-dose spirometry:
o
FEV1 and FVC at +15 min, +30 min, +1h, and +2h.
o
IC at + 1h and + 2h. The slow manoeuvre for IC assessment is always 
performed prior to the forced manoeuvre for FEV1 and FVC.
o
Spirometry assessments need to be conducted within specific time windows 
relative to each of the timed assessments. Details will be available in the 
spirometer software/instructions.
∀
The ePRO will be collected after the patient has recorded the IP administration at 
the visit
∀
Site personnel should collect empty containers
∀
Site personnel should check IP compliance 
∀
Retrieval of rescue medication
∀
Patient will be instructed by study personnel to resume the COPD medication taken 
before study start, or any other appropriate inhaled maintenance for COPD 


Clinical Study Protocol
Drug Substance Glycopyrronium/Formoterol Fumarate
Study Code D5970C00002
Version 2
Date 14 July 2017
59 (129)
according to medical judgement. Consideration should be given to maintaining 
patients on at least double therapy, while ensuring appropriate follow-up and further 
evaluation of the prescribed treatment.
∀
IWRS/IVRS Withdrawal call should be recorded in the system
4.3
Follow-up period
4.3.1
Follow-up call
A follow-up call should be performed approximately 14 days after last IP dose intake for 
patients completing the treatment or discontinuing IP prematurely, in order to assess new or 
ongoing AE (as well as any concomitant medication administered to treat the mentioned AE) 
and COPD exacerbations. IWRS/IVRS Follow-up call “Study completion” should be recorded 
in the system. Follow-up call will not be performed if Early Discontinuation/Withdrawal visit 
was done 14 or more days since the last dose of IP. 
4.4
Rescreening and rescheduling of visits.
4.4.1
Rescreening  
Patients with an event, such as a COPD exacerbation or pneumonia, occurring within the 
exclusion criteria specified time requirements prior to Visit 1, should not be screened; if this is 
done in error, these patients should be screen failed. Patients who experience an event during 
the screening period, which is specified in the exclusion criteria, should also be screen failed. 
Screen-failed patients may be re-screened observing timelines described in the exclusion 
criteria. 
Other instances where rescreening is being considered should be discussed with the AZ study 
physician.
Re-screening is only allowed once per patient.
If a patient is re-screened, a new informed consent form is to be signed, and re-screening Visit 
1 procedures must be initiated within 3 working days from the date of the new ICF. 
Rescreened patient keeps an originally assigned enrolment number.
4.4.2
Rescheduling of visits
Rescheduling of a visit will be allowed within the specified visit window for reasons such as 
incorrect dosing/time of dosing of IP the day prior to a visit, intake of disallowed medication 
or other disallowed events related to spirometry, or technical issues with spirometry or ePRO. 
If rescheduling is not possible within the specified visit window, the rescheduled visit should 
occur as soon as possible. If a visit needs to be rescheduled, no assessments will be performed, 
or if already partly done they will need to be repeated at the rescheduled visit. An important 
note regarding spirometry: during screening, for the spirometer technical reasons, each visit 
can be rescheduled only once and only if spirometry was not yet started at the original visit. 


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During treatment, spirometry cannot be repeated when rescheduled using the same visit, and 
then an unscheduled visit would need to be used.
5.
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling. The Investigator will ensure that data are recorded on the electronic Case 
Report Forms as specified in the Clinical Study Protocol and in accordance with the 
instructions provided.
The Investigator will ensure the accuracy, completeness and timeliness of the data recorded as 
well as provision of answers to data queries according to the Clinical Study Agreement. The 
Investigator will sign the completed electronic Case Report Forms. A copy of the completed 
electronic Case Report Forms will be archived at the study site.
5.1
Efficacy assessments
5.1.1
Spirometry Assessments at Clinic Visits
5.1.1.1
General requirements
Lung function (IC, FEV1 and FVC) will be measured by spirometry using equipment provided 
by a central vendor. Spirometry will be performed by the Investigator or authorized delegate 
according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines 
(Miller et al 2005).
The central spirometry vendor is responsible for assuring that the spirometer meets ATS/ERS 
recommendations and that the study site personnel who will be performing the testing are 
properly certified. Spirometry calibration will be detailed in a separate spirometry procedures 
manual.
Important! 
Patients should be instructed not to use their IP in the morning before site visits, as this 
will affect the spirometry results; IP will be taken at the site. For the same reason 
patients should not use their rescue albuterol/salbutamol MDI or their screening period 
ipratropium bromide MDI within approximately 6 hours of a scheduled site visit 
spirometry.
Options for handling patients who have inadvertently taken their COPD medication within the 
restricted window are described in Section 7.7.1.2. 
N.B. There are no restrictions regarding medications taken prior to Visit 1, as spirometry at 
this visit will only measure lung function values following maximal bronchodilation.


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5.1.1.2
Time of day for scheduled site visit spirometry
Spirometry testing should be done according to the schedule provided in Table 1 and Table 2. 
It is recommended to start spirometry testing in the morning between 6 and 9AM.  Following 
randomisation, the spirometry assessment should be performed within approximately ±1 hour 
of the time at which spirometry was tested on Visit 3 (Randomisation).  It is understood that 
this will not always be possible for patients or Investigators. The priority should be given to 
dosing of IP approximately 12 hours after the evening dose and 24 hours after the morning 
dose of IP, and to start spirometry approximately 60 minutes before these timepoints. 
The time for the spirometry assessments depends on the time chosen for IP administration, 
which should be planned to occur at approximately the same time the patient prefers to 
administer IP in the mornings between the visits (for further details on the timing of IP 
administration, please see Section 4.2). For example, if the patient prefers to administer IP at 9 
AM (and 9 PM), then the pre-dose randomisation spirometry would be planned to start at 8 
AM (so as to be 60 minutes prior to IP dosing), and all subsequent pre-dose spirometry testing 
should be initiated between 7 AM and 9 AM. 
5.1.1.3
Spirometry technique
Patients should avoid engaging in strenuous exertion for at least 30 minutes prior to 
spirometry measurements. Patients should also avoid eating a large meal for at least 2 hours 
prior to spirometry measurements. Smoking should be avoided for at least 1 hour, and 
consuming alcohol for 4 hours. 
For information about the slow manoeuvre technique used for IC assessment, please see 
Section 5.1.1.5.
Forced expiratory manoeuvres should be performed with the patient seated in an upright 
position. If this is not comfortable for the patient, standing is permitted. The same position 
should be used by the patient for each forced expiratory manoeuvre from enrolment 
throughout the study. The head must not be tilted during manoeuvres and the thorax should be 
able to move freely; hence tight clothing should be loosened. A nose-clip should be used for 
the manoeuvre. The patient from enrolment throughout the study should use mouthpieces of 
the same dimension and shape.
The forced expiratory manoeuvre (FEV1 and FVC) should start with a maximal inspiration 
and then followed by a fast and forceful expiration that should last for at least 6 seconds. It is 
important to encourage the patient to continue the expiration to be fast and forceful throughout 
the manoeuvre. Ensure that none of the following has occurred: coughing during the first 
second, glottis closure, leak or obstruction of the mouthpiece (by the tongue).
Multiple forced expiratory efforts (at least 3 but no more than 8) will be performed for each 
site spirometry session. An adequate test should consist of three acceptable manoeuvers. The 
best effort that meets the ATS/ERS acceptability and reproducibility criteria (Miller et al 
2005) will be recorded. The best efforts will be based on the highest FEV1.


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The absolute measurement (for FEV1 and FVC), and the percentage of predicted normal value 
(Quanjer et al 2012) will be recorded. The highest FVC will also be reported regardless of the 
effort in which it occurred (even if the effort did not result in the highest FEV1).
5.1.1.4
Post-bronchodilator spirometry
Post-BD spirometry following maximal bronchodilation will be performed at Visit 1 (with no 
pre-BD spirometry) to confirm COPD diagnosis and disease severity, and at Visit 2 (after pre-
BD spirometry) to assess BD responsiveness.  
Maximal bronchodilation will be induced using 4 inhalations of albuterol (90 μg metered 
dose) or salbutamol (100 μg metered dose) with or without a spacer device. At visit 2, this will 
occur within 30 minutes ± 15 minutes of the final pre-BD spirometry measurement. Post-BD 
spirometry will be performed 20-30 minutes after administration of albuterol/salbutamol MDI. 
If a patient cannot tolerate 4 inhalations of beta agonist, a lower number of inhalations may be 
considered at the Investigator’s clinical judgment (minimum 2 inhalations). BD 
responsiveness at Visit 2 will be a comparison of the average of the best FEV1 effort obtained 
at 60 minute and 30 minute pre-BD to the best FEV1 effort obtained at 20-30 minutes post-
BD. 
5.1.1.5
Inspiratory Capacity
IC assessments will be conducted at Visits 3-7. Pre-dose assessments will be at 60 minutes 
and 30 minutes prior to IP administration at Visit 3 only. Post-dose assessments will be 1 and 
2 hours after administration of IP. The average of the two pre-dose assessments at Visit 3 will 
be used to establish the baseline IC. IC assessments are always performed prior to any other 
spirometry assessments.
All patients will be instructed on the performance of the slow manoeuvre technique used for 
IC assessment. Patients must be tested in the seated position wearing a nose clip with no air 
leaks between the mouth and mouthpiece. Patients should be relaxed with shoulders down and 
asked to breathe regularly for several breaths until the end-expiratory lung volume is stable 
(this usually requires at least five tidal manoeuvres). They are then urged to take a deep breath 
to total lung capacity with no hesitation. At least three acceptable manoeuvers should be 
performed. Reporting will be done as per ATS/ERS guidelines (Miller et al 2005).
5.1.1.6
Record keeping
A signed and dated copy of the pre- and post- BD printout must be kept at the study site for 
source data verification. The printout must be marked with the study code, enrolment code, 
date and time of measurement, visit number.
5.1.1.7
Spirometry references
The Global Lung Function Initiative (GLI) equations will be used to determine the patients 
predicted normal (PN) values and will be pre-programmed into the spirometer (Quanjer et al 
2012).


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FEV1 expressed as percent of the PN value will be calculated as follows: FEV1% of PN = 
FEV1 measured/ FEV1PN x 100.
5.1.2
Patient Reported Outcomes
Patients will complete PRO assessments at the study site and at home using a handheld 
electronic device (ePRO). PRO assessments must be collected in a systematic way to ensure 
data integrity. The following best practice guidelines should be followed when collecting PRO 
data at the site or at home via an ePRO device:
For PRO instruments administered during site visits using ePRO device
∀
Administer before other procedures
!
Always administer PRO instruments before other study procedures. For details 
how to activate them, refer to the ePRO materials.
∀
Provide the right environment
!
Provide a quiet and private location to complete the instrument.
∀
No right or wrong answers
!
Remind patients that there are no right or wrong answers and that we are asking 
them to complete these questionnaires because we’re interested in hearing 
directly from them on how they feel.
∀
Help with procedural questions
!
Make sure the patient understands how to complete the instrument. Instrument 
instructions are usually self-explanatory but staff may answer questions about 
procedural issues like what it means to “tick a box”.
∀
Avoid bias: do not clarify the meaning of questions or responses
!
Sometimes patients will ask site staff to clarify the meaning of a question or 
response. To avoid introducing any bias, politely tell the patient that you cannot 
clarify items. Remind them that there are no right or wrong answers. Tell them 
that they should select the response that best answers the question as they 
understand it.
∀
No time limits. Although most instruments require only a few minutes to complete 
the patient should be given as much time as is needed.
∀
Review for completeness


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!
Prompt review of the questionnaire for completeness will minimize missing 
data and data queries. 
For PRO instruments captured at home using an ePRO device.
∀
Guidelines similar to PRO completion at the visits
!
Same principles apply for ePRO for home based assessments as assessment at 
site. Remind patients that there are no right or wrong answers, avoid bias by not 
clarifying items, remind patients that they should complete the ePRO questions 
in a quiet and private location without help from others.
∀
Train the patient on ePRO device usage
!
Train the patient on how to use the ePRO device using the materials and 
training provided by the ePRO vendor.
!
Provide guidance on whom the patient should call if they have problems
∀
Monitor compliance
!
Minimizing missing data is a key aspect of study success. Compliance must be 
checked at each study visit and should be checked more frequently to identify 
problems early. If compliance drops below 80% a check-in call from the site to 
ask the patient if they are having difficulties is highly recommended. 
5.1.2.1
Baseline/Transitional Dyspnea Index (BDI/TDI)
The BDI/TDI is an instrument developed to provide a multidimensional measure of dyspnea 
in relation to activities of daily living (Mahler et al 1984). The Baseline Dyspnea Index (BDI) 
provides a measure of dyspnea at a single state, the baseline, and the Transitional Dyspnea 
Index (TDI) evaluates changes in dyspnea from the baseline state. The instrument consists of 
three components: functional impairment, magnitude of task, and magnitude of effort. For the 
BDI, each of these three components are rated in five grades from 0 (severe) to 4 
(unimpaired), and are summed to form a baseline total score from 0 to 12. For the TDI, 
changes in dyspnea are rated for each component by seven grades from -3 (major 
deterioration) to +3 (major improvement), and are added to form a total TDI score from -9 to 
+9. Positive scores indicate an improvement, and a change from the BDI or a difference 
between treatments of 1 point has been estimated to constitute the minimum clinically 
important difference (MCID) (Mahler et al 2005).
The BDI/TDI is completed by a trained interviewer, who asks the respondent various 
questions as part of a medical history, and selects a grade (score) using specific criteria for 
each of the three components. The same interviewer will complete the BDI and the TDI for an 
individual patient. The questionnaires should be completed in a quiet area, and the patient 
should be allowed to ask questions. Site personnel should take care not to influence the 
patient’s responses.  The interviewer must be blinded to other assessments evaluated for the 


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patient.  BDI/TDI will be recorded in the ePRO, provided by the ePRO vendor in relevant 
local language. BDI will be completed at Visit 3, and TDI at Visit 4, Visit 5, Visit 6, Visit 7 
and Early Discontinuation/Withdrawal Visit (except in those cases when the IP has already 
been discontinued and not used according to protocol on the day before the visit).
5.1.2.2
COPD Assessment Test (CAT)
The CAT is an 8-item PRO developed to measure the impact of COPD on health status (Jones 
et al 2009). The instrument uses semantic differential six-point response scales which are 
defined by contrasting adjectives to capture the impact of COPD. Content includes items 
related to cough, phlegm, chest tightness, breathlessness going up hills/stairs, activity 
limitation at home, confidence leaving home, sleep and energy. A CAT total score is the sum 
of item responses. Scores range from 0-40 with higher scores indicative of greater COPD 
impact on health status. CAT will be recorded by the patient in the ePRO, provided by the 
ePRO vendor in relevant local language, at Visit 1, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7 and 
Early Discontinuation/Withdrawal Visit (except in those cases when the IP has already been 
discontinued and not used according to protocol on the day before the visit).
5.1.2.3
Night-time and Early morning symptoms of COPD instrument (NiSCI and 
EMSCI)
The questionnaire is made up of two parts. The first part covering “last night” symptoms (time 
elapsed from the time patient went to bed until woke up and got out of bed to start his/her day) 
and the second part covering “this morning” symptoms (time elapsed since patient got out of 
bed to start the day).
The EMSCI was developed to collect data about the frequency and severity of early morning 
symptoms and the impact of COPD symptoms on early morning activity in patients with 
COPD.
The NiSCI was developed to collect data about the frequency and severity of night-time 
symptoms and the impact of COPD symptoms on night-time awakenings in patients with 
COPD.
The data collected can be used to generate the following scores:
1.
The six-Item Symptom Severity score is derived by averaging the responses from a 
patient on the six item-level symptom scores and can be used to quantify the 
severity of early morning and night-time symptoms. 
2.
The Overall COPD Symptom Severity score is comprised of a single item asking 
about overall COPD symptom severity in the early morning and at night. 
3.
The Early Morning Activity score obtains information on the reduction in early 
morning activity limitation due to COPD symptoms. The Night-time Awakenings 
score can be used to obtain information on the number (or proportion) of days 
without night-time awakening due to COPD symptoms.


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The NiSCI and EMSCI (see Appendix E) will be recorded by the patient in the ePRO, 
provided by the ePRO vendor in relevant local language, every morning approximately 
between 7 AM and 11 AM, preferably approximately 1 hour or later after taking IP. The 
questionnaire will be collected from the day after Visit 2 (Screening) and up to Visit 7. The 
NiSCI and EMSCI will not be recorded on Visit days.
5.1.3
Investigational Product Use
Administration of IP taken will be recorded by the patient in the ePRO twice daily (morning 
and evening), from Visit 3 to the end of the study.
5.1.4
Rescue Medication Use
The number of inhalations of rescue medication taken will be recorded by the patient in the 
ePRO twice daily (morning and evening), from Visit 2 to the end of the study. Patients will 
report nighttime use (since last evening when completing the ePRO) in the morning, and 
daytime use in the evening.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at Visit 1. Fasting is not required. If the result is not available at Visit 1, it must 
be available by Visit 2 at the latest.
The clinical chemistry, haematology and urinalysis will be performed at a local laboratory at 
or near to the Investigator site.  Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site.
The following laboratory variables will be measured:


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Table 3
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)
Urinalysis (dipstick)
S/P-Albumin
U-Hb/Erythrocytes/Blood 
S/P-Potassium
U-Protein/Albumin 
S/P-Calcium, total
U-Glucose 
S/P-Sodium
S/P-Gamma-GT (gammaglutamyl
transpeptidase)
S/P-Glucose
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at site 
as source data for laboratory variables.  For information on how AEs based on laboratory tests 
should be recorded and reported, see Section 6.3
Note: In case a patient shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN please 
refer to Section 6.3.7, for further instructions.
5.2.1.1
Pregnancy Test
Urine HCG test will be performed in female patients (when appropriate) using a urine 
dipstick. The test should be performed at the study site at Visit 1, and before IP administration 
at Visit 3, Visit 5, Visit 7 and at an Early Discontinuation/Withdrawal Visit. 
5.2.2
Physical examination
A complete physical examination will be performed at Visit 1 and include an assessment of 
the following: general appearance, respiratory, cardiovascular, abdomen. According to the 
Investigator’s judgement, assessment will also include skin, head and neck (including ears, 
eyes, nose and throat), lymph nodes, thyroid, abdomen, musculo-skeletal (including spine and 
extremities) and neurological systems.
Only relevant findings, detected at Screening Visit, will be recorded in the Medical 
History/Physical examination at the eCRF. Body weight and height will be measured only at 
Visit 1 (screening) (allowing calculation of Body Mass Index done automatically by the eCRF 
system) which will be recorded on the MasterScope CT. Patients should be in light indoor 
clothes without shoes.


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5.3
Other assessments
5.3.1
Clinical Outcome Assessments/Patient Reported Outcomes
5.3.1.1
EQ-5D-5L EuroQol 5 Dimensions Questionnaire
The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, 
slight problems, moderate problems, severe problems, and extreme problems) that reflect 
increasing levels of difficulty.
The patient will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual 
analogue scale, where the patient will be asked to rate current health status on a scale of 0-
100, with 0 being the worst imaginable health state.
The EQ-5D-5L will be completed at randomisation Visit 3 at visit 7 and Early 
Discontinuation/Withdrawal Visit using the ePRO device.
5.3.1.2
Work Productivity and Activity Impairment Questionnaire - General Health 
(WPAI - GH)
The WPAI-GH will be used to measure self-reported productivity loss and consists of 
questions on COPD impact on patient’s general health, ability to work and perform regular 
activities in daily living within the previous 7 days.
The questionnaire will initially be completed at the study site on Visit 3 (Day 1) on the ePRO 
device. Patients will then be prompted to complete the WPAI-GH on the ePRO device at Visit 
4, Visit 5, Visit 6, Visit 7 and Early Discontinuation/Withdrawal Visit.
5.3.1.3
Healthcare Resource Utilization
Broad-based COPD-related health care resource utilization event information will be collected 
by the Investigator/authorized delegate in accordance with the schedule provided in Table 1 
and recorded in the appropriate eCRF module.
At Visit 3, COPD-related Healthcare Resource Utilization information will be collected with a 
one year recall period. All the subsequent visits will collect COPD related Healthcare 
Resource Utilization and COPD exacerbation information with a recall period of ‘since last 
scheduled visit’.
Note: Cases of hospitalization must also be reported as an SAE (see Section 6.2 and 6.4).


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5.4
Pharmacokinetics – Not Applicable
5.5
Pharmacodynamics – Not Applicable
5.6
Genetics – Not Applicable
6.
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.
6.1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a patient or 
clinical study patient administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
screening or washout periods, even if no study treatment has been administered.
6.2
Definitions of serious adverse event
A serious adverse event (SAE) is an AE occurring during any study phase (ie, screening, 
treatment, or follow-up), that fulfils one or more of the following criteria:
∀
Results in death
∀
Is immediately life-threatening
∀
Requires in- patient hospitalisation or prolongation of existing hospitalisation 
∀
Results in persistent or significant disability or incapacity. 
∀
Is a congenital abnormality or birth defect
∀
Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol.


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6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
AEs and SAEs will be collected from time of signature of informed consent throughout the 
treatment period and until the follow-up telephone call.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the time of the follow-up telephone call are followed up by 
the Investigator for as long as medically indicated, but without further recording in the CRF. 
AstraZeneca retains the right to request additional information for any patient with ongoing 
AEs/SAEs at the end of the study, if judged necessary.
6.3.3
Variables 
The following variables will be collected for each AE;
∀
AE (verbatim)
∀
The date and time when the AE started and stopped
∀
Severity
- Maximum intensity
- The Investigator must categorize the severity of each AE according to the 
following guidelines:
1 
mild (awareness of sign or symptom, but easily tolerated)
2 
moderate (discomfort sufficient to cause interference with normal activities)
3 
severe (incapacitating, with inability to perform normal activities)
∀
Whether the AE is serious or not
∀
Investigator causality rating against the IP (yes or no)
∀
Action taken with regard to IP
∀
AE caused patient’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


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∀
Date Investigator became aware of serious AE
∀
Reason that the AE is serious
If the following two seriousness criteria, collect the following variables:
Hospitalization
- Date of hospital admission
- Date of discharge
Death
- Probable cause of death
- Date of death
- Autopsy results
- Causality assessment in relation to Study procedure(s)
∀
Causality assessment to other medication
∀
Causality assessment to additional study drug
∀
Description of AE.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the IP?’
For SAEs 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 to the Clinical 
Study Protocol.


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6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site personnel: ‘Have you had any health problems since the previous visit?’, 
or revealed by observation will be collected and recorded in the CRF. When collecting AEs, 
the recording of diagnoses is preferred (when possible) rather than 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.
6.3.6
Adverse events based on examinations and tests
The Clinical Study Protocol mandates laboratory testing, physical examination, and 
assessment of vital signs at screening only. Further testing may however be performed by the 
Investigator during the course of the trial. 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.  
Values and/or vital signs that fulfil any of the SAE criteria or are the reason for 
discontinuation of treatment with the IP should be reported.  Wherever possible the reporting 
Investigator uses the clinical, rather than the laboratory term (eg, anaemia versus low 
haemoglobin value). In the absence of clinical signs or symptoms, clinically relevant 
deteriorations should be reported as AEs. 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,unless the finding is associated with a medical condition reported as an AE.
6.3.7
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to 
be reported as SAEs. Please contact the AstraZeneca study physician for further instruction on 
cases of increases in liver biochemistry and evaluation of a potential Hy’s Law case. 
Investigators should be vigilant for potential Hy’s Law cases from ad hoc laboratory tests or 
AEs.
6.3.8
Disease under Study (DUS)
COPD symptoms or signs, such as bronchitis, cough, phlegm, sputum increased, dyspnea and 
wheeze, will be recorded as AEs when:
∀
the sign or symptom is serious according to definitions, see Section 6.2 and/or
∀
the patient discontinues the study due to the sign or symptom and/or
∀
the sign or symptom is new to the patient or not consistent with the patient’s 
preexisting COPD history (defined as within 1 year of Visit 1) as judged by the 
Investigator


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6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedures. All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system,
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed. 
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure for the AstraZeneca drug and the EU Summary of Product Characteristics for the 
active comparator product.
6.5
Overdose
This refers to the administration of a quantity of a medicinal product given per administration 
or cumulatively, which is above the maximum recommended dose according to the authorised 
product information. Clinical judgement should always be applied.
∀
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.
∀
An overdose without associated symptoms is only reported on the Overdose CRF 
module.


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If an overdose of an AstraZeneca IP occurs in the course of the study, then the Investigator or 
other site personnel inform appropriate AstraZeneca representatives immediately, or no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study the IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
6.7
Medication error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the subject or 
has the potential to cause harm to the subject. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error:


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∀
occurred
∀
was identified and intercepted before the subject received the drug
∀
did not occur, but circumstances were recognized that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:
∀
Drug name confusion
∀
Dispensing error
∀
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
∀
Drug not taken as indicated, for example, nasal inhalation used instead of oral 
inhalation
∀
Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature 
∀
Wrong subject received the medication (excluding IWRS/IVRS errors)
∀
Wrong drug administered to subject (excluding IWRS/IVRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
∀
Errors related to or resulting from IWRS/IVRS – including those which lead to one 
of the above listed events that would otherwise have been a medication error 
∀
Subject accidentally missed drug dose(s) e.g. forgot to take medication
∀
Accidental overdose (will be captured as an overdose)
∀
Subject failed to return unused medication or empty packaging
∀
Errors related to background and rescue medication, even if an AZ product
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately 
but no later than 24 hours of when he or she becomes aware of it.


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The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors.
6.8
Management of IP related toxicities - Not Applicable 
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Table 4
Identification of investigational product(s)
Investigational product
Dosage form and strength
Manufacturer
GFF 
Metered dose inhaler (MDI), 
contains 
glycopyrronium/formoterol 
fumarate fixed-dose 
combination 7.2/4.8 μg per 
actuation
AstraZeneca
Anoro Ellipta 
(UV) 
Dry powder inhaler (DPI), 
Each metered dose contains 
umeclidinium/vilanterol 62.5/ 
25μg fixed-dose combination 
per inhalation
GlaxoSmithKline 
Placebo
MDI, Formulation does not 
contain active ingredient
AstraZeneca
Placebo
DPI, Formulation does not 
contain active ingredient
GlaxoSmithKline
Open-label supplies include albuterol/salbutamol MDI 90 μg ex-actuator and ipratropium 
bromide MDI 17 μg ex-actuator.  For both albuterol/salbutamol MDI and ipratropium 
bromide MDI, it is preferred that these be US-sourced products (Ventolin inhalation aerosol 
and Atrovent, respectively).  In cases where it is not possible for the US-sourced product to be 
used, a locally available product may be provided by the Sponsor.   
7.2
Dose and treatment regimens
Each patient will undergo a screening period of 1 to 4 weeks (-28 to -9 days).  Patients will be 
provided albuterol/salbutamol MDI to be taken as needed (rescue medication) during the 
screening period and throughout the study. Patients will be provided ipratropium bromide 
MDI taken as 2 inhalations QDS for use as COPD maintenance therapy during the screening 
period. 
The first dose of IP will be taken at Visit 3 (Day 1). During the 24 week double-blind 
treatment period, patients will take two inhalations in the morning and in the evening from the 


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GFF inhaler (active or placebo) and one inhalation in the morning from the UV inhaler (active 
or placebo). 
Patients will be trained on how to use both IP inhalers at Visit 1 through Visit 6.  
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language.
For blinded GFF/placebo supplies, each inhaler will be labelled with a single label.  The 
actuator will be labeled with a single label.  The foil pouch will be labeled with a single label.
For blinded UV/placebo supplies, each inhaler will be labelled with a single label.  The foil 
pouch will be labeled with a single label.
Open-label albuterol/salbutamol MDI and ipratropium bromide MDI will be provided as 
individually labeled MDIs.  Each MDI will contain a single label.  The MDI actuator will be 
labeled with a single label. 
Both single and two-part labels will be printed with black ink. 
The label may include the following information:
Packaging Lot Trace ID #
Space for entry of screening #
Component ID #
Space for entry of randomisation #
Fill Count & Dosage Form
Space for entry of Interval ID (Visit # only)
Re-evaluation/Expiration date (if applicable)
Dosing Instructions
Storage Conditions
Compound ID - Protocol #
Country regulatory requirements
Sponsor address (If applicable)
Translation Key (If applicable)
Blinded IP inhalers and open-label albuterol/salbutamol MDI and ipratropium bromide MDI 
supplies will be packaged in individual boxes. Each box will be labeled with a two-part label 
printed with black ink and may include the following text:


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Packaging Lot ID #
Space for entry of screening #
Component ID #
Space for entry of randomisation #
Kit Contents (1 MDI)
Space for entry of Interval ID
Re-evaluation/Expiration date (if applicable)
Dosing Instructions (if applicable)
Storage Conditions
Compound ID - Protocol #
Country regulatory requirements
Sponsor address (If applicable)
Translation Key (If applicable)
Individual GFF and Placebo inhaler, UV and Placebo inhaler will be packaged in a foil pouch 
and contained in an individual visit treatment box.  Both the visit treatment box and the foil 
overwrap will have a label with a component ID number.  Confirm that the identifier given by 
IWRS/IVRS and the component ID number written on the label are the same.  The visit 
treatment box is labeled with a two part label.  Write the patient number and treatment visit 
number on each of the two-part labels.  The ‘tear-off’ part of the label is to be placed onto the 
medical records.
Each open-label albuterol/salbutamol MDI and ipratropium bromide MDI will be contained in 
an individual visit treatment box.  The visit treatment box will have a label with a component 
ID number. Confirm that the identifier given by IWRS/IVRS and the component ID number 
written on the label are the same.  The visit treatment box is labeled with a two part label.  
Write the patient number and treatment visit number on each of the two-part labels.  The ‘tear-
off’ part of the label is to be placed onto the medical records.
7.4
Storage
All study medications should be kept in a secure place under appropriate storage conditions.  
The IP label on the IP inhalers and boxes specifies the appropriate storage.
The clinical supplies storage area at the site must be monitored by the site personnel for 
temperature consistency with the acceptable storage temperature range specified in 
accordance with the product label.  Documentation of temperature monitoring should be 
maintained.
7.5
Compliance
The technique for inhalation from an MDI (GFF) is different from the technique used with a 
DPI (UV). It is important to ensure that patients apply correct inhalation technique for 
both types of inhalers. Training devices will be available at each study site for instructional 
purposes, as well as for patients to practice the correct inhalation technique. Instruction and 
practice should occur prior to dispensing study medication, and review of patients' inhalation 
technique should be done at each visit.
The administration of all study medications (including IPs) should be recorded in the 
appropriate sections of the Case Report Form.


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Administration of study medication will be recorded twice daily in the patient’s ePRO. If IP 
use drops below 80%, or if IP use is not recorded on two consecutive days, an e-mail alert will 
be sent to the investigator; the patient should be contacted and the compliance problems 
investigated. Furthermore, site personnel will check study medication compliance in the ePRO 
at each visit, and any issues identified will be documented in the appropriate study files. If 
appropriate, site personnel will retrain the patient on the proper use of the IP inhalers. In case 
of repeated compliance alerts and/or if IP compliance drops below 50%, withdrawal of the 
patient should be considered. Before withdrawal of a patient due to low compliance, a 
discussion with the study physician is mandated.
7.6
Accountability
The study medications provided for this study will be used only as directed in the Clinical 
Study Protocol.
The study site personnel will account for all study medication, including IP, dispensed to and 
returned from the patient.
The supplies that are returned and accounted for or have never been used, shall be destroyed 
as applicable in a given country. Study site personnel or AZ monitor will account for all IPs 
received at the site, unused IPs and for appropriate destruction.  Certificates of delivery, 
destruction and return should be signed. 
7.7
Concomitant and other treatments 
For permitted medications during the study, see Table 5, Table 6, Table 7and Table 10. For 
prohibited medications during the study, see Table 8 and Table 9.
Table 5
Permitted medications
Allowed Medication/Class of drug
Antitussives PRN not containing ephedrine or other bronchodilators
Antihistamines not containing ephedrine or other bronchodilators
Mucolytics not containing ephedrine
Nasal, ophthalmic and topical corticosteroids without systemic effects
Nasal decongestants
Antibiotics for acute infections
Influenza and pneumonia vaccines
Ophthalmic β-blocking agents (selective and non-selective), only if used at a constant dose for 2 
months prior to Visit 1 without evidence of bronchospasm
Oral cardio-selective β-blocking agents, only if used at a constant dose for 2 months prior to Visit 1 
without evidence of bronchospasm


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Allowed Medication/Class of drug
All medications for other disorders as long as the dose remains constant wherever possible and their 
use would not be expected to affect lung function
Table 6
Restricted Medications
Restricted Medication/Class of drug
Usage/restrictions
Systemic corticosteroids (oral or injections) 
Prohibited within 4 weeks (depot corticosteroids 
within 6 weeks) prior to Visit 1 and throughout 
the study.
Exceptions:
- Allowed to treat a COPD exacerbation, but no 
more than 14 days.
- In patients who are steroid dependent, an 
equivalent of 5 mg prednisone per day or 10 mg 
every other day is allowed, provided stable 
dosing for at least 3 months prior to Visit 1 and 
throughout the study. 
Theophylline
Allowed taken regularly ≤ 200 mg BD 
throughout the IP treatment period, provided 
stable dosing for at least 4 weeks prior to Visit 1.
Should be withheld from 6h prior to site visits 
until visit completion.
Phosphodiesterase-4 Inhibitors
Allowed provided stable dosing for at least 2 
months prior to Visit 1 and throughout the study.
Leukotriene antagonists
Allowed provided stable dosing for at least 1 
month prior to Visit 1 and throughout the study.
Cromoglycate
Allowed provided stable dosing for at least 1 
month prior to Visit 1 and throughout the study.
Oxygen
Allowed for intermittent use or ≤12 hours per 
day


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Table 7
Screening period Medication and Rescue medication
Screening period Medication and Rescue 
medication
Usage
Study-supplied ipratropium bromide MDI  17 μg 
ex-actuator
2 inhalations QDS during the screening period.
6h of wash-out before Visit 2 and 3.
Study-supplied albuterol/salbutamol MDI  90 μg 
ex-actuator 
As needed throughout the study, from Visit 1 to 
Visit 7.
6h of wash-out before each site visit.
Table 8
Prohibited COPD Medications
Prohibited COPD Medication/Class of drug
Minimum Washout Period Prior to Visit 2
LAMAs
Aclidinium: 3 days
Umeclidinium: 3 days 
GP: 14 days
Tiotropium: 14 days
LABAs (inhaled)
2 days (14 days for indacaterol and olodaterol)
Fixed combinations of LAMA/LABA
Umeclidinium/vilanterol: 7 days
Aclidinium/formoterol 7 days
GP/formoterol: 14 days
Tiotropium/olodaterol: 14 days
GP/indacaterol: 14 days
ICS
7 days
Any combination treatment of ICS/LABA
7 days (14 days for combinations with 
indacaterol or olodaterol)
SAMA 
6 hours
Fixed combinations of SABAs and SAMAs 
6 hours
SABAsa
6 hours
Oral β-agonists
2 days 
Theophylline (total daily dose >400 mg/day)b
7 days
Ephedrine containing medications
2 days
a
Discontinue and use only sponsor-provided rescue albuterol/salbutamol MDI throughout the study.
b
Theophylline (≤200 mg BD) is allowed provided stable dosing for at least 4 weeks prior to Visit 1.


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Table 9
Other prohibited Medications
Other prohibited Medication/Class of drug
Minimum Washout Period 
Oral non-selective β-blocking agents
2 weeks prior to Visit 1
Any other investigational drug
30 days or five half-lives (whichever is longer) 
prior to Visit 1
Any  monoclonal or polyclonal antibody 
6 months prior to Visit 1
Monoamine oxidase inhibitors, tricyclic 
antidepressants, and other drugs known to 
prolong the QTc interval 
2 weeks prior to Visit 3
Strong CYP3A4 inhibitors
30 days prior to Visit 3
7.7.1
COPD Medication restrictions
7.7.1.1
Use of short-acting anticholinergics and short-acting β2-agonists
Patients will be provided ipratropium bromide MDI taken as 2 inhalations QDS for use as 
COPD maintenance therapy during the screening period. Use of any SAMA as rescue 
treatment for worsening COPD symptoms is not allowed from Visit 1 and throughout the 
study duration, with the exception of treatment during a COPD exacerbation. 
Albuterol/salbutamol MDI will be dispensed at Visit 1 for use as rescue medication for 
worsening of COPD symptoms. No other SABA is allowed during the study outside of 
managing a COPD exacerbation. Rescue use of albuterol/salbutamol MDI will be recorded in
the ePRO as number of inhalations per day (see Section 7, Table 7). Regularly scheduled use 
of albuterol/salbutamol MDI is not allowed. Prophylactic use in the absence of symptoms is 
discouraged. However, if deemed necessary by the patient and Investigator (e.g. prior to 
planned exercise), it can be used, but prophylactic inhalations should not be recorded in the 
daily ePRO. Such use should be documented in the medical notes and recorded in the eCRF.
Albuterol/salbutamol MDI rescue medication is not regarded as an IP, but will be provided by 
AstraZeneca, in order to ensure access for this therapy from enrolment and up to Week 24, 
unless the patient is withdrawn from the study.
7.7.1.2
COPD medication restrictions on the days of scheduled spirometry visits
Spirometry assessments will be performed at scheduled site visits (see Section 4, Table 1 ). 
There are no restrictions regarding patients’ COPD medications prior to the spirometry at 
Visit 1 (other than those related to study eligibility), whereas important restrictions apply prior 
to the spirometry at the following visits:
Visit 2: patients will be asked to withhold ipratropium bromide MDI and albuterol/salbutamol 
MDI within approximately 6 hours of the first (pre-BD) spirometry assessment. Use of 
albuterol/salbutamol MDI should be avoided until the screening lung function assessments are 


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completed. Ipratropium bromide MDI may be administered following completion of the lung 
function assessments.
Visit 3: patients will be asked to withhold ipratropium bromide MDI and albuterol/salbutamol 
MDI within approximately 6 hours of the first (pre-BD) spirometry assessment. The treatment 
with ipratropium bromide MDI will be stopped, and the first doses of the two IP inhalers will 
be administered after completion of all pre-dose assessments. Use of albuterol/salbutamol 
MDI should be avoided until all lung function assessments are completed.
Visits 4-7: patients will be asked to withhold IP in the morning before the visits. The time 
from the previous dose until dosing of IP at the visit should be approximately 12 hours for the 
GFF/placebo inhaler, and approximately 24 hours for the UV/placebo inhaler. Use of 
albuterol/salbutamol MDI should be avoided for at least approximately 6 hours prior to the 
first scheduled spirometry. IP will be administered after completion of all pre-dose 
assessments. Albuterol/salbutamol MDI intake should be avoided until all lung function 
assessments are completed. 
If IP was dosed incorrectly (missed or not taken as directed) on the day prior to a visit, the 
visit should be rescheduled to another day, as soon as possible and preferably within the visit 
window. 
If IP was dosed at an incorrect time on the day prior to a visit (see Section 4.2), it is strongly 
recommended that the visit is rescheduled as above, but if this is not feasible for the patient, 
spirometry may be performed with a notation of the incorrect timing of IP.
If rescue medication was taken within 6 hours of the planned site visit spirometry, the patient 
should ideally remain at the site until such time that the 6 hours withholding time has been 
reached, given it does not exceed the spirometry window (see Section 5.1.1.2) or the 
stipulated time interval since IP intake on the previous day (see Section 4.2). Alternatively, 
patients can return on another day, as soon as possible and preferably within the visit window. 
If neither of options is feasible for the patient, spirometry may be performed with a notation 
indicating that the spirometry was conducted within 6 hours of rescue medication use.
7.7.1.3
Allowed Medications to treat a COPD exacerbation
For allowed medications to treat a COPD exacerbation, see Table 5.
Rescue use of SABA and/or SAMA administered via nebulization is allowed to manage an 
acute COPD exacerbation.
Medications to treat an exacerbation should not be used for more than 14 days. Recent data 
suggest that treatment with systemic steroids for shorter periods of time results in similar 
outcomes with less systemic steroid exposure. Therefore, it is recommended that patients are 
treated with a 5 day course. A single depot injectable dose of corticosteroids will be 
considered equivalent to a 3-day course of systemic corticosteroids.


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Table 10
Allowed Medications to treat a COPD exacerbation
Allowed Medication to treat a COPD 
exacerbations
Usage
Systemic corticosteroids (oral or injections)
No more than 14 days. 4-week washout required 
before next scheduled spirometry (6 weeks for 
depot injections). The remaining visit assessments 
may proceed.
Antibiotics
No more than 14 days
ICS (including nebulized)
Only during hospitalization/ER treatment. 7-day 
washout required before next scheduled site visit.
Additional SABAs and SAMAs, including 
nebulized treatment
Only concomitantly with systemic steroids and/or 
antibiotics
Xanthines (other than theophylline ≤400 mg/day 
ongoing since randomisation)
Only concomitantly with systemic steroids and/or 
antibiotics. 7-day washout required before next 
scheduled site visit.
Ephedrine containing medications
Only concomitantly with systemic steroids and/or 
antibiotics. 2-day washout required before next 
scheduled site visit.
7.7.2
Other concomitant treatment
Medication other than that described above, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the Case Report Form.
7.8
Post Study Access to Study Treatment 
After completion of study treatment, patients will be prescribed appropriate COPD 
maintenance medication according to the Investigator’s judgment and local medical practice. 
Consideration should be given to maintaining patients on at least double therapy, while 
ensuring appropriate follow-up and further evaluation of the prescribed treatment.
8.
STATISTICAL ANALYSES
8.1
Statistical considerations
The primary objective of this study is to assess the effects of GFF relative to UV on lung 
function. This will be addressed by the following co-primary hypothesis tests: 
∀
non-inferiority of GFF relative to UV in the change from baseline in morning pre-
dose trough FEV1 over 24 weeks; 


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∀
non-inferiority of GFF relative to UV in the peak change from baseline in FEV1
within 2 hours post-dosing over 24 weeks;
∀
superiority of GFF relative to UV in the peak change from baseline in FEV1 within 
2 hours post-dosing over 24 weeks.
The non-inferiority null (H0) and alternative (H1) hypotheses, with μ representing the mean 
change from baseline in each treatment group, correspond to a null hypothesis of inferiority 
and an alternative hypothesis of non-inferiority, as follows: 
H0: μGFF – μUV ≤ -Δ 
(GFF is inferior to UV by Δ or more) 
H1: μGFF – μUV > -Δ 
(GFF is inferior to UV by less than Δ)
The non-inferiority analysis for each endpoint is assessed within a Per Protocol analysis set 
and if non-inferiority is demonstrated the consistency of this conclusion will be assessed 
within the full analysis set.
If non-inferiority is demonstrated, then for selected endpoints superiority hypotheses will also 
be addressed within the full analysis set. Here the null (H0) and alternative (H1) hypotheses are 
as follows: 
H0: μGFF – μUV ≤ 0 
(GFF is not superior to UV) 
H1: μGFF – μUV > 0 
(GFF is superior to UV)
The exception to this sequential testing of non-inferiority followed by superiority is the 
analysis of the proportion of patients with increase in FEV1 of ≥100 ml from baseline at 5 
minutes. For this endpoint testing will immediately be in terms of superiority hypotheses.
P-values will thus be reported as one-sided for both the non-inferiority and superiority 
hypothesis testing. This will equivalently be presented by comparing the lower bound of 
confidence intervals to the pre-specified margin.A comprehensive Statistical Analysis Plan 
(SAP) will be signed off prior to unblinding or to the review of any potentially treatment 
revealing data. Analyses will be performed by AstraZeneca or its representatives.
All personnel involved with the analysis of the study will remain blinded until the database is 
locked and all protocol violations are identified.
8.2
Sample size estimate
1000 patients (500 patients each in the GFF and UV treatment arms) are to be randomised in 
this study. Based upon Phase III studies of GFF, it is estimated that 12% of the patients 
randomised will be excluded from the Per Protocol Analysis Set, leaving around 440 patients 
in the co-primary non-inferiority analyses. This sample size will provide around 94% power to 
demonstrate that the difference between GFF vs UV in change from baseline in morning pre-
dose trough FEV1 over 24 weeks is greater than the non-inferiority margin of -50 mL. This 


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calculation assumes a one-sided significance level of 2.5% and a true difference of -10 mL. 
Should testing be conducted at a one-sided significance level of 1.25% then the power would 
be 90%. Assumptions regarding variability for the co-primary endpoints are based on 
experience in previous GFF Phase III clinical studies. An effective standard deviation (SD) of 
167 mL for the change from baseline in morning pre-dose trough FEV1 over 24 weeks has 
been assumed. This value is based on a per-visit SD of 200 mL and a within-patient (between-
visit) correlation of 60%. Under these assumptions, for non-inferiority to be achieved the point 
estimate of the difference in pre-dose trough FEV1 over 24 weeks must be above -28mL when 
testing at a 2.5% significance level, or above -24.5mL when testing at a 1.25% significance 
level. 
For the co-primary endpoint of peak FEV1 over 24 weeks and secondary lung function 
endpoint of peak IC over 24 weeks, the power to show non-inferiority is expected to be at 
least that of the co-primary endpoint of trough FEV1. Assuming an effective SD of 188mL for 
peak FEV1, and a true difference of 50mL then 500 patients would provide at least 97% power 
to demonstrate superiority of GFF to UV in peak FEV1 with a one-sided significance level of 
1.25%.
For the secondary endpoint of the TDI focal score over 24 weeks a non-inferiority margin of -
1 unit is defined. However, note that the power to show non-inferiority would remain at least 
90% with a margin of -0.75 units (three quarters of the MCID), assuming no difference 
between treatments and a standard deviation of 3 units.
8.3
Definitions of analysis sets
The co-primary non-inferiority analyses and all other non-inferiority analyses in this study 
will primarily be conducted using the per protocol analysis set. This will be used to compare 
GFF and UV when the treatments are used as planned at each visit, in the intended patients 
and without important protocol deviations which may affect efficacy. This will provide an 
estimate of the true biological efficacy of the treatments and counters the tendency for 
intention-to-treat analyses to favour a conclusion of equivalence. Non-inferiority comparisons 
will also be conducted in the full analysis set of all patients receiving IP, allowing for 
variation in clinical application whilst on treatment, as a comparison of their effectiveness 
when used in practice. For selected endpoints this full analysis set will be used to provide an 
assessment of superiority, including for the co-primary analysis of the superiority of GFF 
relative to UV in Peak FEV1.
The All Patients Analysis Set
This analysis set comprises all patients screened for the study and may be used for the 
reporting of disposition and screening failures.


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8.3.1
Efficacy analysis sets
Full Analysis Set
The Full Analysis Set will be defined as all patients randomised who received at least one 
inhalation of IP. Patients will be analysed according to the treatment they were assigned to at 
randomisation.  
This analysis set will be used to demonstrate consistency in non-inferiority hypothesis tests 
and as the primary means of assessing superiority hypotheses.
Per Protocol Analysis Set
The Per Protocol (PP) Analysis Set will be used as the primary means of assessing non-
inferiority hypotheses.
The Per Protocol Analysis Set is the subset of the full analysis set containing patients with 
post-randomisation data obtained prior to important protocol deviations which may affect 
efficacy. Data obtained after such important protocol deviations, i.e. those which may affect 
efficacy, will be excluded from analyses using this set. The use of certain prohibited 
medications (such as inhaled corticosteroids) outside of the limitations described in Section 
7.7 will be defined in the SAP as important protocol deviations and so data after the initiation 
of these will be excluded from per protocol analyses. Since receiving the wrong treatment will 
be a major protocol deviation, patients in the PP analysis set will be analysed as randomised 
(which for this population is identical to analysis by the actual treatment received). Patients 
must also have a valid spirometry baseline to be included given that this is required to ensure 
that key inclusion criteria are met.
Patients who are found not to meet the inclusion criteria for clinical diagnosis of COPD or the 
COPD severity criteria or who did not have the required washout of prohibited medications 
prior to baseline will be excluded entirely for the PP analysis set. In addition, data from visits 
where patients do not comply with required restrictions will be removed from analyses which 
use the per protocol analysis set (see Section 8.4.3). 
A detailed definition of the Per Protocol Analysis Set and data points to be excluded will be 
given in the Statistical Analysis Plan and defined prior to the review of any potentially 
treatment revealing data.
8.3.2
Safety analysis sets
Safety Analysis Set
All patients who received any IP will be included in the safety analysis set. Patients will be 
classified according to the treatment they actually received. If a patient received more than 
one randomised treatment, they will be analysed and included in summaries according to the 
treatment they received the most. Any major deviations from the randomised treatment 
assignment will be listed and considered when interpreting the safety data.


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8.3.3
Other analysis sets
Rescue Medication User analysis set
Regional differences in rescue albuterol/salbutamol MDI usage are expected with some 
regions using virtually no rescue albuterol/salbutamol MDI at study entry. Therefore, the 
Rescue Medication User analysis set is defined as all patients in the full analysis set with 
average baseline rescue albuterol/salbutamol MDI use of ≥ 1 inhalation/day. 
8.4
Outcome measures for analyses
8.4.1
Definition of baseline
All efficacy assessments are relative to pre-dose baseline obtained at randomisation at Visit 3. 
For spirometry endpoints the mean of all available evaluable -60 and -30 minute pre-dose 
spirometry assessments conducted at Day 1 (Visit 3) will be used to establish baseline for all 
FEV1, FVC, and IC parameters. 
For the diary symptom score parameters and rescue medication usage, baseline will be the 
average of the non-missing values from the ePRO data collected in the last seven days before 
randomisation (i.e. excluding data recorded on the day of visit 3).
8.4.2
Visit windows
Data will be summarised according to the protocol-scheduled week for that visit. Data 
collected in spirometry and ePRO systems will be allocated to visit weeks based upon 
assigned windows so as to allow rescheduled assessments to be included. Detailed definitions 
of visit windows and periods will be provided in the SAP.
For efficacy endpoints or derivation of AUC based on assessment times pre and post dosing, 
the assessments will be allocated to derived nominal collection time windows of minutes from 
IP dosing. These will be specified in the SAP.
8.4.3
Pulmonary Function Outcomes
All pulmonary function assessments that have at least one effort that meets ATS/ERS criteria 
for acceptability will be considered acceptable and contribute to the post-dose assessments for 
analyses using the full analysis set. If all the assessments at a specific timepoint were deemed 
to be of unacceptable quality the pulmonary function assessments obtained at the timepoint 
will not be included in any efficacy analysis and will be considered missing.
Further requirements will have to be met in addition to the ATS/ERS criteria in order for 
pulmonary function data to be used in the Per Protocol analyses. Patients who do not comply 
with selected restrictions during a study visit (for example on smoking and bronchodilator or 
rescue medication use) will have their data from that visit removed from analyses which use 
the per protocol analysis set. Patients who do not take the morning and evening doses of 
blinded study inhalers on the day preceding a study visit will also have their data from that 
visit removed. 


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8.4.3.1
Morning pre-dose trough FEV1
The co-primary endpoint of change from baseline in morning pre-dose trough FEV1 is defined 
as the average of the -60 and -30 minute pre-dose values at each visit minus baseline. Baseline 
is defined as the average of the non-missing -60 minute and -30 minute values obtained prior 
to dosing at Visit 3.
In patients missing either of these pre-dose assessments, the value will be calculated from the 
single measurement. In patients missing both pre-dose values, morning pre-dose trough FEV1 
at that visit will not be calculated.
The change from baseline in morning pre-dose trough FVC will be derived similarly.
8.4.3.2
Peak FEV1 and Inspiratory Capacity post-dosing
The co-primary endpoint of peak change from baseline in FEV1 is defined as the maximum of 
the FEV1 assessments within 2 hours post-dosing at each visit minus baseline. Similarly, the 
secondary endpoint of peak change from baseline in IC is defined as the maximum of the IC
assessments within 2 hours post-dosing at each visit minus baseline.
Further additional spirometry endpoints will also be derived. Peak change from baseline in 
FVC within 2 hours post-dose will be derived similarly to Peak FEV1. The trapezoidal rule 
will be used to derive estimates of AUC0-2 for FEV1 and FVC, normalised by time from first 
to last non-missing value, as long as there are at least 2 non-missing time points during the 
first 2 hours post-dose.
8.4.3.3
Increase in FEV1 at 5 minutes post-dosing
To assess the early onset of action, a secondary endpoint of this study will be the proportion of 
patients with increase of FEV1 of ≥100 ml from baseline at 5 minutes on day 1. Only data 
assigned to the 5 minute window will be used to determine response. Patients with missing 
data will be considered to be non-responders for the analysis.
Additional categorical endpoints will be derived similarly as the proportion of patients with 
increase of FEV1 of ≥150 ml from baseline at 5 minutes and the proportion of patients with 
increase of FEV1 of ≥12% from baseline at 5 minutes.
8.4.4
Patient Reported Outcomes 
8.4.4.1
Transition Dyspnea Index (TDI) focal score
As a secondary endpoint assessing dyspnea, the TDI focal score will be derived at post-
randomisation visits relative to the baseline severity of dyspnea assessed using the BDI at visit 
3. The BDI and TDI consist of 3 individual components: functional impairment, magnitude of 
task, and magnitude of effort. These are summed to form a baseline total score for BDI (range 
0-12) and a total TDI score (range -9 to +9). For the TDI, at each visit, if a response to any of 
the three questions is missing, then the focal score will also be considered missing. Otherwise, 
scoring and handling of missing items will be conducted in accordance with the user’s guide 
for the TDI score. 


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The percentage of patients achieving the threshold of 1 unit or more in TDI focal score will be 
derived at each visit. For the TDI responder analyses, patients with missing data will be 
considered to be non-responders for the analysis.
8.4.4.2
Early Morning Symptoms COPD Instrument (EMSCI) and Night Time 
Symptoms COPD Instrument (NiSCI)
Patients will complete a daily ePRO questionnaire of their COPD symptoms with two parts 
covering symptoms “last night” and “this morning”.
The change from baseline in the 6-item EMSCI Symptom Severity Score is a secondary 
endpoint. This is derived by averaging the responses from a patient on the six item-level 
symptom scores
The change from baseline in the 6-item NiSCI Symptom Severity Score will also be assessed. 
The change from baseline in the Overall COPD Symptom Severity score, Early Morning 
Activity score and Night-time Awakenings score will also be derived.
Each daily measure will be aggregated based upon the time periods between clinic visits. Data 
from the day of the clinic visit will not be used in these aggregates. These periods will be 
specified in detail in the SAP. If the measure is available on more than half of the days in a 
given period then an aggregate score will be computed as the average of all present daily 
values. Otherwise the score will be considered missing for that period. ePRO data recorded 
during the last 7 days of the screening period prior to Visit 3 will be used to calculate the 
baseline.
8.4.4.3
COPD Assessment Test (CAT) score
The COPD Assessment Test (CAT) is used to quantify the impact of COPD symptoms on 
health status. The CAT has a scoring range of 0-40, and it is calculated as the sum of the 
responses given for each of the 8 items (scored on a 6-point scale from 0 to 5), with higher 
scores indicating a higher impact of COPD symptoms on health status. If the response to 1 of 
the 8 items is missing, the missing item will be considered equal to the average of the 7 non-
missing items for that patient. If more than 1 item is missing the score will be considered 
missing.
The change from baseline in CAT score will be derived at each visit relative to the baseline at 
visit 3. The percentage of patients achieving a MCID threshold for CAT of 2 units or more
will be derived at each visit, with patients with missing data considered to be non-responders.
8.4.4.4
Daily rescue medication use
The number of inhalations of rescue albuterol/salbutamol MDI will be recorded in the patient 
ePRO in the morning and evening and these summed. The mean daily number of inhalations 
of rescue albuterol/salbutamol MDI will be calculated overall and in time periods between 
each clinic visit. These periods will be specified in detail in the SAP. ePRO data recorded 
during the last 7 days of the screening period prior to randomisation will be used to calculate 
the baseline. Change from baseline in mean daily rescue (albuterol/salbutamol MDI) use will 


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then be derived. The denominator will be adjusted based on the number of days (or half days) 
with non-missing values.
A ‘day with no rescue use’ is defined from days where rescue albuterol/salbutamol MDI usage 
data is non-missing as any day where the patient reported no inhalations of rescue 
albuterol/salbutamol MDI in both the morning and evening. The percentage of days with no 
rescue use will be derived using a denominator of the number of full days in the period with 
no missing data. 
8.4.4.5
EuroQol 5 Dimensions Questionnaire (EQ-5D-5L)
The EQ-5D-5L questionnaire assesses 5 dimensions which will be derived separately: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. 
The patient will also be asked to rate current health status on a visual analogue scale from 0 -
100, with 0 being the worst imaginable health state. The change from baseline in visual 
analogue scale will be calculated.
8.4.4.6
Healthcare Resource Utilisation (HCRU)
Broad-based health care utilization event information will be collected by the 
Investigator/authorized delegate via patient interview at each visit and recorded in the 
appropriate eCRF module. Examples include aspects such as physician visits or telephone 
calls. 
The number of moderate exacerbations (defined as those requiring antibiotics or ≥3 days of 
systemic steroids) or severe COPD exacerbations (defined as those leading to in patient 
hospitalisation, including >24 hours in emergency department/urgent care setting) will also be 
recorded.
8.4.4.7
Work Productivity and Activity Impairment – General Health (WPAI-GH)
The Work Productivity and Activity Impairment – General Health (WPAI-GH) will be 
collected. Measures summarised will include the patient’s work time missed (absenteeism), 
impairment at work or reduced on-the-job effectiveness (presenteeism), overall work 
impairment (abseentism and presenteeism, ie, work productivity loss), and activity impairment 
outside the work environment. The WPAI-GH outcomes are expressed as impairment 
percentages whereby higher scores indicate greater impairment and less productivity (ie, 
worse outcomes).
8.4.5
Safety and tolerability
AEs experienced by the patients will be collected throughout the entire study and will be 
coded by the AstraZeneca designee using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA).


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8.5
Methods for statistical analyses
8.5.1
Analysis of the primary variable (s)
8.5.1.1
Trough FEV1
The co-primary analysis of trough FEV1 will be conducted using the Per Protocol analysis set. 
The change from baseline in morning pre-dose trough FEV1 will be analysed using a linear 
mixed effects model repeated measures (MMRM) approach. The model will include baseline 
FEV1 and bronchodilator responsiveness to albuterol/salbutamol MDI as continuous 
covariates and stratification factors (prior treatment - rescue/maintenance monotherapy vs 
double maintenance therapy), region, visit, treatment, and treatment by visit, as categorical 
covariates (fixed effects). Patient will be considered a random effect. Baseline is defined as 
the average of the non-missing -60 min and -30 min values obtained prior to dosing at Visit 3. 
An unstructured matrix will be used to model the variance-covariance structure within patient.  
If this model fit fails to converge, more parsimonious covariance structures will be considered 
to model correlation between time-points from the same patient. 
A contrast will be used to obtain an estimate of the treatment difference over the entire 24-
week Treatment Period with two-sided 95% confidence interval (CI) and 97.5% CI. Non-
inferiority will be concluded using a 1-sided hypothesis test according to a significance level 
of either 1.25% or 2.5% based upon the hierarchical testing and recycling procedure described 
in section 8.5.1.3. This is equivalent to the lower bound of the 95% or 97.5% 2-sided 
confidence interval being greater than the pre-specified margin of -50 mL. 1-sided p-values 
will be produced accordingly.
From the same model contrasts will also be used to produce estimates of the treatment 
difference at each individual time-point (for example at week 24).
A similar analysis will be conducted in the full analysis set using all data obtained while on 
treatment. 
8.5.1.2
Peak FEV1
The peak change from baseline in FEV1 within 2 hours post-dosing will be analysed using a 
similar MMRM model to trough FEV1. Testing of non-inferiority between GFF and UV will 
first be conducted in the Per Protocol analysis set. The estimates of treatment difference over 
24 weeks and associated 95% and 97.5% 2-sided CIs will be referred to a non-inferiority 
margin of -50mL.
The Full Analysis Set will be used to assess the consistency of the non-inferiority conclusion 
using all evaluable data and a similar repeated measures model. This model will then be used 
for the formal assessment of superiority hypotheses. Testing of non-inferiority and superiority 
will be at a significance level of either 1.25% or 2.5% based upon the hierarchical testing and 
recycling procedure described in section 8.5.1.3. 1-sided p-values will be produced 
accordingly for both non-inferiority analyses and the superiority analysis.
Contrasts will be used to produce estimates at individual visits.


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8.5.1.3
Hierarchical testing strategy – primary endpoints
In order to strongly control the 1-sided type I error rate at 2.5% across all co-primary endpoint 
hypothesis tests and the non-inferiority hypothesis tests of the secondary endpoints a 
hierarchical testing procedure with recycling will be defined. 
To account for the multiplicity of the two co-primary endpoints, the test mass (1 sided alpha 
of 2.5%) will initially be split equally between the tests of the non-inferiority null hypothesis 
for each of trough FEV1 and peak FEV1 (1-sided alpha of 1.25% each).
Should either of these null hypotheses be rejected, the test mass will be recycled (Burman et al 
2009), as described in Figure 2. That is, after respective null hypotheses are rejected there will 
be recycling from each test as follows:
∀
from trough FEV1 non-inferiority testing to peak FEV1 non-inferiority testing
∀
from peak FEV1 non-inferiority testing to peak FEV1 superiority testing
∀
from peak FEV1 superiority testing to trough FEV1 non-inferiority testing
As such, respective hypothesis tests will be conducted at either a 1-sided 1.25% or 2.5% 
significance level depending upon this recycling.
Figure 2
Testing hierarchy for primary endpoints
NI = Non-inferiority, Sup = Superiority
Should all three null hypotheses relating to the co-primary endpoints be rejected then testing 
will proceed to the secondary endpoints using a 1-sided 2.5% significance level.


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8.5.2
Analysis of the secondary variable(s)
8.5.2.1
Hierarchical testing strategy – secondary endpoints
A sequential testing hierarchy will be defined so as to strongly control 1-sided type I error at 
2.5% across all non-inferiority hypothesis tests of secondary endpoints. The secondary 
endpoints over 24 weeks will be tested against their respective non-inferiority margins in the 
following sequence using a 1-sided significance level of 2.5%: 
1.
Peak change from baseline in Inspiratory Capacity within 2 hours post-dosing over 
24 weeks (non-inferiority with option to proceed to superiority), 
2.
Proportion of patients with increase of FEV1 of ≥100 ml from baseline at 5 minutes 
on Day 1 (superiority only), 
3.
Change from baseline in TDI focal score over 24 weeks (non-inferiority only)
4.
Change from baseline in EMSCI  Symptom Severity Score over 24 weeks (non-
inferiority with option to proceed to superiority),
If non-inferiority is demonstrated for an endpoint, then testing may proceed to the next 
endpoint in the hierarchy, and a superiority test of the endpoint will also be conducted in the 
full analysis set for those endpoints indicated. Proceeding to the next endpoint is not 
contingent on demonstrating superiority.
An exception to this sequential non-inferiority/superiority testing procedure is the secondary 
endpoint Onset of action (proportion of patients with increase in FEV1 of ≥100 ml from 
baseline at 5 minutes at day 1). For this endpoint, superiority testing will immediately be 
carried out and superiority is required in order to move to the next step in the testing 
hierarchy.
This sequential testing hierarchy is illustrated in Figure 3:


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Figure 3
Sequential testing hierarchy for secondary endpoints
NI = Non-inferiority, Sup = Superiority
Other secondary endpoints not included in the sequential testing procedure include the 
following:
∀
Change from baseline in CAT score over 24 weeks and proportion of patients 
achieving a MCID threshold for CAT of 2 units or more at week 24
∀
Change from baseline in NiSCI symptom severity score over 24 weeks
∀
Proportion of patients achieving a MCID threshold of 1 unit or more in TDI focal 
score at week 24
∀
Change from baseline in mean daily rescue (albuterol/salbutamol MDI ) use over 24 
weeks
∀
Change from baseline in morning pre-dose trough FVC over 24 weeks 
∀
Peak change from baseline in FVC within 2 hours post-dose over 24 weeks
∀
Change from baseline FEV1 AUC0-2 and FVC AUC0-2 over 24 weeks
8.5.2.2
Pulmonary Function over 24 weeks
The peak change from baseline in IC within 2 hours post-dosing will be analysed using a 
similar MMRM model to peak FEV1. The estimates of treatment difference over 24 weeks 
will also be referred to a non-inferiority margin of -50mL. 


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If non-inferiority is demonstrated in the Per Protocol analysis then the Full Analysis Set will 
be used to assess the consistency of the non-inferiority conclusion using all evaluable data and 
a similar repeated measures model. This model will be used for the formal assessment of 
superiority hypotheses and 1-sided p-values and 2-sided 95% confidence intervals will be 
produced.
Contrasts will be used to produce estimates at individual visits. Other continuous pulmonary 
function endpoints such as morning pre-dose trough and peak post-dose FVC and AUC0-2 for 
FEV1 and FVC will be analysed similarly. Estimated treatment differences will be interpreted 
using 95% CIs, but will not be formally assessed for non-inferiority.
8.5.2.3
Pulmonary Function at Day 1
On Day 1 at the assessment 5 minutes post-dosing, the proportion of patients achieving an 
improvement from baseline in FEV1 of ≥100 ml will be estimated for each treatment. Logistic 
regression will be used to compare the treatment groups with baseline and bronchodilator 
responsiveness to albuterol/salbutamol MDI as continuous covariates and treatment, region 
and stratification factors as categorical covariates. This analysis will use the full analysis set 
and proceed immediately to testing of the superiority hypothesis. One-sided p-values and odds 
ratios with 2-sided 95% CI will be produced.
Similar analyses will be conducted at 5 minutes on day 1 using alternative thresholds (increase 
in FEV1 of ≥150 ml from baseline and increase in FEV1 of ≥12% from baseline).
8.5.2.4
Transition Dyspnea Index Focal Score
The difference between treatment groups in TDI over 24 weeks will be evaluated using a 
similar MMRM approach as for the co-primary endpoints. The model will include BDI (in 
place of baseline) and bronchodilator responsiveness as continuous covariates. Stratification 
factors, region, visit, treatment, and treatment by visit will be included as categorical 
covariates. Patient will be considered a random effect. 
One-sided p-values and point estimates with two-sided 95% CIs will be produced for the 
treatment difference over 24 weeks. Non-inferiority will be concluded if the lower bound of 
this confidence interval is greater than the pre-specified margin of -1.0 units (the minimum 
clinically important difference). Estimates of treatment difference will also be produced at 
each individual timepoint. A supportive analysis will also be produced using the Full Analysis 
Set.
The individual components of the TDI: functional impairment, magnitude of task, and 
magnitude of effort will also be summarised. Furthermore as supportive analyses, responder 
analyses will be performed at each visit, where responders are defined as a response of 1.0 
point or more. Logistic regression will be used to compare the treatment groups with BDI as a 
continuous covariate and treatment group, region and stratification factors as categorical 
covariates. Odds ratios with 95% CIs will be produced.


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8.5.2.5
Early Morning Symptoms COPD Instrument (EMSCI) and Night Time 
Symptoms COPD Instrument (NiSCI)
The difference between treatment groups in the change from baseline in EMSCI symptom 
severity score over 24 weeks will be evaluated using a similar MMRM approach as for the co-
primary endpoints. Instead of visit, the relevant time interval will be used as a categorical 
covariate in the model. The model will include baseline and bronchodilator responsiveness as 
continuous covariates and stratification factors, region, time interval, treatment, and treatment 
by time interval, will be included as categorical covariates. Patient will be considered a 
random effect. 
One-sided p-values and point estimates with two-sided 95% CIs will be produced for the 
treatment difference over 24 weeks. Non-inferiority will be concluded if the lower bound of 
this confidence interval is greater than the pre-specified margin of -0.1 units. Estimates of 
treatment difference will also be produced at each individual time-point. 
If non-inferiority is demonstrated in the Per Protocol analysis then the Full Analysis Set will 
be used to assess the consistency of the non-inferiority conclusion using all evaluable data and 
a similar repeated measures model. This model will be used for the formal assessment of 
superiority hypotheses and 1-sided p-values and 2-sided 95% confidence intervals will be 
produced.
Estimates of treatment differences will be produced similarly for the NiSCI symptom severity 
score. These will be interpreted using 95% CIs, but will not be formally assessed for non-
inferiority. Other sub-scales and responses will be summarised descriptively by treatment 
group.
8.5.2.6
COPD Assessment Test (CAT) score
The difference between treatment groups in the change from baseline in CAT score over 24 
weeks will be evaluated using a similar MMRM approach as for the co-primary endpoints. 
Treatment differences will be interpreted using 95% CIs in relation to a non-inferiority margin 
of 2 units.
Responder analyses will be performed at each visit, where responders are defined as a 
response of 2 units or more. Logistic regression will be used to compare the treatment groups 
with baseline CAT score as a continuous covariates and treatment group, region and 
stratification factors as categorical covariates. Odds ratios with 95% CI will be produced for 
each treatment comparison.
8.5.2.7
Daily Rescue Medication Use
The difference between treatment groups in the change from baseline in mean daily rescue 
albuterol/salbutamol MDI use will be evaluated using a MMRM approach using the Rescue 
Medication User Analysis Set. Instead of visit, the relevant time interval will be used as a 
categorical covariate in the model. The model will include baseline and bronchodilator 
responsiveness as continuous covariates and stratification factors, region, time interval, 
treatment, and treatment by time interval, will be included as categorical covariates. Patient 


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will be considered a random effect. Treatment differences will be interpreted using 95% CIs, 
but will not be formally assessed for non-inferiority.
Additionally daytime and night-time mean albuterol/salbutamol MDI use and the percentage 
of days with ‘no rescue use’ will be evaluated and summarized. 
8.5.3
Subgroup analysis
Subgroup analyses of the co-primary endpoints will be produced according to prior treatment 
at entry (rescue therapy only, single maintenance therapy, LABA/LAMA maintenance 
therapy, LABA/ICS maintenance therapy).
Selected symptomatic endpoints will be analysed within subgroups of patients with varying 
levels of baseline symptom scores as measured by CAT.
Further subgroup analyses may be defined in the SAP.
8.5.4
Interim analysis - Not applicable
No interim analyses are planned for this study.
8.5.5
Sensitivity analysis 
Although the co-primary and secondary endpoints are primarily addressed using estimates of 
the effects over 24 weeks contrasts will also be used to produce estimates at each individual 
visit. 
As described in Section 8.3, the co-primary analyses and all other non-inferiority analyses in 
this study will primarily be conducted using the per protocol analysis set and non-inferiority 
comparisons will also be conducted in the full analysis set to assess consistency when all 
patients and evaluable data are used. 
The methods used primarily in these analyses rely on the assumption that data is missing at 
random (MAR) given the covariates included in the models. Sensitivity analyses will be 
conducted to assess the robustness of conclusions to this assumption, including under Missing 
Not at Random (MNAR) scenarios. 
Multiple imputation methods will be used under varying assumptions about treatment effects 
in the unobserved data and assuming differing effects according to the patterns of missingness 
and reason for withdrawal. Full details will be given in the Statistical Analysis Plan. 
8.5.6
Safety and tolerability
All safety variables will be summarized using the safety analysis set and data presented 
according to treatment received. No hypothesis tests will be performed.
AEs will be summarized by System Organ Class and Preferred Term assigned to the event 
using MedDRA. For each PT, the number and percentage of patients reporting at least one 
occurrence will be presented by treatment group i.e., for a patient multiple occurrences of an 


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AE will only be counted once. SAEs, Deaths, AEs leading to discontinuation (DAEs) and AEs 
deemed causally related to IP by the Investigator will be summarised by treatment group.
8.5.7
Exploratory analysis 
The EQ-5D-5L responses from each dimension and the visual analogue scale (VAS) will be
summarised descriptively by treatment group and period. 
COPD-related and non-COPD-related health resource utilisation will be summarized by 
treatment group. The frequency and rate per year of COPD exacerbations will also be 
summarised.
Time to the first moderate or severe COPD exacerbation will be analysed using Cox 
regression model for the full analysis set. The model will include baseline percent predicted 
FEV1, baseline CAT score, and bronchodilator responsiveness to albuterol/salbutamol MDI as 
continuous covariates and stratification factors (prior treatment - rescue/maintenance 
monotherapy vs double maintenance therapy), COPD exacerbation history, region and 
treatment as categorical covariates (fixed effects). The estimated adjusted hazard ratio for GFF 
relative to UV will be displayed along with the associated Wald two-sided 95% confidence 
interval and p-values. Time to first moderate or severe COPD exacerbation will be displayed 
graphically for each treatment group using a Kaplan-Meier curve. Subjects who did not 
experience a COPD exacerbation will be censored at the Week 24 visit or day 183, whichever 
is earlier. Subjects who withdrew from the study without experiencing a COPD exacerbation 
will be censored at the date of withdrawal.
WPAI-GH responses will be summarised using descriptive statistics by treatment group.
9.
STUDY AND DATA MANAGEMENT
9.1
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the ePRO, eCRF, 
IWRS/IVRS systems utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, 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).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:


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∀
Provide information and support to the Investigator(s)
∀
Confirm that facilities remain acceptable
∀
Confirm that the investigational team is adhering to the Clinical Study Protocol, that 
data are being accurately and timely recorded in the CRFs and that IP accountability 
checks are being performed
∀
Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients. This 
will require direct access to all original records for each patient (e.g., clinic charts)
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the site needs information and advice about the study conduct.
9.2.1
Risk based quality management
Quality by design will be implemented, including a focus on identifying key risks to patient 
safety, data quality, and GCP/regulatory compliance. A risk based approach to monitoring will 
be applied. A mix of monitoring strategies will be implemented: on-site monitoring, remote 
monitoring (site level monitoring activities performed at a location other than the research 
site) and centralized monitoring systems. Monitoring strategies will be tailored to risks, permit 
timely oversight (through central/remote monitoring and use of technology), and will be 
focused on Critical Processes and Critical Data.
Central monitoring will be used to check that data is consistent and complete, identify unusual 
distribution of data, identify higher risk sites to target additional monitoring, and to ensure 
routine review of data is completed in real time.
9.2.2
Source data
The location of source data is defined in the Clinical Study Agreement. The Principal 
Investigator must provide direct access to source data/documents for study-related monitoring, 
audits, IRB/IEC review, and regulatory inspection.
9.2.3
Study agreements
The Principal Investigator at each/the site should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.


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9.2.4
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA).
9.3
Study timetable and end of study
The study is expected to start in Q2 2017 and to end by Q3 2018. The end of the study is 
defined as ‘the last visit of the last patient undergoing the study’.
The expected recruitment period is 6-8 months and AstraZeneca will notify Investigators 
when recruitment is complete.
The study may be terminated at individual sites if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with GFF.
9.4
Data management by AstraZeneca 
Data management will be performed by AstraZeneca Data Management Centre staff at 
Cognizant, according to the Data Management Plan.
The data collected through third party sources will be obtained and reconciled against study 
data.
AEs and medical/surgical history will be classified according to the terminology of the latest 
version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications will be 
classified according to the WHO Drug Dictionary.  All coding will be performed by the 
Medical Coding Team at the AstraZeneca Data Management Centre.
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database and 
eCRF. 


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10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
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 ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
10.3
Ethics and regulatory review
An Ethics Committee should approve the final Clinical Study Protocol, including the final 
version of the Informed Consent Form and any other written information and/or materials to 
be provided to the patients.  The Investigator will ensure the distribution of these documents 
to the applicable Ethics Committee, and to the study site personnel.
The opinion of the Ethics Committee should be given in writing. The Investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study. 
The Ethics Committee should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the Clinical Study Protocol should be re-approved by the 
Ethics Committee annually.
Before enrolment of any patient into the study, the final Clinical Study Protocol, including the 
final version of the Informed Consent Form, is approved by the national regulatory authority 
or a notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements.
For the US and Canada, may also be applicable to other countries: 
Each Principal Investigator is responsible for providing the Ethics Committees/IRB with 
reports of any serious and unexpected adverse drug reactions from any other study conducted 


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with the IP.  AstraZeneca will provide this information to the Principal Investigator so that 
he/she can meet these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) at each site will:
∀
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study
∀
Ensure each patient is notified that they are free to discontinue from the study at any 
time
∀
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided
∀
Ensure each patient 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 patient
∀
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an Ethics Committee.
10.5
Changes to the Clinical Study Protocol and Informed Consent 
Form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a new version of the study protocol.
The new version of the Clinical Study Protocol is to be approved by the relevant Ethics 
Committee and if applicable, also the national regulatory authority approval, before 
implementation.  Local requirements are to be followed for new versions of Clinical Study 
Protocols.
AstraZeneca will distribute any new versions of the Clinical Study Protocol to each Principal 
Investigator(s). For distribution to Ethics Committee see Section 10.3.


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If a change to a Clinical Study Protocol requires a change to a centre’s Informed Consent 
Form, AstraZeneca and the centre’s Ethics Committee are to approve the revised Informed 
Consent Form before the revised form is used. 
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the site, including source data verification.  The purpose 
of an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analysed, and accurately reported according to the Clinical Study Protocol, Good 
Clinical Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), 
and any applicable regulatory requirements.  The Investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the site.
11.
LIST OF REFERENCES 
Anoro™ Ellipta™ prescribing information, 2016. 
Available at https://www.gsksource.com/gskprm/htdocs/documents/ANORO-ELLIPTA-PI-
MG.PDF.  Accessed on 28 Nov 2016.
Bevespi Aerosphere™ prescribing information, 2016. 
Available at https://www.azpicentral.com/bevespi/bevespi_pi.pdf Accessed on 28 Nov 2016.
Buhl et al 2015
Buhl R, Gessner C, Schuermann W, Foerster K, Sieder C, et al. Efficacy and safety of once-
daily QVA149 compared with the free combination of once-daily tiotropium plus twice-daily 
formoterol in patients with moderate-to-severe COPD (QUANTIFY): a randomised, non-
inferiority study. Thorax 2015:70:311-9.
Burman et al 2009
Burman C-F, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni-based multiple tests. Statist. Med. 2009; 28:739-761
Cazzola et al 2010
Cazzola M, Molimard M. The scientific rationale for combining long-acting beta2-agonists 
and muscarinic antagonists in COPD. Pulm Pharmacol Ther. 2010; 23:257-67.
Chapman et al 2014
Chapman KR, Beeh KM, Beier J, et al. A blinded evaluation of the efficacy and safety of 
glycopyrronium a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients 
with COPD: the GLOW5 study. BMC Pulm Med. 2014; 14:4. 


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Donohue 2005
Donohue JF. Minimal clinically important differences in COPD lung function. COPD. 
2005;2:111-24.
Donohue et al 2013
Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and 
safety of once-daily uneclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med. 
2013;107:1538-46.
Dransfield et al 2011
Dransfield, MT, Bailey W, Crater G, O’Dell DM, Yawn B. Disease severity and symptoms 
among patients receiving monotherapy for COPD. Prim Care Respir J 2011; 20: 46-53
D’Urzo et al 2014
Anthony D D’Urzo1, Stephen I Rennard, Edward M Kerwin, Victor Mergel, Anne R 
Leselbaum, Cynthia F Caracta4 on behalf of the AUGMENT COPD study investigators. 
Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate:
the 24-week, randomized, placebo-controlled AUGMENT COPD study. Available at 
http://respiratory-research.com/content/15/1/123, Respiratory Research 2014, 15:123
Duaklir® Genuair® Summary of Product Characteristics 2015
Duaklir® Genuair®, Summary of Product Characteristics. March 2015
GOLD 2017
D’Urzo AD, Rennard SI, Kerwin EM, Mergel V, Leselbaum AR, Caracta CF. Efficacy and 
safety of fixed dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, 
randomised, placebo-controlled AUGMENT COPD study. Respiratory Research 2014; 
15:123-140. Global Initiative for Chronic Obstructive Lung Disease [GOLD]. Global strategy 
for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 
2017. Available at http://www.goldcopd.org.  Accessed on 28 Nov 2017. 
Jones et al 2009
Jones PW, Harding G, Berry P, Wiklund I, et al. Development and First validation of the
COPD Assessment Test. Eur Respir J. 2009; 34: 648-654.
Kalberg et al 2016
Kalberg C, O’Dell D, Galkin D, Newlands A, Fahy W. Dual bronchodilator therapy with UV 
versus tiotropium plus indacaterol in chronic obstructive pulmonary disease: A randomiszed 
controlled trial. Drugs. 2016;16:217-227.


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Mahler et al 1984
The measurement of dyspnea. Contents, interobserver agreement, and physiologic correlates 
of two new clinical indexes.
Mahler DA, Weinberg DH, Wells CK, Feinstein AR.
Chest. 1984 Jun;85(6):751-8.
Mahler et al 2005
Mahler DA, Witek TJ Jr. The MCID of the transition dyspnea index is a total score of one 
unit.  COPD. 2005;2:99-103.
Martinez et al 2016
Martinez FJ, Rabe KF, , Ferguson GT, Fabbri LM, Rennard S et al. Efficacy and safety of 
glycopyrrolate/formoterol MDI formulated using Co-suspension™ delivery technology in 
patients with COPD. Chest. 2017; doi.10.1016/j.chest.2016.11.028. 
Miller et al 2005
Miller MR, Hankinson J, Barbee RA, Goldman MD, Gross NJ, et al. Standardisation of 
spirometry. Eur Respir J. 2005;26:319-338.
Quanjer et al 2012
Quanjer PH, Stanojevic S, Cole TJ, Baur X, L Hall GL, Culver B, Enright PL, Hankinson JL, 
Zheng J, Stocks J and the ERS Global Lung Function Initiative. Multi ethnic reference values 
for spirometry for the 3-95 year age range: the global lung function 2012 equations. Report of 
the Global Lung Function Initiative (GLI), ERS Task Force to establish improved Lung 
Function Reference Values. Eur Respire J. 2012;40(6):1324-43.
Roche et al 2013
Roche et al. Respiratory Research. COPD symptoms in the morning: impact,
evaluation and management 2013, 14:112. Available at http://respiratory-
research.com/content/14/1/112
Stiolto® Respimat® prescribing information 2016 
Available at https://www.docs.boehringer-
ingelheim.com/Prescribing%20Information/.../Stiolto%.pdf. Accessed on 28 Nov 2016.
Utibron™ Neohaler® prescribing information 2016. 
Available at https://www.pharma.us.novartis.com/product/pi/pdf/utibron.pdf. Accessed on 28 
Nov 2016.
Volgelmeier et al 2010
Volgelmeier C, Ramos-Barbon D, Jack D, et al. Indacaterol provides 24-hour bronchodilation 
in COPD: a placebo-controlled blinded comparison with tiotropium. Respir Res. 2010;11:135.


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Wedzicha et al 2016
Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N. et al. Indacaterol-
Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med. 2016; 374: 2222-
34.


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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 patient 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 patient’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
Outpatient treatment in an emergency room is not in itself 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 AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the patient or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
∀
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
∀
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine
∀
Intensive treatment in an emergency room or at home for allergic bronchospasm
∀
Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.


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∀
Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?
∀
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
∀
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?
∀
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
∀
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.
∀
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
∀
Is this a recognized feature of overdose of the drug?
∀
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With 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


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Appendix B
COPD Assessment Test (CAT)


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Appendix C
EuroQol 5 Dimensions Questionnaire (EQ-5D-5L)


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Appendix D
Work Productivity and Activity Impairment Questionnaire -
General Health (WPAI-GH)


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Appendix E
Nighttime Symptoms of COPD Instrument and Early 
Morning Symptoms of COPD Instrument (NiSCI and 
EMSCI)


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Appendix F
Baseline/Transitional Dyspnea Index (BDI/TDI)


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SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D5970C00002
Edition Number
2.0
Date
08 Jun 2018
A Randomised, Double-Blind, Double-Dummy, Multicentre, Parallel Group 
Study to Assess the Efficacy and Safety of Glycopyrronium/Formoterol 
Fumarate fixed-dose combination relative to Umeclidinium/Vilanterol 
fixed-dose combination over 24 Weeks in Patients with Moderate to Very 
Severe Chronic Obstructive Pulmonary Disease (AERISTO)


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Statistical Analysis Plan 
Study Code D5970C00002
Edition Number 2.0
Date 08 Jun 2018
4
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
TABLE OF CONTENTS.....................................................................................4
LIST OF ABBREVIATIONS ..............................................................................7
AMENDMENT HISTORY..................................................................................9
1.
STUDY DETAILS.............................................................................................11
1.1
Study objectives................................................................................................. 11
1.1.1
Primary objective...............................................................................................11
1.1.2
Secondary objectives..........................................................................................11
1.1.3
Safety objectives................................................................................................12
1.1.4
Exploratory objectives .......................................................................................12
1.2
Study design ...................................................................................................... 12
1.3
Number of subjects ............................................................................................13
2.
ANALYSIS SETS .............................................................................................14
2.1
Definition of analysis sets .................................................................................. 14
2.1.1
Efficacy analysis sets .........................................................................................14
2.1.2
Safety analysis sets ............................................................................................ 15
2.1.3
Other analysis sets.............................................................................................. 15
2.2
Violations and deviations ................................................................................... 15
2.2.1
Important protocol deviations.............................................................................15
2.2.2
Other deviations.................................................................................................17
3.
PRIMARY AND SECONDARY VARIABLES.................................................18
3.1
General Definitions............................................................................................ 18
3.1.1
Definition of baseline.........................................................................................18
3.1.2
Visit windows.................................................................................................... 19
3.2
Pulmonary Function Outcomes .......................................................................... 21
3.2.1
Morning pre-dose trough FEV1 ..........................................................................22
3.2.2
Peak FEV1 and Inspiratory Capacity post-dosing................................................22
3.2.3
Increase in FEV1 at 5 minutes post-dosing .........................................................23
3.3
Patient Reported Outcomes ................................................................................ 23
3.3.1
Transition Dyspnea Index (TDI) focal score.......................................................23
3.3.2
Early Morning Symptoms COPD Instrument (EMSCI) and Night Time 
Symptoms COPD Instrument (NiSCI)................................................................ 24


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3.3.3
COPD Assessment Test (CAT) score.................................................................24
3.3.4
Daily rescue medication use...............................................................................25
3.3.5
EuroQol 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L).............................. 25
3.3.6
Healthcare Resource Utilisation .........................................................................26
3.3.7
Work Productivity and Activity Impairment – General Health (WPAI-GH) .......27
3.4
Safety and Tolerability.......................................................................................28
4.
ANALYSIS METHODS....................................................................................28
4.1
General principles.............................................................................................. 28
4.1.1
Statistical considerations....................................................................................29
4.2
Analysis methods...............................................................................................30
4.2.1
Patient disposition..............................................................................................30
4.2.2
Demography data and patient characteristics ...................................................... 30
4.2.3
Prior and concomitant medications.....................................................................31
4.2.4
Extent of exposure .............................................................................................31
4.2.5
Compliance........................................................................................................32
4.2.6
Analysis of the primary variables .......................................................................33
4.2.6.1
Trough FEV1......................................................................................................33
4.2.6.2
Peak FEV1 .........................................................................................................35
4.2.6.3
Hierarchical testing strategy – primary endpoints ...............................................36
4.2.7
Analysis of the secondary variables....................................................................37
4.2.7.1
Hierarchical testing strategy – secondary endpoints............................................38
4.2.7.2
Pulmonary Function over 24 weeks....................................................................39
4.2.7.3
Pulmonary Function at Day 1.............................................................................40
4.2.7.4
Transition Dyspnea Index (TDI) Focal Score .....................................................40
4.2.7.5
Early Morning Symptoms COPD Instrument (EMSCI) and Night Time 
Symptoms COPD Instrument (NiSCI)................................................................ 41
4.2.7.6
COPD Assessment Test (CAT) score.................................................................42
4.2.7.7
Daily Rescue Medication Use ............................................................................42
4.2.8
Safety and tolerability ........................................................................................43
4.2.9
Exploratory analysis...........................................................................................44
5.
INTERIM ANALYSES .....................................................................................44
6.
CHANGES OF ANALYSIS FROM PROTOCOL .............................................44
7.
REFERENCES ..................................................................................................45
8.
APPENDIX .......................................................................................................46
LIST OF TABLES
Table 1
Visit windows for assessments conducted at every visit of Visit 4-
Visit 7 ...................................................................................................19
Table 2
Time windows for FEV1 and FVC assessments.....................................20


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Table 3
Time windows for IC assessments.........................................................20
Table 4
Time period for symptom scores and rescue medication usage ..............21
Table 5
Statistical analyses and analysis populations..........................................37
LIST OF FIGURES
Figure 1
Study flow chart....................................................................................13
Figure 2
Testing hierarchy for primary endpoints................................................36
Figure 3
Sequential testing hierarchy for secondary endpoints.............................39


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LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical
ATS/ERS
American Thoracic Society/European Respiratory Society
AUC
Area Under Curve
BDI
Baseline Dyspnea Index
CAT
COPD Assessment Test
CRF
Case Report Form
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
CSP
Clinical Study Protocol
DAE
Adverse Event Leading to Treatment Discontinuation
EMSCI
Early Morning Symptoms COPD Instrument
ePRO
electronic Patient Reported Outcomes device
EQ-5D-5L
EuroQol 5 Dimensions 5 Levels Questionnaire
FEV1
Forced Expiratory Volume in 1 Second
FVC
Forced Vital Capacity
GFF
Glycopyrronium/ Formoterol Fumarate
GOLD
Global Initiative for Chronic Obstructive Lung Disease
IC
Inspiratory Capacity
ICS
Inhaled Corticosteroids
IP
Investigational Product
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LABA
Long-Acting β2-Agonist
LAMA
Long-Acting Muscarinic Antagonist
MAR
Missing At Random
MCID
Minimum Clinically Important Difference
MDI
Metered Dose Inhaler
MedDRA
Medical Dictionary for Regulatory Activities
NiSCI
Night Time Symptoms COPD Instrument
MCMC
Monte Carlo Markov Chain
MI
Multiple Imputation
MMRM
Mixed effects Model Repeated Measures


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Abbreviation or 
special term
Explanation
MNAR
Missing Not at Random
PN
Predicted Normal
PT
Preferred Term
SAE
Serious Adverse Event
SD
Standard Deviation
SOC
System Organ Class
TDI
Transition Dyspnea Index
TEAE
Treatment Emergent Adverse Event
UV
Umeclidinium/Vilanterol
WHO-DD
World Health Organisation Drug Dictionary
WPAI-GH
Work Productivity and Activity Impairment - General Health


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AMENDMENT HISTORY
Date
Brief description of change
08 Jun 2018
Section 2.2.1: Small edits to the definition of important protocol deviation 
2; small edits to add a location for information detailing data removal due 
to severe site misconduct or duplicated patients.
Section 2.2.2: Additional data exclusion conditions added to exclude pre-
dose spirometry assessments not within required window since GFF 
(active or placebo) dosing in the evening of the day prior to visit or UV 
(active or placebo) dosing in the morning of the day prior to visit from 
per-protocol analyses.   
Section 3.1.1: ePRO baseline definition updated to account for delays 
between ePRO and spirometry completion at Visit 3.
Sections 3.1.1 and 3.1.2: Updated to set the aggregated value as missing 
if at least half of the daily measures/scores within a time period are 
missing, for consistency with Section 3.3.2 and the CSP.  
Section 3.1.2: Small change to refer to Week 4 visit instead of first post 
baseline visit when defining visit windows as post-baseline spirometry is 
conducted on Day 1. Added clarification of how to define time period for 
symptom score parameters and rescue medication usage, if a scheduled 
visit is missing for a patient.
Section 3.3.6: Added clarification of the timeframe used to define the 
number of exacerbations in the rate of COPD exacerbations calculation 
and time to first moderate or severe COPD exacerbation endpoint 
Section 4.1: P-value reporting changed to 4 decimal places for 
consistency with previous Bevespi studies.
Section 4.2.1: The reason for partial data exclusion from the Per Protocol 
analysis set will not be tabulated. This is not applicable, as the Per 
Protocol analysis set is defined at the subject-level. The number of 
patients randomised by region (in addition to country and centre) will be 
summarised in the full analysis set to support the subgroup analyses.
Section 4.2.3: Rescue albuterol/salbutamol MDI will be included in 
medication tables, so reference to omission from tables removed. 
Medications at study entry updated to include medications that stopped 
on the day of visit 1, or within 7 days prior to visit 1. Added clarification 
that the March 2017 version of WHO-DD will be used.
Section 4.2.4: Exposure categories updated.


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Date
Brief description of change
Section 4.2.5: Definition of treatment compliance in ePRO data updated. 
Expected number of inhalations on the last day of treatment redefined for 
visit days. Clarification added so that denominators adjust for half days 
where ePRO data is collected. Added calculations for morning and 
evening compliance.
Section 4.2.6.1: Subgroup analyses added for baseline CAT score and 
smoking status.
Section 4.2.7 and 4.2.7.5: NiSCI non-inferiority margin added.
Section 4.2.7.4: Subgroup analyses updated to be consistent with Section 
4.2.6.1 - smoking status subgroup added.
Section 4.2.7.4 and 4.2.7.6: Cumulative distribution function plots 
wording updated to be produced at week 24 instead of over week 24
Section 4.2.7.5 and 4.2.7.6: References to Section 4.2.7.4 updates to refer 
to Section 4.2.6.1 for subgroup analyses.
Section 4.2.8: Definitions of event rate updated for consistency with 
previous Bevespi studies. Most common AEs percentage threshold 
reduced.
Section 4.2.9: Clarified the 1-sided p-value corresponding to superiority 
assessment.  


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1.
STUDY DETAILS
This statistical analysis plan outlines the analyses to be generated for the global clinical study 
report. 
1.1
Study objectives
1.1.1
Primary objective
Primary Objective:
Outcome Measure:
To assess the effects of Glycopyrronium/ 
Formoterol Fumarate (GFF) relative to 
Umeclidinium/Vilanterol (UV) on lung function 
as measured by trough forced expiratory volume 
in 1 second (FEV1) and peak FEV1 in patients 
with moderate to very severe Chronic 
Obstructive Pulmonary Disease (COPD)
Co-primary endpoints:
! Change from baseline in morning pre-dose trough 
FEV1 over 24 weeks
! Peak change from baseline in FEV1 within 2 
hours post-dosing over 24 weeks
1.1.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To further assess the effects of GFF relative to 
UV on lung function.
Secondary endpoints:
! Onset of action on day 1; proportion of patients 
with increase of FEV1 of ≥100 mL from baseline 
at 5 minutes 
! Peak change from baseline in Inspiratory Capacity 
(IC) within 2 hours post-dosing over 24 weeks
To assess the effects of GFF relative to UV on 
dyspnea
Secondary endpoint:
Transition Dyspnea Index (TDI) focal score over 24 
weeks
To assess the effects of GFF relative to UV on 
symptoms of COPD
Secondary endpoint:
Change from baseline in Early Morning Symptoms 
COPD Instrument (EMSCI) over 24 weeks
Other endpoints:
! Change from baseline in Night Time Symptoms 
COPD Instrument (NiSCI) over 24 weeks
! Change from baseline in daily rescue 
(albuterol/salbutamol metered dose inhaler 
[MDI]) use over 24 week
To assess the effects of GFF relative to UV on 
health-related quality of life
Other endpoint:
Change from baseline in COPD Assessment Test 
(CAT) score over 24 weeks


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1.1.3
Safety objectives
Safety Objective:
Outcome Measure:
To assess the safety of GFF
Adverse events (AEs), serious adverse events (SAEs), 
adverse events leading to treatment discontinuation 
(DAEs)
1.1.4
Exploratory objectives
Exploratory Objective:
Outcome Measure:
To assess health status for COPD patients 
treated with GFF
Change from baseline in EuroQol 5 Dimensions 5 
Levels Questionnaire (EQ-5D-5L) over 24 weeks
To assess overall and COPD-specific 
Healthcare Resource Utilisation and work 
productivity loss for GFF
Health Economics Questionnaire for healthcare 
resource utilisation. 
Time to the first moderate or severe COPD 
exacerbation.
Work Productivity and Activity Impairment - General 
Health (WPAI-GH)
1.2
Study design
This is a phase IIIb randomised, double-blind, double-dummy, multicentre, parallel group, 24 
week study to assess the efficacy and safety of GFF 7.2/4.8 μg fixed-dose combination 2 
inhalations twice daily compared to UV 62.5/25 μg fixed-dose combination 1 inhalation once 
daily in patients 40-95 years of age with moderate to very severe COPD. 
Approximately 1400 patients will be screened, with 1000 patients expected to be randomised 
at approximately 150 sites in a 1:1 scheme to receive GFF or UV treatment. All patients will 
be required to be symptomatic (CAT ≥10) at randomisation (Visit 3). Patients will be stratified
based on incoming COPD treatment at screening: rescue only/maintenance monotherapy 
(long-acting muscarinic antagonist [LAMA] or selective long-acting β2-agonist [LABA] or 
inhaled corticosteroids [ICS] only) vs. double maintenance therapy (LAMA/LABA or 
ICS/LABA). Patients on triple maintenance therapy will not be eligible.
Each patient will undergo a screening period of 1 to 4 weeks (-28 to -9 days). Post-
bronchodilator FEV1 will be tested to determine eligibility and COPD severity. Any treatment 
with ICS, LAMA, LABA and existing rescue medications will be stopped at the screening 
visit. During the screening period, patients will be treated with ipratropium bromide MDI 2 
inhalations 4 times daily and albuterol/salbutamol MDI as needed. Albuterol/salbutamol MDI 
will also be used as rescue medication throughout the 24-week treatment period. 
The first dose of investigational product (IP) will be taken at Visit 3 (Day 1). Since there are 2
different IP inhalers, a double-dummy technique will be applied to ensure the double-blinding 
of the study. Matched placebo to GFF and UV will be present with the same external 
appearance. During the 24-week double-blind treatment period, patients will take 2 inhalations 


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in the morning and in the evening from the GFF inhaler (active or placebo) and 1 inhalation in 
the morning from the UV inhaler (active or placebo). 
After Visit 3, Patients will be evaluated at Visit 4 (Week 4), Visit 5 (Week 12), Visit 6 (Week 
18) and Visit 7 (Week 24) using spirometry and patient reported outcomes. From Visit 2 
onwards, patients will also enter data daily in an electronic Patient Reported Outcomes device 
(ePRO). For patients who remain on treatment throughout the study (i.e., complete Visit 7), a 
follow-up telephone call will be performed approximately 14 days after the last IP dose, in 
order to assess new or ongoing AE (as well as any concomitant medication administered to 
treat the mentioned AE) and COPD exacerbations. 
Patients who discontinue study treatment prior to Week 24 (Visit 7) will complete a Treatment 
Discontinuation/Withdrawal Visit and be withdrawn from the study. A follow-up telephone 
call will be performed approximately 14 days after the last IP dose. No further data will be 
collected. In the event the Treatment Discontinuation/Withdrawal Visit is performed 
approximately 14 days post last IP dosing, a follow-up telephone call will not be required.
The study flow chart is shown in Figure 1 (see below). The study plans are presented in Tables 
1 and 2 of the clinical study protocol (CSP).
Figure 1
Study flow chart
1.3
Number of subjects
1000 patients (500 patients each in the GFF and UV treatment arms) are to be randomised in 
this study. Based upon Phase III studies of GFF, it is estimated that 12% of the patients 
randomised will be excluded from the Per Protocol analysis set, leaving around 440 patients in 
the co-primary non-inferiority analyses. This sample size will provide around 94% power to 
demonstrate that the difference between GFF vs UV in change from baseline in morning pre-
dose trough FEV1 over 24 weeks is greater than the non-inferiority margin of -50 mL. This 
calculation assumes a 1-sided significance level of 2.5% and a true difference of -10 mL. 
Should testing be conducted at a 1-sided significance level of 1.25% then the power would be 
90%. Assumptions regarding variability for the co-primary endpoints are based on experience 
in previous GFF Phase III clinical studies. An effective standard deviation (SD) of 167 mL for 


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the change from baseline in morning pre-dose trough FEV1 over 24 weeks has been assumed. 
This value is based on a per-visit SD of 200 mL and a within-patient (between-visit) 
correlation of 60%. Under these assumptions, for non-inferiority to be achieved the point 
estimate of the difference in pre-dose trough FEV1 over 24 weeks must be above -28 mL
when testing at a 2.5% significance level, or above -24.5 mL when testing at a 1.25% 
significance level. 
For the co-primary endpoint of peak FEV1 over 24 weeks and secondary lung function 
endpoint of peak IC over 24 weeks, the power to show non-inferiority is expected to be at 
least that of the co-primary endpoint of trough FEV1. Assuming an effective SD of 188 mL for 
peak FEV1, and a true difference of 50 mL then 500 patients would provide at least 97% 
power to demonstrate superiority of GFF to UV in peak FEV1 with a 1-sided significance 
level of 1.25%.
For the secondary endpoint of the TDI focal score over 24 weeks a non-inferiority margin of -
1 unit is defined. However, note that the power to show non-inferiority would remain at least 
90% with a margin of -0.75 units (three quarters of the minimum clinically important 
difference [MCID]), assuming no difference between treatments and a standard deviation of 3 
units.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
The co-primary non-inferiority analyses and all other non-inferiority analyses in this study 
will primarily be conducted using the Per Protocol analysis set. This will be used to compare 
GFF and UV when the treatments are used as planned at each visit, in the intended patients 
and without important protocol deviations which may affect efficacy. This will provide an 
estimate of the true biological efficacy of the treatments and counters the tendency for 
intention-to-treat analyses to favour a conclusion of equivalence. Non-inferiority comparisons 
will also be conducted in the full analysis set of all patients receiving randomised IP, allowing 
for variation in clinical application whilst on treatment, as a comparison of their effectiveness 
when used in practice. For selected endpoints this full analysis set will be used to provide an 
assessment of superiority, including for the co-primary analysis of the superiority of GFF 
relative to UV in peak FEV1.
For consistency, demographic and disease-related baseline characteristics will be presented 
using both Per Protocol analysis set and full analysis set.
All Patients Analysis Set
This analysis set comprises all patients screened for the study and may be used for the 
reporting of disposition and screening failures.
2.1.1
Efficacy analysis sets
Full Analysis Set


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The full analysis set will be defined as all patients randomised who received at least 1 
inhalation of IP from the GFF or UV inhaler (active or placebo). Patients will be analysed 
according to the treatment they were assigned to at randomisation, regardless of the treatment 
actually received.  
This analysis set will be used to demonstrate consistency in non-inferiority hypothesis tests 
and as the primary means of assessing superiority hypotheses.
Per Protocol Analysis Set
The Per Protocol analysis set will be used as the primary means of assessing non-inferiority 
hypotheses.
The Per Protocol analysis set is the subset of the full analysis set containing patients with post-
randomisation data obtained prior to important protocol deviations which may affect efficacy. 
Data obtained after such important protocol deviations will be excluded from analyses using 
this set. A detailed definition of the important protocol deviations and data points to be 
excluded are given in Section 2.2. Since receiving the wrong treatment will be a major 
protocol deviation, patients in the Per Protocol analysis set will be analysed as randomised 
(which for this population is identical to analysis by the actual treatment received). 
2.1.2
Safety analysis sets
Safety Analysis Set
All patients who received at least 1 inhalation of the randomised active IP that they were 
assigned to will be included in the safety analysis set. Patients will be classified according to 
the treatment they actually received. If a patient received more than 1 randomised treatment, 
they will be analysed and included in summaries according to the treatment they received the 
most. Any major deviations from the randomised treatment assignment will be listed and 
considered when interpreting the safety data. All safety summaries will be based on this 
analysis set.
2.1.3
Other analysis sets
Rescue Medication User analysis set
Regional differences in rescue albuterol/salbutamol MDI usage are expected with some 
regions using virtually no rescue albuterol/salbutamol MDI at study entry. Therefore, the 
Rescue Medication User analysis set is defined as all patients in the full analysis set with 
average baseline rescue albuterol/salbutamol MDI use of ≥ 1 inhalation/day. 
2.2
Violations and deviations
2.2.1
Important protocol deviations
The following general categories will be considered important protocol deviations and will be 
programmatically derived from the data.
!
Patients without informed consent provided (Deviation 1). 


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!
Patients with a severe COPD exacerbation (requiring hospitalisation) or more than 1
moderate exacerbation (requiring antibiotics or ≥3 days of systemic steroids) who 
did not discontinue IP by the time of next clinical visit or 7 days after the 
investigator was made aware of SAE following a severe exacerbation (Deviation 2).
!
Patients requiring discontinuation from the study due to safety-related reasons who 
were not withdrawn (Deviation 3).
!
Patients who deviate from key entry criteria relating to clinical diagnosis and 
severity of COPD (Deviation 4). These are inclusion criteria 3, 4, 5, 6, 7 and 
exclusion criteria 1 in the CSP version 2. 
!
Patients with treatment compliance in complete study period <70% or >130% for 
either the GFF or UV inhaler (Deviation 5).
!
Patients who do not have the required washout of prohibited medications prior to 
baseline (Deviation 6). Please refer to CSP Section 7.7 for minimum washout 
periods. Exclusion criteria, the anatomical therapeutic chemical (ATC) codes and 
additional physician reviews will be used to identify the medications, where 
possible. Specifically:
∀
Insufficient washout of prohibited COPD medications in CSP Table 8 except 
for short acting and ephedrine-containing medications. Theophylline or other 
xanthines are not considered an important protocol deviation if taken as a 
stable low dose prior to and throughout the study as defined in CSP Table 6.  
∀
Insufficient washout of any other investigational drug, any monoclonal or 
polyclonal antibody or strong CYP3A4 inhibitors with washout as defined in 
CSP Table 9.
∀
Insufficient washout of systemic corticosteroids, other than a stable dose of an 
equivalent of 5 mg prednisone per day or 10 mg every other day, as per CSP 
Table 6.
!
Patients who use certain prohibited or restricted medications outside of the 
limitations (Deviation 7). Please refer to CSP Section 7.7 for the permitted usage 
and restrictions of the medications during the study. Medications will be identified 
using ATC codes and additional physician reviews. Specifically:
∀
The initiation of prohibited COPD medications in CSP Table 8 on or after Visit
2 except for short acting and ephedrine-containing medications. The initiation 
of theophylline or other xanthines is not considered an important protocol 
deviation if taken as a stable low dose prior to and throughout the study as 
defined in CSP Table 6 or if used to treat a COPD exacerbation for ≤14 days as 
per CSP Table 10. The ICS use to treat a COPD exacerbation for ≤14 days is 
allowed.  


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∀
The initiation of any other investigational drug or any monoclonal or 
polyclonal antibody after Visit 1, or of strong CYP3A4 inhibitors used for >4 
weeks after Visit 3, as included in CSP Table 9.
∀
The initiation of systemic corticosteroids and phosphodiesterase-4 inhibitors 
throughout the study, unless at a stable dose prior to and throughout the study 
as defined in CSP Table 6. The use of systemic corticosteroids to treat a COPD 
exacerbation for ≤14 days is allowed.
∀
The use of antibiotics to treat a COPD exacerbation for >14 days, as per CSP 
Table 10.
!
Patients who received IP other than that to which they were randomised to
(Deviation 8). 
The important protocol deviations will be listed and summarised by randomised treatment 
group. Some of these deviations that may affect efficacy will lead to exclusion of all data from 
a particular patient from the Per Protocol analysis set (Deviations 4, 5, 6), or require exclusion 
of data from the time point of deviations onwards from analyses using the Per Protocol 
analysis set (Deviations 7, 8). Deviations 1, 2, 3 above will not lead to any exclusion from the 
Per Protocol analysis set. None of the deviations will lead to patients or data points being 
excluded from other analysis sets described in Section 2.1.
In the case of severe site misconduct or duplicated patients (those included in the study more 
than once) it may be appropriate to remove sites, patients, or repeated patient information 
from the reporting of the trial, however this must be assessed dependent on the individual 
circumstance, and would be detailed prior to unblinding in a formal file note and in the 
documentation detailing the finalization of important protocol deviations as approved by 
AstraZeneca.
2.2.2
Other deviations
In addition to the important protocol deviations, patients with the following deviations will 
have their data from the affected visits removed from Per Protocol analyses of pulmonary 
function outcomes:
!
Patients who do not take the correct morning and evening doses of blinded study 
inhalers (both GFF and UV, active or placebo) on the day preceding a study visit.
!
Patients who do not comply with required restrictions prior to spirometry. The 
restrictions are: patient was not to smoke for at least 1 hour prior to study visit;
patient was not to have rescue albuterol/salbutamol MDI or their screening period 
ipratropium bromide MDI (please refer to CSP Table 7) for at least 6 hours prior to 
study visit; patient was not to take IP in the morning prior to study visit during the 
treatment period. 


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The spirometry assessments at each post-baseline visit with the deviations below will be 
excluded from the Per Protocol analyses of pre-dose trough change from baseline endpoints in 
Section 3.2.1. Only assessments with non-missing time from IP dosing the previous day will 
be considered for exclusion.
!
Pre-dose 60 min assessments (i.e. ≥45 min prior to IP dosing at the visit) that are 
not within 11±1.5 hours of GFF (active or placebo) dosing in the evening of the day 
prior to visit or not within 23±1.5 hours of UV (active or placebo) dosing in the 
morning of the day prior to visit. 
!
Pre-dose 30 min assessments (i.e. <45 min and ≥0 min prior to IP dosing at the 
visit) that are not within 11.5±1.5 hours of GFF (active or placebo) dosing in the 
evening of the day prior to visit or not within 23.5±1.5 hours of UV (active or 
placebo) dosing in the morning of the day prior to visit. 
The deviations in sections above will be programmatically determined. In addition, 
monitoring notes or data listings will be reviewed to ensure that no other important protocol 
deviations need to be derived, and to check that those identified via programming are correctly 
classified. The final classification of important protocol deviations and other deviations 
relating to single visits and assessments will be made prior to database lock. Decisions made 
will be documented and approved by AstraZeneca prior to unblinding of the data.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
General Definitions
3.1.1
Definition of baseline 
All efficacy assessments are relative to pre-dose baseline obtained at randomisation at Visit 3.
If there is no pre-dose value at Visit 3, then the baseline value will not be imputed and will be 
set to missing. No data known to be collected post first dose will be used in determining the 
baseline value.
For spirometry endpoints the mean of all available evaluable (meeting ATS/ERS criteria for 
acceptability) -60 and -30 minute pre-dose spirometry assessments conducted at Day 1 (Visit 
3) will be used to establish baseline for all FEV1, forced vital capacity (FVC), and IC 
parameters. If patients missing either of these pre-dose assessments, the baseline value will be 
calculated from the single measurement. In patients missing both pre-dose values, the 
spirometry assessments from the screening period will not be used and the baseline will be set 
to missing. 
For the diary symptom score parameters and rescue medication usage, baseline will be the 
average of the non-missing values from the ePRO data collected in the last 7 days before 
randomisation (i.e. excluding data recorded on the day of Visit 3). If at least half of the daily 
measures/scores within that period are missing, then baseline will be set to missing.


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For TDI/Baseline Dyspnea Index (BDI), CAT, EQ-5D-5L and WPAI-GH, the latest pre-dose 
assessments at randomisation (Visit 3) or during the 7 days prior to randomisation will be 
used as the respective baselines.
3.1.2
Visit windows
For endpoints that present visit-based data, variables will be summarised according to the 
protocol-scheduled week for that visit. Data collected in spirometry and ePRO systems will be 
allocated to visit weeks based upon assigned windows so as to allow rescheduled assessments 
to be included.
The windows for the visits following baseline will be constructed in such a way that the upper 
limit of the interval falls half way between the 2 visits (the lower limit of the Week 4 visit will 
be Day 2). If an even number of days exists between 2 consecutive visits then the upper limit 
will be taken as the midpoint value minus 1 day. Visit windows are constructed so that every 
observation collected can be allocated to a particular visit. No visit windows will be defined 
for screening visits. Listings will display all values contributing to a visit week for a patient.
The visit windows for assessments conducted at every visit of Visit 4-Visit 7 are summarised
in Table 1. 
Table 1
Visit windows for assessments conducted at every visit of Visit 4-Visit 7
Protocol-Scheduled Visit Week
Target Study Day
Visit Windows
Week 0 / Baseline
1 
Study Day = 1 
Week 4 
29 
2 ≤ Study Days ≤ 56
Week 12 
85 
57 ≤Study Days ≤105
Week 18
127
106 ≤Study Days ≤147
Week 24 
169 
148 ≤Study Days 
For assignment of data to visit windows, study day will be defined as follows:
(Date of assessment – date of randomisation) +1
By this definition, the day of randomisation will be study day 1 and the planned date of Visit 4
(Week 4) will be study day 29 (=28+1), for example.  
For visit-based patient reported outcomes, if multiple assessments are recorded within a single 
visit window, please refer to the rules below. 
!
If there are 2 or more observations within the same visit window, then the non-
missing observation closest to the scheduled visit will be used in the analysis. 
!
If 2 observations are equidistant from the scheduled visit, then the non-missing 
observation with the later collection date will be used in the analysis. 


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!
If 2 observations are collected on the same day then the non-missing observation 
with the later collection time will be included in the analysis. 
For spirometry assessments, multiple assessments pre and post dosing will be conducted at 
each scheduled visit. The non-missing values that have at least 1 effort that meets ATS/ERS 
criteria for acceptability will contribute to the analysis. The ATS/ERS criteria (as described in 
Section 3.2) will be applied in order to select the representative value from a series of repeat 
efforts before assigning the windows. 
If multiple assessments with acceptable quality after applying the ATS/ERS criteria but with 
different study days are recorded within a single visit window, please refer to the rules below.  
!
If there are 2 or more study days within the same visit window, then the study day
closest to the scheduled visit will be chosen and observations with acceptable 
quality on that study day will be used in the analysis. 
!
If 2 study days are equidistant from the scheduled visit, then the study day with the 
later collection date will be chosen and observations with acceptable quality on that
study day will be used in the analysis. 
Additionally, the spirometry assessments at each visit will be allocated to the derived nominal 
collection time windows using the time intervals specified in Table 2 and Table 3.
Table 2
Time windows for FEV1 and FVC assessments
Protocol-Scheduled Collection Time
Time Windows of Minutes from IP dosing
Pre-dose 60 min
Time ≤- 45
Pre-dose 30 min
-45 < Time ≤0
Post-dose 5 min
0 < Time < 10
Post-dose 15 min
10 ≤Time < 23
Post-dose 30 min
23 ≤Time < 45
Post-dose 1 hour
45 ≤Time < 90
Post-dose 2 hours
90 ≤Time < 180
Table 3
Time windows for IC assessments
Protocol-Scheduled Collection Time
Time Windows of Minutes from IP dosing
Pre-dose 60 min
Time ≤- 45
Pre-dose 30 min
-45 < Time ≤0
Post-dose 1 hour
0 < Time < 90
Post-dose 2 hours
90 ≤Time < 180
If multiple spirometry values with acceptable quality for the same parameter are recorded 
within a single time window, then the closest value (in minute and second) to the scheduled 


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time point will be used in the analysis, with the exception of peak change from baseline 
endpoints in Section 3.2.2 which are derived using all spirometry values with acceptable 
quality from the time of IP dosing to the end of the post-dose 2 hour time window.   
If a visit window or a time window does not contain any observations, then the data will 
remain missing. 
For Per Protocol analyses, data with important protocol deviations and other deviations 
relating to spirometry outcomes will not be considered when choosing observations in a visit 
or a time window for the parameters. These deviations and corresponding data exclusion are 
specified in Section 2.2. For spirometry outcomes, time windows will only be applied once 
both the ATS/ERS criteria have been applied and the data with deviations in Section 2.2 are
excluded. 
For symptom score parameters and rescue medication usage, the daily measurements will be 
aggregated based upon the time periods between clinic visits as specified in Table 4. Data 
from the day of the clinic visit will not be used. The definition of time period will depend on 
the actual days of the scheduled visits (as date of visit – date of randomisation + 1), instead of 
the scheduled days for those visits (i.e. allowing for the variation of ±3 days for a visit 
schedule). Scheduled visits will be used to define the time periods, and if a scheduled visit is 
missing for a patient, the scheduled day for that visit (for example Day 29 for Week 4; refer to 
target day in 1) will be used for the lower or upper limit of the corresponding time period. If 
data is collected on the scheduled day of visit used to define the upper or lower limit of the 
time period, it will not contribute to the aggregate value for either time period.     
If at least half of the daily measures/scores within a time period are missing, then the 
aggregated measures/scores for that period will be set to missing.
Table 4
Time period for symptom scores and rescue medication usage
Between Clinic Visits
Time Period
Baseline
-7 ≤ Study Days ≤ -1
Week 0 – Week 4
2 ≤ Study Days ≤ (Day of Visit 4) -1
Week 4 – Week 12
(Day of Visit 4) +1 ≤Study Days ≤(Day of Visit 5) -1
Week 12 – Week 18
(Day of Visit 5) +1 ≤Study Days ≤(Day of Visit 6) -1
Week 18 – Week 24
(Day of Visit 6) +1 ≤Study Days ≤(Day of Visit 7) -1
3.2
Pulmonary Function Outcomes
All pulmonary function assessments that have at least 1 effort that meets ATS/ERS criteria for 
acceptability will be considered in the following steps to select a value at each time-point to 
be used in the analyses. The ATS/ERS criteria will be applied before assigning the visit or 
time windows. 


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!
For FEV1 and FVC, the largest acceptable and reproducible result from each set of 
repeat efforts at a protocol-scheduled time-point will be used in analyses. If 
reproducibility cannot be achieved then the largest result meeting acceptability 
criteria will be taken.
!
For IC, after the removal of unacceptable efforts, if all remaining efforts are 
acceptable and reproducible results and there are at least 3 results, then the average 
of these will be used in analyses. If acceptability and reproducibility cannot be 
achieved for all remaining efforts, then the average of the results meeting 
acceptability criteria will be taken.
!
If all the assessments at a specific time-point were deemed to be of unacceptable 
quality the pulmonary function assessments obtained at the time-point will not be 
included in any analyses and will be considered missing.
Further requirements specified in Section 2.2 will have to be met in addition to the ATS/ERS 
criteria in order for pulmonary function data to be used in the Per Protocol analyses.
3.2.1
Morning pre-dose trough FEV1
The co-primary endpoint of change from baseline in morning pre-dose trough FEV1 is defined 
as the average of the -60 and -30 minute pre-dose values at each visit minus baseline. Baseline 
is defined as the average of the non-missing -60 minute and -30 minute values obtained prior 
to dosing at Visit 3.
In patients missing either of these pre-dose assessments, the morning pre-dose trough FEV1
will be calculated from a single measurement. In patients missing both pre-dose values, the 
morning pre-dose trough FEV1 at that visit will not be calculated.
The change from baseline in morning pre-dose trough FVC will be derived similarly.
3.2.2
Peak FEV1 and Inspiratory Capacity post-dosing
The co-primary endpoint of peak change from baseline in FEV1 is defined as the maximum of 
the FEV1 assessments within the up to 2 hours post-dosing time windows (Table 2) at each 
visit minus baseline. Similarly, the secondary endpoint of peak change from baseline in IC is 
defined as the maximum of the IC assessments within the up to 2 hours post-dosing time 
windows (Table 3) at each visit minus baseline.
Further additional spirometry endpoints will also be derived. Peak change from baseline in 
FVC within 2 hours post-dose will be derived similarly to peak FEV1. The trapezoidal rule 
will be used to derive estimates of AUC0-2 for FEV1 and FVC at each visit, normalised by time 
from first to last non-missing value used in the derivation, as long as there are at least 2 non-
missing time points during the first 2 hours post-dose time windows (Table 2). The derivation 
of AUC0-2 endpoints will consider the spirometry time windows to use only those spirometry
values selected within each time window. When applying the trapezoidal rule, change from 
baseline values at each time point will be used with their actual time of evaluation, and the 


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value at time 0 will be the average of -60 and -30 minute pre-dose trough values at that visit 
for the parameter. 
3.2.3
Increase in FEV1 at 5 minutes post-dosing
To assess the early onset of action, a secondary endpoint of this study will be the proportion of 
patients with increase of FEV1 of ≥100 mL from baseline at 5 minutes on day 1. Only data 
assigned to the 5 minute window will be used to determine response. Patients with missing 
data will be considered to be non-responders for the analysis.
Additional categorical endpoints will be derived similarly as the proportion of patients with 
increase of FEV1 of ≥150 mL from baseline at 5 minutes and the proportion of patients with 
increase of FEV1 of ≥12% from baseline at 5 minutes. In addition the change from baseline in 
FEV1 at each post-dose timepoint in Table 2 on day 1 will also be derived.
3.3
Patient Reported Outcomes
3.3.1
Transition Dyspnea Index (TDI) focal score
As a secondary endpoint assessing dyspnea, the TDI focal score will be derived at post-
randomisation visits relative to the baseline severity of dyspnea assessed using the BDI at 
Visit 3. The BDI/TDI is an instrument developed to provide a multidimensional measure of 
dyspnea in relation to activities of daily living. The BDI and TDI consist of 3 individual 
components: functional impairment, magnitude of task, and magnitude of effort. For the BDI, 
each of these 3 components are rated in 5 grades from 0 (i.e. very severe) to 4 (i.e. no 
impairment), and are summed to form a baseline total score from 0 to 12. For the TDI, 
changes in dyspnea are rated for each component by 7 grades from -3 (major deterioration) to 
+3 (major improvement), and are added to form a TDI focal score from -9 to +9. For the TDI, 
at each visit, if a response to any of the 3 questions is missing, then the focal score will also be 
considered missing. Otherwise, scoring and handling of missing items will be conducted in 
accordance with the user’s guide for the TDI score.
The percentage of patients achieving the threshold of 1 unit or more in TDI focal score will be 
derived at each visit:
!
TDI focal score ≥ 1 → Improvement
!
-1 < TDI focal score < 1 → No change
!
TDI focal score ≤ -1 → Deterioration
For the TDI responder analyses, responders will be defined as patients with TDI focal scores 
categorised as improvement. Patients with missing data will be considered to be non-
responders for the analyses.


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3.3.2
Early Morning Symptoms COPD Instrument (EMSCI) and Night Time 
Symptoms COPD Instrument (NiSCI)
Patients will complete a daily ePRO questionnaire for their COPD symptoms with 2 parts 
covering symptoms “last night” and “this morning”.
The EMSCI collects data about the frequency and severity of early morning symptoms and the 
impact of COPD symptoms on early morning activity in patients with COPD. 
The NiSCI collects data about the frequency and severity of night-time symptoms and the 
impact of COPD symptoms on night-time awakenings in patients with COPD.
The change from baseline in the 6-item EMSCI Symptom Severity Score is a secondary 
endpoint. The endpoint is derived by averaging the responses from a patient on the 6 item-
level symptom scores (scored on a 4-point scale from 1 to 4); if the response to any score is 
missing, then the derived value will be considered missing.
The change from baseline in the 6-item NiSCI Symptom Severity Score will be derived 
similarly. 
The change from baseline in the Overall COPD Symptom Severity scores (a single item 
asking about overall severity on a 5-point scale from 0 to 4) in the early morning and at night, 
Early Morning Activity score and Night-time Awakenings score (number of times the patient 
woke up during the night due to COPD symptoms) will also be derived.
Each daily measure will be aggregated based upon the time periods between clinic visits. Data 
from the day of the clinic visit will not be used in these aggregates, because IP is not taken in 
the morning on these days. The time periods are specified in Section 3.1.2. If the measure is 
available on more than half of the days in a given period then an aggregate score will be 
computed as the average of all present daily values. Otherwise the score will be considered 
missing for that period. ePRO data recorded during the last 7 days of the screening period 
prior to Visit 3 will be used to calculate the baseline.
3.3.3
COPD Assessment Test (CAT) score
The COPD Assessment Test (CAT) is used to quantify the impact of COPD symptoms on 
health status. The CAT has a scoring range of 0-40, and it is calculated as the sum of the 
responses given for each of the 8 items (scored on a 6-point scale from 0 to 5), with higher 
scores indicating a higher impact of COPD symptoms on health status. If the response to 1 of 
the 8 items is missing, the missing item will be considered equal to the average of the 7 non-
missing items for that patient. If more than 1 item is missing the score will be considered 
missing.
The change from baseline in CAT score will be derived at each visit relative to the baseline at 
Visit 3. The percentage of patients achieving a MCID threshold for CAT of 2 units or more 
will be derived at each visit:


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!
CAT score (change from baseline) ≤-2 → Improvement
!
-2 < CAT score (change from baseline) < 2 → No change
!
CAT score (change from baseline) ≥2 → Deterioration
A CAT responder at the visit will be defined as a patient who had improvement based on the 
change from baseline in CAT score. Patients with missing data will be considered to be non-
responders for the analyses.
3.3.4
Daily rescue medication use
The number of inhalations of rescue albuterol/salbutamol MDI will be recorded in the patient 
ePRO in the morning and evening. The mean daily number of inhalations of rescue 
albuterol/salbutamol MDI will be calculated overall and in the time periods between each 
clinic visit. These periods are specified in Section 3.1.2. ePRO data recorded during the last 7 
days of the screening period prior to randomisation will be used to calculate the baseline. 
Change from baseline in mean daily rescue (albuterol/salbutamol MDI) use will then be 
derived. The denominator will be adjusted based on the number of days (or half days) with 
non-missing values (for example, a half day for daily number of inhalations if only daytime or 
night-time use is recorded on that day). The mean daytime and night-time rescue use and 
change in these parameters from baseline will be derived similarly. 
A ‘day with no rescue use’ is defined from days where rescue albuterol/salbutamol MDI usage 
data is non-missing as any day where the patient reported no inhalations of rescue 
albuterol/salbutamol MDI in both the morning and evening. The percentage of days with no
rescue use will be derived using a denominator of the number of full days in the period with 
no missing data. 
3.3.5
EuroQol 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L)
The EQ-5D-5L questionnaire assesses 5 dimensions which will be derived separately: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension 
has 5 response options (no problems, slight problems, moderate problems, severe problems, 
and extreme problems) that reflect increasing levels of difficulty. A unique EQ-5D health state 
is referred to by a 5 digit code allowing for a total of 3125 health states. For example, state 
11111 indicates no problems on any of the 5 dimensions. Utility values will be calculated by 
mapping the EQ-5D-5L descriptive system data onto the EQ-5D-3L valuation set. Mapping 
function developed by Van Hout et al 2012 et al will be used for the calculation.
The patient will also be asked to rate current health status on a visual analogue scale from 0 to 
100, with 0 being the worst imaginable health state. The change from baseline in visual 
analogue scale will be calculated.


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3.3.6
Healthcare Resource Utilisation 
Broad-based health care utilisation event information will be collected by the 
Investigator/authorised delegate via patient interview at each visit and recorded in the case 
report form (CRF) modules. 
The number of days/times the following resources were utilised due to COPD-related and
non-COPD-related events will be presented for each patient:
!
Ambulance transport
!
Hospitalisation, intensive care (days in intensive care)
!
Hospitalisation, general care (days in general care)
!
Emergency room visit
!
Hospital admission or emergency department lasting over 24 hours
!
Visit to specialist
!
Visit to primary health care physician
!
Other health care visit
!
Home visit, physician
!
Home visit, other health care
!
Telephone call to physician
!
Telephone call to nurse
!
Telephone contact with other physician/health care provider
!
Spirometry
!
Advanced pulmonary function test
!
Plain chest X-ray
!
Computer tomography
!
Oxygen treatment initiated
The number of moderate COPD exacerbations (defined as those requiring antibiotics or ≥3 
days of systemic steroids) or severe COPD exacerbations (defined as those leading to in 


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patient hospitalisation, including >24 hours in emergency department/urgent care setting) will 
also be recorded.
The rate per year of COPD exacerbations in each treatment group will be calculated as (the
total number of exacerbations from the date of randomisation to Visit 7 or Treatment 
Discontinuation/Withdrawal Visit, whichever occurs, *365.25) divided by the total duration of 
exposure to randomised IP within the treatment group. Exacerbations will be considered as 
separate events provided that 7 or more days are between the recorded stop date of the earlier 
event and start date of the later event. Time during an exacerbation or in the 7 days following 
an exacerbation will not be included in the calculation of exposure for the denominator. The 
rate per year of moderate and severe COPD exacerbations will be calculated similarly.
Time to the first moderate or severe COPD exacerbation will be defined as the time from the 
date of randomisation until the start date of the first moderate or severe COPD exacerbation
up to Visit 7 or Treatment Discontinuation/Withdrawal Visit, whichever occurs. Patients who 
have completed the treatment period and not experienced such an exacerbation will be 
censored at the date of Visit 7 (Week 24) or Day 183, whichever is earlier. Patients who 
withdrew from the study without experiencing a moderate or severe COPD exacerbation will 
be censored at the date of study withdrawal. 
3.3.7
Work Productivity and Activity Impairment – General Health (WPAI-GH)
The WPAI-GH will be used to measure self-reported productivity loss and consists of 
questions on COPD impact on patient’s general health, ability to work and perform regular 
activities in daily living within 7 days.
There are a maximum of 6 questions that will be completed by patients.
Q1 = currently employed (yes/no)
Q2 = hours missed work due to health problems
Q3 = hours missed work due to other reasons
Q4 = hours actually worked
Q5 = degree health affected productivity while working (0-10 scale, with 0 meaning no effect)
Q6 = degree health affected regular activities (other than work) (0-10 scale, with 0 meaning 
no effect)
If the answer to question 1 is ‘No, not currently employed’, then the patient should skip to 
question 6. 
Measures summarised will include the patient’s work time missed (absenteeism), impairment 
at work or reduced on-the-job effectiveness (presenteeism), overall work impairment 
(absenteeism and presenteeism, ie, work productivity loss), and activity impairment outside 


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the work environment. The WPAI-GH outcomes are expressed as impairment percentages 
whereby higher scores indicate greater impairment and less productivity (i.e. worse 
outcomes).
The following calculations will be used to create the outcomes of interest:
!
Number of work hours missed = Q2
!
Absenteeism = Q2/(Q2+Q4)
!
Presenteeism = Q5/10
!
Work Productivity Loss = Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)]
!
Activity Impairment = Q6/10
3.4
Safety and Tolerability
Adverse events experienced by the patients will be collected throughout the entire study and 
will be coded by the AstraZeneca designee using the latest version of the Medical Dictionary 
for Regulatory Activities (MedDRA). A treatment emergent adverse event (TEAE) is an AE
with an onset date on or after the first dose date of randomised treatment through the end of 
the study. 
AEs that have missing causality will be assumed to be related to study drug. AEs with missing 
maximum intensity will be deemed as severe events. The handling of partial/missing dates for 
AEs is detailed in Appendix II.
4.
ANALYSIS METHODS
4.1
General principles
Summary data will be presented in tabular format by treatment group. Categorical data will be 
summarised by the number and percentage of patients in each category. Continuous variables 
for parametric data will be summarised by descriptive statistics including N, mean, SD, 
median, and range. Data listings will be sorted by treatment group and patient number.
Minimum and maximum values will be reported to the same degree of precision as the raw 
data unless otherwise stated. Mean, median, SD and confidence intervals (CIs) will be 
reported to 1 further degree of precision. For categorical data, percentages will be rounded to 
1 decimal place. All p-values will be nominal (i.e., not multiplicity adjusted) and will be 
rounded to 4 decimal places.
The data analyses will be conducted using the SAS® System (SAS Institute Inc., Cary, NC). 


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The change from baseline is computed as (post-baseline value – baseline value). Percent 
change from baseline is computed as ((post-baseline value – baseline value)/baseline value) × 
100%. If either a post-baseline value or the baseline value is missing, the change from 
baseline value and the percent change from baseline will also be set to missing. Additional 
details regarding the definition of baseline are provided in Section 3.1.1.
4.1.1
Statistical considerations
The primary objective of this study is to assess the effects of GFF relative to UV on lung 
function. This will be addressed by the following co-primary hypothesis tests: 
!
non-inferiority of GFF relative to UV in the change from baseline in morning pre-
dose trough FEV1 over 24 weeks; 
!
non-inferiority of GFF relative to UV in the peak change from baseline in FEV1
within 2 hours post-dosing over 24 weeks;
!
superiority of GFF relative to UV in the peak change from baseline in FEV1 within 
2 hours post-dosing over 24 weeks.
The non-inferiority null (H0) and alternative (H1) hypotheses, with μ representing the mean 
change from baseline in each treatment group, correspond to a null hypothesis of inferiority 
and an alternative hypothesis of non-inferiority, as follows: 
H0: μGFF – μUV ≤ -Δ 
(GFF is inferior to UV by Δ or more)
H1: μGFF – μUV > -Δ 
(GFF is inferior to UV by less than Δ)
The non-inferiority analysis for each endpoint is assessed within a Per Protocol analysis set 
and if non-inferiority is demonstrated the consistency of this conclusion will be assessed 
within the full analysis set.
If non-inferiority is demonstrated, then for selected endpoints superiority hypotheses will also 
be addressed within the full analysis set. Here the null (H0) and alternative (H1) hypotheses are 
as follows: 
H0: μGFF – μUV ≤ 0 
(GFF is not superior to UV) 
H1: μGFF – μUV > 0 
(GFF is superior to UV)
The exception to this sequential testing of non-inferiority followed by superiority is the 
analysis of the proportion of patients with increase in FEV1 of ≥100 mL from baseline at 5 
minutes. For this endpoint testing will immediately be in terms of superiority hypotheses.
P-values will be reported as 1-sided for both the non-inferiority and superiority hypothesis 
testing. This will equivalently be presented by comparing the lower bound of CIs to the pre-
specified margin. Further details of the hierarchical testing strategy are given in Sections 
4.2.6.3 and 4.2.7.1.


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The stratification factor for prior treatment in the statistical modelling will be based on the 
values in Interactive Web/Voice Response System (IWRS/IVRS) at randomisation, even if it 
is subsequently discovered that these values were incorrect.
4.2
Analysis methods
4.2.1
Patient disposition
Patient disposition will be summarised using the all patients analysis set. The total number of 
patients will be summarised for the following groups: those who enrolled and those who were 
not randomised (and reason). The number and percentage of patients within each treatment 
group will be presented by the following categories; randomised, received treatment with 
study drug, did not receive treatment with study drug (and reason), completed treatment with 
study drug, discontinued treatment with study drug (and reason), completed study, and 
withdrawn from study (and reason).
The number of randomised patients who were included in each analysis set will be displayed. 
The reason for exclusion from the Per Protocol analysis set of a patient due to important 
protocol deviations will be listed and tabulated, in addition to any patients excluded from 
other analysis sets. 
The time to withdrawal from the study will be presented using the Kaplan Meier plot for the 
full analysis set and the Per Protocol analysis set.
The number of patients randomised by region, country and centre will be summarised by 
treatment group in the full analysis set.
4.2.2
Demography data and patient characteristics
Demography data such as age, gender, race, and ethnicity will be summarised by treatment 
group for all patients in the full analysis set and the Per Protocol analysis set. Age will be 
derived from the date of informed consent minus date of birth, rounded down to the nearest 
integer. For patients in a country where date of birth is not recorded the age as recorded in the 
CRF will be used.
Various baseline characteristics will also be summarised by treatment for the full analysis set 
and the Per Protocol analysis set. These include patient characteristics (weight, height and 
BMI), pre and post bronchodilator lung function data at screening visit 2 and/or at baseline 
(i.e. FEV1, FVC, FEV1/FVC, bronchodilator responsiveness), and COPD-related disease 
characteristics such as smoking status, CAT score, COPD severity and duration, age at onset 
of COPD, and COPD exacerbation history.  
Medical and surgical histories will be summarised by MedDRA Preferred Term (PT) within 
MedDRA System Organ Class (SOC) for the full analysis set.
Summaries of stratification factors as per IWRS/IVRS will be provided for the full analysis 
set and the Per Protocol analysis set. 


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4.2.3
Prior and concomitant medications
Medications recorded during the study will be classified into the following periods:
!
Prior: Medications with stop date on or before the date of randomisation
!
Concomitant: Medications with start date < the last day of IP and stop date > the 
date of randomisation  
!
Post–treatment: Medications with start date ≥the last day of IP
The handling of partial or missing dates for medications is detailed in Appendix II.
The number and percentage of patients who received each concomitant medications (by 
Anatomical Therapeutic Chemical [ATC] classification system codes and generic name) will 
be presented by treatment group for the full analysis set. Concomitant medications will be 
tabulated separately for those which are potentially prohibited/restricted and those which are 
allowed medications. Any prior (with the exception of medications at entry) or post-treatment 
medication will be included in the medication listing, but will not be included in the summary 
tables.
Prohibited/restricted medications will be defined following a physician review (prior to 
database lock) of the unique combinations of ATC code classifications and generic terms 
captured. Concomitant medication tables will not consider usage or washout criteria of 
prohibited/restricted medications, as defined in CSP Tables 6, 8, 9 and 10, only the identified 
medication or class. Randomised treatment will not be included in the medication tables.  
The number and percentage of patients who received COPD and non-COPD treatment at entry
will be summarised by treatment group for the full analysis set separately. These include 
medications with start date < the date of Visit 1 and stop date ≥ (the date of Visit 1 - 7). COPD 
treatment at entry will additionally be tabulated based on the Per Protocol analysis set. Non-
COPD treatment at entry will be tabulated by ATC codes only. Medications at entry will be 
flagged in the medication listing.
Medications will be classified according to the March 2017 version of the World Health 
Organisation Drug Dictionary (WHO-DD). Percentages will be calculated relative to the 
number of patients in the corresponding analysis set.
4.2.4
Extent of exposure
Extent of exposure summaries will be provided for the safety analysis set. The number of days 
on randomised treatment (duration of exposure = date of last dose of IP from active inhaler 
minus date of first dose of IP from active inhaler +1) will be summarised for each treatment 
group. In addition the following exposure categories will be derived: ≤28 days, 29-84 days, 
85-126 days, 127-165 days, 166-172 days, 173-182 days and ≥183 days. The numbers and 
percentages of patients falling into each category will be presented for each treatment group.


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4.2.5
Compliance
Study treatment compliance and ePRO use compliance will be summarised descriptively for 
the full analysis set and the Per Protocol analysis set. The treatment period is defined as any 
day between the date of randomisation (Visit 3) to the date of last dose day inclusively.  
Treatment compliance will be derived for the GFF inhaler (active or placebo) and UV inhaler 
(active or placebo) separately. This will be based on:
!
Compliance in complete study period is defined as: total number of inhalations 
during the treatment period / (total number of inhalations expected in the morning 
and in the evening on a study day that is not the last day of treatment * [days during 
the treatment period - 1] + total number of inhalations expected in the morning and 
evening on the last day of treatment) *100
!
Overall compliance in reported ePRO data is defined as: total number of inhalations 
during the treatment period / (number of inhalations expected in the morning on a 
study day * days with ePRO data entered in the morning during the treatment period
+ number of inhalations expected in the evening on a study day * days with ePRO
data entered in the evening during the treatment period) *100
!
Morning compliance in reported ePRO data is defined as: total number of 
inhalations in the morning during the treatment period / (number of inhalations 
expected in the morning on a study day * days with ePRO data entered in the 
morning during the treatment period) *100
!
Evening compliance in reported ePRO data is defined as: total number of 
inhalations in the evening during the treatment period / (number of inhalations 
expected in the evening on a study day * days with ePRO data entered in the 
evening during the treatment period) *100
If the last day of treatment is a visit day, the expected number of evening inhalations on the 
last day of treatment is 0 from the GFF inhaler. Otherwise, the expected number of inhalations 
for each study day is 2 in the morning and 2 in the evening from the GFF inhaler and 1 in the 
morning from the UV inhaler. The UV inhaler recorded as taken in the evening will be 
considered as 1 inhalation in the calculation of compliance. Patients who received no 
randomised treatment will have zero compliance.
ePRO use compliance will be derived based on the actual number of morning and evening 
ePRO entries during the treatment period compared to the expected number of entries during 
that period. 0 evening ePRO entries are expected on the last day of treatment if it is also a visit 
day. Otherwise, 1 morning and 1 evening ePRO entry is expected on a study day. 
Overall, morning and evening ePRO use compliance during the treatment period will also be 
calculated:


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!
Overall ePRO use compliance is defined as: total number of morning and evening 
ePRO entries during the treatment period / ([days during the treatment period - 1
]*2 + expected number of morning and evening ePRO entries on the last day of 
treatment) *100
!
Morning ePRO use compliance is defined as: total number of morning ePRO entries
during the treatment period / days during the treatment period *100
!
Evening ePRO use compliance is defined as: total number of evening ePRO entries 
during the treatment period / (days during the treatment period - 1 + expected 
number of evening ePRO entries on the last day of treatment) *100
Treatment compliance will be summarised for GFF inhaler and UV inhaler separately in each 
treatment group. In addition the following compliance categories will be derived: >130%, 
>110% - ≤130%, >90% - ≤110%, ≥70% - ≤90%, <70%. The numbers and percentages of 
patients falling into each category will be presented for GFF inhaler and UV inhaler separately 
in each treatment group. ePRO compliance will be summarised descriptively and using the 
compliance categories by treatment group.
4.2.6
Analysis of the primary variables
4.2.6.1
Trough FEV1
The co-primary analysis of trough FEV1 will be conducted using the Per Protocol analysis set. 
The change from baseline in morning pre-dose trough FEV1 will be analysed using a linear 
mixed effects model repeated measures (MMRM) approach. The model will include baseline 
FEV1 and bronchodilator responsiveness to albuterol/salbutamol MDI (%) as continuous 
covariates and stratification factor (prior treatment - rescue/maintenance monotherapy vs 
double maintenance therapy), region (North America vs Europe), visit, treatment, and 
treatment by visit, as categorical covariates (fixed effects). Baseline is defined as the average 
of the non-missing -60 min and -30 min values obtained prior to dosing at Visit 3. The 
Kenward-Roger approximation will be used to estimate the degrees of freedom.
An unstructured matrix will be used to model the variance-covariance structure within patient. 
If this model fit fails to converge, more parsimonious covariance structures will be considered 
to model the correlation between time-points from the same patient. The following covariance 
structures will be tried in order until convergence is reached: Toeplitz with heterogeneity, 
autoregressive with heterogeneity, Toeplitz, autoregressive and compound symmetry. If either 
the autoregressive with heterogeneity or autoregressive structure is used, patient will be 
included as a random effect. 
A contrast will be used to obtain an estimate of the treatment difference over the entire 24-
week treatment period (i.e. average treatment difference over visits giving each visit equal 
weight) with 2-sided 95% CI and 97.5% CI. Non-inferiority will be concluded using a 1-sided 
hypothesis test according to a significance level of either 1.25% or 2.5% based upon the 
hierarchical testing and recycling procedure described in Section 4.2.6.3. This is equivalent to 


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the lower bound of the 2-sided 95% or 97.5% CI being greater than the pre-specified margin 
of -50 mL. The 1-sided p-values will be produced accordingly.
From the same model contrasts will also be used to produce estimates of treatment difference 
and the corresponding 95% CI and 97.5% CI at each individual time-point (for example at 
Week 24). In addition, least squares means and corresponding 95% CIs will be provided for 
each treatment group at individual time-points and over 24 weeks, and presented on a line 
plot.
A similar analysis will be conducted in the full analysis set using all data obtained while on 
treatment. 
Summary statistics for absolute values and change from baseline in morning pre-dose trough 
FEV1 will be produced by treatment group and visit for both Per Protocol analysis set and full 
analysis set. 
The assumption of normality in the data will be checked by visually inspecting the distribution 
of the residuals. Also, the model fit and the assumption of homogeneity of variance will be 
verified by inspecting scatter plots of residuals vs predicted values and residuals vs continuous 
covariates, and by inspecting box plots of residuals for categorical covariates (prior treatment, 
region, visit, treatment). A sensitivity analysis, if appropriate, will be performed using the
MMRM approach allowing for heterogeneous variances in covariates that a lack of
homogeneity of variance is evident.
The MMRM approach used in primary analysis relies on the assumption that data is missing at 
random (MAR) given the covariates included in the model. Supportive analyses to assess the 
robustness of conclusions to this assumption, including under Missing Not at Random 
(MNAR) scenarios, are outlined in Appendix I. In this analysis, data that are missing due to 
treatment discontinuation where the reason is reasonably attributable to treatment (for 
example tolerability or lack of efficacy) and data following initiation of prohibited medication 
(as described in important protocol deviation 7, Section 2.2.1) will be imputed under an 
assumption that such patients would have had a poorer outcome had they been followed for 24 
weeks and not been able to escalate treatment. This outcome will use imputation from a 
random intercept model, with imputation centred at the model based estimate of the 5% 
percentile for the endpoint at the corresponding visit (conditional on covariates). A (multiply) 
imputed change from baseline value will be drawn from a normal distribution with mean 
based on the 5th percentile of this distribution at the corresponding visit, as described in 
Appendix I. Other missing data that could not be reasonably attributed to treatment are to be 
imputed using their conditional distributions as implied by MAR. Treatment discontinuations 
reasonably attributable to tolerability or lack of efficacy will be identified and documented 
prior to unblinding. Principles are outlined in Appendix I.
Subgroup analyses will be conducted comparing the co-primary endpoint trough FEV1
between the treatments in the following subgroups of the Per Protocol analysis set:
!
Baseline CAT score (10-14, 15-19, ≥20)


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!
Prior treatment at entry (rescue therapy only, single maintenance therapy, 
LAMA/LABA maintenance therapy, LABA/ICS maintenance therapy)
!
Region (North America, Europe)
!
Bronchodilator responsiveness at Visit 2 (≥12% and ≥200 mL, <12% or <200 mL)
!
COPD severity at entry, as defined by Global Initiative for Chronic Obstructive 
Lung Disease (GOLD) criteria (moderate, severe, very severe)
!
Smoking status (current smoker, former smoker)
For each subgroup, a MMRM model will be fitted using the same model terms as used for the 
primary analysis for each level of the subgroup separately. The prior treatment, region and 
bronchodilator responsiveness will not be included in the model when these are the subgroups
being analysed. Similar output will be presented for the subgroups as for the primary analysis.
Note that the study has not been designed or powered to assess efficacy within any pre-
defined subgroups, and as such these analyses are considered exploratory. 
4.2.6.2
Peak FEV1
The peak change from baseline in FEV1 within 2 hours post-dosing will be analysed using a 
similar MMRM model to trough FEV1 in Section 4.2.6.1. Testing of non-inferiority between 
GFF and UV will first be conducted in the Per Protocol analysis set. The estimates of 
treatment difference over 24 weeks and associated 2-sided 95% and 97.5% CIs will be 
referred to a non-inferiority margin of -50 mL.
The full analysis set will be used to assess the consistency of the non-inferiority conclusion 
using all evaluable data and a similar repeated measures model. This model will then be used 
for the formal assessment of superiority hypotheses. Testing of non-inferiority and superiority 
will be at a significance level of either 1.25% or 2.5% based upon the hierarchical testing and 
recycling procedure described in Section 4.2.6.3. The 1-sided p-values will be produced 
accordingly for both non-inferiority analyses and the superiority analysis.
Contrasts will be used to produce estimates of treatment difference at individual visits. Least 
squares means and corresponding 95% CIs will be provided for each treatment group at 
individual visits and over 24 weeks, and presented on a line plot. The peak change from 
baseline values will also be summarised descriptively by visit for each treatment group.
Subgroup analyses will be generated comparing the peak change from baseline in FEV1
between treatment groups in the same way as previously specified for trough FEV1 in Section 
4.2.6.1 based on the full analysis set. Supportive analyses will be conducted on the full 
analysis set to assess the robustness of conclusions from the MMRM approach to the MAR 
assumption as described in Section 4.2.6.1 and Appendix I.


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4.2.6.3
Hierarchical testing strategy – primary endpoints
In order to strongly control the 1-sided type I error rate at 2.5% across all co-primary endpoint 
hypothesis tests and the non-inferiority hypothesis tests of the secondary endpoints a 
hierarchical testing procedure with recycling will be defined. 
To account for the multiplicity of the two co-primary endpoints, the test mass (1-sided alpha 
of 2.5%) will initially be split equally between the tests of the non-inferiority null hypothesis 
for each of trough FEV1 and peak FEV1 (1-sided alpha of 1.25% each).
Should either of these null hypotheses be rejected, the test mass will be recycled (Burman et al 
2009), as described in Figure 2. That is, after respective null hypotheses are rejected there will 
be recycling from each test as follows:
!
from trough FEV1 non-inferiority testing to peak FEV1 non-inferiority testing
!
from peak FEV1 non-inferiority testing to peak FEV1 superiority testing
!
from peak FEV1 superiority testing to trough FEV1 non-inferiority testing
As such, respective hypothesis tests will be conducted at either a 1-sided 1.25% or 2.5% 
significance level depending upon this recycling.
Figure 2
Testing hierarchy for primary endpoints
NI = Non-inferiority, Sup = Superiority
Should all 3 null hypotheses relating to the co-primary endpoints be rejected then testing will 
proceed to the secondary endpoints using a 1-sided 2.5% significance level.


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4.2.7
Analysis of the secondary variables
Table 5 details the analyses to be performed for the endpoints, including the pre-planned 
subgroup and supportive analyses making clear which analysis and population is regarded as 
primary for that endpoint. 
Table 5
Statistical analyses and analysis populations
Variable
Per Protocol 
analysis set
Full analysis set
Rescue Medication 
User analysis set
Pre-dose trough FEV1**
MMRM, for NI
Subgroup analysis
MMRM
MAR/MNAR analysis
-
Peak post-dose FEV1**
MMRM, for NI
MMRM, for Sup
Subgroup analysis
MAR/MNAR analysis
-
Peak post-dose IC*
MMRM, for NI
MMRM, for Sup
Subgroup analysis
MAR/MNAR analysis
-
Pre-dose trough FVC 
MMRM 
MMRM
-
Peak post-dose FVC
MMRM
MMRM
-
AUC0-2 for FEV1
-
MMRM
-
AUC0-2 for FVC
-
MMRM
-
Δ FEV1 ≥100 mL at 5min, Day 1*
-
Logistic regression, for 
Sup
-
Δ FEV1 ≥150 mL at 5min, Day 1
-
Logistic regression
-
Δ FEV1 ≥ 12% at 5 min, Day 1
-
Logistic regression
-
FEV1 post-dose timepoints, Day 1
-
MMRM
-
TDI focal score*
MMRM, for NI
Subgroup analysis
Responder analysis
MMRM
Responder analysis
MAR/MNAR analysis
-
TDI individual components 
MMRM
MMRM
-
EMSCI symptom severity score *
MMRM, for NI
MMRM, for Sup
Subgroup analysis
-
NiSCI symptom severity score
MMRM
MMRM
Subgroup analysis
-
Overall COPD severity scores
Descriptive only
Descriptive only
-
Early morning activity score
Descriptive only
Descriptive only
-
Night-time awakening score
Descriptive only
Descriptive only
-
CAT score
MMRM
Responder analysis
MMRM
Subgroup analysis
Responder analysis
-
Daily rescue use
-
-
MMRM
Daytime rescue use
-
-
MMRM
Night-time rescue use
-
-
MMRM


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Variable
Per Protocol 
analysis set
Full analysis set
Rescue Medication 
User analysis set
Day with no rescue use
-
-
Descriptive only
** Co-primary endpoints; * Secondary endpoints in hierarchical testing; NI = Non-inferiority, Sup = Superiority.
Note: For endpoints with NI concluded on Per Protocol analysis set, supportive analyses will be conducted on 
full analysis set to demonstrate the consistency of this conclusion. CAT score and NiSCI will have treatment 
differences interpreted in relation to NI margin but not in hierarchical testing.
4.2.7.1
Hierarchical testing strategy – secondary endpoints
A sequential testing hierarchy will be defined so as to strongly control 1-sided type I error at 
2.5% across all non-inferiority hypothesis tests of secondary endpoints. The secondary 
endpoints over 24 weeks will be tested against their respective non-inferiority margins in the 
following sequence using a 1-sided significance level of 2.5%: 
1.
Peak change from baseline in IC within 2 hours post-dosing over 24 weeks (non-
inferiority with option to proceed to superiority), 
2.
Proportion of patients with increase of FEV1 of ≥100 mL from baseline at 5 minutes 
on Day 1 (superiority only), 
3.
Change from baseline in TDI focal score over 24 weeks (non-inferiority only)
4.
Change from baseline in EMSCI Symptom Severity Score over 24 weeks (non-
inferiority with option to proceed to superiority),
If non-inferiority is demonstrated for an endpoint, then testing may proceed to the next 
endpoint in the hierarchy, and a superiority test of the endpoint will also be conducted in the 
full analysis set for those endpoints indicated. Proceeding to the next endpoint is not 
contingent on demonstrating superiority.
An exception to this sequential non-inferiority/superiority testing procedure is the secondary 
endpoint Onset of action (proportion of patients with increase in FEV1 of ≥100 mL from 
baseline at 5 minutes on Day 1). For this endpoint, superiority testing will immediately be 
carried out and superiority is required in order to move to the next step in the testing 
hierarchy.
This sequential testing hierarchy is illustrated in Figure 3:


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Figure 3
Sequential testing hierarchy for secondary endpoints
NI = Non-inferiority, Sup = Superiority
4.2.7.2
Pulmonary Function over 24 weeks
The peak change from baseline in IC within 2 hours post-dosing will be analysed using a 
similar MMRM model to peak FEV1 described in Section 4.2.6.2. The estimates of treatment 
difference over 24 weeks will also be referred to a non-inferiority margin of -50 mL. 
If non-inferiority is demonstrated in the Per Protocol analysis then the full analysis set will be 
used to assess the consistency of the non-inferiority conclusion using all evaluable data and a 
similar repeated measures model. This model will be used for the formal assessment of 
superiority hypotheses and 1-sided p-values and 2-sided 95% CIs will be produced. The 
estimated treatment differences over 24 weeks and 95% CIs for peak change from baseline in 
IC will be presented graphically on a forest plot, along with the results of the co-primary 
variables. 
Contrasts will be used to produce estimates of treatment difference at individual visits. Least 
squares means and corresponding 95% CIs will be provided for each treatment group at 
individual visits and over 24 weeks, and presented on a line plot. The peak change from
baseline values will also be summarised descriptively by visit for each treatment group. 
Subgroup analyses will be generated comparing peak change from baseline in IC between 
treatment groups in the same way as previously specified for morning pre-dose trough FEV1 in 
Section 4.2.6.1 based on the full analysis set. Supportive analyses to assess the robustness of 
the repeated measures analyses to missing data as described in Section 4.2.6.1 are outlined in 
Appendix I. 


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Other continuous pulmonary function endpoints morning pre-dose trough and peak post-dose 
FVC will be analysed similarly using both the Per Protocol analysis set and full analysis set, 
and AUC0-2 for FEV1 and FVC will be analysed similarly using the full analysis set. The 
model term of baseline value will not be included (not applicable) when analysing AUC0-2 for 
FEV1 and FVC. Estimated treatment differences will be interpreted using 95% CIs, but will 
not be formally assessed for non-inferiority. Subgroup and supportive analyses above will not 
be performed for these endpoints. 
4.2.7.3
Pulmonary Function at Day 1
On Day 1 at the assessment 5 minutes post-dosing, the proportion of patients achieving an 
improvement from baseline in FEV1 of ≥100 mL will be estimated for each treatment. Logistic 
regression will be used to compare the treatment groups with baseline and bronchodilator 
responsiveness to albuterol/salbutamol MDI as continuous covariates and treatment, region 
and stratification factor as categorical covariates. This analysis will use the full analysis set 
and proceed immediately to testing of the superiority hypothesis. One-sided p-values and odds 
ratios with 2-sided 95% CIs will be produced.
Similar analyses will be conducted at 5 minutes on Day 1 using alternative thresholds 
(increase in FEV1 of ≥150 mL from baseline and increase in FEV1 of ≥12% from baseline). A 
cumulative distribution function plot of the absolute increase in FEV1 at 5 minutes on Day 1 
will also be presented by treatment group.
In addition, onset of action on day 1 will be assessed by analysing the change from baseline to 
each post-dose timepoint within the first 2 hours using the full analysis set. A similar MMRM 
model will be used to the co-primary analyses, but replacing visit with the post-dose 
timepoints in Table 2. Differences will be interpreted using 95% CIs and least square means 
will be presented on a line plot illustrating the onset of action over the first 2 hours on day 1.
4.2.7.4
Transition Dyspnea Index (TDI) Focal Score
The difference between treatment groups in TDI over 24 weeks will be evaluated using a 
similar MMRM approach as for the co-primary endpoints described in Section 4.2.6. The 
model will include BDI (in place of baseline) and bronchodilator responsiveness as 
continuous covariates. Stratification factor, region, visit, treatment, and treatment by visit will 
be included as categorical covariates. 
One-sided p-values and point estimates with 2-sided 95% CIs will be produced for the 
treatment difference over 24 weeks. Non-inferiority will be evaluated on the Per Protocol 
analysis set, and concluded if the lower bound of this confidence interval is greater than the 
pre-specified margin of -1.0 units (the minimum clinically important difference). Estimates of 
treatment difference will also be produced at each individual time-point. Additionally, least 
squares means and corresponding 95% CIs will be provided for each treatment group at 
individual time-points and over 24 weeks, and presented on a line plot. A supportive analysis 
will also be produced using the full analysis set. Cumulative distribution function plots of TDI 
focal score at Week 24 will be presented by treatment group. 


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Subgroup analyses will be conducted comparing TDI focal score over 24 weeks between the 
treatment groups in the same subgroups as previously specified for morning pre-dose trough 
FEV1 in Section 4.2.6.1 based on the Per Protocol analysis set.
For each subgroup, the same MMRM model defined above will be fitted separately for each 
level of the subgroup. The prior treatment, region and bronchodilator responsiveness will not 
be included in the model when these are the subgroups being analysed. Results from the 
model contrast will be presented in terms of the point estimate of treatment difference and 
corresponding 95% CI. The subgroup analyses will be considered exploratory and may only 
be supportive of the primary analysis of this endpoint.
Supportive analyses will be conducted on the full analysis set to assess the robustness of 
conclusions from the MMRM approach to the MAR assumption as described in Section 
4.2.6.1 and Appendix I.
The individual components of the TDI: functional impairment, magnitude of task, and 
magnitude of effort will each be summarised relative to their corresponding BDI individual 
component score at baseline, using the same MMRM approach with estimated treatment 
differences over 24 weeks and at each visit, based on the Per Protocol analysis set and the full 
analysis set.
Furthermore as supportive analyses, responder analyses will be performed at each visit for the 
Per Protocol analysis set and the full analysis set, where responders are defined as an increase
of 1.0 point or more in TDI focal score, and patients with missing data will be considered to 
be non-responders. Logistic regression will be used to compare the treatment groups with BDI 
as a continuous covariate and treatment group, region and stratification factor as categorical 
covariates. Odds ratios with 95% CIs will be produced. Summaries of the number and 
percentage of patients achieving an improvement, no change and deterioration will be 
provided by visit for each treatment group.
4.2.7.5
Early Morning Symptoms COPD Instrument (EMSCI) and Night Time 
Symptoms COPD Instrument (NiSCI)
The difference between treatment groups in the change from baseline in EMSCI Symptom 
Severity Score over 24 weeks will be evaluated using a similar MMRM approach as for the 
co-primary endpoints described in Section 4.2.6. Instead of visit, the relevant time interval 
will be used as a categorical covariate in the model. The model will include baseline and 
bronchodilator responsiveness as continuous covariates and stratification factor, region, time 
interval, treatment, and treatment by time interval, will be included as categorical covariates. 
One-sided p-values and point estimates with 2-sided 95% CIs will be produced for the 
treatment difference over 24 weeks. Non-inferiority will be concluded if the lower bound of 
this confidence interval is greater than the pre-specified margin of -0.1 units. Estimates of 
treatment difference will also be produced at each individual time interval. Additionally, least 
squares means and corresponding 95% CIs will be provided for each treatment group at 
individual visits and over 24 weeks, and presented on a line plot.


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If non-inferiority is demonstrated in the Per Protocol analysis then the full analysis set will be 
used to assess the consistency of the non-inferiority conclusion using all evaluable data and a 
similar repeated measures model. This model will be used for the formal assessment of 
superiority hypotheses and 1-sided p-values and 2-sided 95% CIs will be produced.
Estimates of least squares means from each treatment group and treatment differences will be 
produced similarly for the NiSCI Symptom Severity Score, based on the Per Protocol analysis 
set and the full analysis set. These will be interpreted using 95% CIs, in relation to a non-
inferiority margin of -0.1.
Subgroup analyses, using the same approach and subgroup factor as specified in Section 
4.2.6.1, will be performed for change from baseline in EMSCI and NiSCI Symptom Severity
Scores respectively comparing the treatment difference over 24 weeks at each level of the 
subgroups, for patients in the full analysis set. 
The change from baseline in Overall COPD Symptom Severity scores in the early morning
and at night, Early Morning Activity score and Night-time Awakenings score, will be 
summarised descriptively by treatment group and time interval.
4.2.7.6
COPD Assessment Test (CAT) score
The difference between treatment groups in the change from baseline in CAT score over 24 
weeks will be evaluated using a similar MMRM approach as for the co-primary endpoints
described in Section 4.2.6, for the Per Protocol analysis set and the full analysis set. Treatment 
differences will be interpreted using 95% CIs in relation to non-inferiority margin of 2 units.
Cumulative distribution function plot of the change from baseline values at Week 24 will be 
presented by treatment group for the full analysis set.
Subgroup analyses will be generated comparing the change from baseline in CAT score over 
24 weeks between treatments in the same way as previously specified in Section 4.2.6.1, for 
the full analysis set. Baseline CAT score will not be included in the repeated measure models
when it is the subgroup being analysed. 
Responder analyses will be performed at each visit for the Per Protocol analysis set and the 
full analysis set, where responders are defined as a decrease of 2 units or more in the change 
from baseline value, and patients with missing data will be considered to be non-responders. 
Logistic regression will be used to compare the treatment groups with baseline CAT score as a 
continuous covariate and treatment group, region and stratification factor as categorical 
covariates. Odds ratios with 95% CI will be produced for each treatment comparison.
Summaries of the number and percentage of patients achieving an improvement, no change 
and deterioration will be provided by visit for each treatment group.
4.2.7.7
Daily Rescue Medication Use
The difference between treatment groups in the change from baseline in mean daily rescue 
albuterol/salbutamol MDI use will be evaluated using a MMRM approach similar to the ones
for co-primary endpoints described in Section 4.2.6, for patients in the Rescue Medication 
User analysis set. Instead of visit, the relevant time interval will be used as a categorical 


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covariate in the model. The model will include baseline and bronchodilator responsiveness as 
continuous covariates and stratification factor, region, time interval, treatment, and treatment 
by time interval, will be included as categorical covariates. Treatment differences will be 
interpreted using 95% CIs, but will not be formally assessed for non-inferiority.
The change from baseline in daytime and night-time mean albuterol/salbutamol MDI use will 
each be evaluated using the same MMRM approach as described above. Included in the 
models will be their corresponding baseline values. Summary statistics for these variables and 
percentage of days with no rescue use will be produced by treatment group and time period. 
The overall daily, daytime and night-time rescue albuterol/salbutamol MDI use during the 
treatment period will also be summarised descriptively for each treatment group.    
4.2.8
Safety and tolerability
Adverse event summaries, unless stated otherwise, will be based on TEAEs, as defined in 
Section 3.4. All AEs will be listed for each patient, regardless of whether or not they are 
treatment-emergent. All summaries will use the safety analysis set, and be presented by 
treatment group according to treatment received. No hypothesis tests will be performed.
An overall summary table will be produced showing the number and percentage of patients 
with at least 1 AE in any of the following categories: AEs, SAEs, AEs with outcome of death, 
AEs leading to discontinuation of IP (DAEs), and AEs deemed causally related to IP by the 
Investigator. The total number of AEs in the different AE categories in terms of AE counts 
will also be presented (i.e., accounting for multiple occurrences of the same event in a 
patient).  
Adverse events, AEs with outcome of death, SAEs, DAEs, and AEs causally related to IP by 
the Investigator will be summarised by SOC and PT assigned to the event by MedDRA. For 
each PT, the number and percentage of patients reporting at least 1 occurrence will be 
presented, i.e. for a patient multiple occurrences of an AE will only be counted once. Serious 
adverse events deemed causally related to IP by the Investigator and/or AstraZeneca will also 
be summarised. 
Each AE event rate (per 1000 patient years) will also be summarised by PT within SOC. For 
each PT, the event rate is defined as the total number of AEs divided by the total drug
exposure of patients and then multiplied by 365.25 x 1000 to present in terms of per 1000
patient years. 
Summaries of the most common (frequency of >1% in any treatment group) AEs and non-
serious AEs will be presented by PT. Adverse events will be summarised by preferred term 
and maximum intensity. If a patient reports multiple occurrences of the same AE, the 
maximum intensity will be taken as the highest recorded maximum intensity (the order being 
mild, moderate, and severe). 
Separate listings of patients with AEs, AEs with outcome of death, SAEs, or DAEs will be 
presented.


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4.2.9
Exploratory analysis 
Exploratory variables as defined in Sections 3.3.5, 3.3.6 and 3.3.7 will be reported using the 
full analysis set. 
The EQ-5D-5L responses from each dimension, the index score and the visual analogue scale 
will be summarised by treatment group. Shift tables will be produced for each dimension, and 
the change from baseline in index score and visual analogue scale will be summarised with 
descriptive statistics by visit.
The number and percentage of patients with COPD-related and non-COPD-related health 
resource utilisation will be presented by treatment group. The frequency and rate per year of 
COPD exacerbations, and moderate and severe COPD exacerbations will also be summarised.
Time to the first moderate or severe COPD exacerbation will be analysed using a Cox 
proportional hazards model. The model will include baseline FEV1 (% PN), baseline CAT 
score, and bronchodilator responsiveness to albuterol/salbutamol MDI (%) as continuous 
covariates and stratification factor (prior treatment - rescue/maintenance monotherapy vs 
double maintenance therapy), COPD exacerbations in previous year (yes vs no), region (North 
America vs Europe) and treatment as categorical covariates. The estimated adjusted hazard 
ratio for GFF relative to UV will be displayed along with the associated Wald 2-sided 95% CI
and 1-sided p-value for superiority assessment. Time to the first moderate or severe COPD 
exacerbation will be displayed graphically for each treatment group using a Kaplan-Meier 
curve. 
WPAI-GH responses will be summarised using descriptive statistics by treatment group and 
visit.
5.
INTERIM ANALYSES
No interim analyses are planned for this study.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
The CSP states that for the analysis of the co-primary endpoints and other similar analysis 
models patient will be considered a random effect. It is also stated that an unstructured 
covariance matrix will be used. These two statements are contradictory as if a random effect 
for patient is included there will be a diagonal residual covariance matrix. In the statistical 
analysis plan it is clarified that patient will only be included as a random effect if an 
autoregressive covariance structure is required, but that this will not be required if an 
unstructured or Toeplitz covariance structure can be used.


Statistical Analysis Plan 
Study Code D5970C00002
Edition Number 2.0
Date 08 Jun 2018
45
7.
REFERENCES
Burman et al 2009
Burman C-F, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni-based multiple tests. Statist. Med. 2009; 28:739-761
Van Hout et al 2012
Van Hout B, Janssen M, Feng Y, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone L, 
Kind P, Pickard AS. Interim scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to EQ-5D-3L 
value sets. Value in Health. 2012; 15: 708-15