Clinical trial NCT03022097
Conditions: COPD
Sponsor: AstraZeneca
Start date: 2017-02-02; Completion date: 2022-04-14
Enrollment: 1625 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multiple dose, randomised, parallel, double blind, double dummy, multicentre and multinational Phase III study to determine the efficacy and safety of Aclidinium bromide/Formoterol fumarate compared with individual components and placebo and Aclidinium bromide compared with Placebo when administered to patients with stable Chronic Obstructive Pulmonary Disease (COPD).

Detailed description:

Arms: arm 1: Aclidinium bromide 400μg/Formoterol fumarate 12 μg arm 2: Aclidinium bromide 400 μg arm 3: Formoterol fumarate 12 μg arm 4: Placebo
Interventions: intervention 1: Aclidinium bromide/formoterol Fixed-Dose Combination intervention 2: Aclidinium bromide intervention 3: Formoterol Fumarate intervention 4: Placebo
Intervention descriptions: intervention 1: Inhaled Aclidinium bromide/formoterol Fixed-Dose Combination, twice per day via Genuair intervention 2: Inhaled Aclidinium bromide 400 μg, twice per day via Genuair intervention 3: Inhaled Formoterol Fumarate 12 μg, twice per day via Turbuhaler intervention 4: Inhaled dose-matched placebo, twice per day via Genuair or via Turbuhaler

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
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Clinical Study Protocol 
Drug Substance
Aclidinium bromide/ Formoterol 
fumarate
Study Code
M-AS464-30 
(AZ code: D6570C00002)
Version
4.0 
Date
08 Jul 2021
A 24-week Treatment, Randomised, Parallel-group, Double 
blinded, Double-Dummy, Multicenter Study to Assess the Efficacy 
and Safety of Aclidinium bromide/Formoterol fumarate compared 
with Individual Components and Placebo and Aclidinium bromide 
compared with Placebo when Administered to Patients with Stable 
Chronic Obstructive Pulmonary Disease
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden










Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
6 of 136
PROTOCOL SYNOPSIS
A 24-week Treatment, Randomised, Parallel-group, Double
blinded, Double-Dummy, Multicenter Study to Assess the Efficacy
and Safety of Aclidinium bromide/Formoterol fumarate compared
with Individual Components and Placebo and Aclidinium bromide 
compared with Placebo when Administered to Patients with Stable 
Chronic Obstructive Pulmonary Disease
International Co-ordinating Investigator:
 
 
Study site(s) and number of subjects planned
Approximately 1515 patients will be enrolled to randomise 1060 patients (265 
patients/treatment arm) considering an estimated ineligibility rate of 30% prior to 
randomisation.
Approximately 85 sites will participate in China and other Asia countries including India, 
Taiwan, Vietnam and Philippines.
Study period
Phase of development
Estimated date of first subject enrolled
Q1 2017
III
Estimated date of last subject completed
Q2 2022
Study design
This is a multiple dose, randomised, parallel, double blind, double dummy, multicentre and 
multinational Phase III study to determine the efficacy and safety of Aclidinium 
bromide/Formoterol fumarate compared with individual components and placebo and 
Aclidinium bromide compared with Placebo when administered to patients with stable 
Chronic Obstructive Pulmonary Disease (COPD).


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
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Patients’ informed consent form (ICF) signature must be obtained before performing any 
procedure related to the trial. ICF must be signed after the patient has received sufficient 
information about the trial, after he/she has had the opportunity to ask any questions related to 
the study and considered the options.
At Screening Visit (Visit 1) inclusion and exclusion criteria will be checked by means of 
patient’s medical history review, physical examination, laboratory, electrocardiogram (ECG) 
measurement and COPD severity stage, according to Global Initiative for Chronic Obstructive 
Lung Disease (GOLD 2015).
Patients fulfilling inclusion/exclusion criteria at the time of the screening will be entered into a 
run-in period of 14 ±3 days to assess patient’s disease stability. At the Screening Visit (Visit 
1) patients are provided with the e-diary to record the use of rescue medication and their 
COPD symptoms every night.
Patients who meet entry criteria at Randomisation Visit (Visit 2) will be randomised in a ratio 
1:1:1:1 to one of the 4 treatment arms. Smoking status (current smokers vs former smokers) 
and country will be the treatment allocation factors.
At Visit 2, after randomisation, patient will receive investigational product for 24 weeks and 
will come for scheduled visits at Visit 3 (Week 1), Visit 4 (Week 4), Visit 5 (Week 12), Visit 
6 (Week 18), and Visit 7 (Week 24) for assessments of clinical efficacy and safety.
At the on-site visits over the treatment period pre-morning dose assessments will include: two 
Pulmonary Function Test (PFT) 30 min apart, physical examination, blood pressure and ECG 
measurement. CAT, Baseline/Transition Dyspnoea Index (BDI/TDI) and St. George´s 
Respiratory Questionnaire (SGRQ) will be also collected pre-morning dose at visits 2, 4, 5 
and 7. Post-morning assessments include +1h post-dose PFT at all visits and +1h post-dose 
blood pressure and ECG at all visits except Visit 4. At visits 2 and 7, additional PFTs will be 
performed at +5 min, +30 min, +1h, +2h and +3h post-morning dose.
Laboratory test will be performed at Screening Visit (Visit 1) and at the end of the treatment 
period (Visit 7).
Patients will be provided with rescue medication, salbutamol pressurised metered dose inhaler 
(pMDI) 100 μg/puff, to be used on a needed basis, from the time of the informed consent 
signature until the end of the study.
From Screening Visit (Visit 1) to the end of the study, patients will use an electronic Patient 
Diary to be completed in the evening to record the intake of rescue medication as well as 
COPD symptoms by means of the Exacerbations of Chronic Pulmonary Disease Tool 
(EXACT) questionnaire. Patients will also use a paper Patient Diary to record any AE and the 


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
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intake of any concomitant medications from Screening Visit (Visit 1) until the end of the 
study.
During the entire duration of the study, AEs, COPD exacerbations and the use of any 
concomitant medication will be assessed and recorded by the investigator.
Patients who prematurely discontinue investigational product (IP) will participate in an End of 
Treatment (EOT) Visit followed by a post-treatment follow-up period. The EOT visit will 
include physical examination, laboratory test, ECG and blood pressure to ensure patient´s 
safety. The IP will be returned at the EOT visit but the paper diary, electronic diary and rescue 
medication will be redispensed to be used during the post-treatment follow-up. The post-
treatment follow-up period will include telephone contacts in place of on-site visits for the 
remainder of the study duration and an on-site Visit 7 in order to return the study material. 
During the post-treatment follow-up period the SAEs, COPD exacerbations and concomitant 
medication will be followed-up.
Patients who prematurely discontinue from the study (withdrawal) will participate in an End 
of Study (EOS) Visit that will include physical examination, laboratory test, ECG and blood 
pressure to ensure patient´s safety. The IP, rescue medication, paper diary and electronic diary 
will be returned at the EOS visit.
For patients that complete the treatment or prematurely discontinue from the study 
(withdrawals), a follow-up contact will be performed 2 weeks after last IP intake to assess 
new or ongoing adverse event (AE), as well as any concomitant medication administered to 
treat the mentioned AE.
Objectives
Primary Objectives:
Outcome Measures:

To assess the bronchodilatory effect of 
Aclidinium bromide 400 µg /Formoterol 
fumarate 12 µg compared to individual 
components and placebo when administered 
twice daily via inhalation to COPD patients.

To assess the bronchodilatory effect of 
Aclidinium bromide 400 µg compared to 
placebo when administered twice daily via 
inhalation to COPD patients.

Change from baseline in 1-hour morning post-dose 
FEV1 of Aclidinium bromide 400 µg/Formoterol 
fumarate 12 µg compared to Aclidinium bromide at 
Week 24.

Change from baseline in morning pre-dose (trough) 
FEV1 of Aclidinium bromide 400 µg/Formoterol 
fumarate 12 µg compared to Formoterol fumarate at 
Week 24.

Change from baseline in trough FEV1 of Aclidinium 
bromide 400 µg compared to placebo at Week 24


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
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Secondary Objectives:
Outcome Measures:

To assess the benefits of Aclidinium 
bromide 400 µg /Formoterol fumarate 12 µg 
in COPD symptoms, disease-related health
status and COPD exacerbations compared to 
placebo, when administered BID via 
inhalation to COPD patients.

To assess the benefits of Aclidinium 
bromide 400 µg in COPD symptoms, 
disease- related health status and COPD 
exacerbations compared to placebo, when
administered BID via inhalation to COPD 
patients. 

Change from baseline in peak FEV1 of Aclidinium 
bromide 400 µg compared to placebo at week 24

Improvements TDI focal score of Aclidinium bromide 
400 µg/Formoterol fumarate 12 µg compared to 
placebo at week 24

Improvements TDI focal score of Aclidinium bromide 
400µg compared to placebo at week 24

Change from baseline in SGRQ total score of 
Aclidinium bromide 400 µg/Formoterol fumarate 12 
µg compared to placebo at week 24

Change from baseline in SGRQ total score of 
Aclidinium bromide 400µg compared to placebo at 
week 24
Additional efficacy variables:

Pulmonary function variables (FEV1, FVC) at each 
time point and average (ie Area Under the Curve, 
AUC0-3)

Symptomatic and health related quality of life 
outcomes (TDI, SGRQ, CAT, E-RS)

COPD exacerbations (as defined by HCRU and 
EXACT)

Use of rescue medication
Safety Objective:
Outcome Measure:

To evaluate the safety profile of Aclidinium 
bromide 400 µg /Formoterol fumarate 12 µg 
and Aclidinium bromide 400 µg in the same 
patient population.

Adverse events

Clinical laboratory test

Blood pressure

ECG
Target subject population
The study will include patients who are aged ≥40, current or former smokers with a smoking 
history of ≥ 10 pack-years, and with stable, moderate to severe COPD (GOLD guidelines). 
Patient must have screening post-bronchodilator test FEV1/FVC < 70% and FEV1 ≥30 and < 
80% of the predicted normal value.
Duration of treatment
The total duration of the trial for each patient will be approximately 28 weeks (including 
Screening Visit and follow up contact). There will be a run-in period of 2 weeks followed by 


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
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treatment period of 24 weeks, and a follow up contact that will be performed 2 weeks after 
last study treatment.
Investigational product, dosage and mode of administration
A double-dummy design will be adopted in the study to achieve blinding. Aclidinium bromide 
400 µg /Formoterol fumarate 12 µg, Aclidinium bromide 400 µg and placebo to Aclidinium 
bromide 400 µg /Formoterol fumarate 12 µg and Aclidinium bromide 400 µg will be 
administered via the Genuair® device, and Formoterol fumarate 12 µg and placebo to 
Formoterol fumarate 12 µg will be administered via de Turbuhaler® device. The patient will 
inhale 1 puff twice daily (12 hours apart, morning and evening), morning dosing at 08:00 to 
10:00 am and evening dose at 08:00 to 10:00 pm approximately, from each inhaler.
Note: The strengths are expressed as metered dose.
Substance and strength:
Aclidinium bromide 400µg/Formoterol fumarate 12 µg
Dosage form:
Inhalation powder.
Administration route:
Oral Inhalation (by Genuair® Dry Powder Inhaler, DPI) 
Substance and strength:
Aclidinium bromide 400 µg
Dosage form:
Inhalation powder.
Administration route:
Oral Inhalation (by Genuair® Dry Powder Inhaler, DPI) 
Substance and strength:
Formoterol fumarate 12 µg
Dosage form:
Inhalation powder.
Administration route:
Oral Inhalation (by Turbuhaler® Dry Powder Inhaler, DPI) 
Substance and strength:
Placebo to Aclidinium bromide 400µg/Formoterol fumarate 12 µg
and Aclidinium bromide 400 µg
Dosage form:
Inhalation powder.
Administration route:
Oral Inhalation (by Genuair® Dry Powder Inhaler, DPI) 
Substance and strength:
Placebo to Formoterol fumarate 12 µg
Dosage form:
Inhalation powder.
Administration route:
Oral Inhalation (by Turbuhaler® Dry Powder Inhaler, DPI)
The delivered dose of Formoterol fumarate in the mono-formulation used in the study is 9 µg.


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
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Statistical methods
Assumptions for the sample size:
A sample size of 1,060 randomised patients (265 patients per treatment arm) will provide 90% 
power, after adjusting for multiplicity, to test the following primary endpoints:

Change from baseline in 1-hour morning post-dose dose FEV1 of Aclidinium bromide 
400 µg/Formoterol fumarate 12 µg compared to Aclidinium bromide at Week 24.

Change from baseline in morning pre-dose (trough) FEV1 of Aclidinium bromide 400 
µg/Formoterol fumarate 12 µg compared to Formoterol fumarate at Week 24.

Change from baseline in trough FEV1 of Aclidinium bromide 400 µg compared to 
placebo at Week 24 
The same sample size will provide at least 90% power to test the following secondary 
endpoints:

Change from baseline in peak FEV1 of Aclidinium bromide 400 µg compared to placebo 
at Week 24

Improvements TDI focal score of Aclidinium bromide 400 µg /Formoterol fumarate 12 
µg and Aclidinium bromide 400 µg compared to placebo at Week 24

Change from baseline in St George’s Respiratory Questionnaire (SGRQ) total scores of 
Aclidinium bromide 400 µg/Formoterol fumarate 12 µg and Aclidinium bromide 400 µg 
compared to placebo at Week 24
Statistical analyses:
The analyses of the primary and secondary variables will be performed on the Intention-to-
Treat (ITT) and Per Protocol (PP) populations while all other analyses will be performed for 
the ITT population. Safety outcomes and COPD exacerbations will be analysed on the Safety 
population. Moreover, smoking-status and country will be used as a treatment allocation 
factor during the randomisation process.
The primary efficacy variables will be analysed by means of mixed models for repeated 
measures (MMRM), adjusted for pre and post bronchodilator (salbutamol) FEV1 at screening 
visit, age, and baseline FEV1 as covariates, and treatment group, country, smoking-status, 
visit, and treatment group-by-visit interaction as fixed effect factors. To assess the robustness 
to variations of the missing data assumptions underlying the primary analysis on the primary 
efficacy endpoints, sensitivity analyses will be conducted such as copy reference approach.
Improvement in TDI focal score and change from baseline in SGRQ total score at Week 24 
will be analysed by means of MMRM, adjusted by the corresponding baseline value (BDI or 


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
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SGRQ at baseline) and age as covariates, and treatment group, country, smoking-status, visit, 
and treatment group-by-visit interaction as fixed effect factors.
Additional endpoints like the area under the curve (AUC0-3), COPD exacerbations, symptoms 
based on CAT and E-RS questionnaires, and rescue medication will be analysed.
Safety outcomes will be summarised by means of descriptive statistics across time by 
treatment group.


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
PROTOCOL SYNOPSIS...................................................................................................... 6
TABLE OF CONTENTS
           ...................................................................................... 13
1
INTRODUCTION............................................................................................ 23
1.1
Background and rationale for conducting this study .......................................... 23
1.2
Rationale for study design, doses and control groups ........................................ 24
1.3
Benefit/risk and ethical assessment ................................................................... 26
1.4
Study Design .................................................................................................... 28
1.4.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 30
2
STUDY OBJECTIVES..................................................................................... 31
2.1
Primary objective.............................................................................................. 31
2.2
Secondary objectives ........................................................................................ 32
2.3
Safety objectives............................................................................................... 32
3
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ................... 33
3.1
Inclusion criteria............................................................................................... 33
3.2
Exclusion criteria.............................................................................................. 34
3.3
Subject enrolment and randomisation................................................................ 37
3.4
Procedures for handling incorrectly enrolled or randomised subjects................. 37
3.5
Methods for assigning treatment groups............................................................ 38
3.6
Methods for ensuring blinding .......................................................................... 38
3.7
Methods for unblinding..................................................................................... 39
3.8
Restrictions....................................................................................................... 39
3.9
Patient discontinuation of investigational product ............................................. 40
3.9.1
Procedures for discontinuation of a subject from investigational product .......... 41
3.10
Patient discontinuation from the study (withdrawal).......................................... 41
3.10.1
Withdrawal of the informed consent ................................................................. 43
3.10.2
Procedures for discontinuation of a subject from the study................................ 43
3.11
Premature termination of the study.................................................................... 43
4
STUDY PLAN AND TIMING OF PROCEDURES ......................................... 44
4.1
Enrolment/screening period .............................................................................. 47
4.1.1
Visit 1 (screening)............................................................................................. 47
4.2
Treatment period............................................................................................... 48
4.2.1
Visit 2 (Randomisation Visit)............................................................................ 48


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
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4.2.2
Visit 3: Week 1................................................................................................. 50
4.2.3
Visit 4: Week 4................................................................................................. 51
4.2.4
Visit 5: Week 12............................................................................................... 52
4.2.5
Visit 6: Week 18............................................................................................... 53
4.2.6
Visit 7: Week 24............................................................................................... 55
4.2.7
End of Treatment (EOT)................................................................................... 56
4.2.8
End of Study (EOS) visit .................................................................................. 57
4.2.8.1
EOS visit for patients that discontinue from the study....................................... 57
4.2.8.2
EOS visit for patients that discontinue from the post-treatment follow-up 
period ............................................................................................................... 58
4.3
Follow-up period .............................................................................................. 58
4.4
Re-scheduling visits rules and repeated tests..................................................... 59
5
STUDY ASSESSMENTS................................................................................. 60
5.1
Efficacy assessments......................................................................................... 60
5.1.1
Pulmonary function test (spirometry)................................................................ 60
5.1.1.1
General Conditions ........................................................................................... 60
5.1.1.2
Practical Considerations.................................................................................... 61
5.1.2
COPD Assessment Test (CAT)......................................................................... 63
5.1.3
Evaluation of Dyspnoea through BDI-TDI questionnaire .................................. 63
5.1.4
St. George’s Respiratory Questionnaire (SGRQ)............................................... 65
5.1.5
Exacerbations of Chronic Pulmonary Disease Tool (EXACT) and EXACT-
Respiratory Symptoms (E-RS).......................................................................... 66
5.1.6
COPD Exacerbation.......................................................................................... 67
5.1.7
Rescue medication............................................................................................ 68
5.2
Safety assessments............................................................................................ 68
5.2.1
Laboratory safety assessments .......................................................................... 68
5.2.1.1
Hy’s Law.......................................................................................................... 69
5.2.2
Medical History/Physical examination.............................................................. 69
5.2.3
ECG ................................................................................................................. 70
5.2.4
Blood pressure.................................................................................................. 71
5.2.5
Adverse Events................................................................................................. 71
5.2.5.1
MACE (major adverse cardiac event) adjudication............................................ 71
5.3
Other assessments............................................................................................. 72
5.4
Pharmacokinetics.............................................................................................. 72
5.5
Pharmacodynamics........................................................................................... 72
5.6
Pharmacogenetics ............................................................................................. 72
5.6.1
Storage, re-use and destruction of biological samples........................................ 72
5.6.2
Labelling and shipment of biological samples................................................... 72
5.6.3
Chain of custody of biological samples............................................................. 72
5.6.4
Withdrawal of Informed Consent for donated biological samples...................... 73
6
SAFETY REPORTING AND MEDICAL MANAGEMENT............................ 73
6.1
Definition of adverse events.............................................................................. 73
6.2
Definitions of serious adverse event.................................................................. 74


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
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6.3
Recording of adverse events ............................................................................. 74
6.3.1
Time period for collection of adverse events..................................................... 74
6.3.2
Follow-up of unresolved adverse events............................................................ 74
6.3.3
Variables .......................................................................................................... 74
6.3.3.1
Assessment of intensity..................................................................................... 75
6.3.4
Causality collection........................................................................................... 76
6.3.5
Adverse events based on signs and symptoms................................................... 76
6.3.6
Adverse events based on examinations and tests ............................................... 76
6.3.7
Disease progression .......................................................................................... 77
6.4
Reporting of serious adverse events .................................................................. 77
6.5
Overdose .......................................................................................................... 78
6.6
Pregnancy......................................................................................................... 79
6.6.1
Maternal exposure ............................................................................................ 79
6.6.2
Paternal exposure.............................................................................................. 80
6.7
Management of IP related toxicities .................................................................. 80
6.8
Study governance and oversight........................................................................ 80
7
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS.................. 80
7.1
Identity of investigational product(s)................................................................. 80
7.2
Additional Drug................................................................................................ 81
7.3
Dose and treatment regimens ............................................................................ 81
7.4
Labelling .......................................................................................................... 82
7.5
Storage ............................................................................................................. 83
7.6
Compliance....................................................................................................... 83
7.7
Accountability .................................................................................................. 84
7.8
Concomitant and other treatments..................................................................... 84
7.8.1
Restricted and prohibited concomitant treatment............................................... 84
7.8.2
Rescue medication............................................................................................ 87
7.8.3
Other concomitant treatment............................................................................. 87
7.8.4
Vaccination Against COVID-19 ....................................................................... 87
8
STATISTICAL ANALYSES BY ASTRAZENECA......................................... 87
8.1
Statistical considerations................................................................................... 87
8.2
Sample size estimate......................................................................................... 88
8.3
Definitions of analysis sets................................................................................ 89
8.3.1
Screening analysis set ....................................................................................... 89
8.3.2
Randomised analysis set ................................................................................... 90
8.3.3
Safety analysis set............................................................................................. 90
8.3.4
Patient disposition............................................................................................. 90
8.3.5
Efficacy analysis set.......................................................................................... 90
8.3.6
PK analysis set.................................................................................................. 90
8.3.7
PRO analysis set ............................................................................................... 90
8.4
Outcome measures for analyses ........................................................................ 90


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
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8.4.1
Primary efficacy variables................................................................................. 90
8.4.2
Secondary efficacy variables............................................................................. 91
8.4.3
Additional efficacy variables: ........................................................................... 91
8.4.4
Safety outcomes................................................................................................ 92
8.5
Methods for statistical analyses......................................................................... 92
8.5.1
Exposure........................................................................................................... 93
8.5.2
Prior and Concomitant Medication.................................................................... 93
8.5.3
Analysis of the primary variable (s) .................................................................. 93
8.5.4
Analysis of the secondary variable(s)................................................................ 94
8.5.5
Multiplicity control........................................................................................... 94
8.5.6
Subgroup analysis (if applicable) ...................................................................... 95
8.5.7
Interim analysis ................................................................................................ 95
8.5.8
Sensitivity analysis (if applicable)..................................................................... 95
8.5.9
Analysis of additional efficacy variables........................................................... 96
8.5.10
Analyses of safety and tolerability outcomes..................................................... 96
8.5.11
Exploratory analysis ......................................................................................... 97
8.5.12
Deviations from the planned analyses ............................................................... 97
9
STUDY AND DATA MANAGEMENT BY ASTRAZENECA........................ 97
9.1
Training of study site personnel ........................................................................ 97
9.2
Monitoring of the study..................................................................................... 98
9.2.1
Source data....................................................................................................... 98
9.2.2
Study agreements.............................................................................................. 98
9.2.3
Archiving of study documents .......................................................................... 99
9.3
Study timetable and end of study ...................................................................... 99
9.4
Data management ............................................................................................. 99
10
ETHICAL AND REGULATORY REQUIREMENTS.................................... 100
10.1
Ethical conduct of the study............................................................................ 100
10.2
Subject data protection.................................................................................... 101
10.3
Ethics and regulatory review........................................................................... 101
10.4
Informed consent ............................................................................................ 101
10.5
Changes to the Protocol and Informed Consent Form...................................... 102
10.6
Audits and inspections .................................................................................... 102
11
LIST OF REFERENCES................................................................................ 103
LIST OF TABLES
Table 1
Schema of IP administration to ensure double-blind trial ......................... 39
Table 2
Study Plan detailing the procedures ......................................................... 44


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
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LIST OF FIGURES
Figure 1
Study flow chart ...................................................................................... 30
LIST OF APPENDICES
Appendix A
Signatures.............................................................................................. 108
Appendix B
Additional Safety Information................................................................ 109
Appendix C
IATA 6.2 Guidance Document .............................................................. 111
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry............... 112
Appendix E
COPD ASSESSMENT TEST (CAT)..................................................... 116
Appendix F
BDI-TDI................................................................................................ 117
Appendix G
Saint George Respiratory Questionnaire (SGRQ)................................... 123
Appendix H
EXACT-RESPIRATORY SYMPTOMS (E-RS).................................... 129
Appendix I
CHANGES RELATED TO MITIGATION OF STUDY DISRUPTIONS 
DUE TO CASES OF CIVIL CRISIS, NATUARAL DISASTER, OR 
PUBLIC HEALTH CRISIS................................................................... 135


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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.


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Abbreviation or special term
Explanation
AE
Adverse event
ALT
Alanine aminotransferase, also named GPT
AST
Aspartate aminotransferase, also named GOT 
ATC
Anatomical Therapeutic Chemical
ATS
American Thoracic Society
AUC
Area under the curve
AUC0-3
Area under curve from time 0 to 3 hours
BDI
Baseline Dyspnoea Index
BDRM
Blind Data Review Meeting 
BID
Bis In Die (twice daily) 
BUN
Blood urea nitrogen
CAT
COPD assessment test
CC-16
Circulating levels of Clara cell secretory protein-16
CDSIC
Clinical Data Interchange Standards Consortium
CI
Confidence intervals
COPD
Chronic obstructive pulmonary disease
CRA
Clinical Research Associate
CRF
Case Report Form (electronic/paper) 
CRO
Clinical Research Organization
CRP
C-reactive protein
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report 
CT
Computed Tomography 
CV
Cardiovascular
CVAC
Cardiovascular Adjudication Committee
DLCO
Carbon monoxide diffusion capacity
DM
Data Management
DMP
Data Management Plan
DPI
Dry Powder Inhaler
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG
Electrocardiogram
EDC
Electronic Data Capture
EOS
End of Study
EOT
End of treatment
ePRO
Electronic Patient Reported Outcomes
ERS
European Respiratory Society
E-RS
EXACT Respiratory Symptoms


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EXACT
Exacerbations of Chronic Pulmonary Disease Tool
FDA
U.S. Food and Drug Administration
FDC
Fixed-dose Combination
FEV1
Forced expiratory volume in 1 second 
FSTL1
Follistatin-related protein 1
FVC
Forced vital capacity
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GOT
Glutamic Oxalacetic Transaminase, also named AST
GPT
Glutamic Pyruvic transaminase, also named ALT
GREM1
Gremlin1
HBcAg
Hepatitis B core antigen
HBsAg
Hepatitis B surface antigen 
HCV
Hepatitis C virus
HRCT
High-resolution computed tomography
HU
Hounsfield units
IATA
International Air Transport Association
ICC
Innovation Center of China
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICS
Inhaled corticosteroids
IL
Interleukin
IL-6
Interleukin-6
IL-8
Interleukin-8
International Co-ordinating 
investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally.
IP
Investigational Product
ITT
Intention-to-Treat
IUDRs
Imputation using drop out reasons
IUDs
Intrauterine devices
IUS
Intrauterine system
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LABA
Long-acting beta2-adrenergic agonist
LAMA
Long-acting muscarinic antagonist/inhaled anticholinergic
LDH
Lactate dehydrogenase
LPCAT1
Lysophosphatidylcholine acyltransferase 1
LSMeans
Least Square means
MACE
Major Adverse Cardiac Events


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MedDRA
Medical Dictionary for Regulatory Activities
MIF
Macrophage migration inhibitory factor
MMP
Matrix metalloproteinase
MMP-9
Matrix metalloproteinase-9
MMRM
Mixed model for repeated measures
P
A deflection in an electrocardiographic tracing that represents atrial 
activity of the heart. The P-wave precedes the QRS complex.
PCT
Procalcitonin
PDE IV inhibitor
Phosphodiesterase type 4 inhibitor
PFT
Pulmonary Function test
PI
Principal Investigator
PK
Pharmacokinetics
pMDI
Pressurised metered dose inhaler
PP
Per Protocol
PR interval
Duration in milliseconds from the beginning of wave P to onset of 
ventricular depolarisation (Q and R)
PRO
Patient reported outcomes
Pro-BNP
Pro-B-type-Natriuretic Peptide
QRS
ECG interval measured from the beginning of the Q wave (or the R wave 
if
Q is missing) to the J point; the time interval of ventricular depolarisation
QRS interval
Duration in milliseconds of the QRS complex
QT
ECG interval measured from the onset of the QRS complex to the end of 
the T wave
QT interval
Duration in milliseconds from the beginning of Q wave to the end of the T
wave
QTc
QT corrected
QTc interval
QT interval corrected by heart rate
QTcB interval
QT interval corrected, Bazett formulae
QTcF
QT corrected, Fridericia formulae
QTcF interval
QT interval corrected, Fridericia formulae
RR interval
Duration in milliseconds between two R peaks of two consecutive QRS
complexes
RV
Residual volume
SABA
Short-acting beta2-adrenergic agonists
SAE
Serious adverse event
SAMA
Short-acting muscarinic antagonist/ inhaled anticholinergics
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SD
Standard Deviation
SDTM
Study Data Tabulation Model 
SE
Standard errors


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SGRQ
St George’s Respiratory Questionnaire
SmPC
Summary of Product Characteristics
SP-B
Surfactant Protein-B
SP-D
Surfactant Protein D
ST segment
Part of an electrocardiogram between the QRS complex and the T wave
TDI
Transition Dyspnoea Index
TEAE
Treatment-emergent adverse event 
TLC
Total lung capacity
TNF-α
Tumor Necrosis Factor-alfa
WA%
Wall area percentage
WHO
World Health Organisation
γ-GT
Gamma-glutamyl transferase/ gamma-glutamyl transpeptidase


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1
INTRODUCTION
1.1
Background and rationale for conducting this study
Chronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, 
is characterised by persistent airflow limitation that is usually progressive and associated with 
an enhanced chronic inflammatory response in the airways and the lung to noxious particles or 
gases. Cigarette smoking is the most common risk factor for COPD. Exacerbation and 
comorbidities contribute to the overall severity in individual patients. COPD is a major cause 
of morbidity and mortality worldwide and results in economic and social burden which is both 
substantial and increasing. In a study of the burden of obstructive lung disease (BOLD Study), 
the crude prevalence of COPD, all stages, among the study populations ranged from 11.4% in 
Guangzhou, China to 26.1% in Salzburg, Austria (Buist et al 2007). The prevalence of COPD 
in China is 8.2% in those aged over 40 years old (Zhong et al 2007).
COPD is characterized by structural changes in the airways resulting from repeated injury and 
repair and by bronchoconstriction, which is an important target for pharmacologic 
interventions (GOLD 2015). Dyspnoea, chronic cough and sputum production are the most 
common clinical symptoms. Adrenergic and cholinergic pathways mediate 
bronchoconstriction in COPD.
Anticholinergic compounds such as ipratropium, oxitropium, tiotropium, aclidinium, 
glycopyrronium or umeclidinium have been shown to provide clinical benefit in the treatment 
of COPD. These therapeutic agents block muscarinic acetylcholine receptors in bronchial 
smooth muscle and thus decrease cholinergic tone (muscarinic antagonism). β2-adrenergic 
agonists such as albuterol, formoterol, salmeterol or indacaterol stimulate β2-receptors in the 
bronchial smooth muscle resulting in similar effects to those of anticholinergics. Both 
anticholinergic drugs and β2-adrenergic agonists decrease bronchoconstriction (increased 
FEV1) and thereby reduce dyspnoea and COPD exacerbations, increase exercise tolerance, 
and improve quality of life.
As a result of their differing mechanisms of action and similar pharmacodynamic effects, β2-
agonists and muscarinic antagonists have been used simultaneously in the same inhalation 
device for the treatment of COPD. Administration of an inhaled fixed-dose combination of 
ipratropium (muscarinic antagonist) and albuterol (β2-agonist) has been shown to produce a 
significantly greater improvement in pulmonary function than either ipratropium or albuterol 
monotherapies (Combivent® UDVs® United Kingdom (UK) SmPC). The safety and 
tolerability profile of ipratropium/albuterol is similar to those of the individual components. 
However, one significant drawback is the short-lived duration of action of both of the 
components, which necessitates repeated dosing 3-4 times daily.


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Several combinations of LABA and LAMAs have been recently approved worldwide for the 
treatment of COPD, ie Ultibro (indacaterol/glycopyrronium) and Anoro 
(vilanterol/umeclidinium). The clinical studies have shown that the combined use of a LABA 
and a LAMA results in greater improvement of bronchodilation as well as a better symptoms 
control compared with monotherapies (Pelaia et al 2014, Maltais et al 2014, Maleki-Yazdi et 
al 2014). 
Duaklir® Genuair®/Brimica® Genuair® is a combination product of LAMA (aclidinium 
bromide) and LABA (formoterol fumarate) approved in Europe for the treatment of COPD at 
a dose of 400/12 μg (delivered as 340/12 μg) twice daily in November 2014 (Duaklir® 
Genuair® SmPC 2021).
Aclidinium bromide is a novel LAMA (long acting muscarinic agent) marketed as Eklira® 
and Bretaris® Genuair® (Eklira® Genuair® SmPC 2021) indicated as a twice daily (BID) 
maintenance bronchodilator treatment to rescue symptoms of patients with COPD.
The current Phase III study is designed to investigate the long term bronchodilator efficacy of 
aclidinium bromide 400 µg/formoterol fumarate 12 µg and aclidinium bromide 400 µg 
delivered by inhalation on a BID schedule in an Asiatic population. The study will also assess 
the potential benefits of the Investigational Product (IPs) on disease-related health status, 
COPD symptoms and other outcomes in patients with moderate to severe COPD in China and 
other Asian countries. In addition, the study will evaluate the safety and tolerability of both 
products in the same patient population.
1.2
Rationale for study design, doses and control groups
The objectives of this study are to assess the bronchodilator efficacy and safety of Aclidinium 
bromide 400 μg /formoterol fumarate 12 μg compared to the individual components 
(Aclidinium bromide 400 μg and Formoterol fumarate 12 μg) and placebo and Aclidinium 
bromide 400 μg compared to placebo.
The Guideline on Clinical Development of Fixed Combination Medicinal Products 
(CHMP/EWP/240/95 2009) and FDA Code of Federal Regulations, Title 21, Section 300-50, 
state that each substance of a fixed combination must have a documented contribution within 
the combination to the claimed effects. Therefore, the objectives of the present trial will be to 
demonstrate statistically significant bronchodilation of Aclidinium bromide/Formoterol 
fumarate compared with Aclidinium bromide and Formoterol fumarate in terms of 
bronchodilation and an acceptable safety profile of the combination compared to the 
individual components in Asian population. In addition, this study will assess the efficacy and 
safety of Aclidinium bromide compared with placebo in the same patient population.


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The target study population of this study (Stage II or Stage III according to the GOLD 2015: 
post-bronchodilator FEV1 ≥30% and < 80% of the predicted normal and FEV1/FVC < 70%) 
has been commonly investigated in similar trials.
The proposed trial duration of 24 weeks has been chosen considering the intended indication 
for Aclidinium bromide/Formoterol fumarate and Aclidinium bromide, ie maintenance 
bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive 
pulmonary disease (COPD) in accordance to CPMP/EWP/562/98 1999 and the FDA 
Guidance for Industry Chronic Obstructive Pulmonary Disease: Developing Drugs for 
Treatment (Draft November 2007) that state that any indication for the symptomatic rescue of 
COPD should be supported by the results from a trial of at least 6 months duration.
The IP doses and dose regimen for the Aclidinium bromide 400µg/Formoterol fumarate 12 µg 
and the individual components are the approved dose and dose regimen in the EU (Aclidinium 
bromide 400 µg/Formoterol fumarate 12 µg BID, Aclidinium bromide 400 µg BID and 
Formoterol fumarate 12 µg BID corresponding to a delivered dose of 9 µg).
The inclusion of a placebo arm is considered the most reliable method to minimise patient and 
investigator bias and is recommended by FDA Guidance for Industry ICH E10 on Choice of 
Control Group in Clinical Trials (FDA Guidance for industry ICH-E10 2001), Note for 
Guidance on Choice of Control Group in Clinical Trials (CPMP/ICH/364/96 2001), 
CPMP/EWP/562/98 1999 and CHMP/EWP/240/95 2009. Exposure to placebo is deemed 
necessary to allow a reliable evaluation of the net pharmacological effect of the study drug, as 
well as of the adverse events caused by the drug compared with those resulting from the 
COPD natural course or other underlying diseases in this type of population. A placebo 
control group has been also included in studies with similar patient population and at least the 
same treatment duration (Donohue et al 2013, Celli et al. 2014, Bateman et al 2013). In 
addition, the comparison to placebo arm is needed to assess the efficacy and safety of 
Aclidinium bromide in China where it is not yet approved.
Rescue medication (salbutamol pMDI 100 μg/puff) will be permitted as needed throughout the 
study duration for all participants. In addition, several background medications for the 
treatment of COPD (e.g., inhaled corticosteroids, oral or parenteral corticosteroids, oxygen 
therapy, and oral sustained-release teophyllines) will be permitted. Rescue and background 
therapies are allowed to help controlling patient’s COPD symptoms as well as to minimise the 
risk of COPD exacerbations.
Inhalers and medication kits containing study drug will present the same external appearance 
to ensure the double-blind nature of the trial. The blinding and randomisation of study drug 
will avoid the chance of bias in patient treatment assignation as well as patient management 
during the study and data interpretation. Additionally, by randomly assigning patients to any 


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of the possible treatment arms, differences in baseline characteristics of the treatment groups 
will be minimised. Patient’s smoking status at the time of randomisation will be used as 
treatment allocation factor following the recommendation from CPMP/EWP/562/98 1999.
The parameters to be measured have been selected based on the objectives and outcomes to be 
assessed. Thus, the study will assess FEV1 (as a measure of lung function) and other lung 
function parameters, as well as symptomatic benefits, including the Baseline/Transition 
Dyspnoea Index (BDI/TDI), COPD Assessment Test (CAT) and St. George Respiratory 
Questionnaire (SGRQ), COPD exacerbation and use of rescue medication, all previously used 
in similar studies (Donohue et al 2013, Celli et al. 2014, Bateman et al 2013). Similarly, 
adverse events and commonly used tolerability assessments (e.g., ECG, blood pressure and 
clinical laboratory test) will be performed to monitor study drug safety profile and patient’s 
wellbeing throughout the trial.
1.3
Benefit/risk and ethical assessment
The Aclidinium Bromide 400 µg/Formoterol fumarate 12 µg and Aclidinium bromide 400 µg 
are currently approved in Europe as a maintenance bronchodilator treatment to relieve 
symptoms in adult patients with chronic obstructive pulmonary disease (COPD) while 
Formoterol fumarate 12 µg is approved in Europe and indicated for the rescue of broncho-
obstructive symptoms in the same population.
The 3 pivotal clinical studies of aclidinium bromide 400 μg have demonstrated a clinically and 
statistically significant bronchodilatory effect when compared to the placebo throughout the 
12 and 24 weeks treatment period.  Moreover, treatment with aclidinium bromide 400 μg BID 
was associated with improvements in dyspnoea, disease-related health status (St. George's 
Respiratory Questionnaire [SGRQ]) and daily and night-time symptoms (Jones et al. 2012, 
Kerwin et al 2012). Furthermore, Phase II Studies M/34273/23 (Fuhr et al Chest 2012) and 
M/34273/29 (Singh et al. 2012) showed the overall bronchodilation of aclidinium bromide 
400 µg BID to be broadly comparable to that of commercially available bronchodilators, 
tiotropium and formoterol. Evidence of the benefits of aclidinium bromide on exercise 
endurance, lung hyperinflation, exertional dyspnoea and daily physical activity was observed 
in Study M/34273/40 (Beeh et al. 2014).
The clinical development programme for Aclidinium Bromide 400 µg/Formoterol fumarate 12 
µg has shown to provide additional efficacy benefits compared to those associated with 
aclidinium or formoterol fumarate monotherapies (as assessed by measures of lung function, 
COPD symptoms and disease-specific health status) and yet the safety and tolerability of 
aclidinium 400 µg/formoterol fumarate 12µg is generally comparable to that of the component 
monotherapies (D’Urzo et al. 2014, Singh et al. 2014).


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Aclidinium/bromide 400/12 µg appears to have comparable efficacy to other recently 
approved LABA/LAMA fixed combinations with regard to symptomatic and disease-specific 
health status benefits. Its symptomatic and disease-specific health status benefits compared to 
placebo (as assessed by TDI and SGRQ) were comparable to those observed with the recently 
approved fixed-dose LABA/LAMA combinations of indacaterol/glycopyrronium (Committee 
for Medicinal Products for Human Us, CHMP Assessment report for Ultibro Breezhaler, 
EMA/CHMP/296722/2013, 25 July 2013) or umeclidinium/vilanterol (CHMP Assessment 
report for Anoro, EMA/CHMP/163509/2014, 28 March 2014.). Furthermore, the magnitudes 
of improvements in breathlessness (TDI), daily symptoms (E-RS), early morning and night-
time symptoms, disease-specific health status (SGRQ-C) and exacerbation prevention were 
comparable with aclidinium 400 µg /formoterol fumarate 12µg and the fixed-dose ICS/LABA 
combination of salmeterol/fluticasone propionate 50/500 µg BID (Vogelmeier et al. 2015).
LABA/LAMA fixed combinations which are administered once daily have recently received 
marketing authorisation in the EU and other territories (glycopyrronium/indacaterol and 
umeclidinium/vilanterol). BID dosing of a LABA/LAMA fixed combination, such as with 
aclidinium/formoterol fumarate, may be a useful approach to the control of night-time and 
early morning symptoms, which epidemiological studies indicate are the most troublesome for 
patients with COPD (Kessler et al. 2011).
The safety profile for Aclidinium Bromide 400 µg/Formoterol fumarate 12 µg is based on the 
clinical experience after exposure at the recommended therapeutic dose for up to 12 months. 
No relevant post-marketing experience data is available. The safety profile of Aclidinium 
bromide 400 µg and Formoterol fumarate 12 µg are based on clinical and post-marketing 
experience.
As the IP contains Aclidinium bromide and Formoterol fumarate, the type and severity of 
adverse reactions associated with each of the components are the ones expected with 
Aclidinium Bromide 400 µg/Formoterol fumarate 12 µg.
Common adverse events which may be expected with aclidinium bromide treatment includes 
sinusitis, nasopharyngitis, headache, cough and diarrhoea. Common adverse event to be 
expected with formoterol fumarate are palpitations, headache and tremor.
The most frequently reported adverse reactions with Aclidinium bromide 400 µg/Formoterol 
fumarate 12 µg were nasopharyngitis (7.9%) and headache (6.8%).
Other commonly reported adverse reactions with Aclidinium bromide 400 µg/Formoterol 
fumarate 12 µg are urinary tract infection, sinusitis, tooth abscess, insomnia, anxiety, 
headache, dizziness, tremor, cough, diarrhoea, nausea, dry mouth, myalgia, muscle spasms, 
oedema peripheral and blood creatine phosphokinase increased.


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Hypokalaemia, hyperglycaemia, agitation, dysgeusia, tachycardia, electrocardiogram QTc 
prolonged, palpitations, rash, pruritus, blurred vision, dysphonia, throat irritation, urinary 
retention and blood pressure increased are uncommon adverse reactions that could be 
observed with the Aclidinium bromide 400 µg/Formoterol fumarate 12 µg or the individual 
components, while bronchospasm and hypersensitivity could rarely occur when administering 
the individual components.
There is limited evidence on the management of overdose with Duaklir® Genuair®, Eklira® 
Genuair®. High doses may lead to exaggerated anticholinergic and/or β2-adrenergic signs and 
symptoms; the most frequent of which include blurred vision, dry mouth, nausea, muscle 
spasm, tremor, headache, palpitations and systolic hypertension.
For more details on the safety and tolerability profile of the aforementioned compounds, 
please see the approved Investigator´s Brochures.
Based on the study drug safety profile, no specific risk is anticipated with the doses and the 
dose regimen proposed in this trial. Still, investigators will ensure adequate medical care of 
the trial participants at all times throughout the course of the study.
1.4
Study Design 
This is a multiple dose, randomised, parallel, double blind, double dummy, multicentre and 
multinational Phase III study to determine the efficacy and safety of Aclidinium 
bromide/Formoterol fumarate compared to individual components and placebo and 
Aclidinium bromide compared to placebo when administered to patients with stable Chronic 
Obstructive Pulmonary Disease.
The study will consist of a Screening Visit (Visit 1) conducted after signature of the informed 
consent form, where medical history, COPD history, physical examination, laboratory 
analysis, ECG and COPD severity stage (post-bronchodilator FEV1 according to Global 
Initiative for Chronic Obstructive Lung Disease, GOLD guidelines) will be conducted.
Patients fulfilling inclusion/exclusion criteria at the time of the screening will be entered into a 
run-in period of 14 ±3 days to assess patient’s disease stability.
Patients who are still meeting entry criteria at Visit 2 will be randomised in a ratio 1:1:1:1 to 
one of the 4 treatment arms to start a 24 weeks treatment period. Smoking status (current 
smokers vs former smokers) and country will be the treatment allocation factors.
─
Aclidinium bromide 400 µg/Formoterol fumarate 12 µg
─
Aclidinium bromide 400 μg
─
Formoterol fumarate 12 μg


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─
Placebo
After randomisation, patients will be assigned one medication kit with 4 Genuair® inhalers 
containing Aclidinium bromide 400 µg/Formoterol fumarate 12µg, or Aclidinium bromide 
400 µg or matching placebo and 4 Turbuhaler® inhalers containing formoterol fumarate12 µg 
or matching placebo. At Visit 5 a second kit will be dispensed with 4 additional Genuair and 4 
Turbuhaler inhalers.
Each Genuair® inhaler will contain at least 60 doses (and a maximum of 68 doses). Each 
Turbuhaler inhaler will contain at least 60 doses.
Patients will be instructed to take 1 puff from the Genuair® and 1 puff from the Turbuhaler® in 
the morning (09:00 ± 1 h) and 1 puff from the Genuair® and 1 puff from the Turbuhaler® in 
the evening (21:00 ± 1 h) during the 24 weeks of treatment. It is important that the evening 
administrations are consistently performed approximately 12 hours after morning 
administrations. During the double-blind treatment period, patients will visit the site to assess 
clinical efficacy and safety on 5 more occasions, after 1 week of treatment (Visit 3), after 4 
weeks of treatment (Visit 4), after 12 weeks of treatment (Visit 5), after 18 weeks of treatment 
(Visit 6) and after 24 weeks of treatment (Visit 7). A follow-up contact will be performed 2 
weeks after the last IP administration for patient that complete the treatment and patient that 
discontinue from the trial (withdrawals). Patients completing the trial will be the patients on 
treatment up to Visit 7, even if they do not complete the follow-up contact.
Patients who prematurely discontinue investigational product (IP) will perform an EOT visit 
and will participate in a post-treatment follow-up period. The follow-up period will include 
phone calls to collect COPD exacerbations, concomitant medications, and SAEs for the 
remainder of the study duration and an on-site visit in place of Visit 7 (EOS visit). Moreover, 
the EXACT (E-RS) questionnaire will be completed by patients every night during the post-
treatment follow-up period.




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investigator or designee should contact the study Sponsor to discuss whether the mitigation 
plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of the study participants, maintain 
compliance with Good Clinical Practice, and minimise risks to study integrity.
Where allowable by local authorities, ethics committees, healthcare provider guidelines (e.g. 
hospital policies) or local government, these changes may include the following options:

Pausing recruitment and screening of new patients

Rescheduling of visits

Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the Informed Consent Form (ICF) should be signed as soon as is 
feasible ie at the patient’s next visit).

Telemedicine visit: Remote contact with the patient using telecommunication technology 
including phone calls, virtual or video visits.

Home delivery of Investigational Product 
Further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix I.
2
STUDY OBJECTIVES
Primary and secondary objectives are to be assessed regardless the adherence to the randomised 
treatment.
2.1
Primary objective
Primary Objective:
Outcome Measure:


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
To assess the bronchodilatory effect of 
Aclidinium bromide 400 µg/Formoterol 
fumarate 12 µg compared to individual 
components and placebo when 
administered twice daily via inhalation to 
COPD patients.

To assess the bronchodilatory effect of 
Aclidinium bromide 400 µg compared to 
placebo when administered twice daily via 
inhalation to COPD patients.

Change from baseline in 1-hour morning post-dose 
dose FEV1 of Aclidinium bromide 400 µg/Formoterol 
fumarate 12 µg compared to Aclidinium bromide at 
Week 24.

Change from baseline in morning pre-dose (trough) 
FEV1 of Aclidinium bromide 400 µg/Formoterol 
fumarate 12 µg compared to Formoterol fumarate at 
Week 24.

Change from baseline in trough FEV1 of Aclidinium 
bromide 400 µg compared to placebo at Week 24
2.2
Secondary objectives
Secondary Objectives:
Outcome Measures:

To assess the benefits of Aclidinium 
bromide 400 µg /Formoterol fumarate 12 
µg in COPD symptoms, disease-related 
health status and COPD exacerbations 
compared to placebo, when administered 
BID via inhalation to COPD patients.

To assess the benefits of Aclidinium 
bromide 400 µg in COPD symptoms, 
disease- related health status and COPD 
exacerbations compared to placebo, when 
administered BID via inhalation to COPD 
patients. 

Change from baseline in peak FEV1 of Aclidinium 
bromide 400 µg compared to placebo at week 24

Improvements TDI focal score of Aclidinium bromide 
400 µg/Formoterol fumarate 12 µg compared to 
placebo at week 24

Improvements TDI focal score of Aclidinium bromide 
400µg compared to placebo at week 24

Change from baseline in SGRQ total score of 
Aclidinium bromide 400 µg/Formoterol fumarate 12 
µg compared to placebo at week 24

Change from baseline in SGRQ total score of 
Aclidinium bromide 400µg compared to placebo at 
week 24
Additional efficacy variables:

Pulmonary function variables (FEV1, FVC) at each 
time point and average (ie Area Under the Curve, 
AUC0-3)

Symptomatic and health related quality of life 
outcomes (TDI, SGRQ, CAT, E-RS)

COPD exacerbations (HCRU and EXACT)

Use of rescue medication
2.3
Safety objectives
Safety Objective:
Outcome Measure:


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
To evaluate the safety profile of 
Aclidinium bromide 400 µg /Formoterol 
fumarate 12 µg and Aclidinium bromide 
400 µg in the same patient population.

Adverse events

Clinical laboratory test

Blood pressure

ECG
3
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject 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 subjects should fulfil the following criteria:
1.
Adult male or non-pregnant, non-lactating female patients aged ≥40
─
Explanatory notes: A female is considered to be of childbearing potential unless is at 
least one year post-menopausal or permanently sterilised (e.g. tubal occlusion, 
hysterectomy, bilateral salpingectomy). Women of childbearing potential are allowed 
to enter the trial if they show to have a negative pregnancy test at the Screening Visit 
and are using, during the last two months before the Screening Visit and during the 
whole duration of the trial, at least one medically approved and highly effective 
method of birth control defined as those, alone or in combination, which result in a 
low failure rate (ie less than 1% per year) when used consistently and correctly. Male 
participants are not requested to use contraception methods during their participation 
on the trial.
2.
Patients with a diagnosis of COPD (GOLD 2015) prior to Visit 1 (screening). 
3.
Patients with moderate to severe stable COPD (Stage II or Stage III, according to GOLD 
2015) at Visit 1: post-bronchodilator FEV1 ≥30% and < 80% and post-bronchodilator 
FEV1/FVC < 70%
─
Explanatory note: “post” means FEV1 and FVC between 10 to 15 minutes after 
inhalation of 400 μg of salbutamol from acceptable and repeatable pulmonary 
function testing according to the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) 2005 criteria. Predicted normal values to be used for 
calculation purposes are based on the Global Lung Function Initiative predicted 
values (Quanjer et al 2012).
4.
Current or former smokers with a smoking history of ≥ 10 pack-years.
─
Explanatory notes:
a.
Former smoker condition defined as having quit smoking ≥ 6 months before 
Visit 1 (Screening).


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b.
Pack-years is calculated by dividing the number of cigarettes smoked per day by 
20 (the number of cigarettes in a pack) and multiplying this figure by the number 
of years a person has smoked. For example, a person who smokes 40 cigarettes a 
day and has smoked for 10 years would have a 20 pack-year smoking history (40 
cigarettes per day ÷ 20 cigarettes per pack = 2; 2 × 10 years of smoking = 20 
pack-year history). In case of intermittent smoking/non-smoking periods, pack-
years is calculated by summing all periods pack-years.
c.
Patients smoking other tobacco types will not be allowed, unless they meet the 
cigarette criterion as well.
5.
Patients able to perform repeatable pulmonary function testing for FEV1 according to the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 criteria at 
Visit 1 (screening).
6.
Patients who understand the study procedures and are willing to participate in the study as 
indicated by signing the informed consent.
3.2
Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff 
and/or site staff) or patients employed by or relatives of the employees of the site or 
sponsor.
2.
Previous enrolment or randomisation in the present study
3.
History or current diagnosis of asthma.
4.
Any respiratory tract infection (including the upper respiratory tract) or COPD 
exacerbation (including the mild COPD exacerbation) within 6 weeks prior to screening 
or during the run-in period.
5.
Patients hospitalized for COPD exacerbation (an emergency room visit for longer than 24 
hours will be considered a hospitalization) within 3 months prior to screening and during 
the run-in period.
6.
Clinically significant respiratory conditions other than COPD
─
Explanatory note: Clinically significant respiratory conditions, some examples are:
a.
Known active tuberculosis.
b.
History of interstitial lung disease or massive pulmonary thromboembolic 
disease.
c.
Pulmonary resection or lung volume reduction surgery. 
d.
History of lung transplantation.


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e.
Patients who in the Investigator’s opinion might have needed thoracotomy or 
other lung surgery during the study. 
f.
Clinically significant bronchiectasis.
g.
Known α1-antitrypsin deficiency.
7.
Patients who in the Investigator’s opinion may need to start a pulmonary rehabilitation 
program during the study and/or patients who started/finished it within 3 months prior to 
screening.
8.
Use of long-term oxygen therapy (≥15 hours/day).
9.
Patient who does not maintain regular day/night, waking/sleeping cycles including night 
shift workers.
─
Explanatory note: patients with symptomatic sleep apnoea syndrome, any disease 
related to sleep disturbances such as restless-legs syndrome or somnambulism are to 
be excluded from the study. However, the use of continuous positive airway pressure 
is not an exclusion criterion
10.
Clinically significant cardiovascular conditions:
─
Explanatory note: Clinically significant cardiovascular conditions, some examples 
are:
a.
Myocardial infarction within the 6 months prior to screening.
b.
Thoracic surgery within 12 months prior to Visit 1 (screening).
c.
Unstable angina or unstable arrhythmia which had required changes in the 
pharmacological therapy or other intervention within 12 months prior to Visit 1 
(screening), or newly diagnosed arrhythmia within the 3 months prior to 
screening.
d.
Hospitalization within 12 months prior to screening for heart failure functional 
classes III (marked limitation of activity and only comfortable at rest) and IV 
(need of complete rest, confinement to bed or chair, discomfort at any physical 
activity and presence of symptoms at rest) as per the New York Heart 
Association.
11. Patients with Type I or uncontrolled Type II diabetes, uncontrolled hypo-or 
hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled or untreated 
hypertension.
12. Patients with QT corrected interval (QTc) using Fridericia formula (QTcF) 
(QTc=QT/RR1/3) >470 msec as indicated in the centralised reading report assessed at 
Screening (Visit 1).
13. Patients with clinically significant abnormalities in the clinical laboratory tests, ECG 
parameters (other than QTcF) or in the physical examination at Visit 1 (screening).


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14. Patients with abnormal liver function tests defined as AST, ALT, or total bilirubin ≥ 2.5 
times upper limit of normal ranges at screening
15. Patient with known non-controlled history of infection with human immunodeficiency 
virus and/or active hepatitis 
─
Explanatory note: Active hepatitis is defined as clinical symptoms associated with 
chronic portal inflammation with regional necrosis and fibrosis, which may progress 
to nodular postnecrotic cirrhosis or patients with antibody to hepatitis B core antigen 
(HBcAg) and hepatitis B surface antigen (HBsAg) test with positive results or 
antihepatitis C virus (HCV) antibody and HCV recombinant immunoblot assay HCV 
positive tests or genetic material (ribonucleic acid) testing positive results.
16. Patient with a history of hypersensitivity reaction to inhaled anticholinergic drugs, 
sympathomimetic amines, inhaled medication or any component thereof.
17. Patient with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute 
urinary retention, or patients with symptomatic non-stable prostatic hypertrophy.
─
Explanatory note: Patients with well-controlled, stable, asymptomatic benign 
prostatic hypertrophy are not excluded.
18. History of malignancy of any organ system (including lung cancer), treated or untreated, 
within the past 5 years other than basal or squamous cell skin cancer.
─
Explanatory note: Patients are excluded whether or not there is evidence of local 
recurrence or metastases.
19. Any other serious or uncontrolled physical or mental dysfunction.
─
Explanatory note: as judged by the Investigator, the dysfunction could place the 
patient at a higher risk as a result of his/her participation in the study, or confound the 
results of the study, or would be likely to prevent the patient from complying with 
the requirements of the study or completing the study
20. Patients with a history (within 2 years prior to Visit 1 (screening) of drug and/or alcohol 
abuse that may prevent study compliance based on the Investigator judgment.
21. Patients unlikely to be cooperative or cannot comply with the study procedures
─
Explanatory note: patients who may have difficulties following the treatment, 
completing the patient diary, or attending the clinic at the required times, or unable to 
properly use a DPI or pressured metered dose inhaler device, or performing 
spirometry measurements.
22. Patients treated with any investigational drug within 30 days (or 6 half-lives, whichever is 
longer) prior to screening.
23. Patients who intended to use any concomitant medication not permitted by this protocol 
or who had not undergone the required washout period for a particular prohibited 
medication.


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24. Patients unable to give consent, or patients of consenting age but under guardianship, or 
vulnerable patients.
25. Any other conditions that, in the Investigator’s opinion, might have indicated the patient 
to be unsuitable for the study.
Procedures for withdrawal of incorrectly enrolled subjects see Section 3.4.
3.3
Subject enrolment and randomisation
Investigator(s) should keep a record, the subject screening log, of subjects who entered pre-
study screening.
The Investigator(s) will:
1.
Obtain signed informed consent from the potential subject or their guardian/legal 
representative before any study specific procedures are performed.
2.
Call/access IVRS/IWRS to assign potential a unique Patient Identification number 
consisting of 2 parts, the site number (4-digits) and the screening number (3 digits).
3.
At Randomisation Visit (Visit 2), the investigator will determine subject eligibility. See 
Section 3.
4.
For patients fulfilling the eligibility criteria, the investigator will call/access IVRS/IWRS 
to assign eligible subject unique randomisation code and first medication kit number.
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.
Randomisation codes will be assigned strictly sequentially as subjects become eligible for 
randomisation.
3.4
Procedures for handling incorrectly enrolled or randomised 
subjects
Subjects 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. Subjects 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 subject 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/CRO immediately, and a discussion should occur between the AstraZeneca study 
physician/CRO and the investigator regarding whether to continue or discontinue the patient 


Clinical Study Protocol - 4.0
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from treatment. The AstraZeneca study physician/CRO must ensure all decisions are 
appropriately documented.
3.5
Methods for assigning treatment groups
Subjects will be allocated to the four treatment groups in a 1:1:1:1 ratio:
─
Aclidinium bromide 400 μg/Formoterol fumarate 12 μg administered via Genuair inhaler
─
Aclidinium bromide 400 μg administered via Genuair inhaler
─
Formoterol fumarate 12 μg administered via Turbuhaler inhaler
─
Placebo
The randomisation will be stratified by country and smoking status (smoker or former smoker) 
and the randomisation numbers will be grouped in blocks. The block size will not be 
communicated to the investigators.
The randomisation will be performed using a centralized Interactive Voice/Web Response 
System (IVRS/IWRS) at Visit 2 (Day 1). Specific information concerning the use of the 
IVRS/IWRS will be provided in a separate manual. Randomised subjects who discontinue 
from the treatment will not be replaced.
At the randomisation, the IVRS/IWRS will inform the site about the first medication kit 
number to be administered and dispensed to each particular patient.
3.6
Methods for ensuring blinding
All medication kits will have identical appearance regardless of the investigational product 
contained and will be labelled using a unique medication identification number (Kit ID) that is 
linked to a treatment arm. IVRS/IWRS will assign the study medication to be dispensed to 
each subject at Visit 2 and Visit 5 (after 12 weeks of treatment).
Active compounds have no perceivable taste, appearance, odour or colour that could unmask 
the blinded design.
This is a double-dummy study because the Aclidinium bromide 400µg/Formoterol fumarate 
12 µg and the Aclidinium bromide 400 μg will be administered via Genuair inhaler and the 
Formoterol fumarate 12 μg will be administered via Turbuhaler inhaler. Therefore, in order to 
ensure the double blind nature of the trial, patients will have to inhale from both inhalers twice 
daily following the schema below.


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Table 1
Schema of IP administration to ensure double-blind trial
Treatment arm
Morning inhalation
(8-10 AM)
Evening inhalation
(8-10 PM)
Aclidinium bromide
/Formoterol fumarate 
400/12 μg
1 puff of Aclidinium 
bromide/Formoterol fumarate 400/12 
μg via Genuair
1 puff of placebo via Turbuhaler
1 puff of Aclidinium 
bromide/Formoterol fumarate 400/12 μg 
via Genuair
1 puff of placebo via Turbuhaler
Aclidinium bromide 
400 μg
1 puff of Aclidinium bromide 400 μg
via Genuair
1 puff of placebo via Turbuhaler
1 puff of Aclidinium bromide 400 μg
via Genuair
1 puff of placebo via Turbuhaler
Formoterol fumarate 
12 μg
1 puff of placebo via Genuair
1 puff of Formoterol fumarate 12 μg
via Turbuhaler
1 puff of placebo via Genuair
1 puff of Formoterol fumarate 12 μg via
Turbuhaler
Placebo
1 puff of placebo via Genuair
1 puff of placebo via Turbuhaler
1 puff of placebo via Genuair
1 puff of placebo via Turbuhaler
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
subject, will be available to the Investigator(s) or pharmacists from the IVRS/IWRS. Only 
authorised personnel at the research site will receive unblinding permits in IVRS/IWRS. 
Patient will be immediately withdrawn from the study once his/her treatment has been 
unblinded.
Routines for this will be described in the IVRS/IWRS user manual that will be provided to 
each centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomisation. The 
Investigator documents and reports the action to AstraZeneca/CRO, without revealing the 
treatment given to subject to the AstraZeneca/CRO staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product 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 
subject have been made and documented.
3.8
Restrictions
─
Donation of blood is not allowed throughout the study


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─
Patient should keep regular night/day shifts.
The activities that should preferably be avoided prior to lung function testing are:
─
Smoking within at least 1 h of testing
─
Consuming alcohol within 4 h of testing
─
Performing vigorous exercise within 30 min of testing
─
Wearing clothing that substantially restricts full chest and abdominal expansion
─
Eating a large meal within 2 h of testing
─
Subjects should avoid taking inhaled bronchodilators prior to spirometry (see Section 7.7)
─
Restrictions regarding concomitant medication are described in Section 7.
Any event likely to interfere with the objectives of the trial will be communicated to the 
investigator and reported without delay to AstraZeneca.
3.9
Patient discontinuation of investigational product
Subjects may be discontinued from investigational product (IP) in the following situations:

Adverse Event: if a patient experiences an AE, its premature discontinuation will be 
considered at the discretion of either the investigator or the patient regardless of the 
causal relationship to the IP. AE should be indicated as the reason for discontinuation in 
the eCRF.

Progressive disease: if at investigator’s or patient’s discretion the severity of the COPD 
exacerbation episode jeopardises the current medical condition of the patient, the patient 
should be discontinued from the treatment and progressive disease should be indicated as 
the reason for discontinuation in the eCRF.

Protocol deviation: This will include patients that have been wrongly randomised: not 
fulfilling inclusion/exclusion criteria but detected after randomisation. After 
randomisation, any protocol deviations detected should be corrected when possible and 
the patient should be allowed to continue. The following major deviations could lead to 
patient discontinuation after discussion between the AstraZeneca study physician/CRO 
and the investigator (see section 3.4): those which could affect patient's safety (e.g., 
illness requiring treatment(s) which in the clinical judgement of the investigator [or after 
discussion with the trial monitor might invalidate the trial by interfering with the IP) or 
which are due to patient unwillingness to comply with the trial activities or those 
violations of inclusion and/or exclusion criteria detected after randomisation.

Lack of efficacy: only if at the investigators discretion the response to the treatment is 
considered as unsatisfactory

Pregnancy


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3.9.1
Procedures for discontinuation of a subject from investigational 
product 
At any time, subjects are free to discontinue investigational product, without prejudice to 
further treatment. A subject that decides to discontinue investigational product will always be 
asked about the reason(s) and the presence of any adverse events.
Discontinuation of IP does not necessarily mean discontinuation of follow-up or termination 
of study participation. Compliant subjects who are discontinued from the IP should be 
encouraged to continue to undergo all study related visits for the full study period. The reason 
for premature discontinuation of IP will be documented in the source documentation.
If possible, subjects who discontinue investigational product will be seen and assessed by an 
Investigator(s) in an End of treatment (EOT) visit.
From the EOT visit on the patients will start a post-treatment follow-up period where the on-
site visits will be replaced by telephone calls in order to follow-up the SAEs, COPD 
exacerbations and Concomitant Medication. During this post-treatment follow-up period the 
patients will not have IP but they will keep the paper diary to record the concomitant 
medication and the e-diary to continue recording the use of rescue medication and EXACT 
questionnaire.
The Visit 7 will be performed as an on-site visit in order to return the e-diary, paper diary and 
rescue mediation and to follow-up any new SAE, COPD exacerbation and Concomitant 
medication.
For any patient who withdraws from the IP, the investigator will:
1.
Ask the patient to undergo the End of Treatment (EOT) visit AS SOON AS POSSIBLE
after discontinuation of IP.
2.
Arrange for alternative medical care of the withdrawn patient.
3.
Appoint the telephone contacts replacing on-site visits and on-site Visit 7. 
The date and cause of discontinuation from IP will be collected in the eCRF.
If the patient decides to discontinue from the study after having discontinued from the IP, an 
EOS visit should be performed so that the patient returns the e-diary, paper diary and rescue 
mediation and to follow-up any new SAE, COPD exacerbation and Concomitant medication. 
The date and cause of discontinuation from the study will also be collected in the eCRF.
3.10
Patient discontinuation from the study (withdrawal)
Subjects may be discontinued from the study in the following situations:


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
Screen failures: 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 recorded as ‘Screen Failure (Non-fulfilment of inclusion/exclusion criteria)’ 
(ie, patient does not meet the required inclusion/exclusion criteria). This reason for study 
withdrawal is only valid for screen failures (not randomised patients).

Adverse Event (ex: death, long-term disability/hospitalization): if a patient experiences an 
AE, its premature discontinuation will be considered at the discretion of either the 
investigator or the patient regardless of the causal relationship to the IP. AE should be 
indicated as the reason for discontinuation in the eCRF.

Progressive disease (ex: death, long-term disability/hospitalization): if at investigator’s or 
patient’s discretion the severity of the COPD exacerbation episode jeopardises the current
medical condition of the patient, the patient should be discontinued from the treatment 
and progressive disease should be indicated as the reason for discontinuation in the eCRF.

Protocol deviation: This will include patients that have been wrongly randomised: not 
fulfilling inclusion/exclusion criteria but detected after randomisation. After 
randomisation, any protocol deviations detected should be corrected when possible and 
the patient should be allowed to continue. The following major deviations could lead to 
patient discontinuation after discussion between the AstraZeneca study physician/CRO 
and the investigator (see section 3.4): those which could affect patient's safety (e.g., 
illness requiring treatment(s) which in the clinical judgement of the investigator [or after 
discussion with the trial monitor might invalidate the trial by interfering with the IP) or 
which are due to patient unwillingness to comply with the trial activities or those 
violations of inclusion and/or exclusion criteria detected after randomisation.

Lack of efficacy: only if at the investigators discretion the response to the treatment is 
considered as unsatisfactory

Pregnancy

Lost to follow-up: Non-attendance to visits. In these cases, every effort should be made 
by the investigator to ascertain the reason and to assure patient’s attendance as soon as 
possible. Every effort (at least three documented attempts) should be made to contact the 
patient and documented in the medical records. If patient could not be reached after that, 
a registered mail letter will be sent to the patient and documented in the medical records.

Withdrawal by the subject: The patient is permitted to stop his/her participation at any 
time during the trial without incurring any loss in his/her medical care. The investigator 
should ensure that such withdrawal is not due to AEs or COPD exacerbation, in which 
case the corresponding reason should be selected.

Others: At the investigator´s or Sponsor’s request, study cancellation or any other reason 
not described above.


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3.10.1
Withdrawal of the informed consent
Subjects are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow up AEs outside of the clinical study. 
The subject will return electronic PRO (ePRO) devices.  
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn subjects will not be replaced. 
3.10.2
Procedures for discontinuation of a subject from the study
For any patient who withdraws from the study, the investigator will:
1.
Ask the patient to undergo the End of Study visit AS SOON AS POSSIBLE after 
discontinuation.
2. Arrange for alternative medical care of the withdrawn patient.
3.
Appoint the follow-up call within 14+3 days after the last IP (if applicable) 
The date and cause of discontinuation from the study will be collected in the eCRF.
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn subjects will not be replaced.
3.11
Premature termination of the study
The “end of trial” is defined as the date when all patients randomised in the trial performed the 
last contact (either Visit 7 or Follow-up contact) and will be communicated to Regulatory 
Authorities and Ethics Committees on due time according to local regulations.
Sponsor reserves the right to prematurely terminate (ie, suspend) the trial for reasons such as:

The principal investigator and the sponsor feel that the type, number and /or severity of 
AEs justify discontinuation of the trial.

Data not known before becoming available and raising concern about the safety of the 
study drug so that continuation would pose potential risks to the patient.

The sponsor decides to discontinue the study.
If the study is terminated or suspended, the sponsor will promptly inform the 
investigators/institutions and the Regulatory Authorities and provided with the reason(s) for 
the termination or suspension. Independent Ethics Committee (IEC) will be informed by the 
investigator or sponsor, according to local regulations.


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The investigator will inform the patients and will collect and keep all the data up to the date of 
discontinuation.
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
If the trial is terminated or suspended, study results will be reported according to the 
requirements outlined in this protocol as far as applicable.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.
4
STUDY PLAN AND TIMING OF PROCEDURES 
Table 2
Study Plan detailing the procedures 
Period
Run
-in
Treatment
Follow-up
Visit
1 
2
3
4
5
6
7
EOT12/
EOS
Phone 
contact 13
Week
-2
0
1
4
12
18
24 
NA
26
Day
-14
(±3)
1
7
(±3)
28
(±3)
84
(±3)
126
(±3)
168
(±3)
NA
182
(+3)
Informed Consent1
X
Medical and COPD History
X
Laboratory analysis 
(haematology and 
biochemistry) and serum
pregnancy test (for women 
of childbearing potential
only)
X
X
X
Physical exam2
X
X
X
Bronchodilator test3
X
Inclusion/exclusion criteria
X
X
Randomisation
X
IP kit assignment and 
dispensing
X
X
IP administration at the 
clinic
X
X
X
X
X
X


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
45 of 136
Period
Run
-in
Treatment
Follow-up
Visit
1 
2
3
4
5
6
7
EOT12/
EOS
Phone 
contact 13
Week
-2
0
1
4
12
18
24 
NA
26
Day
-14
(±3)
1
7
(±3)
28
(±3)
84
(±3)
126
(±3)
168
(±3)
NA
182
(+3)
CAT, BDI/TDI and SGRQ4
X
X
X
X
ECG and Blood Pressure5
X
X
X
X
X
X
X
Pre-dose spirometry6
X
X
X
X
X
X
X
Post-dose spirometry7
X
X
X
X
X
X
Provide ediary8 and paper
diary9
X
X
X
X
X
X
Review ediary and paper
diary
X
X
X
X
X
X
X
EXACT and rescue 
medication
Daily since Screening Visit (Visit 1) (in the evening)
Provide rescue medication, 
if needed
X
X
X
X
X
X
Collect IP and drug 
accountability10
X
X
X
Collect rescue medication, 
ediary and paper diary11
X
X
Adverse Events and COPD 
Exacerbations
X
X
X
X
X
X
X
X11
X
Concomitant medications
X
X
X
X
X
X
X
X
X12
1.
Patients requiring the washout of prohibited COPD medications before performing the Screening Visit 
should sign the informed consent before starting the washout period (one day to one month before, depending on 
the length of wash-out period required). Patients will be registered in IVRS/IWRS at the moment of the ICF 
signature.
2.
Height and Weight only at Visit 1 1 (screening).
3.
Bronchodilator test will be done 10-15 minutes after the inhalation on 400 mcg of salbutamol through a 
Spacer device.
4.
Questionnaires will be completed in the following order: The preferred order for completing the 
questionnaires will be: first BDI/TDI, second CAT and finally the SGRQ. For BDI/TDI: BDI will be used at 
Visit 2 and TDI at succeeding visits. Questionnaires should be assessed before any study procedures or IP 
administration. Questionnaires cannot be repeated.
5.
ECG and Blood Pressure will be performed once at Visit 1 to determine patient eligibility. Afterwards, ECG 
and Blood Pressure will be performed pre-morning dose and 1 hours post-morning dose at the above indicated 
visits. At EOT/EOS visit, only one ECG will be performed.
6.
From Baseline (Visit 2) onwards, 2 sets of pre-dose forced manoeuvres will be performed 30 minutes apart.
7.
Post-morning dose spirometry at Visit 2 and Visit 7: at 5 and 30 min, and at 1, 2, 3 hours. At Visits 3, 4, 5 
and 6 at 1h post-dose.


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
46 of 136
8.
Electronic Patient Diary: patients will record the number of doses taken of study drug and rescue 
medication every morning and evening; EXACT questionnaire will be filled in every evening.
9.
Paper Patient Diary: patients will record any adverse event and/or concomitant medication taken. Paper 
diary should be dispensed to the patients starting at Visit 1 and at every visit to record any AEs and changes on 
the concomitant medications.
10.
IP dispensed at Randomisation will be collected when dispensing a new kit at Visit 5.
11.
Rescue medication: Empty inhalers will be collected throughout the study treatment, as applicable, if 
dispensed more than once.
12.
In case of premature discontinuation of IP or discontinuation from study, End of Treatment (EOT) or End of 
Study (EOS) visit should be performed as soon as possible in order to check the patient safety. Compliant 
subjects who are discontinued from the IP should be encouraged to continue to undergo the post-treatment 
follow-up period. The post-treatment follow up period will include phone calls to collect COPD exacerbations, 
concomitant medications, and SAEs for the remainder of the study duration as well as an on-site Visit 7 to return 
the study material. During this post-treatment follow-up period the patients will not have IP but they will keep 
the paper diary to record the concomitant medication and the e-diary to continue recording the use of rescue 
medication and EXACT questionnaire.
13. Only concomitant medication related to AEs must be recorded at follow-up contact.


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
47 of 136
4.1
Enrolment/screening period
This period will start with the signature of the Informed Consent Form (ICF) and subject 
registration in IVRS/IWRS, will follow with Visit 1 (Screening) and will end at the 
randomisation visit (Visit 2).
Prior to ICF signing, investigators will evaluate suitability of patients for entry in the trial by 
comparing past and current medical status, as documented in the patient's medical records, to 
the inclusion/exclusion criteria of this study protocol.
Patients’ informed consent signature must be obtained before performing any procedure 
related to the trial. ICF must be signed after the patient has received sufficient information 
about the trial, after he/she has had the opportunity to ask any questions related to the study 
and considered the options.
Patients who require a washout period from prohibited concomitant treatments should be seen 
and sign the ICF prior to Visit 1, to ensure the necessary washout before this visit. No trial 
assessments will be performed that date, and Visit 1 will be scheduled later according to the 
wash-out length required for the specific medication stopped. Patient will be dispensed one 
inhaler of rescue medication and trained on its use.
If no wash-out period is required, Visit 1 assessments will start after signing the ICF. Any 
patient signing the ICF should be recorded in IVRS/IWRS and should be assigned a patient ID 
number.
4.1.1
Visit 1 (screening)
Screening Visit will be scheduled in the morning, at a similar start time of all the other visits if 
the patient was enrolled in the study. The following assessments and processes will be 
performed and data reviewed:
─
Prior medication and concomitant medication review: Confirm that no prohibited 
medication was taken during the washout period and that the appropriate withholds have 
been made. Record in the eCRF Prior and Concomitant medications.
─
Review of any Adverse Event during wash-out period.
─
Sign the ICF and register patient in IVRS/IWRS (if not done yet). Note: patients must be 
registered in IVRS/IWRS at the moment of the ICF signature.
─
Review medical history, demographic, COPD history (date of COPD diagnosis, number 
of COPD exacerbations during last year and date of last COPD exacerbation and if 
hospitalization) and smoking information (ie, date of smoking initiation, current smoker 
or former smoker, date of smoking cessation and total-pack years).


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
48 of 136
─
Physical examination including body weight (in light indoor clothes, without shoes) and 
height measurement
─
Blood pressure.
─
12-lead ECG.
─
Blood sampling for haematology and biochemistry analysis and, when appropriate, 
pregnancy test.
─
Spirometry Forced manoeuvre test (FEV1 and FVC measurement): 1 set of tests will be 
performed.
─
Bronchodilator test (Reversibility test): administer inhaled salbutamol (100 μg x 4 puffs) 
through a spacer device at least 10 minutes after previous spirometry test. Afterwards, 10 
to 15 minutes after salbutamol inhalation, perform again 1 set of Spirometry Forced 
manoeuvre.
─
Review inclusion/exclusion criteria.
Only patients who meet all inclusion/exclusion criteria at this point will be allowed to 
continue. Otherwise, the screening failure will be recorded in the IVRS/IWRS. When patient 
fulfilled inclusion/exclusion criteria, the following will occur:
─
Patient will be trained and dispensed the rescue medication inhaler (if not done pre-wash-
out).
─
Patient will be trained on the use of Genuair® and Turbuhaler® with the empty training 
inhalers.
─
Patient will be trained and provided with the electronic Patient Diary and will be asked to 
start its recording that night onwards.
─
Patient will be trained and provided with the paper Patient Diary and will be asked to start 
its recording as needed.
─
Next protocol visit will be scheduled. Patient will be reminded to avoid the intake of 
rescue medication for at least 6 hours before attending the next visit, and to bring back the 
rescue medication inhaler, the electronic and the paper Patient Diary.
4.2
Treatment period
4.2.1
Visit 2 (Randomisation Visit)
The following assessments will be performed pre-randomisation and pre-morning IP dose:
─
Paper Patient Diary review: Adverse events, COPD exacerbation, and concomitant 
medication review.
─
Electronic Patient Diary review. In case of low compliance with the e-diary (e.g. less than 
75% of entries), patient should be retrained on how to use the e-diary and, if possible, 
visit 2 should be rescheduled in order to get minimum baseline data.


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
49 of 136
─
Confirmation of inclusion/exclusion criteria.
Only patients who meet all inclusion/exclusion criteria at this point will be allowed to 
continue. Otherwise the screening failure will be recorded in the IVRS/IWRS.
When patient fulfils inclusion/exclusion criteria, the following assessments will be performed:
A.
Randomisation
─
Randomise the patient via the IWRS/IVRS, and obtain kit number assignment. 
Document the randomisation date on the medical notes.
B.
Pre-dose assessments (baseline)
─
BDI by an independent interviewer unaware of available patient status (if possible 
this questionnaire should be complete before the others).
─
CAT
─
SGRQ
─
Blood pressure.
─
12-lead ECG.
─
Spirometry forced manoeuvre tests (FEV1 and FVC): 2 sets will be performed during 
the hour preceding the scheduled morning IP dose, allowing approximately 30 min 
between them.
C.
Morning IP administration
─
Patient will be re-trained on the use of Genuair® and Turbuhaler® with the empty 
training inhalers. The investigator will evaluate proper use of the device by the 
patient and provide additional training if needed.
─
Dispense the kit number assigned by IWRS/IVRS and record the kit number 
dispensed on the Drug Accountability Log.
─
Administer the first dose of IP at approximately 09:00±1h by inhalation of 1 puff 
from the Genuair® inhaler #1 and 1 puff from the Turbuhaler® inhaler #1. The 
investigator or study personnel should check that the patient has correctly used the 
inhaler.
─
Instruct the patient to inhale from both inhalers every morning and evening until the 
last evening before next visit. Remind the patient to come to next visit with the 
medication kit to assess the drug accountability.
─
Record the date and time of the first IP administration in the Masterscope CT. 
D.
Post-dose assessments
─
Post-dose PFT (FEV1 and FVC): at +5min, +30 min, +1h, +2h, and +3h.
─
Blood pressure: at +1h
─
12-lead ECG: at +1h


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
50 of 136
Note: for T+1h the ECG and blood pressure should be measured before the PFT manoeuvre.
The following procedures will be performed at any time after post-morning IP dose:
─
IP kit will be given to the patient and reminded about the correct dose regimen and 
timing.
─
Rescue medication will be dispensed, as needed.
─
Patient will be provided with a paper patient diary.
─
The electronic Patient Diary will be re-dispensed.
─
Next protocol visit will be scheduled. Patient will be reminded to hold the morning IP 
dose that day, avoid the intake of rescue medication for at least 6 hours before attending 
the next visit, and to bring the IP kit, the rescue medication inhaler, the electronic and the 
paper Patient Diary to the clinic.
4.2.2
Visit 3: Week 1
A.
Pre-dose assessments (baseline)
─
Paper Patient Diary review: Adverse events, COPD exacerbation, and concomitant 
medication review.
─
Electronic Patient Diary review.
─
Check appropriate wash-out before visit (at least 6h since last rescue medication 
intake).
─
Blood pressure.
─
12-lead ECG.
─
Spirometry forced manoeuvre tests (FEV1 and FVC): 2 sets will be performed during 
the hour preceding the scheduled morning IP dose, allowing approximately 30 min 
between them.
B.
Morning IP administration
─
If needed, patient will be re-trained on the use of Genuair® and Turbuhaler® with 
the empty training inhalers. The investigator will evaluate proper use of the device by 
the patient and provide additional training if needed.
─
Administer IP at approximately 09:00±1h by inhalation of 1 puff from the Genuair® 
inhaler and 1 puff from the Turbuhaler® inhaler. The investigator or study personnel 
should check that the patient has correctly used the inhaler.
─
Remind the patient to inhale from both inhalers every morning and evening until the 
last evening before next visit. Remind the patient to come to next visit with the 
medication kit to assess the drug accountability.
─
Record the date and time of the IP administration in the Masterscope CT.
C.
Post-dose assessments


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
51 of 136
─
Blood pressure: at +1h
─
12-lead ECG: at +1h
─
Post-dose PFT (FEV1 and FVC): at +1h.
The following procedures will be performed at any time after post-morning IP dose:
─
Same IP kit will be redispensed to the patient and reminded about the correct dose 
regimen and timing.
─
Rescue medication will be dispensed, as needed.
─
Patient will be provided with a paper patient diary.
─
The electronic Patient Diary will be re-dispensed.
─
Next protocol visit will be scheduled. Patient will be reminded to hold the morning IP 
dose that day, avoid the intake of rescue medication for at least 6 hours before attending 
the next visit, and to bring the IP kit, the rescue medication inhaler, the electronic and the 
paper Patient Diary to the clinic.
4.2.3
Visit 4: Week 4
A.
Pre-dose assessments (baseline)
─
Paper Patient Diary review: Adverse events, COPD exacerbation and concomitant 
medication review.
─
Electronic Patient Diary review.
─
Check drug accountability and record it in the paper Drug Accountability Log. 
Collect locked Genuair® and empty Turbuhaler® inhalers.
─
Check appropriate wash-out before visit (at least 6h since last rescue medication 
intake).
─
TDI by an independent interviewer unaware of available patient status.
─
CAT
─
SGRQ
─
Spirometry forced manoeuvre tests (FEV1 and FVC): 2 sets will be performed during 
the hour preceding the scheduled morning IP dose, allowing approximately 30 min 
between them.
B.
Morning IP administration
─
If needed, patient will be re-trained on the use of Genuair® and Turbuhaler® with 
the empty training inhalers. The investigator will evaluate proper use of the device by 
the patient and provide additional training if needed.
─
Administer IP at approximately 09:00±1h by inhalation of 1 puff from the Genuair® 
inhaler and 1 puff from the Turbuhaler® inhaler. The investigator or study personnel 
should check that the patient has correctly used the inhaler.


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
52 of 136
─
Remind the patient to inhale from both inhalers every morning and evening until the 
last evening before next visit. Remind the patient to come to next visit with the 
medication kit to assess the drug accountability.
─
Record the date and time of the IP administration in the Masterscope CT.
C.
Post-dose assessments
─
Post-dose PFT (FEV1 and FVC): at +1h.
The following procedures will be performed at any time after post-morning IP dose:
─
IP kit will be redispensed to the patient and reminded about the correct dose regimen 
and timing.
─
Rescue medication will be dispensed, as needed.
─
Patient will be provided with a paper patient diary.
─
The electronic Patient Diary will be re-dispensed.
─
Next protocol visit will be scheduled. Patient will be reminded to hold the morning IP 
dose that day, avoid the intake of rescue medication for at least 6 hours before 
attending the next visit, and to bring the IP kit, the rescue medication inhaler, the 
electronic and the paper Patient Diary to the clinic.
4.2.4
Visit 5: Week 12
A.
Pre-dose assessments (baseline)
─
Paper Patient Diary review: Adverse events, COPD exacerbation, and concomitant 
medication review.
─
Electronic Patient Diary review.
─
Check appropriate wash-out before visit (at least 6h since last rescue medication 
intake).
─
Collect ALL Genuair® and Turbuhaler® inhalers and check them in order to assess 
drug accountability
─
TDI by an independent interviewer unaware of available patient status.
─
CAT
─
SGRQ
─
Blood pressure.
─
12-lead ECG.


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
53 of 136
─
Spirometry forced manoeuvre tests (FEV1 and FVC): 2 sets will be performed during 
the hour preceding the scheduled morning IP dose, allowing approximately 30 min 
between them.
B.
Morning IP administration
─
If needed, patient will be re-trained on the use of Genuair® and Turbuhaler® with 
the empty training inhalers. The investigator will evaluate proper use of the device by 
the patient and provide additional training if needed.
─
Call IVRS/access IWRS to assign a new medication kit and record the kit number in 
the drug accountability log
─
Administer IP at approximately 09:00±1h by inhalation of 1 puff from the Genuair® 
inhaler and 1 puff from the Turbuhaler® inhaler. The investigator or study personnel 
should check that the patient has correctly used the inhaler.
─
Remind the patient to inhale from both inhalers every morning and evening until the 
last evening before next visit. Remind the patient to come to next visit with the 
medication kit to assess the drug accountability.
─
Record the date and time of the IP administration in the Masterscope CT. 
C.
Post-dose assessments
─
Blood pressure: at +1h
─
12-lead ECG: at +1h
─
Post-dose PFT (FEV1 and FVC): at +1h.
The following procedures will be performed at any time after post-morning IP dose:
─
IP kit will be dispensed to the patient and reminded about the correct dose regimen and 
timing.
─
Rescue medication will be dispensed, as needed.
─
Patient will be provided with a paper patient diary.
─
The electronic Patient Diary will be re-dispensed.
─
Next protocol visit will be scheduled. Patient will be reminded to hold the morning IP 
dose that day, avoid the intake of rescue medication for at least 6 hours before attending 
the next visit, and to bring the IP kit, the rescue medication inhaler, the electronic and the 
paper Patient Diary to the clinic.
4.2.5
Visit 6: Week 18
A.
Pre-dose assessments (baseline)
─
Paper Patient Diary review: Adverse events, COPD exacerbation, and concomitant 
medication review.
─
Electronic Patient Diary review.


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
54 of 136
─
Check appropriate wash-out before visit (at least 6h since last rescue medication 
intake).
─
Check drug accountability and record it in the paper Drug Accountability Log.
─
Collect locked Genuair® and empty Turbuhaler® inhalers.
─
Blood pressure.
─
12-lead ECG.
─
Spirometry forced manoeuvre tests (FEV1 and FVC): 2 sets will be performed during 
the hour preceding the scheduled morning IP dose, allowing approximately 30 min 
between them.
B.
Morning IP administration
─
If needed, patient will be re-trained on the use of Genuair® and Turbuhaler® with 
the empty training inhalers. The investigator will evaluate proper use of the device by 
the patient and provide additional training if needed.
─
Administer IP at approximately 09:00±1h by inhalation of 1 puff from the Genuair® 
inhaler and 1 puff from the Turbuhaler® inhaler. The investigator or study personnel 
should check that the patient has correctly used the inhaler.
─
Remind the patient to inhale from both inhalers every morning and evening until the 
last evening before next visit. Remind the patient to come to next visit with the 
medication kit to assess the drug accountability.
─
Record the date and time of the IP administration in the Masterscope CT. 
C.
Post-dose assessments
─
Blood pressure: at +1h
─
12-lead ECG: at +1h
─
Post-dose PFT (FEV1 and FVC): at +1h.
The following procedures will be performed at any time after post-morning IP dose:
─
Same IP kit will be redispensed to the patient and reminded about the correct dose 
regimen and timing.
─
Rescue medication will be dispensed, as needed.
─
Patient will be provided with a paper patient diary.
─
The electronic Patient Diary will be re-dispensed.
─
Next protocol visit will be scheduled. Patient will be reminded to hold the morning IP 
dose that day, avoid the intake of rescue medication for at least 6 hours before attending 
the next visit, and to bring the IP kit, the rescue medication inhaler, the electronic and the 
paper Patient Diary to the clinic.


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
55 of 136
4.2.6
Visit 7: Week 24
A.
Pre-dose assessments (baseline)
─
Paper Patient Diary review: Adverse events, COPD exacerbation and concomitant 
medication review.
─
Electronic Patient Diary review.
─
Check appropriate wash-out before visit (at least 6h since last rescue medication 
intake).
─
Collect ALL Genuair® and Turbuhaler® inhalers and check them in order to assess 
drug accountability and record it in the paper Drug Accountability Log.
─
TDI by an independent interviewer unaware of available patient status.
─
Blood sampling for haematology and biochemistry analysis and, when appropriate, 
pregnancy test.
─
CAT
─
SGRQ
─
12-lead ECG.
─
Blood pressure.
─
Physical examination (any new or worsened finding will be recorded in the AE form 
of the EDC).
─
Spirometry forced manoeuvre tests (FEV1 and FVC): 2 sets will be performed during 
the hour preceding the scheduled morning IP dose, allowing approximately 30 min 
between them.
B.
Morning IP administration
─
If needed, patient will be re-trained on the use of Genuair® and Turbuhaler® with 
the empty training inhalers. The investigator will evaluate proper use of the device by 
the patient and provide additional training if needed.
─
Administer IP at approximately 09:00±1h by inhalation of 1 puff from the Genuair® 
inhaler and 1 puff from the Turbuhaler® inhaler. The investigator or study personnel 
should check that the patient has correctly used the inhaler.
─
Record the date and time of the IP administration in the Masterscope CT. 
C.
Post-dose assessments
─
Blood pressure: at +1h
─
12-lead ECG: at +1h
─
Post-dose PFT (FEV1 and FVC): at +5min, +30 min, +1h, +2h, and +3h. 
The following procedures will be performed at any time after post-morning IP dose:
─
Review and retrieve paper and electronic Patient Diary.


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
56 of 136
─
Retrieval of rescue medication.
─
Research personnel will register patient´s completion of the treatment in IVRS/IWRS.
─
The follow-up call will be scheduled.
─
Patient will be instructed by study personnel to resume the COPD medication taken 
before trial start, or any other treatment deemed appropriate according to medical 
judgement.
4.2.7
End of Treatment (EOT)
The following procedures will be performed for patients that discontinue from the IP and 
accept to participate in the post-treatment follow-up period:
─
Paper Patient Diary review: Adverse events, COPD exacerbation and concomitant 
medication review.
─
Electronic Patient Diary review.
─
Collect ALL Genuair® and Turbuhaler® inhalers and check them in order to assess drug 
accountability and record it in the Drug Accountability Log.
─
Blood sampling for haematology and biochemistry analysis and, when appropriate, 
pregnancy test.
─
12-lead ECG.
─
Blood pressure.
─
Physical examination (any new or worsened finding will be recorded in the AE form of 
the EDC).
─
If deemed appropriate by the investigator, one forced spirometry test may be performed to 
assess patient lung condition.
─
Research personnel will register patient´s discontinuation of the treatment in IVRS/IWRS 
and will complete the corresponding EOT visit in the EDC.
─
Patient will be instructed by study personnel to resume the COPD medication taken 
before trial start, or any other treatment deemed appropriate according to medical 
judgement.
At the end of the visit the investigator will:
─
Redispense the paper diary and electronic diary. Patients will be followed up for SAEs 
and concomitant medication and they will be requested to record daily the EXACT 
questionnaire in the e-diary.
─
Inform the patient that he/she will be contacted as per the planned study visits via 
telephone calls until the 24 weeks of treatment are completed (if the EOT occurs within 
two weeks of the next scheduled visit (call) the next visit (call) can be skipped). The Visit 


Clinical Study Protocol - 4.0
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
57 of 136
7 must always be done as an on-site visit in order to return the paper and electronic diary 
as well as the rescue medication.
─
Schedule telephone calls and on-site Visit 7 after 24 weeks of treatment. 
Patients that discontinue from the treatment and accept participation on the post-treatment 
follow-up should complete the EXACT questionnaire in the ediary every night and should 
attend phone calls instead of regular visits up to Visit 7, that will always be an on-site visit. 
During the phone calls patient will be asked about adverse events.
Patients attending Visit 7 will be considered patients discontinued from the treatment but 
completed the follow-up so they will have a date and reason for treatment discontinuation 
collected in the EOT visit and a date of study completion to be collected at Visit 7.
If any patient accepting the participation in the post-treatment follow-up period decided to 
discontinue from the follow-up before performing Visit 7, an EOS visit should be scheduled in 
order to return the paper and electronic diaries as well as the rescue medication (see section 
4.2.8). These patients will be considered patients discontinued from the treatment and 
discontinued from the follow-up so they will have a date and reason for treatment 
discontinuation collected in the EOT visit and a date and reason for follow-up discontinuation 
collected in the EOS visit.
4.2.8
End of Study (EOS) visit
The procedures to be performed during the EOS visit will be different depending on whether 
the patient decides to discontinue from the study (patient discontinued from the treatment who 
does not accept to enter in the post-treatment follow-up period) or whether the patient decides 
to discontinue from the post-treatment follow-up (patient discontinued from the treatment who 
accept to enter in the post-treatment follow-up period but discontinue from the follow-up 
before performing Visit 7).
4.2.8.1
EOS visit for patients that discontinue from the study
Patients that discontinue from the treatment and do not accept to participate in the post-
treatment follow-up period will be considered as “discontinued from the study” and will have 
to perform a visit that will be a combination of the EOT visit and EOS visit.
The following procedures will be performed for patients that discontinue from the study:
─
Paper Patient Diary review: Adverse events, COPD exacerbation and concomitant 
medication review.
─
Electronic Patient Diary review.
─
Collect ALL Genuair® and Turbuhaler® inhalers and check them in order to assess drug 
accountability and record it in the Drug Accountability Log.


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─
Blood sampling for haematology and biochemistry analysis and, when appropriate, 
pregnancy test.
─
12-lead ECG.
─
Blood pressure.
─
Physical examination (any new or worsened finding will be recorded in the AE form of 
the EDC).
─
If deemed appropriate by the investigator, one forced spirometry test may be performed to 
assess patient lung condition.
─
Research personnel will register patient´s discontinuation of the study in IVRS/IWRS and 
will complete the corresponding EOS visit in the EDC respectively.
─
Patient will be instructed by study personnel to resume the COPD medication taken 
before trial start, or any other treatment deemed appropriate according to medical 
judgement.
─
Retrieve paper and electronic Patient Diary.
─
Retrieval of rescue medication.
─
Schedule the follow-up call 14+3 days after the last IP (if still applicable)
4.2.8.2
EOS visit for patients that discontinue from the post-treatment follow-up
period
If a patient discontinue from the post-treatment follow-up for any reason (ie withdrawal of 
informed consent), an EOS visit should be performed as soon as possible in order to retrieve 
the study material (paper diary, electronic diary and rescue medication).
No additional tests are required in this visit unless the investigator considers them necessary to 
ensure the patients safety.
The activities to be performed in the EOS visit for patients that had previously discontinued 
from the IP are:
─
Research personnel will register patient´s discontinuation from the follow-up in 
IVRS/IWRS and will complete the corresponding EOS visit in the EDC respectively.
─
Retrieve paper and electronic Patient Diary.
─
Retrieval of rescue medication
4.3
Follow-up period
A follow-up should be performed for patients completing the treatment or discontinued from 
the study by means of a visit or a phone contact, as considered appropriate, 14 (+ 3) days after 
last IP intake in order to assess new or ongoing AE (as well as any concomitant medication 
administered to treat the mentioned AE) and COPD exacerbations.


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4.4
Re-scheduling visits rules and repeated tests
At Visit 1 (screening) any individual test(s) might be repeated before randomisation e.g., in 
case of impaired results (e.g., blood sample haemolysed) or results requiring confirmation (to 
ensure patient eligibility or results inconsistent with patient’s known past medical conditions), 
etc. The full Visit 1 will not be repeated. If any of the specific tests of the Screening Visit 
needs to be repeated, and more than 28 days has elapsed since first test date, the patient will 
be screen failed.
As deemed necessary by the investigator, ECGs and laboratory test can be repeated at any 
time during the study in order to follow-up the progress of any clinically relevant abnormal 
finding, investigate any potential new adverse event, etc. Also for monitoring purposes, 
additional spirometry tests may be performed in between protocol visits.
However, individual spirometry tests within a protocol visit (PFT scheduled timepoints) as 
well as CAT, BDI/TDI, and SGRQ must not be repeated.
Before starting any visit procedure, research personnel will review the data recorded on the 
electronic and paper Patient Diary and will ask the patient about his/her overall status. The 
following rules with respect to postponing the visit will be adhered to:

The occurrence of any COPD exacerbation episode.

The maintenance of the relevant wash-out (6 hours (six) for salbutamol: the visit will be 
postponed unless it can be slightly delayed, that is morning IP dose can still happen 
before 10:00 am.).

The intake of any prohibited medication (except when related to treat a COPD 
exacerbation): the visit will be postponed (no assessment performed) according to the 
wash-out length required for the specific prohibited medication taken as long as delay fits 
the protocol allowed time window. If the delay is longer than the protocol allowed time 
window, please contact your Clinical Research Associate (CRA).

For logistic reasons: Patient or Investigator are not able to perform the visit on the 
scheduled date due to technical or personal issues by site/patient.
After visit assessments have started:

In case of intake of salbutamol during the course of a visit before morning IP dose, the 
visit may be re-scheduled if at all possible. Should this happen, all assessments (except 
CAT, BDI/TDI, and SGRQ) planned for the visit must be (again) performed, even if this 
results in the repetition of some assessments. If visit re-schedule is not possible, safety 
assessments will be performed and spirometries skipped.


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
In case of intake of salbutamol during the course of a visit after morning IP dose, all 
planned safety assessments will be performed and spirometry assessments will be 
skipped. After IP intake, re-scheduling of visits is not allowed. 
See Appendix I for re-scheduling rules due to civil crisis, natural disaster, or public health 
crisis disruption. 
5
STUDY ASSESSMENTS
The Electronic Data Capture (EDC) 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 study protocol and in accordance with the instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the 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
Pulmonary function test (spirometry)
5.1.1.1
General Conditions
A centralized spirometry company (ERT) will provide the spirometers and all necessary 
equipment (computer, calibration syringe, printer, paper, ink, etc.), a detailed study manual 
and training to the technicians and principal investigator (as needed) in charge of conducting 
the spirometries for this clinical trial. Spirometer will measure:
─
FVC (maximal volume of air exhaled with maximally forced expiratory effort from a 
position of maximal inspiration).
─
FEV1 (volume of air expressed in litres exhaled during the first second of performance of 
the FVC).
The ATS and ERS guidelines should be followed to provide accurate and comparable 
spirometric data. Spirometer will be configured to meet ATS/ERS recommendations for 
accuracy and precision (Standardisation of Lung Function Testing, Miller et al 2005). The 
computerised spirometer will generally check the consistency between tests and some of the 
requirements set out in the ATS/ERS spirometry guidelines, and will automatically alert the 
technician to the presence of some deviations from some ATS/ERS requirements.  However, 
the technician must ensure that tests are performed with the correct technique, manually 
deselecting efforts which do not meet minimum standards. The technician must use their 


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judgement to ensure that the optimum spirometry data is gained from the patient at each test 
session.
The technical details about the system set up are part of the Project Requirement 
Specifications, including the spirometry’s timepoints described in section 4 and the time-
windows allowed in this study.
These data will be electronically transmitted by the investigator to ERT at least at the end of 
each patient protocol visit. Throughout the study, a centralised reading of spirometric values 
will be performed by an independent spirometric expert at ERT, blinded to patient’s IP 
allocation and patient’s identity, in a two-steps quality control:
─
“Over-Read” process: The first review of the spirometry data (including review of tests 
that rejected by the technician) qualifies spirometric curves according to ATS/ERS 
criteria. No changes are made to the data.
─
“Best Test Review” process: During this procedure, the acceptability of tests is assessed 
first followed by repeatability. If problems are encountered on the spirometric curve 
identified by the technician as the “best test”, ERT will check if there is another curve 
that is acceptable. If a better “best test”, the sites will be queried. If the site accepts the 
proposed new “best test” (as indicated by the investigator signing a query form), this 
newly accepted measure will represent the “best test” in all analysis and reporting. No 
identification of “best test” will be made without the approval of the investigator. All tests 
will be saved.
Inclusion of patient in the study will be based on the post Best Test Review values.
5.1.1.2
Practical Considerations
Prior to the first spirometry, the trained technician should demonstrate the procedure to the 
patient by using a detached mouthpiece then, allow some practise attempts. Demonstration 
should be repeated and the patient should practise the procedure as many times during the trial 
course as deemed necessary.
Patients who are unable to produce acceptable spirometry tests must not be included in the 
study.  Investigators should pay particular attention to the geometry of a patients flow loop. 
This should be reasonably constant for a specific patient over time. There is often a learning 
component to spirometry and the investigator should ensure that the patient technique is stable 
prior to randomisation.
The activities that should preferably be avoided prior to lung function testing are:
─
Smoking within at least 1 h of testing
─
Consuming alcohol within 4 h of testing


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─
Performing vigorous exercise within 30 min of testing
─
Wearing clothing that substantially restricts full chest and abdominal expansion
─
Eating a large meal within 2 h of testing
Testing may be performed either in the sitting or standing position. Sitting is preferable for 
safety reasons in order to avoid falling due to syncope. The chair should have arms and be 
without wheels. If a wheelchair is used, the wheels should be locked. If the standing position 
is used, a chair can be placed behind the patient/subject, so that they can be quickly and easily 
moved into a sitting position if they become lightheaded during the manoeuvre.
Each manoeuvre at each timepoint comprises one “set of tests”: 3 measurements (curves) 
technically adequate are needed according to the acceptability and repeatability criteria of the 
ATS/ERS spirometry guidelines. If both the acceptability and repeatability criteria are met, 
the manoeuvre session can conclude after 3 measurements. If one or both of these criteria are 
not met, additional tests should be performed.
In case a patient becomes fatigued during the procedure due to the intensive serial repetitions, 
patient will rest for approximately 10 minutes and the affected timepoint will be skipped until 
patient recovers. Salbutamol use will be avoided if at all possible by letting patient rest as
needed.
Any bronchoconstriction that appears after consecutive measurements should be recorded on 
the AE form of the EDC.
The paragraph below describes the process to perform forced manoeuvres to measure FEV1
and FVC:

Place the mouthpiece in the mouth and close the lips around the mouthpiece.

Breathe normally approximately 3 times.

Inhale completely and rapidly with a pause of <1 second at total lung capacity.

Exhale maximally during at least 6 seconds taking care that lips are sealed around the 
mouthpiece and while maintaining an upright posture.

Breathe in again and relax.
At the time of forced manoeuvre, the technician performing the measurement should prompt 
the patient to blast, not just blow the air from their lungs, and then continue to actively 
encourage him/her to fully exhale. Throughout all manoeuvres, the technician should 
enthusiastically coach the patient by word and body language.
Investigator must print every spirometry test, sign and date them.


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5.1.2
COPD Assessment Test (CAT)
The CAT is an 8-item questionnaire designed to assess and quantify the impact of COPD 
symptoms on health status. The validation studies show that it has properties very similar to 
much more complex health status questionnaires such as the Saint George Respiratory 
Questionnaire (SGRQ, Jones et al 2009).
Based on the strong correlation between the CAT and SGRQ, a difference or change of 2 or 
more units in the CAT score has been suggested as a clinically significant difference or 
change in health status (Jones et al 2011).
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 (Scores ranging from 0 to 5, Appendix E), with higher scores 
indicating a higher impact of COPD symptoms on health status.
A validated electronic version of the questionnaire will be used, in the relevant validated 
language versions. Data will be recorded by the patient in the e-diary (logpad) provided by 
ERT. Data will be transferred after each session. During the study CAT data will be accessible 
to investigators on an online website. The electronic entries on the logpad are considered a 
source document and will be kept at site in a CD/DVD sent by ERT at the end of the trial.
5.1.3
Evaluation of Dyspnoea through BDI-TDI questionnaire
Evaluation of dyspnoea (both at baseline and during treatment) MUST be performed by an 
independent interviewer experienced in taking history of respiratory disease who must be 
not aware of other parameters evaluated for this patient in order to avoid any bias. This 
information includes any data which could reveal patient status (e.g. CAT, SGRQ, spirometric 
data, AEs, etc).
In addition, the assessment must take place always BEFORE the IP dose.
The objective of the Baseline and Transition Dyspnoea Indexes (BDI/TDI) (Appendix F) is to 
measure the severity of breathlessness in symptomatic patients. The BDI measures the 
severity of dyspnoea at the beginning of the trial and the TDI evaluates changes from this 
baseline (Mahler et al 1984).
Each index (BDI and TDI) contains an arbitrary rating for three categories which are major 
factors affecting the development of dyspnoea:

Functional impairment which determines the impact of breathlessness on the ability to 
carry out activities

Magnitude of task which determines the type of task that causes breathlessness

Magnitude of effort which establishes the level of effort needed to evoke breathlessness


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To evaluate the status in each domain, the interviewer will ask open-ended questions 
concerning patient’s breathlessness. Based on patient’s response, a grade reflecting the degree 
of impairment related to dyspnoea in each category will be selected in the e-diary (logpad) 
provided by ERT.
The logpad will be set-up to restrict the access to the BDI/TDI questionnaire only to the 
independent interviewer.
Baseline Dyspnoea Index (BDI)
The BDI includes three categories, each one with five grades of severity from zero (severe) to 
four (unimpaired) and the categories are summed to create the focal score (zero to twelve). 
The lower the focal score (total score), the worse the severity of dyspnoea.
Provision is made for circumstances when dyspnoea cannot be rated: “W” if no information 
on the severity can be obtained, “X” if there is generally insufficient information, or “Y” if the 
patient’s capacity is compromised by factors other than respiratory.
Transition Dyspnoea Index (TDI)
This index includes three categories, each one with ranges from minus three (major 
deterioration) to plus three (major improvement) including a zero score to indicate “no 
change”. Also for the TDI the three categories are added to obtain a focal score ranging from 
minus nine, including zero, to plus nine.
Provision is made for circumstances when dyspnoea cannot be rated: “Z” if reduction of 
activities, effort or functional impairment is caused by reasons other than respiratory.
A change of 1 unit in TDI has been defined as a minimal meaningful improvement (Witek and 
Mahler 2003).
Full BDI and TDI is located in Appendix F. The validated version in local language for each 
participating country will be used. Official instructions for the administration of BDI and TDI 
will be provided to the investigators in a separate manual.
BDI/TDI grade will be recorded in the logpad provided by ERT to each research site. Data 
recorded will be transferred to ERT after each session. During the study BDI/TDI data will be 
accessible to investigators on an online website. The electronic entries on the logpad are 
considered a source document and will be kept at site in a CD/DVD sent by ERT at the end of 
the trial.


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5.1.4
St. George’s Respiratory Questionnaire (SGRQ)
The disease-specific health status will be evaluated by means of a self-administered 
instrument, the SGRQ (Jones et al 1992). This questionnaire is a standardised self-completed 
tool for measuring impaired health and perceived well-being (“quality of life”) in respiratory 
diseases (Jones et al 1991).
A validated electronic version of the questionnaire will be used, in the relevant validated 
language versions. Data will be recorded by the patient in the e-diary (logpad) provided by 
ERT. Data will be transferred to ERT after each session. During the study SGRQ data will be 
accessible to investigators on an online website. However, after randomisation, patients will 
NOT be provided with any information on the data recorded at the previous visits. The 
electronic patient’s entries on the logpad are considered a source document and will be kept at 
site in a CD/DVD sent by ERT at the end of the trial.
The questionnaire contains 50 items divided into three dimensions:

Symptoms which contains items concerned with the level of symptomatology, including 
frequency of cough, sputum production, wheeze, breathlessness, and the duration and 
frequency of attacks of breathless or wheeze. A typical question in this dimension is “In 
an average week, how many good days (with little chest trouble) have you had?”. There 
are 5 possible responses to this item (ie, 5-point Likert scale): none; one or two; three or 
four; nearly every day; and every day.

Activity which is concerned with physical activities that cause or are limited by 
breathlessness. A typical item in this dimension is “Because of my breathing, jobs such as 
house work take a long time or I have to stop for rests?”. Responses in this dimension are 
dichotomous (ie, either true or false).

Impacts which covers a range of aspects related to social functional and psychological 
disturbances resulting from the disease, such as employment, being in control of health, 
panic, stigmatisation, the need for medications and its side effects, expectations for health 
and disturbances in daily life. An example of these items is “I get afraid or panic when I 
cannot catch my breath”. Responses to items in this dimension are dichotomous (ie, either 
true or false).
Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 
100%, zero score indicating no impairment of life quality. A summary score utilising 
responses to all items is the total SGRQ score which also ranges from 0 to 100%. The SGRQ 
scores are calculated using weights attached to each item of the questionnaire which provides 
an estimate of the distress associated with the symptoms or state described in each item. 
Higher scores indicate poorer health.


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A decrease of 4 units in the SGRQ total score has been established as the criterion for minimal 
meaningful improvement (Jones 2005). SGRQ responders will be those with a SGRQ total 
score ≥4 unit decrease.
The SGRQ and further instructions is located in Appendix G. The official manual with 
instructions for the administration of SGRQ will be provided to the investigators in a separate 
manual.
5.1.5
Exacerbations of Chronic Pulmonary Disease Tool (EXACT) and 
EXACT- Respiratory Symptoms (E-RS)
The Exacerbations of Chronic Pulmonary Disease Tool (EXACT) is a single patient-reported 
outcome (PRO) measure to evaluate the effects of pharmacologic treatment (preventive and 
curative) on exacerbations of COPD, including chronic bronchitis presence/frequency, 
severity, duration and resolution (Leidy et al 2010, Leidy et al 2010, Jones et al 2010). It 
captures the cardinal symptoms of COPD (dyspnoea, cough, sputum production).
The EXACT questionnaire consists of 14 questions that will be recorded by the patient in an 
electronic Patient Diary (logpad) provided by ERT validated in different languages (see 
Appendix H) each day in the evening before going to bed, starting at Screening Visit night. 
The recall period is “today”.
An EXACT Total score is computed for each day of diary collection. The EXACT Total score 
is computed across the 14 items and has a theoretical range of 0 to 100, with higher values 
indicating a more severe condition. An EXACT-identified event will be defined as a persistent 
increase from baseline in total EXACT score of ≥9 points for ≥3 days or ≥ 12 points for ≥ 2 
days.
The EXACT-Respiratory Symptoms (E-RS) is a reliable, valid and responsive measure of 
respiratory symptoms of COPD suitable for use in clinical trials (Leidy et al 2014). The E- RS 
is based on the 11 respiratory symptom items from the 14-item EXACT. The E-RS yields a 
total score (ranging from 0 to 40), quantifying respiratory symptom severity overall, and 3 
subscale scores assessing breathlessness (derived sum of 5 items); cough and sputum (derived 
sum of 3 items); and chest symptoms (derived sum of 3 items). A change of 2 units in the RS-
total score has been proposed as cut off to define responder definition for symptomatic 
improvement (Leidy et al 2014).
Data recorded will be transferred to ERT after each session. During the study EXACT data 
will be accessible to investigators on an online website.
The electronic entries on the electronic Patient Diary (logpad) are considered source document 
and will be kept at site in a CD/DVD sent by ERT at the end of the trial.


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5.1.6
COPD Exacerbation
For this study purposes, a COPD exacerbation is defined according to the following severity 
categories:
Severity
Definition
Mild
Increase of COPD symptoms during at least 2 consecutive days, self-
managed by the patient at home by increasing usual COPD medication 
(short-acting bronchodilator and/or inhaled corticosteroid use)
Moderate
Increase of COPD symptoms during at least 2 consecutive days, which 
does not lead to hospitalisation but is treated with antibiotics and/or 
systemic corticosteroids or an increase in dose of systemic 
corticosteroids.
Severe
Increase in COPD symptoms during at least 2 consecutive days, which 
leads to hospitalisation (overnight stay at hospital or emergency room) 
or death
COPD exacerbation according to the health care utilisation definition will be evaluated by the 
investigator at each visit on the basis of the information registered by the patient (and 
subsequently checked by the investigator at each visit) into the electronic Patient Diary and 
paper Patient Diary. COPD exacerbation episodes will be recorded in the AE form of the 
EDC.
Information to be recorded in the COPD Exacerbation includes start and stop date, treatment 
received (antibiotics, systemic corticosteroids, increase in rescue medication), outcome, need 
of hospitalisation, etc. The onset of an exacerbation will be defined by the onset of symptoms 
worsening. The end of the exacerbation will be defined by the investigator based on symptoms 
recovery or stabilization and end of treatment received for the episode.
A new COPD exacerbation episode is defined as the patient being off oral steroids and 
antibiotics for ≥7 days since prior exacerbation. If the patient is off oral steroids and 
antibiotics for less than 7 days, then it will be considered as a “relapse” of the previous 
exacerbation, and it will be treated as the same COPD exacerbation episode within the COPD 
exacerbation form of the EDC.
In case of a COPD exacerbation after randomisation:
─
The next study visit (Va, other than Visit 7) must be postponed until 4 weeks after the 
resolution of a moderate to severe episode, or 2 weeks after a mild episode. If the re-
scheduled visit (Va) date falls within less than 2 weeks from the following per protocol 
visit (Va+1), then the first (visit Va) will be skipped. Subsequent visits should be 


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scheduled and performed as indicated in the protocol (ie, with respect to Randomisation 
Visit day).
─
The next study visit is Visit 7 and patient keeps on IP dosing: Visit 7 will never be 
skipped, since the whole assessments for study completion are due to be performed, nor it 
will be postponed, since it would extend study treatment exposure. Thus, Visit 7 will be 
maintained on the scheduled day but only safety assessments will be performed.
─
The next study visit is Visit 7 and patient interrupted IP dosing due to exacerbation 
treatment/interventions: Premature Discontinuation Visit will be performed
COPD exacerbations will be analysed in this study on the basis of EXACT questionnaire 
(section 5.1.5) as well as on the basis of health care utilisation definition (increase of COPD 
symptoms during at least 2 consecutive days that require a change in COPD treatment).
5.1.7
Rescue medication
Patients will record once daily in the electronic Patient Diary (logpad) the number of 
inhalations (puffs) of rescue medication (salbutamol) taken during the last 24h. The question 
displayed on the device will be: “How many puffs of rescue medication (salbutamol) have you 
inhaled in the last 24 hours (from yesterday when you went to bed until now)?”
The electronic Patient Diary recording will start at Visit 1 (screening) night and will end the 
night before Visit 7.
Data recorded will be transferred to ERT on ongoing basis during the study. Data will be 
accessible to investigators on an online website.
The electronic entries on the electronic Patient Diary (logpad) are considered source document 
and will be kept at site in a CD/DVD sent by ERT at the end of the trial.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood samples for determination of clinical chemistry and haematology will be taken at the 
times indicated in the Study Plan (see Section 4).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The clinical chemistry and haematology will be performed by the central laboratory which 
will provide the report to sites. A specific manual will be distributed by the central 
laboratory.


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The following laboratory variables will be measured:

Haematology: Haematocrit, haemoglobin, erythrocytes (red blood cells), leucocytes 
(white blood cells), differential blood count (neutrophils, lymphocytes, monocytes, 
eosinophils and basophils), thrombocytes (platelets).

Biochemistry:
─
Electrolytes: Sodium, potassium, calcium, chloride and inorganic phosphorus.
─
Enzymes: GOT (AST), GPT (ALT), alkaline phosphatase, γ-GT, LDH and creatine 
kinase and isoenzymes (CK-MM, CK-MB, or CK-BB).
─
Substrates: Glucose, total cholesterol, triglycerides, creatinine, total bilirubin, total 
protein, albumin, uric acid and BUN.

Pregnancy: Serum pregnancy test only for women of childbearing potential.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be retained at centre as source data for 
laboratory variables.
All along the trial, clinically relevant new findings or worsening of a pre-existing finding in 
the laboratory results must be considered an adverse event and must be recorded on the 
Adverse Event EDC form. For information on how AEs based on laboratory tests should be 
recorded and reported, see Section 6.3.
In case of technical problems, or if the investigator considers that a result is clinically relevant 
or doubtful, additional blood samples may be collected within a reasonable time and will be 
sent to the central laboratory for analysis.
Should pregnancy occur during the participation in the trial, the patient must immediately 
discontinue from the trial. The pregnancy should be reported as described in section 6.6.
5.2.1.1
Hy’s Law
Cases where a subject 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 refer to Appendix D for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law
5.2.2
Medical History/Physical examination
A medical history of screened patients will be obtained at the Visit 1, recording only the 
relevant demography and medical data, as required in the Medical History /Physical 
examination EDC form and excluding the target indication (i.e COPD).


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A complete physical examination will be performed at Visit 1 and Visit 7. Only relevant 
findings, detected at Screening Visit, will be recorded in the Medical History/Physical 
examination EDC form.
Body weight and height will be measured only at Visit 1 (screening) (allowing calculation of 
Body Mass Index) and will be recorded on the MasterScope® CT. Patients should be in light 
indoor clothes without shoes.
5.2.3
ECG
Standard 12-lead ECG evaluations will be recorded after approximately 5 minutes resting in 
supine position before any blood sampling and spirometry test. 12-lead ECGs will be recorded 
preferably always by the same technician for each patient.
ERT, as the responsible company for the centralized electrocardiographic assessments, will 
provide the research sites with the 12-lead ECG equipment and supplies, specific training and 
written instructions.
Following an acquisition of a quality ECG tracing, the investigator or designee will 
electronically transfer the data to ERT.
Within 72 hours of reception, a specialized cardiac safety technician and cardiologist at ERT 
will read and interpret the ECG tracings according to the ERT internal processes (“manual 
reading”) and will make available the ECG report to the research personnel on an online 
website.
When any 12-lead ECG result exceeds normal ranges alert reports will be immediately sent by 
ERT by e-mail to the investigator.
The personnel in charge or the reading an interpretation of the ECG tracings at ERT will be 
blinded to patient’s IP allocation and patient’s identity.
The investigator will review the “manual reading” reports to assess the clinical relevance of 
any abnormal findings and/or to decide if the patient is or remains eligible for the study.
However, the responsibility for inclusion or continuation of the subject in the study will lie 
within the investigator in consultancy with the sponsor.
The 12-lead ECG will be recorded at 25 mm/sec and will consist of a recording of leads I, II, 
III, aVR, aVL, aVF and V1 to V6 and 10 seconds recording of lead II (rhythm strip). At least 
3 complete evaluable complexes per lead will be recorded. The following ECG parameters 
will be determined: Heart rate, RR interval, PR interval, QRS interval, QT interval, QTc 
interval, QTcB interval and QTcF interval.


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At Visit 1 (screening), the 12-lead ECG should be recorded at a similar time to that to be 
obtained pre-dose during the course of the trial. Investigators will assess patients’ eligibility 
according to the manual reading report of Visit 1.
Any abnormal finding in the ECG tracing (rhythm, ectopy, conduction, morphology, 
myocardial infarction, ST segment, T wave and U wave observations) will be evaluated by the 
investigator and will be specifically documented.
Throughout the trial, clinically relevant new findings or worsening of a pre-existing finding in 
the ECGs (parameters or abnormal findings in the tracing) must be considered an adverse 
event and must be recorded on the Adverse Event EDC form.
In case of technical problems, the investigator considers any result is clinically relevant or 
doubtful, additional 12-lead ECGs may be performed, using the same equipment, within a 
reasonable time.
5.2.4
Blood pressure 
Systolic and diastolic pressure (in mmHg) will be measured after at least 5 minutes resting, 
and also, before taking any blood sample and conducting any spirometry. Measurements will 
be carried out with patient in the supine position and preferably always on the same arm. Data 
will be recorded on the EDC.
If there is any suspicion of unreliable measurement, blood pressure will be measured again. 
The value obtained on the second measurement will be considered as definitive and will be the 
one recorded on the EDC.
Throughout the trial, clinically relevant new findings or worsening of a pre-existing finding in 
the medical history/physical examination/blood pressure must be considered an adverse event 
and must be recorded on the AE form of the EDC.
5.2.5
Adverse Events 
Procedures for recording and assessing adverse events are included in section 6.6.
5.2.5.1
MACE (major adverse cardiac event) adjudication
MACE (major adverse cardiac event) is a composite of the total of cardiovascular (CV) death, 
non-fatal myocardial infarction and non-fatal stroke.
A Cardiovascular Adjudication Committee (CVAC) will provide independent and objective 
review and adjudication of MACE and will also adjudicate all deaths. The CVAC chair will 
also choose additional serious and non-serious adverse events for adjudication.


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An external vendor will be used to manage dossier compilation and communication between 
AstraZeneca and CVAC members.
For the procedures related to the MACE adjudication, please refer to the specific charter.
5.3
Other assessments
5.4
Pharmacokinetics
Pharmacokinetic samples will not be taken during the study
5.5
Pharmacodynamics
Pharmacodynamic samples will not be taken during the study
5.6
Pharmacogenetics
Pharmacogenetic samples will not be taken during the study.
5.6.1
Storage, re-use and destruction of biological samples
Samples will be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, after which they will be destroyed. 
5.6.2
Labelling and shipment of biological samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document’.
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
5.6.3
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at participating sites keeps full traceability of collected biological 
samples from the subjects while in storage at the centre until shipment or disposal (where 
appropriate) and keeps documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.


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AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca Biobank or Innovation 
Center of China (ICC) during the entire life cycle.
5.6.4
Withdrawal of Informed Consent for donated biological samples
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological samples is an optional part of the study, then the subject may 
continue in the study.
The Principal Investigator:

Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site

Ensures that the subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
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.
The investigator will closely monitor any adverse event and will adopt the necessary clinical 
measures to ensure the safety of the patient.
6.1
Definition of adverse events
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 


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can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram). In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, 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/incapacity or substantial disruption of the 
ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events will be collected from time of signature of informed consent throughout the 
treatment period and including the follow-up period (ie 2 weeks after the last IP).
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the subject’s last AE assessment in the study 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 subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Variables 
The following variables will be collect for each AE;

AE (verbatim)

The date when the AE started and stopped


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
Assessment of intensity

Whether the AE is serious or not

Investigator causality rating against the Investigational Product (yes or no)

Action taken with regard to investigational product

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

Description of AE.
6.3.3.1
Assessment of intensity
For grading the intensity of an AE, the following intensity rating scale will be used:
1.
Mild - awareness of sign or symptom, but easily tolerated (acceptable)
2.
Moderate - discomfort sufficient to cause interference with normal activities (disturbing)
3.
Severe - incapacitating, with inability to perform normal activities (unacceptable) 
AEs will be collected only once with its maximum intensity.
For grading the intensity of a COPD exacerbation, please refer to section 5.1.6.
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.


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6.3.4
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, 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 investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures 
and additional study drug.  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 B to the Clinical 
Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’,or revealed by observation will be collected and recorded in the eCRF.
Patients should be instructed to record AEs in the Patient Diary on a daily basis between 
visits. Any AE recorded on the Patient Diary will be transcribed in standard medical terms as 
AE on the eCRF AE page by the investigator.
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report.
Medical disorders present at the time of signing the informed consent that are part of the 
patient’s medical history will only be considered AEs if they worsen after this time.
Relevant abnormalities detected before IP administration in physical exam, laboratory 
value/vital sign, ECGs will not be considered AEs if already known as part of the medical 
history or in relation to prior medical conditions, and will be recorded on the eCRF Medical 
History/physical examination form/page. However, abnormalities detected in screening/run-
in/baseline tests, thought to be due to a study procedure, will be considered AEs.
During the trial, abnormalities (newly occurring or worsening of previously known 
abnormalities) detected in laboratory values, vital signs, ECGs and physical examination 


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which are considered clinically relevant by the investigator or which require an intervention or 
a diagnosis test, or may result in the IP discontinuation, should be reported as AEs.
In addition, when an AE meets the criteria of seriousness (SAE), it must also be recorded on 
the SAE form and reported following the defined timelines (section 6.4).
6.3.7
Disease progression
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.
Any worsening of chronic COPD symptoms which do not meet clinical criteria for a COPD 
exacerbation as determined by the investigator, should not be recorded as an adverse event 
unless the study drug was discontinued, the worsening meets the criteria of a Serious Adverse 
Event, or the patient showed clear deterioration from baseline.
COPD exacerbations that meet the criteria for seriousness will be reported in the SAE form 
according to procedure detailed in section 6.4 below.
6.4
Reporting of serious adverse events
Serious Adverse Events will be collected from time of signature of informed consent form 
(ICF) throughout the treatment period and including the follow-up period (ie, 2 weeks after 
last IP administration). For patients who discontinued the IP, SAEs will be collected during 
the post-IP discontinuation follow-up period.
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, 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 adverse events 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


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within one calendar day ie, 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 EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the Investigator or other study site personnel reports a 
SAE to the appropriate AstraZeneca representative by telephone, fax or email.
The AstraZeneca  representative will advise the Investigator/study site personnel how to 
proceed.
The minimum information that has to be included in the initial report is:
─
An event meeting the criteria of SAE.
─
A qualifiable reporter, defined as an investigator of this trial or his/her delegate.
─
A qualified patient defined as a patient who has consented to this trial.
─
A suspect medicinal product
─
The investigator’s causality assessment.
Unless the SAE has been sufficiently documented in the initial report, the investigator will 
provide all available additional information in follow-up reports by updating the EDC form 
and adhering to the same time frames as defined for the initial report. This will be continued 
until the event has been fully documented and reported.
An event reported to the AztraZeneca representative which does not meet the SAE criteria 
shall be nullified by the investigator by a follow up report.
A regulatory report of the SAE (depending on the local requirements) will be produced by 
AztraZeneca and submitted to the Regulatory Authorities, Ethics Committee and/or 
investigators when applicable according to local regulations.
SAEs NOT considered to be reported to the sponsor will be:

Hospitalisation for a treatment/surgical procedure which was elective or pre-planned for a 
pre-existing condition that did not worsen during the participation in the trial.

Hospitalisation or prolongation of an existing hospitalisation for respite care (e.g. patient 
lives too far from the hospital or has no caregiver at home).
6.5
Overdose
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose CRF module.


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An overdose without associated symptoms is only reported on the Overdose CRF module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel should inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work 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 subject becomes pregnant during the course of the study, the investigational product 
should be discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product 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 subject 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 ie, 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.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.


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6.6.2
Paternal exposure 
Provided that nonclinical data with aclidinium and formoterol fumarate based on conventional 
studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic 
potential and toxicity to reproduction and development do not reveal special hazard for 
humans, male participants are not requested to use contraception methods during their 
participation on the trial.
In case of pregnancy of the subject’s partners, the participant will not be necessarily 
discontinued from the trial but the partner’s pregnancy should be reported on the Pregnancy 
form following the same timeframe and routing as described for any participant’s pregnancy. 
These pregnancies will be also followed up, and the outcome of the pregnancy (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should if possible be obtained and documented.
6.7
Management of IP related toxicities 
There will be no dose reductions in this study.
6.8
Study governance and oversight 
Not applicable
7
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
The IP (Aclidinium Bromide 400 µg/Formoterol fumarate 12 µg inhalation powder) consists 
of a fixed dose combination of long-acting anticholinergic drug, namely aclidinium bromide, 
combined with the long-acting β2-agonist formoterol fumarate.
The drug product is an inhalation powder comprising of micronized aclidinium bromide and 
micronized Formoterol fumarate with α-lactose monohydrate as the carrier.
The Aclidinium bromide/Formoterol fumarate will be compared to the individual components, 
aclidinium bromide and formoterol fumarate and placebo. Note: The strengths are expressed 
as metered dose.
Substance and dosage:
Aclidinium bromide/Formoterol fumarate 400/12 µg
Dosage form:
Inhalation powder.
Administration route:
Oral Inhalation (by Genuair® Dry Powder Inhaler, DPI) 
Manufacturer:
Industrias Farmacéuticas Almirall, S.L. (IFA)
Barcelona, Spain


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Substance and dosage:
Aclidinium bromide 400 µg
Dosage form:
Inhalation powder.
Administration route:
Oral Inhalation (by Genuair® Dry Powder Inhaler, DPI) 
Manufacturer:
Industrias Farmacéuticas Almirall, S.L. (IFA)
Barcelona, Spain
Substance and dosage:
Formoterol fumarate 12 µg*
Dosage form:
Inhalation powder.
Administration route:
Oral Inhalation (by Turbuhaler® Dry Powder Inhaler, DPI) 
Manufacturer:
AstraZeneca
Substance and dosage:
Placebo to Aclidinium bromide/Formoterol fumarate 400/12 µg and
Aclidinium bromide 400 µg
Dosage form:
Inhalation powder.
Administration route:
Oral Inhalation (by Genuair® Dry Powder Inhaler, DPI) 
Manufacturer:
Industrias Farmacéuticas Almirall, S.L.
Barcelona, Spain
Substance and dosage:
Placebo to formoterol 12 µg
Dosage form:
Inhalation powder.
Administration route:
Oral Inhalation (by Turbuhaler® Dry Powder Inhaler, DPI) 
Manufacturer:
AstraZeneca
*Placebo to Aclidinium bromide/Formoterol fumarate 400/12 µg and Aclidinium bromide 400 µg
Note: The delivered dose of Formoterol fumarate in the mono-formulation used in the study is 9 µg.
7.2
Additional Drug
Rescue medication Salbutamol pMDI (100 µg/puff) is considered as additional study drug and 
the accepted standard brand available in the country will be sourced. If required by country 
regulations or procedures, CRO/AstraZeneca will locally source or provide reimbursement for 
the cost incurred of this additional study drug
7.3
Dose and treatment regimens
Run-in period
At the moment of the ICF signature or Visit 1 (screening) subjects will receive rescue 
medication (see Section 7.7) to be administered as needed until Visit 2 (randomisation).
Instructions will be given to the subject on how to use the pMDI inhaler (inhalation technique 
and priming instructions). In order to inhale properly according to instructions the subject will 


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practice inhalation technique, as many times as judged necessary by the supervising study 
personnel. Instructions on how to use the pMDI will be provided to the subjects in local 
language.
Double-blind treatment period
Before taking the first dose of double-blind medication the subject will be instructed by the 
study personnel on how to use the Genuair inhaler and Turbuhaler inhaler. Subject will 
practice inhalation technique with empty training devices provided for this purpose. 
Instructions on how to use the Genuair and Turbuhaler inhalers will be provided to the 
subjects in local language.
The Aclidinium bromide/Formoterol fumarate 400/12 μg, the Aclidinium bromide 400 μg and 
the matching placebo will be administered via Genuair inhaler and the formoterol fumarate12 
μg as well as matching placebo will be administered via Turbuhaler. In order to ensure the 
double blind nature of the trial, patients will have to inhale from both inhalers twice daily 
following the schema below:
Treatment arm
Morning inhalation
(8-10 AM)
Evening inhalation
(8-10 PM)
Aclidinium bromide
/Formoterol fumarate 
400/12 μg
1 puff of Aclidinium 
bromide/Formoterol fumarate 400/12 
μg via Genuair
1 puff of placebo via Turbuhaler
1 puff of Aclidinium 
bromide/Formoterol fumarate 400/12 μg 
via Genuair
1 puff of placebo via Turbuhaler
Aclidinium bromide 400 
μg
1 puff of Aclidinium bromide 400 μg
via Genuair
1 puff of placebo via Turbuhaler
1 puff of Aclidinium bromide 400 μg
via Genuair
1 puff of placebo via Turbuhaler
Formoterol fumarate 12 μg
1 puff of placebo via Genuair
1 puff of Formoterol fumarate 12 μg
via Turbuhaler
1 puff of placebo via Genuair
1 puff of Formoterol fumarate 12 μg via
Turbuhaler
Placebo
1 puff of placebo via Genuair
1 puff of placebo via Turbuhaler
1 puff of placebo via Genuair
1 puff of placebo via Turbuhaler
At all study visits, subjects will receive enough double-blind medication and rescue medication to cover for 
treatment need until the next study visit.
7.4
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.


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IP will be supplied in the form of medication kits (medication box). Every medication kit will 
contain Genuair® inhalers, each inserted in a bag, and Turbuhaler® inhalers.
Every medication kit will be identified with a unique kit number. Each bag, Genuair® and 
Turbuhaler® included in the kit will show on the label the kit number they belong to.
In order to allow drug reconciliation and dispensation control, research personnel will record 
the patient number on the labels of every kit dispensed, as well as on the bags label and 
inhalers labels.
The label will include, but not limited to, the following information:
─
Name of sponsor (AstraZeneca)
─
Investigational product/study drug dosage form, route of administration, and quantity of 
dosage units
─
Storage conditions
─
Study code
─
Kit number
─
Directions for use
─
The name of the Principal Investigator, where applicable (this may be pre- printed or to 
be added on the label when the investigational product / study drug is dispensed)
─
The period of use e.g., expiry date.
─
The following standard statements:
─
‘for clinical study use only’
─
‘keep out of reach of children’
7.5
Storage
All study drugs should be kept in a secure place under appropriate storage conditions. The 
investigational product label on the study drug specifies the appropriate storage.
The person responsible for the IP at the drug distribution centre and hospital pharmacy (or any 
facility at the research site) will inventory and acknowledge receipt of all IP supplies received 
as well as its dispensation.
7.6
Compliance
Each subject is required to comply with the prescribed treatment regimen throughout the 
study. Subjects will be instructed on how to use the inhalers correctly. Any subject found to be 
noncompliant would be counselled on the importance of taking their study medication as 
prescribed.


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In order to ensure correct inhalation technique, training devices will be available at each study 
site for instructional purposes as well as for subjects to practice the correct inhalation 
technique. Instruction and practice should occur prior to dispensing study medication. These 
devices will be used in the clinic only and will not be dispensed to subjects for use at home.
The treatment compliance will be calculated for each device (Genuair and Turbuhaler) by the 
Statistical programmer of AstraZeneca as number of doses taken respect to the number of 
doses expected (expressed in percentage). The formula and the cut point will be established in 
the Statistical Analysis Plan (SAP).
To consider a patient as “treatment compliant”, she/he must be compliant with both inhalers, 
Genuair and Turbuhaler. Patients non-compliant will be reported as protocol deviations.
7.7
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to and returned from the 
subject.
Subjects will be asked to bring all used and unused inhalers to the site at each on-site visit. 
The Investigator or delegate will review the inhalers and will record if they are used or unused 
in the Drug Accountability Log.
Any study medication deliberately or accidentally destroyed must be recorded. Any 
discrepancy between dispensed and returned study medication should be explained.
Study site personnel, if applicable, or the AstraZeneca monitor/representative will account for 
all study drugs received at the site, unused study drugs and for appropriate destruction. 
Certificates of delivery, destruction and return should be signed.
Study Drug is destroyed once there are satisfactory records of product accountability by the 
Monitor and the Study Leader has given authorization.
At the end of the trial and after reconciliation all the study medication (IP and rescue 
medication), both used ad unused, will be destroyed in authorized locations/sites. The
destruction will be document appropriately and the certificate of destruction will be filed in 
the Trial Master File.
7.8
Concomitant and other treatments 
7.8.1
Restricted and prohibited concomitant treatment
It is the responsibility of the Investigator to initiate treatment in case of COPD exacerbations 
and adverse events, as he/she deems appropriate. For safety purposes, the use of prohibited 


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and restricted medications listed below to treat a COPD exacerbation or an adverse event is 
allowed during the study. 
Unless the use of prohibited or restricted medication meets the criteria outlined in sections 3.9
and 3.10, it will not constitute a reason for discontinuation of IP nor withdrawal from study. 
Restricted Medication
/Class of drug:
Restrictions
Stabilization period
Inhaled corticosteroids*

Patients who were following a stable regimen of the 
combination for at least 4 weeks can be switched to 
the same inhaled corticosteroid (at the same dose and 
dose regimen) as monotherapy at least 48 hours 
before Visit 1 (screening).
No stabilization period 
is required in this case.

If treatment is switched to a different inhaled 
corticosteroid as monotherapy at an equivalent 
therapeutic dose to the one used for the fixed inhaled 
combination, a stabilisation period of at least 14 days 
or longer, until patient is considered stabilised, 
should occur before Visit 1 (Screening). The patient 
will be considered stabilised if, according to the 
investigator's judgement, during the second week of 
observation there are no changes in symptoms 
beyond the day to day variation, or symptoms 
experienced remain at a similar level of those 
existing before medication change.
2 weeks

If treatment is switched to a different inhaled 
corticosteroid as monotherapy at different therapeutic 
dose to the one used for the fixed inhaled 
combination, a stabilisation period of at least 28 days 
or longer, until patient is considered stabilised, 
should occur before Visit 1 (Screening) . The patient 
will be considered stabilised if, according to the 
investigator's judgement, during the last week of 
observation there are no changes in symptoms 
beyond the day to day variation, or symptoms 
experienced remain at a similar level of those 
existing before medication change.
4 weeks
Continuous oral or 
parenteral corticosteroids*
Dose equivalent of 10 mg of prednisone per day or 20 mg 
every other day or lower that this.
4 weeks
Selective β-blocking 
agents (eg. Atenolol, 
metoprolol, nebivolol)
-
2 weeks
Oxygen therapy*

< 15 hours a day
4 weeks


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Restricted Medication
/Class of drug:
Restrictions
Stabilization period
Oral sustained-release 
theophyllines (less than
400mg/day)*

Theophylline should be avoided the morning of study 
visits and begin after visit completion.
4 weeks
*Change in daily dose, dosing schedule, formulation or treatment is unlikely during the course of the trial (the 
exception being the treatment of a COPD exacerbation).
Prohibited Medication/Class of drug:
Wash-out before V1
Oral, intra-nasal or parenteral anticholinergic agents such as atropine, glycopyrrolate or
biperiden
7 days
Long-acting inhaled anticholinergics, LAMAs (e.g. aclidinium bromide, umeclidinium)
72 h
Long-acting inhaled anticholinergics, LAMAs (e.g. tiotropium bromide, 
glycopyrrolate)a
7 days
Short-acting inhaled anticholinergics, SAMAs (e.g.ipratropium, oxitropium)
12 h
Inhaled and short acting β2-agonists, SABAs (eg, fenoterol or albuterol, except for
salbutamol)
6 h
Oral* and twice-daily long acting β2-agonists, LABAs (eg, terbutaline*, formoterol or
salmeterol)
48 h
Once daily long-acting β2- agonists (LABAs) (eg, indacaterol, oladaterol)
7 days
Combination of LABAs+ICS (eg Advair, Symbicort, Seretide)
Note: Patients can be switched to the same or a different inhaled corticosteroid as 
monotherapy (see restricted medication section for stabilization period)
4 weeks
Once daily combination of LABAs+ICS (eg Breo)
7 days
Combination of SABAs+SAMA (eg Combivent)
12 h
Combination of LABA+LAMA (eg Ultibro, Anoro Ellipta)
7 days
Methyl-xanthines (eg. Theophylline, theobromine tablets)
72 h
Cromolyn sodium, nedocromil
5 days
Leukotriene modifiers (eg montellukast)
48 h
PDE IV inhibitors (eg, roflumilast)
4 weeks
Continuous oral or parenteral corticosteroids used at a dose in excess of the equivalent 
of 10 mg of prednisone per day or 20 mg every other day
Note: can be switched to dose equivalent of 10 mg of prednisone per day or 20 mg every 
other day as long as they are at stable dose for at least 4 weeks prior to V1
4 weeks
Non-selective β-blocking agents (eg. Carvedilol, alprenolol, nadolol, propranolol, 
sotalol, timolol)
Note: can be switched to selective β1-blocking agents, as long as they are at stable dose
for at least 2 weeks prior to V1
2 weeks
Herbal or traditional medicine.
2 weeks


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7.8.2
Rescue medication
Rescue/Supportive Medication/Class of drug:
Usage:
Salbutamol pMDI (100 μg/puff)
Note: marketed salbutamol available in the participating 
countries will be supplied in their original box and with its 
original instructions leaflet (local languages). Where needed 
according to local regulations, salbutamol boxes will be 
provided labelled for the purposes of this trial.

Administration should be on “as needed” 
basis, as per the investigator’s instructions 
from the ICF signature until the end of the 
trial

6h of wash-out is needed before each study 
visit
7.8.3
Other concomitant treatment
Medications other than that described above, which is considered necessary for the subject’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the Case Report Form.
7.8.4
Vaccination Against COVID-19
The sponsor accepts that vaccination against COVID-19, when and where available, and when 
patients are eligible according to the applicable guidelines, should be based on the risks and 
benefits for each individual patient and on what is in the patient’s best interest according to 
the Investigator’s clinical judgement. Consequently, vaccination during the study, is in general 
permitted and any delays in receiving the vaccination due to study participation should be 
minimised.
To avoid potentially confounding the interpretability of safety data, it is recommended that 
patients are not randomised for at least 7 days from the receipt of the COVID-19 vaccine 
(either the first dose or subsequent dose) or as considered appropriate in the clinical 
judgement of the investigator.  Similarly, COVID-19 vaccination should be at least 7 days 
apart from a study assessment visit.  
If and when a patient receives a COVID-19 vaccination, the vaccine information (e.g. vaccine 
type/brand, route, date of administration) will be recorded in the Case Report Form as a 
concomitant medication.
Any AEs suspected to be due to the vaccination should be captured as per Section 6.3 of this 
CSP.
8
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations

All personnel involved with the analysis of the study will remain blinded until database 
lock and protocol violators identified.


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
Analyses will be performed by AstraZeneca or its representatives.
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first subject 
randomised and any subsequent amendments will be documented, with final amendments 
completed prior to unblinding of the data.
A supplementary statistical analysis plan (SAP) will be produced to specify the analyses 
required for China subgroup.
8.2
Sample size estimate
Approximately 1515 patients will be screened in this study in order to achieve 1060
randomised patients, considering an estimated ineligibility rate of 30% prior to randomisation.
Based on previous data, a sample size of 265 randomised patients per group will provide at 
least 90% power to detect a statistically significant difference at week 24 of 100 mL between 
Aclidinium bromide 400 µg/Formoterol fumarate 12 µg and Aclidinium bromide 400 μg in 
change from baseline at 1-hour morning post-dose FEV1, 65 mL between Aclidinium bromide 
400 µg/Formoterol fumarate 12 µg vs Formoterol fumarate 12 μg in change from baseline
morning pre-dose (trough) FEV1, 100 mL between Aclidinium bromide 400 μg vs placebo in 
trough FEV1, and 175 mL between Aclidinium 400 μg vs. placebo in peak FEV1. Previous 
studies on the same drug and for the same spirometric endpoints showed a standard deviation 
of 230 mL.
The sample size is driven by the comparison between Aclidinium bromide/Formoterol 
fumarate 400/12 μg vs. Formoterol fumarate 12 μg in morning pre-dose FEV1, and the 
minimal detectable difference is 39 mL.
The same sample size will provide at least 90% power to detect a statistically significance 
difference at week 24 of at least 1-unit between Aclidinium bromide 400 µg/Formoterol 
fumarate 12 µg and Aclidinium bromide 400μg vs placebo in TDI focal score, assuming a SD 
of 3.5-units, and at least 4-unit difference in change from baseline in SGRQ total score 
assuming a SD of 13.5-unit for the same treatment comparisons.
All tests will be performed using two-sided tests at 5% significance level.
Nominal powers for primary and secondary efficacy variables are as follow:


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Step
Endpoint
Treatment Comparison
Nominal power (%)
Primary Endpoints
1
1-hour postdose FEV1
Aclidinium bromide/Formoterol 
fumarate 400/12 μg vs.
Aclidinium bromide 400 μg
99
2
Morning predose FEV1
Aclidinium bromide/Formoterol 
fumarate 400/12 μg vs.
Formoterol fumarate 12 μg
90
3
Morning predose FEV1
Aclidinium bromide 400 μg vs.
placebo
99
Secondary Endpoints
4
Peak FEV1
Aclidinium bromide 400 μg vs.
placebo
99
5
TDI
Aclidinium
bromide/Formoterol fumarate
400/12 μg vs. placebo
90
6
TDI
Aclidinium bromide 400 μg vs.
placebo
90
7
SGRQ
Aclidinium
bromide/Formoterol fumarate
400/12 μg vs. placebo
92
8
SGRQ
Aclidinium bromide 400 μg vs.
placebo
92
The order of the hierarchy of endpoints and treatment comparisons is detailed in section 8.5.
8.3
Definitions of analysis sets
Demographic and other baseline (screening) characteristics will be analysed using the Safety 
population. The analysis of all efficacy variables will be performed on the ITT population, 
except for COPD exacerbations, which will be analysed using the Safety Population. In 
addition, the primary and secondary efficacy variables will be also analysed using the PP 
Population to assess the robustness of the findings from the ITT Population. All safety 
outcomes and other variables will be analysed using the Safety population.
For the randomised analysis, ITT and PP analyses sets, subjects will be classified to treatment 
arms according to their randomised treatment. For the Safety Population, subjects will be 
classified using the actual treatment they received. Any major deviations from the randomised 
treatment assignment will be listed and considered when interpreting the safety data.
8.3.1
Screening analysis set
The Screened population is defined as all subjects who attended screening visit and received a 
subject number.


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8.3.2
Randomised analysis set
The randomised population is defined as all subjects in the screened population who were 
randomised to a treatment group in the study.
8.3.3
Safety analysis set
The safety population is defined as all randomised patients who took at least one dose of IMP.
8.3.4
Patient disposition
Frequency and percentages of patient disposition and reasons for discontinuation of 
investigational product will be presented. Patients who prematurely discontinue the 
investigational product will be listed along with the reason for discontinuation.
8.3.5
Efficacy analysis set
The Intention-to-Treat (ITT) population is defined as all randomised patients who take at least 
one dose of IP and have at least a baseline FEV1, under the ITT principle and regardless the 
adherence to the randomised treatment.
The Per-Protocol (PP) population is defined as a subset of the ITT population consisting of 
patients who:
a.
met all inclusion/exclusion criteria liable to affect the efficacy assessment 
b.
have sufficient treatment compliance
c.
did not present serious deviations of the protocol that may affect efficacy. The precise 
reasons for excluding patients from the study populations will be fully defined and 
documented in the Blind Data Review Meeting (BDRM).
8.3.6
PK analysis set
Not applicable
8.3.7
PRO analysis set
Not applicable
8.4
Outcome measures for analyses
8.4.1
Primary efficacy variables
The primary efficacy variables are the following:

Change from baseline in 1-hour morning post-dose dose FEV1 of Aclidinium bromide 
400 µg/Formoterol fumarate 12 µg compared to Aclidinium bromide at Week 24.


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
Change from baseline in morning pre-dose (trough) FEV1 of Aclidinium bromide 400 
µg/Formoterol fumarate 12 µg compared to Formoterol fumarate at Week 24.

Change from baseline in trough FEV1 of Aclidinium bromide 400 µg compared to 
placebo at Week 24.
Morning pre-dose (trough) FEV1 is defined as the average of the corresponding -30 and 0 
minute timepoints values before the morning IP administration at Week 24. If one time-point 
is missing then the available one will used as morning pre-dose. Baseline for both variables is 
defined as the average of the two FEV1 values measured just prior to the administration of the 
first dose of IP at Visit 2. If one of the two is missing, then the available one will be used as 
baseline value.
8.4.2
Secondary efficacy variables

Change from baseline in peak FEV1 of Aclidinium bromide 400 µg compared to placebo 
at week 24.

Improvements TDI focal score of Aclidinium bromide 400 µg/Formoterol fumarate 12 µg 
compared to placebo at week 24.

Improvements TDI focal score of Aclidinium bromide 400µg compared to placebo at 
week 24.

Change from baseline in SGRQ total score of Aclidinium bromide 400 µg/Formoterol 
fumarate 12 µg compared to placebo at week 24.

Change from baseline in SGRQ total score of Aclidinium bromide 400µg compared to 
placebo at week 24.
8.4.3
Additional efficacy variables:

Pulmonary Function Tests:
─
Change from baseline in morning pre-dose FEV1 and FVC at all visits, except for 
primary variables at Week 24.
─
Morning pre-dose FEV1 and FVC at all visits.
─
Change from baseline in FEV1 and FVC by time point at all visits, except for the 
primary variable.
─
FEV1 and FVC by time point at all visits.
─
Change from baseline in normalised area under curve from time 0 to 3 hours (AUC0-
3) FEV1 and FVC at Day 1 and at Week 24.
─
Change from baseline in peak FEV1 and FVC at Day 1 and at Week 24.

Signs and Symptoms and Health-related Quality of Life:
─
Improvements in TDI focal score and three component scores at Weeks 4, 12, and 24 
(except for focal score at Week 24).


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─
Number (%) of patients who achieved a clinically meaningful difference in TDI focal 
score (improvement of ≥1 unit) at Weeks 4, 12, and 24.
─
Change from baseline in SGRQ total score and three dimension scores at Weeks 4, 
12, and 24 (except for total score at Week 24).
─
Number (%) of patients achieving a clinically meaningful improvement (≥4 units) 
compared with baseline in SGRQ total score at Weeks 4, 12, and 24.
─
Number (%) of patients achieving a clinically meaningful improvement ≥2 units) in 
CAT total score at Weeks 4, 12 and 24.
─
Change from baseline in the CAT score at Weeks 4, 12 and 24.

COPD Exacerbations
─
Analysed based on Health Resource Utilization definition (worsening of symptoms 
requiring a change in COPD treatment and/or hospitalization and/or emergency room 
treatment)
o
Rate of COPD exacerbations per patient/year (any, and moderate or severe).
o
Time (days) to first COPD exacerbation (any, and moderate or severe).
o
Number (%) of patients with at least 1 COPD exacerbation (any, mild, moderate, 
severe and moderate or severe).
─
Derived from the EXACT questionnaire:
o
Rate of COPD exacerbations per patient/year.
o
Time (days) to first COPD exacerbation.
o
Number (%) of patients with at least 1 COPD exacerbation.

Daily COPD Symptoms and use of rescue medication:
─
Change from baseline in E-RS total score and breathlessness, cough & sputum and 
chest domains at all visits and over 24 weeks.
─
Number (%) of patients with a clinically meaningful improvement in E-RS total 
score, and by domain at all visits (more details in the SAP). Rescue medication:
─
Change from baseline in the use of rescue medication at all visits and over 24 weeks.
8.4.4
Safety outcomes

Adverse events

Clinical laboratory test (haematology, biochemistry and pregnancy test)

Blood pressure

12-lead ECG
8.5
Methods for statistical analyses
Statistical analyses of demographic, baseline characteristics, efficacy and safety and 
tolerability data will be performed by the sponsor. A fully specified Statistical Analysis Plan 


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(SAP) will be prepared by the statistician before data base lock. The Statistical Analysis 
System, SAS v. 9. 3 will be the statistical software used to analyse the data sets. Tables, 
figures and listings will be compiled in the statistical report and appended to the CSR.
For primary and secondary variables, the “estimand” will assume that all patients adhere to 
treatment, ie. missing data will be modelled based on what it was observed during treatment 
using direct likelihood approaches. This assumes data is missing-at-random (MAR). 
Sensitivity analyses will be performed under Missing-Not-At-Random (MNAR) assumptions. 
Further details will be provided in the SAP.
Estimands for all additional variables will be derived “on-treatment”.  Missing data will be 
modelled through direct likelihood approaches.
For all patients exacerbations, SAEs and concomitant medication data up to the final time 
point will be collected, even if a patient stops treatment early, therefore, a sensitivity 
“estimand” based on this data will also be derived and analyses will be performed based on 
this data.
The study population will be described using demographic and baseline characteristics 
recorded during the run in period. Analyses of demographic and baseline characteristics will 
be based on the Safety population.
8.5.1
Exposure
Mean exposure to the study medication (in days), and number and percentage of patients 
exposed during the double-blind study period will be summarised by treatment group. 
Treatment exposure is defined as the number of days between the date of first dose of the 
double-blind medication taken and the date last dose taken plus one.
8.5.2
Prior and Concomitant Medication
The prior and concomitant medications, categorized according to the WHO Drug Reference 
List dictionary which employs the Anatomical Therapeutic Chemical (ATC3 class) 
classification  system, and preferred name, will be summarized by treatment group as 
frequency and percentage of patients reporting usage. Multiple medication use by a patient 
will only be counted once. In addition, prior COPD medications will be grouped and tabulated 
by treatment group, and by therapeutic categories.
8.5.3
Analysis of the primary variable (s)
The analyses of the primary variables will be performed on the Intention-to-Treat (ITT) and 
Per Protocol (PP) populations while all other analyses will be performed for the ITT 


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population. Moreover, smoking- status and country will be used as a treatment allocation 
factor during the randomisation process.
The primary efficacy variables, change from baseline in 1-hour morning post-dose FEV1 at 
Week 24 and change from baseline in morning pre-dose (trough) FEV1, will be analysed by 
means of mixed model for repeated measures (MMRM), adjusted for pre and post 
bronchodilator (salbutamol) FEV1 at screening visit, age, and baseline FEV1 as covariates, and 
treatment group, country, smoking-status, visit, and treatment group-by-visit interaction as 
fixed effect factors.
8.5.4
Analysis of the secondary variable(s)
Change from baseline in peak FEV1 at Week 24 will be analysed with the same statistical 
model than for the primary endpoints.
Improvement in TDI focal score and change from baseline in SGRQ total score at Week 24 
will be analysed by means of MMRM, adjusted by the corresponding baseline value (BDI or 
SGRQ at baseline) and age as covariates, and treatment group, country, smoking-status, visit, 
and treatment group-by-visit interaction as fixed effect factors.
The within-patient correlation will be modelled using the unstructured covariance matrix. The 
analysis will be performed based on all post baseline measurements using only the observed 
cases without imputation of missing values. If the model does not converge, then the 
compound symmetry covariance structure will be used. Restricted maximum likelihood 
method will be used.
Each treatment effect and treatment comparisons will be estimated by the Least Square means 
(LSMeans) and their differences in LSMeans on the treatment-by-visit interaction at Week 24, 
along with their standard errors (SE) and two-sided 95% confidence intervals (CI), and the p-
value corresponding to the between-treatment group difference. Statistical comparisons will 
be two-sided hypothesis tests, and the overall significance level will set at 0.05.
8.5.5
Multiplicity control
Multiplicity adjustment for the control of family-wise type I error will be carried out for 
primary and secondary endpoints. Each endpoint will be tested hierarchically at the 5% level 
as long as the previous one is significant at the 5% level. 
Pre-specified Sequence of Testing for Multiplicity Adjustment
Testing Order in
Hierarchy
Endpoint
(at Week 24)
Treatment Comparison


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1
1-hour morning post-dose
FEV1
Aclidinium bromide/Formoterol fumarate 400/12
μg vs. Aclidinium bromide 400 μg
2
Morning pre-dose FEV1
Aclidinium bromide/Formoterol fumarate 400/12
μg vs. Formoterol fumarate 12 μg
3
Morning pre-dose FEV1
Aclidinium bromide 400 μg vs. placebo
4
Peak FEV1
Aclidinium bromide 400 μg vs. placebo
5
TDI
Aclidinium bromide/Formoterol fumarate 400/12
μg vs. placebo
6
TDI
Aclidinium bromide 400 μg vs. placebo
7
SGRQ
Aclidinium bromide/Formoterol fumarate 400/12
μg vs. placebo
8
SGRQ
Aclidinium bromide 400 μg vs. placebo
8.5.6
Subgroup analysis (if applicable)
The efficacy and safety in China subgroup will be analysed to facilitate a benefit-risk 
assessment for regulatory submission in China.
In addition, to explore the homogeneity of the aclidinium/formoterol treatment over placebo, 
the following subgroups will be explored (but not limited): country, sex, age group, smoking-
status, race, BMI group, COPD severity, bronchodilator reversibility, and inhaled 
corticosteroid use.
For each subgroup the analysis of the primary and secondary analyses will be carried out.
Details of the Subgroup analysis will be specified in SAP.
8.5.7
Interim analysis
Not applicable
8.5.8
Sensitivity analysis (if applicable)
For most variables, missing data will be dealt with direct likelihood approach. In this case, no 
imputation is to be performed; the profile of the patient is used instead to adjust the estimates 
of the parameters when data are not available.
Sensitivity analyses based on imputation using drop out reasons (IUDR) will be explored and 
added to the SAP if deemed appropriate. To assess the robustness to variations of the missing 


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data assumptions underlying the primary analysis on the primary efficacy endpoints, 
sensitivity analyses will be conducted using a copy reference approach.
For COPD exacerbations and concomitant medication, for those patients who prematurely 
discontinue the IP but have follow-up assessments, data that include events collected during 
the follow-up period will be analysed.
8.5.9
Analysis of additional efficacy variables
Continuous variables defined as change from baseline or absolute values will be analysed by 
using the same mixed models as for primary and secondary endpoints. Dichotomous variables 
will be analysed by means of logistic regression models.
Rate of COPD exacerbations per patient/year will be modelled through negative binomial 
regression models. Time to first COPD exacerbation will be analysed through Cox regression 
models. Number of patients with at least 1 COPD exacerbation will be analysed through 
logistic regression models. The primary analysis described above will be based on the data 
collected before treatment discontinuation. In addition, for those patients who prematurely 
discontinue the IP but have follow-up exacerbation assessments, data that include events 
collected during the follow-up period will be analysed to assess the robustness to variations of 
the missing data assumptions underlying this primary analysis. In this case, the exposure time 
will be re-calculated based on the last data collection.
The number and percentage of patients with any prior and concomitant medication will be 
described by ATC text and preferred name and, where applicable, by treatment group. 
Concomitant medication will be analysed following the same criteria described in the previous 
paragraph for COPD exacerbations.
Exposure and compliance to the study medication during the study period will be summarised 
using descriptive statistics and will be presented by treatment group.
More details on how additional efficacy variables will be analysed will be provided in the 
SAP.
8.5.10
Analyses of safety and tolerability outcomes
Adverse events will be coded using the MedDRA dictionary. An adverse event will be 
considered as treatment-emergent (TEAEs) if it started at the time of or after the first IP 
administration. Adverse events that occurred more than 15-days (2 weeks) after last IP intake 
will not be considered a TEAE.
A comprehensive summary of AEs will be presented; Summaries of the number and 
percentage of patients with non-TEAE, Treatment Emergent Adverse Events (TEAE), AE 


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leading to discontinuation, Serious Adverse Events (SAE), Fatal Adverse Events will be 
presented by treatment using descriptive statistics. SAE will be also collected post-
discontinuation and interpretation in the data provided pre- and post- discontinuation 
analysed.
Additionally, TEAEs will be tabulated for all treatments by system organ class, preferred 
term, intensity, causality, seriousness; and outcome and SAEs will be tabulated for all 
treatments by system organ class, preferred term, intensity and causality.
Laboratory data will be summarized by presenting shift tables using normal ranges (baseline 
to most extreme post-baseline value) and by presenting summary statistics of observed and 
change from baseline values (means, medians, quartiles, ranges). The incidence of clinically 
notable lab abnormalities will be summarized.
Blood pressure data will be summarized by presenting summary statistics of observed and 
change from baseline values. The incidence of clinically notable vital sign abnormalities will 
be summarized.
ECG intervals will be summarized by presenting summary statistics of observed and change 
from baseline values. The (uncorrected) QT interval will be corrected according to the Bazett
and Fridericia’s formulas. The incidence of clinically notable ECG abnormalities will be 
summarized.
8.5.11
Exploratory analysis 
Additional efficacy endpoints will be exploratory. In addition, all subgroup analysis specified 
in the Section 8.5.4. will be also exploratory.
8.5.12
Deviations from the planned analyses
Any additional analyses will be detailed in the SAP that will be included in the Final Clinical 
Study Report. Any deviation from the planned analyses will be justified and detailed in the 
Final Clinical Study Report.
9
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first subject is entered into the study, an AstraZeneca representative or delegate 
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 
EDC/and/or ePROs system(s) utilised.


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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 or delegate will have regular contacts with 
the study site, including visits to:

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed

Perform source data verification (a comparison of the data in the CRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (e.g., clinic charts)

Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The AstraZeneca representative or delegate will be available between visits if the 
Investigator(s) or other staff at the centre needs information and advice about the study 
conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.
9.2.2
Study agreements
The Principal Investigator at each/the centre 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 subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail.


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Agreements between AstraZeneca/CRO and the Principal Investigator should be in place 
before any study-related procedures can take place, or subjects are enrolled.
9.2.3
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 end of the study is defined as ‘the last visit of the last subject undergoing the study’.
The study is expected to start in Q1 2016 and to end by Q3 2017.
The study may be terminated at individual centres 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 aclidinium bromide or formoterol fumarate.
9.4
Data management 
DataManagement (DM) of the study will be performed by Parexel and supervised by DM at 
AstraZeneca according upon agreed Standard Operating Procedures.
Main DM activities and procedures will be accurately described in the Data Management Plan 
(DMP), created by Parexel and meeting the sponsor requirements.
An EDC system will be used to collect and manage clinical data in electronic format (eCRF or 
electronic forms).  Parexel will be responsible for EDC and database creation (including all 
data sources) according to the Sponsor structure specifications, following CDSIC standards.
In addition to the AstraZeneca eCRF data, Parexel DM will receive electronic records for 
external data processed by external providers (vendors).  A reconciliation will be performed 
by Parexel of the eCRF data and against the rest of data sources to ensure consistency of the 
common data. Consistency and structural checks to be run in the data and listings for Parexel 
data cleaning and review will be defined in a Data Validation Plan which will be created by 
Parexel to meet sponsor requirements and standards.
Interactive checks on the EDC will provide a first level of filters. Checks will run when data 
has been inserted, informing the research personnel through a flag when data must be verified.
The need of additional queries may also be identified during the study as per the listings 
review by the Parexel DM staff, data coding, SAEs reconciliation process, etc.


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Database, checks, programmes for data visualisation, listings programming (for data review 
and data visualisation) and any programming implying data conversions will be appropriately 
validated by Parexel.
Parexel DM will oversee the status of queries performed by the third party providers. 
Reconciliation of SAEs between the clinical database and Drug Safety database will be 
performed by Parexel DM on ongoing basis and before database soft lock.   Procedures to 
follow will be detailed in the DMP.
Adverse events 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 WHO Drug Dictionary Enhanced extended with Herbal. All 
coding will be performed by medical coding team at the CRO. MedDRA and WHO DRUG 
Enhanced will be used, version number of each dictionary will be documented in the DMP.
Data will be collected during the study execution and transferred to the study data repository 
at the CRO, where data will be mapped into SDTM datasets on an ongoing basis.
Transfers of SDTM datasets from the study data repository will be periodically received at 
AstraZeneca during the study and after Database lock.  Frequency of these transfers will be 
agreed between AstraZeneca and the CRO.
All the processes will be carried out according to the specific pre-established processes and 
timelines documented in the DMP.
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.
When all data have been coded, validated, locked and signed, clinical database lock will be 
declared. Any treatment revealing data (random, PK data, etc) may thereafter be added and 
after clinical database will has been locked.
An audit trail of all databases will be maintained in order to protect the authenticity and 
integrity of the clinical data.
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 


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regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Subject 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 study protocol, including the final version of 
the Informed Consent Form and any other written information and/or materials to be provided 
to the subjects.  The Investigator will ensure the distribution of these documents to the 
applicable Ethics Committee, and to the study site staff.
The opinion of the Ethics Committee should be given in writing. The Investigator should 
submit the written approval to AstraZeneca/CRO before enrolment of any subject into the 
study.
The Ethics Committee should approve all advertising used to recruit subjects 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 protocol should be re-approved by the Ethics Committee 
annually.
Before enrolment of any subject into the study, the final 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/CRO will handle the distribution of any of these documents to the national 
regulatory authorities.
AstraZeneca/CRO will provide Regulatory Authorities, Ethics Committees and Principal
Investigators with safety updates/reports according to local requirements.
10.4
Informed consent
The Principal Investigator(s) at each centre will:

Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study


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
Ensure each subject is notified that they are free to discontinue from the study at any time

Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided

Ensure each subject 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 subject

Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects 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 Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment 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 revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see Section 10.3.
If a protocol amendment 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.
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
10.6
Audits and inspections
Authorised representatives of AstraZeneca/CRO, a regulatory authority, or an Ethics 
Committee may perform audits or inspections at the centre, 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 protocol, Good 


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Clinical Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), 
and any applicable regulatory requirements.  The Investigator will contact AstraZeneca/CRO 
immediately if contacted by a regulatory agency about an inspection at the centre.
11
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Clinical Study Protocol - 4.0 - Appendix A
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Appendix A
Signatures
Use e-signature instead of wet ink signature for CSP V3.0 and any subsequent versions.


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Appendix B
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject 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 
subject’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 subject 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 subject 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 (eg, 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.


Clinical Study Protocol - 4.0 - Appendix B
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
110 of 136

Time Course. Exposure to suspect drug. Has the subject 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.


Clinical Study Protocol - 4.0 - Appendix C
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
111 of 136
Appendix C
IATA 6.2 Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:

UN 3373 – Biological Substance, Category B 

are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations 

Clinical trial samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging  

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and packaging / 
containment materials at all times.  The IATA 650 biological sample containment 
standards are encouraged wherever possible when road or rail transport is used.


Clinical Study Protocol - 4.0 - Appendix D
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
112 of 136
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry
1.
INTRODUCTION
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.   
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Product (IP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
2.
DEFINITIONS
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).  
Hy’s Law (HL)
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (ie on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:


Clinical Study Protocol - 4.0 - Appendix D
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
113 of 136

ALT ≥ 3xULN 

AST ≥ 3xULN 

TBL ≥ 2xULN 
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative).  
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:

Notify the AstraZeneca representative 

Request a repeat of the test (new blood draw) by the central laboratory

Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result 
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the patient meets PHL criteria (see Section 2 of this Appendix for 
definition) by reviewing laboratory reports from all previous visits (including both central 
and local laboratory results) 
4.
FOLLOW-UP
4.1 Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will: 

Inform the AstraZeneca representative that the patient has not met PHL criteria. 

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.
4.2 Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team

The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent 
to this contact the Investigator will: 

Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms 
and signs return to normal or baseline levels, or as long as medically indicated 


Clinical Study Protocol - 4.0 - Appendix D
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
114 of 136

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician.  

Complete the three Liver CRF Modules as information becomes available  

If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures Perform follow-up on 
subsequent laboratory results according to the guidance provided in the Clinical Study 
Protocol.
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES
The instructions in this Section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IP.  
The AstraZeneca Medical Science Director and Global Safety Physician will also be involved 
in this review together with other subject matter experts as appropriate.   
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the AZ standard processes 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes.  

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 


Clinical Study Protocol - 4.0 - Appendix D
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
115 of 136

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above

Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review
6.
REFERENCES
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf
  


Clinical Study Protocol - 4.0 - Appendix E
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
116 of 136
Appendix E
COPD ASSESSMENT TEST (CAT)


Clinical Study Protocol - 4.0 - Appendix F
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
117 of 136
Appendix F
BDI-TDI


Clinical Study Protocol - 4.0 - Appendix F
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
118 of 136


Clinical Study Protocol - 4.0 - Appendix F
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
119 of 136


Clinical Study Protocol - 4.0 - Appendix F
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
120 of 136


Clinical Study Protocol - 4.0 - Appendix F
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
121 of 136


Clinical Study Protocol - 4.0 - Appendix F
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
122 of 136


Clinical Study Protocol - 4.0 - Appendix G
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
123 of 136
Appendix G
Saint George Respiratory Questionnaire (SGRQ)


Clinical Study Protocol - 4.0 - Appendix G
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
124 of 136


Clinical Study Protocol - 4.0 - Appendix G
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
125 of 136


Clinical Study Protocol - 4.0 - Appendix G
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
126 of 136


Clinical Study Protocol - 4.0 - Appendix G
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
127 of 136


Clinical Study Protocol - 4.0 - Appendix G
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
128 of 136


Clinical Study Protocol - 4.0 - Appendix H
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
129 of 136
Appendix H
EXACT-RESPIRATORY SYMPTOMS (E-RS)
Description 
Required Text 
Title  
EXACT Daily Diary 
DD 
Daily Diary 
Q 1 of 14 
Question 1 {1} of 14 
Instructions 
As you answer the following questions, please select the option that best describes your 
experience. 
1 
Did your chest feel congested today? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
2 
How often did you cough today? 
Not at all 
Rarely 
Occasionally 
Frequently 
Almost constantly 
3 
How much mucus (phlegm) did you bring up when coughing today? 


Clinical Study Protocol - 4.0 - Appendix H
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
130 of 136
Description 
Required Text 
None at all  
A little 
Some 
A great deal 
A very great deal 
4 
How difficult was it to bring up mucus (phlegm) today? 
Not at all   
Slightly   
Moderately   
Quite a bit   
Extremely   
5 
Did you have chest discomfort today? 
Not at all   
Slight   
Moderate   
Severe   
Extreme   
6 
Did your chest feel tight today? 
Not at all 


Clinical Study Protocol - 4.0 - Appendix H
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
131 of 136
Description 
Required Text 
 Slightly 
 Moderately 
Severely 
Extremely 
7 
Were you breathless today? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
8 
Describe how breathless you were today: 
Unaware of breathlessness 
Breathless during strenuous activity 
Breathless during light activity 
Breathless when washing or dressing 
Present when resting  
9 
Were you short of breath today when performing your usual personal care activities like 
washing or dressing? 
Not at all 
Slightly 


Clinical Study Protocol - 4.0 - Appendix H
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
132 of 136
Description 
Required Text 
Moderately 
Severely 
Extremely 
Too breathless to do these
10 
Were you short of breath today when performing your usual indoor activities like cleaning or 
household work? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
Too breathless to do these 
11 
Were you short of breath today when performing your usual activities outside the home such 
as yard work or errands? 
Not at all 
Slightly 
 
Moderately 
Severely 
Extremely 
Too breathless to do these 
12


Clinical Study Protocol - 4.0 - Appendix H
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
133 of 136
Description 
Required Text 
Were you tired or weak today? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
13 
Last night, was your sleep disturbed? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
14 
How scared or worried were you about your lung problems today? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
Copyright EXACT© 2013, Evidera, Inc. All rights reserved. 


Clinical Study Protocol - 4.0 - Appendix H
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
134 of 136
Training Material 
Recommended Text 
Standardized instruction given to patients with PDA 
training and with take-home instruction manual 
Please complete your diary every evening, just before 
you go to bed. 


Clinical Study Protocol - 4.0 - Appendix I
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
135 of 136
Appendix I
CHANGES RELATED TO MITIGATION OF STUDY 
DISRUPTIONS DUE TO CASES OF CIVIL CRISIS, 
NATUARAL DISASTER, OR PUBLIC HEALTH CRISIS
Note:  Changes below should be implemented only during study disruptions due to any of or a
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and
resulting site closures, regional travel restrictions and considerations if site personnel or study
patients become infected with SARS-CoV-2 or similar pandemic infection) during which
patients may not wish to or may be unable to visit the study site for study visits. These
changes should only be implemented if allowable by local/regional guidelines and following
notification from the sponsor and instructions on how to perform these procedures will be
provided at the time of implementation.
I 1 Pausing recruitment and screening of new patients
During a civil crisis, natural disaster, or public health crisis, AstraZeneca will approve the 
continuation of the enrolment and randomization or if those activities will need to be 
temporarily placed on hold until the disruption stabilizes in the area.
I 2 Re-scheduling of visits
If, for reasons related to a civil crisis, natural disaster, or public health crisis, a patient is not 
able to attend their scheduled visit within CSP visit window (± 3 days), they can have their 
visit rescheduled within 14 days of the original scheduled visit; however, visits that cannot be 
rescheduled within a 14 day window must be skipped and patient should continue at the next 
scheduled visit. All assessments that cannot be performed should be marked as not done. If a 
patient is not able to attend their scheduled visit due to reasons related to and is running out of 
IP, IP maybe delivered to the patient depending on where allowable as described in Section I5.
I 3 Reconsent of Study Patients During Study Interruptions
During study interruptions, it may not be possible for the patients to complete study visits and
assessments on site and alternative means for carrying out the visits and assessments may be
necessary, eg, remote visits. Reconsent should be obtained for the alternative means of
carrying out visits and assessments and should be obtained prior to performing the procedures
described in Sections I 4 to I 5. Local and regional regulations and/or guidelines regarding
reconsent of study patients should be checked and followed. Reconsent may be verbal if
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should
be signed at the patient’s next contact with the study site). Visiting the study sites for the sole
purpose of obtaining reconsent should be avoided.
I4 Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the patients using
telecommunications technology including phone calls, virtual or video visits, and mobile
health devices.


Clinical Study Protocol - 4.0 - Appendix I
AstraZeneca
Drug Substance Aclidinium bromide/ Formoterol fumarate
Study Code M-AS464-30 (AZ code: D6570C00002)
Date 08 Jul 2021
CONFIDENTIAL AND PROPRIETARY
136 of 136
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact
with the patients will allow adverse events and concomitant medication to be reported and
documented.
1 5 At-home delivery of Investigational Product
If a site visit is not possible, IP maybe delivered to the patients address subject to local laws. 
The option of home delivery of investigational product ensures patients safety in cases of a 
pandemic where patients may be at increased risk by traveling to the site/clinic.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: m-as464-30-csp-v4
Document Title:
M-AS464-30 Clinical Study Protocol version 4
Document ID:
Doc ID-002995633
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
27-Jul-2021 09:12 UTC
Author Approval
26-Jul-2021 16:10 UTC
Content Approval
22-Jul-2021 14:55 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan
Study Code
D6570C00002 (M-AS464-30)
Edition 
3.0
Date
06 May 2022
A 24-week Treatment, Randomised, Parallel-group, Double blinded, Double-
Dummy, Multicenter Study to Assess the Efficacy and Safety of Aclidinium 
bromide/Formoterol fumarate compared with Individual Components and 
Placebo 
and 
Aclidinium 
bromide 
compared 
with 
Placebo 
when 
Administered to Patients with Stable Chronic Obstructive Pulmonary 
Disease


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
2
A 24-week Treatment, Randomised, Parallel-group, Double blinded, Double-
Dummy, Multicenter Study to Assess the Efficacy and Safety of Aclidinium 
bromide/Formoterol fumarate compared with Individual Components and 
Placebo 
and 
Aclidinium 
bromide 
compared 
with 
Placebo 
when 
Administered to Patients with Stable Chronic Obstructive Pulmonary 
Disease
Study Statistician
Date


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
3
A 24-week Treatment, Randomised, Parallel-group, Double blinded, Double-
Dummy, Multicenter Study to Assess the Efficacy and Safety of Aclidinium 
bromide/Formoterol fumarate compared with Individual Components and 
Placebo 
and 
Aclidinium 
bromide 
compared 
with 
Placebo 
when 
Administered to Patients with Stable Chronic Obstructive Pulmonary 
Disease
Global Product Statistician
Date


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
4
A 24-week Treatment, Randomised, Parallel-group, Double blinded, Double-
Dummy, Multicenter Study to Assess the Efficacy and Safety of Aclidinium 
bromide/Formoterol fumarate compared with Individual Components and 
Placebo 
and 
Aclidinium 
bromide 
compared 
with 
Placebo 
when 
Administered to Patients with Stable Chronic Obstructive Pulmonary 
Disease
Biometrics Team Lead
Date


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
5
TABLE OF CONTENTS
TITLE PAGE........................................................................................................................................................1
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN..............................................................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN..............................................................................................3
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN..............................................................................................4
TABLE OF CONTENTS.........................................................................................................................................5
LIST OF ABBREVIATIONS ...................................................................................................................................8
AMENDMENT HISTORY...................................................................................................................................13
1
STUDY DETAILS......................................................................................................................................18
1.1
STUDY OBJECTIVES ................................................................................................................................. 18
Primary objectives .................................................................................................................... 18
Secondary objectives................................................................................................................. 19
Safety objectives....................................................................................................................... 19
1.2
STUDY DESIGN....................................................................................................................................... 20
1.3
NUMBER OF SUBJECTS ............................................................................................................................. 23
2
ANALYSIS SETS.......................................................................................................................................25
2.1
DEFINITION OF ANALYSIS SETS ................................................................................................................... 25
2.2
VIOLATIONS AND DEVIATIONS.................................................................................................................... 26
3
PRIMARY, SECONDARY, AND ADDITIONAL VARIABLES..........................................................................27
3.1
STUDY POPULATION................................................................................................................................ 27
Subject Disposition.................................................................................................................... 27
Demography............................................................................................................................. 28
Relevant Medical History and Physical Examination at Screening............................................... 28
Disease Characteristics at Screening.......................................................................................... 28
Prior, concomitant and post-treatment medications.................................................................. 30
Study Treatment Compliance .................................................................................................... 31
3.2
EFFICACY VARIABLES ............................................................................................................................... 32
Primary Efficacy Variables......................................................................................................... 32
Secondary Efficacy Variables..................................................................................................... 33
Additional Efficacy Variables..................................................................................................... 33
3.3
SAFETY VARIABLES.................................................................................................................................. 39
Extent of Exposure and Study Duration...................................................................................... 39
Adverse Events.......................................................................................................................... 40
Clinical Laboratory Tests ........................................................................................................... 42
Vital Signs................................................................................................................................. 46
Electrocardiogram .................................................................................................................... 47
3.4
ADDITIONAL INFORMATION ON COVID-19 .................................................................................................. 48


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
6
Disruption due to the COVID-19 Pandemic................................................................................. 48
4
ANALYSIS METHODS..............................................................................................................................49
4.1
GENERAL PRINCIPLES............................................................................................................................... 49
Study Estimands ....................................................................................................................... 49
Last IP Dose Date...................................................................................................................... 50
Descriptive Summary Statistics.................................................................................................. 50
Visits Reported and Statistical Comparisons for Efficacy ............................................................ 51
Other Statistical Considerations ................................................................................................ 51
4.2
SUMMARY OF STUDY POPULATIONS............................................................................................................ 52
Subject Disposition.................................................................................................................... 52
Demography and Baseline Characteristics................................................................................. 53
Prior and Concomitant Medication............................................................................................ 53
Study Compliance and Drug Accountability ............................................................................... 54
4.3
EFFICACY ANALYSIS................................................................................................................................. 54
Primary Efficacy Analysis........................................................................................................... 54
Secondary Efficacy Analyses...................................................................................................... 55
Analysis of Additional Efficacy Endpoints................................................................................... 56
4.4
MULTIPLICITY ADJUSTMENT STRATEGY ........................................................................................................ 60
4.5
SAFETY ANALYSIS.................................................................................................................................... 61
Exposure to Treatment.............................................................................................................. 61
Adverse Events.......................................................................................................................... 61
Laboratory Data, Vital Signs and ECG........................................................................................ 65
Drug Induced Liver Injury (DILI) and Possible Hy’s Law (PHL)...................................................... 66
4.6
STATISTICAL CONSIDERATIONS FOR ANALYSES................................................................................................ 66
Graphical Representations and Plots......................................................................................... 66
Selection of Spirometry Data (Best Test Review)........................................................................ 66
Repeated and unscheduled assessments or visits....................................................................... 66
Imputing Missing Event Dates................................................................................................... 67
Imputation of Missing Data....................................................................................................... 68
Professional duplicate subjects.................................................................................................. 70
4.7
SUBGROUP ANALYSES.............................................................................................................................. 70
4.8
SENSITIVITY ANALYSES ............................................................................................................................. 71
Multiple Imputation Models...................................................................................................... 72
Copy Reference (CR) Approach.................................................................................................. 73
4.9
COVID-19 ANALYSES ............................................................................................................................. 73
Disruption due to the COVID-19 Pandemic................................................................................. 73
5
INTERIM ANALYSIS ................................................................................................................................74
6
CHANGES OF ANALYSIS FROM PROTOCOL.............................................................................................74
7
REFERENCES...........................................................................................................................................76
8
APPENDICES...........................................................................................................................................77
8.1
APPENDIX 1: SCHEDULE OF ASSESSMENTS .................................................................................................... 77


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
7
8.2
APPENDIX  2: ALL IMPORTANT PROTOCOL DEVIATIONS (IPDS) WITH THOSE LEADING TO EXCLUSION FROM THE PER 
PROTOCOL ANALYSIS ........................................................................................................................................ 80
8.3
APPENDIX 3: BASELINE AND TRANSITION DYSPNOEA INDEXES (BDI & TDI) .......................................................... 90
8.4
APPENDIX 4: SGRQ QUESTIONNAIRE .......................................................................................................... 91
8.5
APPENDIX 5: COPD ASSESSMENT TEST (CAT) ............................................................................................ 103
8.6
APPENDIX 6: EXACT AND RAW SCORE ASSIGNMENT ..................................................................................... 105
8.7
APPENDIX 7: DERIVATION OF COPD EXACERBATIONS ................................................................................... 108
8.8
APPENDIX 8: ANNOTATED E-RS FOR RAW SCORE ASSIGNMENT....................................................................... 110
8.9
APPENDIX 9: SAS CODE FOR SUBGROUP ANALYSIS INCLUDING CONTRASTS OF HYPOTHESIS...................................... 113












Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
13
AMENDMENT HISTORY
Date
Brief description of change
Primary and secondary endpoints:
June 2021
As per CSP amendment (refer to ‘Version History (Version 4.0), 
Non-Substantial Changes to the Protocol’ in the CSP), sex was 
dropped from all statistical models for primary (section 4.3.1), 
secondary (section 4.3.2) and additional efficacy (section 4.3.3) 
endpoints.
COVID-19 related analyses:
June 2021

Section 2.2 updated to include protocol deviations related to 
COVID-19 pandemic.

Disposition categories (section 3.1.1) updated to include 
disposition events related to COVID-19 pandemic.

Additional section (section 3.4) added to define disruptions due to 
the COVID-19 pandemic.

Section 4.2.1 updated to reflect changes in the summary table of 
important protocol deviations to use new corporate pandemic 
table and listing shells

Description of table for study treatment compliance and drug 
accountability (section 4.2.4) updated to instruct to present 
treatment compliance for all subjects and also separately for 
subjects affected and not affected by COVID-19.

New section 4.9 added detailing COVID-19 related analyses to be 
performed. These analyses are in alignment with AZ corporate 
pandemic TLF shells. 

Section 8.2 (appendix 2) updated to included IPDs related to 
COVID-19.
May 2022

Section 4.2.4 updated to include information on identifying 
adverse events of suspected/confirmed COVID-19 (required for 
producing table of study treatment compliance in subjects 
affected by COVID-19).


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
14
Minor changes to derivations and TLFs
June 2021

Derivation of expected overall intake of study medication (section 
3.1.6) updated to use the first day the question on IP dose intake 
is activated in the e-diary after randomisation instead of Day 1 for 
subjects for whom a randomisation date had not been entered into
the device.

Derivation of E-RS and use of daily rescue medication (section 
3.2.3.4) updated to instruct to exclude last IP dose date for clarity.

A list of specific ECG parameters that can be flagged as 
potentially clinically significant has been added to section 3.3.5.

QTcB parameter has been added to ECG notable abnormality 
criteria in table 3.5 (section 3.3.5).

For subject disposition (section 4.2.1), denominators have been 
clarified for the table of subject recruitment by country and centre 
for the calculations of percentages for country and for centre. 

For demography and baseline characteristics (section 4.2.2), the 
denominator to be used for calculation of percentages in all tables 
has been clarified.

For demography and baseline characteristics (section 4.2.2), 
specific parameters to be summarised for lung function data at 
screening have been added for clarity and the baseline definition 
added.

Reference to table of disallowed medication has been removed 
from the prior and concomitant medication section (section 4.2.3) 
as this table will no longer be presented.

Descriptions of the following adverse event tables (section 4.5.2) 
updated to remove inclusion of the number of TEAEs/related 
events in the top row of the table for consistency with AZ 
corporate standards: Most comment TEAEs (frequency of >1%); 
TEAEs by SOC, PT and maximum reported intensity; TEAEs by 
SOC, PT and investigator’s causality assessment; TEAEs by 
SOC, PT and outcome.

Sorting order for table of non-serious TEAEs occurring in greater 
than 5% of subjects (section 4.5.2) updated to sort alphabetically 
by SOC and PT rather than alphabetically by SOC only. This is as 
per AZ corporate standards.

The sort order for the following adverse event tables (section 
4.5.2) has been updated to align with AZ corporate standards 
(sorting by international order for system organ class and 
alphabetically for preferred term): TEAEs by SOC and PT; 
TEAEs by SOC, PT and maximum reported intensity; TEAEs by 
SOC, PT and investigator’s causality assessment; TEAEs by 
SOC, PT and outcome; Non-serious TEAEs occurring in greater 
than 5% of subjects. For tables of AESIs and MACE by SMQ, 


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
15
SOC and PT, the sort order has been updated to alphabetically for 
SMQ, international order for SOC and alphabetically for PT.

For ECG (section 4.5.3), a new table has been added for the 
number and percentage of ECG abnormal findings not present at 
baseline.

Laboratory data, vital signs and ECG section (section 4.5.3) 
updated to include new listings of TEAEs for subjects with PCS 
values for lab data, vital signs and ECG.

Laboratory data, vital signs and ECG section (section 4.5.3) 
updated to include the following new lab and ECG tables/listings: 
number and percentage of subjects with a result classified as 
abnormally clinically relevant by the investigator (table); TEAEs 
for subjects with abnormal clinically relevant results (listing). 
Additionally, for ECG, a table displaying the distribution of the 
Global evaluation from the cardiologist has been added.

BMI removed as a subgroup for the subgroup analyses in section 
4.7 (and from the SAS code in section 8.9, Appendix 9) as per the 
Changes of Analysis from Protocol table (section 6). This change 
was implemented due to concerns of insufficient numbers in 
some BMI categories in a Chinese population.

Forest plot described in the subgroup analyses section (section 
4.7) updated to additionally present LS mean differences and 95% 
CIs to the right of the plot and number of subjects in each 
subgroup for a given treatment group with the corresponding 
change from baseline LS mean estimate at Week 24 to the left of 
the plot.

For the derivation of TDI focal score, section 8.3 (appendix 3) 
has been updated to clarify only to calculate when all TDI 
components are non-missing.

Section 8.7 (appendix 7) updated to clarify that only one of the 3 
required data points needs to be present when calculating the 3-
day rolling average of the EXACT daily scores. 

Section 8.7 (appendix 7) updated to clarify that recovery from 
exacerbation can occur on a day where an EXACT Daily Score is 
missing, but it has been possible to calculate an EXACT Rolling 
Score.
May 2022

Derivations of time since last COPD exacerbation and time since 
last hospitalization due to a COPD exacerbation updated to 
remove ‘+1’ from the derivation, since these events occur before 
first IP dose.

Section 4.2.2 updated to instruct to also produce summaries of 
demographic, subject and disease characteristics for the ITT 
population.


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
16

Severity/intensity of HCRU exacerbations, defined in Section 8.7 
(appendix 7), updated to be consistent with CSP. 

General statement added to section 4.3.3.3 instructing to combine 
countries where the planned number of subjects is <5% (or n<=13 
subjects per treatment group) for all models of COPD 
exacerbations.

Section 4.3.3.3 on Analysis of COPD exacerbations updated to
clarify that countries with a small number of subjects may be 
combined to address issues of non-convergence in the logistic 
regression model.
Other minor changes:
June 2021

Removed instruction in section 3.1.5 to flag ICS as a disallowed 
mediation for Chinese subjects as disallowed medications are no 
longer presented.

Section 3.2.3.3 on COPD exacerbations updated to list COPD 
exacerbation efficacy variables and their definitions separately for 
HCRU and EXACT.

Preferred terms for ‘unequal pupils’ and ‘edemas peripheral’ have 
been corrected to ‘pupils unequal’ and ‘oedema peripheral’ 
respectively in definition of AESI table (table 3.2; section 3.3.2).

MedDRA version has been removed from footnote of definition 
of AESI table (table 3.2; section 3.3.2).

For descriptive summary statistics (section 4.1.3), further 
instructions on precision have been added, including the 
following: no decimal places (dp) should be presented for 
percentages of exactly 100%; round all summary statistics in PFT 
tables and lab tables to 3dp and 2dp respectively.

Sorting order for the medical and surgical history at screening 
tables in the demography and baseline characteristics section 
(section 4.2.2), has been updated to sort alphabetically by SOC 
and PT rather than alphabetically by SOC and decreasing 
frequency of PT. This is as per AZ corporate standards.

Description of tables related to prior COPD-related treatment, 
prior, concomitant and post-treatment medications in section 
4.2.3 updated to refer to generic term rather than preferred term.

Instruction to use the Breslow approach for handling tied 
observations in the Cox proportional hazards model for time to 
first COPD exacerbation added to section 4.3.3.3.

The definition of ‘at any visit’ in the section on laboratory data, 
vital signs and ECG (section 4.5.3) has been updated for clarity.

Description of listing of key subject information for subjects with 
a treatment emergent PCS abnormality in haematology or 
biochemistry (section 4.5.3) updated to instruct to also flag values 
classed as clinically significant, as assessed by the investigator.


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
17

The handling of repeated and unscheduled assessments/visits 
(section 4.6.3) for efficacy analyses has been updated to clarify to 
exclude unscheduled/premature discontinuation data from 
statistical analyses for all efficacy data (excluding COPD 
exacerbations), rather than just for spirometry data.

Instruction to use CONTRAST statement in the PROC MIXED 
for the subgroup analyses (section 4.7) has be changed to use the 
LSMESTIMATE statement.

Further instructions for the ordering of variables within the VAR 
statement of the PROC MI for imputing non-monotone missing 
primary and secondary efficacy data (section 4.8.1) has been 
added for clarity.

Section on the copy reference approach (4.8.2) for multiple 
imputation of missing primary and secondary efficacy data 
updated to include and correct treatment arms of interest and 
corresponding reference arm to be used for all primary and 
secondary efficacy outcomes. 

SAS code in section 8.9 (appendix 9) updated to reflect change to 
use LSMESTIMATE statement from CONTRAST statement.
May 2022

The definition of ‘at any visit’ in the section on laboratory data, 
vital signs and ECG (section 4.5.3) has been reverted back to the 
original definition, as per edition 1.0 of the SAP.






Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
20
To assess the safety profile of Aclidinium 
Bromide 400 compared to placebo
Adverse events
Clinical laboratory evaluations (haematology, 
biochemistry and serum pregnancy test)
Blood pressure
ECG
1.2 Study Design
This is a 24-week treatment, multiple dose, randomised, parallel-group, double-blind, double-
dummy, multicentre and multinational Phase III superiority trial. Enrolling countries are: China, 
India, Philippines, Taiwan and Vietnam.
The target population comprises males and non-pregnant/non-lactating females:

Aged ≥40;

Current or former smokers, with a cigarette smoking history of ≥10 pack-years;

With a diagnosis of COPD prior to Visit 1 (screening) and a moderate-to-severe stage 
and stable airway obstruction (Global Initiative for Chronic Obstructive Lung Disease
[GOLD], 2015): screening post-bronchodilator test FEV1/forced vital capacity (FVC) < 
70% and with FEV1 ≥ 30% and < 80% of the predicted normal value.
For further inclusion and exclusion criteria please refer to the Clinical Study Protocol (CSP).
The total duration of the trial for each patient is scheduled for approximately 28 weeks, 
including a run-in period of two weeks, followed by 24-week treatment period, and a final 
follow-up contact two weeks after last study dose. The study flow chart is shown in Figure 1-1, 
and details about the schedule of assessments are reported in Appendix 1. 
Following a washout period for prohibited medication (with the duration varying from one day 
to one month, depending on the prohibited drug as per CSP), all subjects who have signed the 
informed consent form (ICF) will undertake a screening visit (Visit 1). At Visit 1, inclusion and 
exclusion criteria will be checked in terms of patient’s medical history (including surgical, 
COPD and smoking history), review of prior medication, a physical examination, laboratory, 
vital sign and ECG measurements, and pulmonary function tests (spirometry forced manoeuvre 
and bronchodilator test). 
Subjects fulfilling all inclusion/exclusion criteria at the time of the screening visit and who have 
done the required washout period of prohibited medication will enter a 14-day run-in period to 
assess patient’s disease stability and baseline characteristics. At Visit 2, eligible subjects will 
be randomised and will start receiving the investigational product (IP). 
Randomisation will be performed by strata using an Interactive Web-response System (IWRS). 
The stratification factors will be smoking status (current smokers vs. former smokers) and 
country (China, India, Philippines, Taiwan and Vietnam). Within each stratum, subjects will be 
randomised in a ratio 1:1:1:1 to one of the following 4 treatment arms:






Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
23
1.3 Number of subjects
Approximately 1515 patients will be screened in this study in order to achieve 1060 
randomised patients, considering an estimated ineligibility rate of 30% prior to
randomisation.
Based on previous data, a sample size of 265 randomised patients per group will
provide at least 90% power to detect a statistically significant difference at week 24
of 100 mL between Aclidinium bromide 400 µg/Formoterol fumarate 12 µg and
Aclidinium bromide 400 μg in change from baseline at 1-hour morning post-dose
FEV1, 65 mL between Aclidinium bromide 400 µg/Formoterol fumarate 12 µg vs
Formoterol fumarate 12 μg in change from baseline morning pre-dose (trough)
FEV1, 100 mL between Aclidinium bromide 400 μg vs placebo in trough FEV1, and
175 mL between Aclidinium 400 μg vs. placebo in peak FEV1. Previous studies on
the same drug and for the same spirometric endpoints showed a standard deviation of
230 mL
The sample size is driven by the comparison between Aclidinium bromide/Formoterol 
fumarate 400/12 μg vs. Formoterol fumarate 12 μg in morning pre-dose FEV1, and the 
minimal detectable difference is 39 mL.
The same sample size will provide at least 90% power to detect a statistically
significance difference at week 24 of at least 1-unit between Aclidinium bromide 400
µg/Formoterol fumarate 12 µg and Aclidinium bromide 400μg vs placebo in TDI
focal score, assuming a SD of 3.5-units, and at least 4-unit difference in change from
baseline in SGRQ total score assuming a SD of 13.5-unit for the same treatment
comparisons.
All tests will be performed using two-sided tests at 5% significance level.
Nominal powers for primary and secondary efficacy variables are as follow:


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
24
Step
Endpoint
Treatment Comparison
Nominal
power (%)
Primary Endpoints
1
1-hour post-dose FEV1
Aclidinium bromide/Formoterol 
fumarate 400/12 μg vs.
Aclidinium bromide 400 μg
99
2
Morning pre-dose FEV1
Aclidinium bromide/Formoterol 
fumarate 400/12 μg vs.
Formoterol fumarate 12 μg
90
3
Morning pre-dose FEV1
Aclidinium bromide 400 μg vs.
placebo
99
Secondary Endpoints
4
Peak FEV11
Aclidinium bromide 400 μg vs.
placebo
99
5
TDI
Aclidinium
bromide/Formoterol fumarate
400/12 μg vs. placebo
90
6
TDI
Aclidinium bromide 400 μg vs.
placebo
90
7
SGRQ
Aclidinium
bromide/Formoterol fumarate
400/12 μg vs. placebo
92
8
SGRQ
Aclidinium bromide 400 μg vs.
placebo
92
The order of the hierarchy of endpoints and treatment comparisons is detailed in Table 4-1.




Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
26
All randomised subjects (a total of 9 subjects) from study site 3512  will be excluded from the 
ITT and PP analysis sets due to significant deviations, which question the validity and 
integrity of the trial data generated from this site.  These subjects will be included in the safety 
analysis set. Primary efficacy variables will be listed.
2.2 Violations and Deviations
The complete list of current protocol deviations (PDs) can be found in the Protocol Deviation 
Specification Form (PDS). This also includes PDs whose occurrence was impacted by the 
COVID-19 pandemic.
PDs will be considered as Important Protocol Deviations (IPDs) if may significantly impact 
the completeness, accuracy, and/or reliability of the study data or that may significantly affect 
a subject’s rights, safety, or well-being, including the following:

Key eligibility criteria not fulfilled but randomized

Have insufficient study compliance (<70%)

Withdrawal criteria fulfilled during the study but not withdrawn 

Incorrect study treatment or study dose received at any time during the treatment period 

Concomitant use of disallowed medications 

Other reasons which are identified by the study team as important.
Appendix 2 contains the full list of IPDs with flags to those which may result in the exclusion 
of a subjects from the PP analysis set. This includes IPDs related to COVID-19.
The final list of IPDs and the ones leading to a PP exclusion will be documented by the study 
team during a joint blind clinical review of data listings prior to Database Lock (DBL) and 
treatment unblinding (Blind Data Review Meeting - BDRM). Reasons for the PP exclusions 
will be documented in the BDRM minutes and a summary table and a listing will be produced 
by the categories of IPDs and by treatment group for the Clinical Study Report (CSR) as an 
appendix. Non-important PDs related to the COVID-19 pandemic will be listed separately.


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
27
3
PRIMARY, SECONDARY, AND ADDITIONAL VARIABLES
In this section, all study variables are described and/or derived. 
3.1 Study Population
Study population summaries will include subject dispositions, demographic and baseline 
characteristics, medical history and physical examination at screening, disease characteristics at 
screening, prior, concomitant, and post-treatment medications, and treatment compliance. 
Subjects are recruited in China, India, Philippines, Taiwan and Vietnam. 
Subject Disposition
For each subject, the following disposition categories will be either collected in the Electronic 
Data Capture (EDC) system or derived:

Enrolment status (Enrolled if subjects signed the ICF). 

Randomization Status (Randomized, Not-Randomized) and Reason for not being 
randomised (Screen failure [non-fulfilment of inclusion/exclusion criteria], Adverse 
event, Progressive disease, Withdrawal by subject, Lost to follow-up, Pregnancy, 
Other).

Treatment Received (Treatment Received, Treatment Not Received) and Reason for not 
receiving treatment (Adverse event, Progressive disease, Lack of efficacy, Protocol 
deviation, Pregnancy, Withdrawal by Subject, Lost to Follow-up, Other).

Treatment Completion Status (Treatment Completed, Treatment Discontinued) and 
Reason for Premature Discontinuation from the EOT Form (Adverse Event, Progressive 
Disease, Lack of efficacy, Protocol Deviation, Pregnancy, Withdrawal by Subject, Lost 
to Follow-up, Other). Discontinuation of treatment due to the COVID-19 pandemic will 
be recorded via a tick-box added to a new page in the EDC for any affected subjects.

Study Completion Status (Study Completed, Study Withdrawn) and Reason for Study 
Withdrawal from the EOS Form (Adverse event, Progressive disease, Protocol 
deviation, Pregnancy, Withdrawal by Subject, Lost to follow-up, Other). Withdrawal 
from the study due to the COVID-19 pandemic will be recorded via a tick-box added to 
a new page in the EDC for any affected subjects.

Follow-up contact Status (Follow-up contact made 14 days after last dose) after Week 
24 (Visit 7) completed or when discontinued without going through the post-IP follow-
up).
Subjects who complete the study are either subjects who made the Visit 7 (regardless of 
whether they made the follow-up phone contact at Week 26), or subjects who prematurely 
discontinue treatment but complete the post-treatment follow-up period until Visit 7 as it 
states in the EOS Form.


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
28
Demography
Demographic and subject characteristics (country, age, sex, race and ethnic population) will be 
collected at Screening (Visit 1). The subject characteristics height and weight will be collected 
as part of the subject physical examination. 
The following variables will be derived: 

Age categorized (age group) as: ≥40 - <60; ≥60 - <70; ≥70.

Body Mass Index (BMI) will be derived as continuous variable as weight in Kg divided 
by height in meter squared (Kg/m2) and categorized (BMI group) as: Underweight 
(<18.5), Normal weight (≥ 18.5 and < 25), Pre-obese (≥ 25 and <30) and Obese (≥ 30).
Relevant Medical History and Physical Examination at Screening
Relevant medical history will be collected at Screening (Visit 1) and coded using the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. 
A complete physical examination will be performed at Visit 1 and Visit 7. Relevant findings 
detected in physical examination at Visit 1 will be recorded under Medical History and those 
found at Visit 7 will be recorded under AE. Recorded medical History data will be split as 
medical history and surgical history. Based on whether these conditions are ongoing at the time 
of randomisation as recorded on the electronic case report form (eCRF), these conditions will 
be categorized as past (prior to screening) or current (ongoing at time of screening). 
Disease Characteristics at Screening
The study population will be described using disease characteristics. 
Smoking history at screening visit: 

Smoking status (current smoker/former smoker)

Smoking consumption (number of pack-year)

Smoking duration 
o
Smoking duration (years): For former smokers is the difference between the year 
they stopped smoking and the year they started to smoke +1, and for current 
smokers the difference between the year of the screening visit and the year they 
started to smoke +1.
COPD history at screening visit:

COPD severity derived per the 2015 GOLD classification of airflow limitation (using 
the post-bronchodilator FEV1):
o Stage I (mild): FEV1 ≥ 80% of the predicted normal values
o Stage II (moderate): FEV1 ≥ 50% and < 80% of the predicted normal values
o Stage III (severe): FEV1 ≥ 30% and < 50% of the predicted normal values
o Stage IV (very severe): FEV1 < 30% of the predicted normal values


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
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
COPD severity derived per the GOLD classification of symptoms based on the COPD 
Assessment Test (CAT) at Baseline (Visit 2) and risk of exacerbation as collected in 
COPD history at Screening (Visit 1):
o A: CAT Score<10, and ≤ 1 exacerbation not requiring hospitalization in the 
previous 12 months
o B: CAT Score ≥10, and ≤ 1 exacerbation not requiring hospitalization in the 
previous 12 months
o C: CAT Score <10, and ≥2 exacerbations or ≥1 exacerbation requiring 
hospitalization in the previous 12 months
o D: CAT Score ≥10, and ≥2 exacerbations or ≥1 exacerbation requiring 
hospitalization in the previous 12 months

COPD duration (years), will be computed as the year of screening visit and the year of 
diagnosis of COPD + 1

Number of COPD exacerbations in the previous 12 months

Time (days) since last COPD exacerbation, calculated as the difference between the 
date of resolution of last COPD exacerbation and the screening visit date

Time (days) since last hospitalization due to a COPD exacerbation, calculated as the 
difference between the date of resolution of last COPD exacerbation and 
the screening visit date

Chronic bronchitis and/or emphysema (yes/no)
Pulmonary function tests at screening visit:

Absolute values of FEV1 and FVC pre- and post-bronchodilator

Percent of predicted FEV1, and FVC pre- and post-bronchodilator

Ratio FEV1/ FVC (post- bronchodilator test)
Bronchodilator test:

Mean absolute bronchodilator change and percentage of bronchodilator reversibility in 
FEV1
o Mean absolute bronchodilator change is the difference between pre- and post-
bronchodilator FEV1 values
o The percentage of bronchodilator reversibility will be computed as: (Mean absolute 
bronchodilator change / Pre-bronchodilator FEV1) x100.

Percentage of subjects with bronchial reversibility (an increase in FEV1 that is both ≥
200 mL and 12% above the pre-bronchodilator FEV1)
Baseline values at Day 1 (visit 2):

Pulmonary function tests pre-IP at baseline 
o Absolute values of FEV1, and FVC
o Percent of predicted FEV1, and FVC

Signs and symptoms of health-related quality of life


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o Total score of SGRQ and scores of the three dimensions 
o Total score of Baseline Dyspnoea Index (BDI) and scores of the three components
o CAT (total) score
Prior, concomitant and post-treatment medications
Prior and concomitant medication will be collected by the investigator at each study visit using 
the information in the patient paper diaries. 
Medications will be coded according to the latest World Health Organization (WHO) drug 
dictionary. 
Prior medications:

As recorded on the eCRF, includes any medication taken between 15 days prior to the 
ICF and the date of first IP dose, and will be summarised using the two categories below:
o Any medication taken within 15 days prior to the ICF (included)
o Any prior medication taken after the date of the ICF (excluded) to the day before the 
first IP dose (included)
Concomitant medications:

Any drug that starts on or after the first IP dose up until the last IP dose (excluded) or 
started before the first IP dose and continued during the IP treatment period. 
Post-treatment medication:
For subjects that discontinue from the IP and accept to participate in the post-treatment follow-
up period 

Any drug collected during the follow-up period after last IP dose date. 
Due to a change in the Chinese pharmacopeia, Chinese subjects randomised after the 30th May 
2018 will not be allowed to use any ICS as concomitant maintenance therapy (see clarification 
letter on March 23rd, 2018). 
Prior COPD-related treatment
Prior medication indicated for COPD only will be any medication for COPD taken prior to the 
ICF. Medications taken for COPD prior to the ICF signature will be identified as ‘Prior 
COPD-related Treatment’ and coded using the latest version of the AstraZeneca Barcelona
COPD Standardised Drug Grouping (AZBC SDG) and categorized into the following 
therapeutic categories:


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
 
 
 
 
 
 
 
 
 
 
 

Short-acting β2 agonists (SABA)*;  

Short-acting muscarinic antagonists (SAMAs)*; 

SABA + SAMA (FDC)*;

Long-acting β2 agonists (LABA) *; 

Long-acting muscarinic antagonists (LAMA) *;

LABA + LAMA (FDC)*; 

Inhaled corticosteroids (ICS)*; 

SABA + ICS (FDC) *;

LABA + ICS (FDC) *;

LAMA + ICS (FDC) *;

LAMA + LABA + ICS (FDC) *;

Muscarinic antagonist β2 adrenoceptor agonist (MABA);

Systemic corticosteroid; 

Xanthines; 

Leukotriene modifiers; 

Oxygen; 

Oral phosphodiesterase type 4 (PDE4); 

Influenza vaccine;

Cromones;

Monoclonal Antibody;

Others
All the above prior-COPD related treatment combinations are intended as FDC. For those 
medications marked with an asterisk, if subjects take more than one monotherapies or 
fixed-dose combinations forming a higher AZBC SDG therapeutic category, drugs will 
be combined and re-categorised to the maximum free-dose (free) drug combination 
(regardless of whether they are taken concomitantly to each other). For example, LABAs 
and LAMAs taken by the same subject as prior COPD-related treatment will be grouped 
into a new LABA + LAMA (free) category; subjects taking both an ICS + LABA (FDC) 
and a LAMA will be re-categorised into the LAMA + LABA + ICS (free) category. If a 
patient has taken any medications, it will be flagged in the patient data listing. See the 
programming Specs for the different groups.
Baseline ICS use will be flagged in the patient data listings for those subjects who use 
any ICS between Screening (Visit 1) and the first IP dose.
Study Treatment Compliance
The variables for treatment compliance are:

Compliance with study treatment for Genuair 

Categorised compliance with study treatment for Genuair (Yes/No)

Compliance with study treatment for Turbuhaler

Categorised compliance with study treatment for Turbuhaler (Yes/No)

Overall compliance (%) with study treatment 

Categorised overall compliance with study treatment (Yes/No)


Statistical Analysis Plan 
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A patient to be compliant they should have ≥70% compliance regardless of the inhaler. 
For overall compliance, the patient should be compliant with each of the inhalers 
Compliance with study medication will be based on the study medication usage recorded 
by the patient in the bedtime e-diaries. Compliance (%) will be calculated for each device 
(Genuair and Turbuhaler) and overall as follows:
	 
verall intake
Expected overall  ∗100
where:

Actual overall intake = sum of the daily numbers of puffs taken as recorded in the 
e-diary from Day 1 until the second-to-last IP dose day (because the morning IP 
dose of the very last day is not included in the e-diaries). For subjects 
discontinuing on Day 1 or Day 2, the actual overall intake will be the numbers of 
puffs taken on Day 1 as recorded on their e-diary.  

Expected overall intake = 2 puffs times the number of days between Day 1  (or 
the first day the question on IP dose intake is activated in the e-diary after 
randomisation) and the second-to-last IP dose day. For subjects discontinuing on 
Day 1 or Day 2, the expected overall intake will be 2 puffs.  
The overall treatment compliance for both inhalers will be calculated as the average of 
the compliance rates of the two inhalers.
Drug accountability consists of the information on the provision and collection of the IP 
kits as recorded on the eCRF. Inhalers will be dispensed at Day 1 (Visit 2) and Week 12 
(Visit 5) and will be collected at Week 12 (Visit 5) and Week 24 (Visit 7)/EOT. Drug 
accountability only includes information regarding the number of inhalers dispensed 
and collected as well as their status (used/unused/lost).
3.2 Efficacy Variables
The efficacy measurements are recorded in the study schedule in Appendix 1. 
Primary Efficacy Variables
The primary efficacy variables and comparisons are the following:

Change from baseline in 1-hour morning post-dose FEV1 at Week 24 for 
comparison of AB/FF 400/12 and AB 400

Change from baseline in morning pre-dose (trough) FEV1 at Week 24 for the 
comparison of AB/FF 400/12 and FF 12

Change from baseline in morning pre-dose (trough) FEV1 at Week 24 for the 
comparison of AB 400 and placebo
Trough FEV1 will be computed as the average of the two FEV1 values at morning pre-
dose. If one value is missing, then the remaining one will be used as the trough value. 


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
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Date: 06 May 2022
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Baseline of FEV1 is defined as the average of the two FEV1 values prior to the 
administration of the first dose of IP on Day 1. If one of the two values is missing, then 
the available one will be used as baseline value. If both values are missing, the Screening 
pre-bronchodilator value will be used as the baseline. Otherwise, the baseline value will 
be considered as missing.
The changes from baseline are calculated as:

Change from Baseline = Post-dose Visit Value – Baseline
Secondary Efficacy Variables
The secondary efficacy variables and comparisons are the following:

Change from baseline in peak FEV1 at Week 24 for the comparison of AB 400 
and placebo

Improvement in TDI focal score at Week 24 for the comparison of AB/FF 400/12 
and placebo

Improvement in TDI focal score at Week 24 for the comparison of AB 400 and 
placebo

Change from baseline in SGRQ total score at Week 24 for the comparison of 
AB/FF 400/12 and placebo 

Change from baseline in SGRQ total score at Week 24 for the comparison of AB 
400 and placebo 
TDI focal score is recorded as a comparison to BDI and no further derivation is required 
for ‘Improvement in TDI’. The derivation of TDI focal score is given in Appendix 3.
Derivations for total score of SGRQ is given in Appendix 4. The baselines for SGRQ is  
the corresponding score derived from the data recorded on Day 1. If this score is missing, 
the baseline is considered as missing.
Peak FEV1 is the highest value of FEV1 recorded at that visit after the morning IP intake.
The change from baseline for SGRQ and FEV1 variables are derived as:

Change from Baseline = Post-dose Visit Value – Baseline
Additional Efficacy Variables
3.2.3.1
Pulmonary Function Test (PFT)
The additional PFT efficacy variables are:

Changes from baseline in 1-h morning post-dose FEV1 at Day 1 and Weeks 1, 4, 
12, 18, and over 24 weeks on treatment

Changes from baseline in morning pre-dose (trough) FEV1 at Weeks 1, 4, 12, 18, 
and over 24 weeks on treatment

Changes from baseline in peak FEV1 at Day 1 


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
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
Changes from baseline in normalized Area Under the Curve (AUC) from 0 to 3 
hours (nAUC0-3h) FEV1 at Day 1, and Week 24 

Absolute values and changes from baseline in FEV1 at all visits by timepoint 

Changes from baseline in 1-h morning post-dose FVC at Day 1 and Weeks 1, 4, 
12, 18, 24, and over 24 weeks on treatment

Changes from baseline in morning pre-dose (trough) FVC at Weeks 1, 4, 12, 18, 
24, and over 24 weeks on treatment

Changes from baseline in peak FVC at Day 1 and Week 24 

Changes from baseline in normalized AUC from 0 to 3 hours (nAUC0-3h) FVC at 
Day 1, and Week 24 

Absolute values and changes from baseline in FVC at all visits by timepoint 

Percentage change from baseline in 1-hour post-dose FEV1 at Day1, at Weeks 1, 
4, 12, 18, 24, and over 24 weeks on treatment

Percentage change from baseline in morning pre-dose (trough) FEV1 at Week 1, 
4, 12, 18, 24, and over 24 weeks on treatment

Percentage change from baseline in 1-hr post-doe FVC at Day1, at Weeks 1, 4, 
12, 18, 24, and over 24 weeks on treatment

Percentage change from baseline in morning pre-dose (trough) FVC at Weeks 1, 
4,  12, 18, 24, and over 24 weeks on treatment
The baseline value for all the FEV1 variables are the same as defined for the primary 
efficacy variables. The baseline for FVC variables are derived similarly using the values 
at morning pre-dose values or, if they are missing, using Screening value. The changes 
from baseline are calculated similar to the primary efficacy variables.
The mean normalized AUC from 0 to 3 hours for FEV1 is derived using the following 
trapezoidal method formulae using time in hours: 
!"#$%& '()* =
1
, −#
./0 −0$*1 ∗
('()*(0) + '()*(0$*))
2
,
06*
where tj(j = 0,1,2,3,4,5 for trough, 5 min, 30 min, 1h, 2h, and 3h, respectively) is the time 
(in hours) at the timepoint j at which FEV1 is measured. The FEV1 at timepoint j=0 is the 
trough FEV1 (and t0 = 0). Note: on Day 1, this will be the baseline value.
At least two FEV1 values must be available, one of which must be the trough FEV1 and 
one FEV1 value between 2h and 3h post-dose (extremes included). Otherwise, the nAUC0-
3h will be considered missing. 
For the derivation of AUC, all actual timepoints should be used, and should be given in 
hours. 
The nAUC0-3h for FVC at Day 1 and Week 24 will be derived similarly.


Statistical Analysis Plan 
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Date: 06 May 2022
35
3.2.3.2
Signs and Symptoms and Health-related Quality of Life
The BDI and TDI focal scores are derived together with the 3 following components:
-
Functional impairment: the impact of breathlessness on the ability to carry out 
activities
-
Magnitude of task: the type of task that causes breathlessness
-
Magnitude of effort: the level of effort needed to evoke breathlessness
The SGRQ total scores are derived together with the following dimensions:
-
Symptoms: the effect of respiratory symptoms, their frequency and severity
-
Activity: activities that cause or are limited by breathlessness
-
Impact: a range of aspects concerned with social functioning or psychological 
disturbances resulting from airways disease
The CAT is an 8-item questionnaire and the CAT score (total) has a scoring range of 0-
40.
The higher scores of SGRQ and CAT indicate a greater deterioration of the COPD 
symptoms on the patient health status. A positive score in TDI indicates an improvement 
which increases with the value of score while a negative score indicates a deterioration 
which deteriorates further with the decrease of score value. The derivation of BDI and 
TDI focal scores and their three component-scores are detailed in Appendix 3. Details 
about the SGRQ questionnaire is given in Appendix 4. The CAT questionnaire is given 
in Appendix 5. 
The baseline for TDI is BDI. The baselines for SGRQ and CAT scores will be the 
corresponding score derived for the questionnaire data recorded on Day 1. If derived 
score on Day 1 is missing, the baseline is considered as missing. 
The Minimum Clinically Important Differences (MCID) are:
-
TDI Focal Score: + 1 unit 
-
SGRQ Total Score: a reduction from baseline of at least 4 units 
-
CAT Total Score: a reduction from baseline of at least 2 units 
The additional BDI/TDI, SGRQ and CAT efficacy variables are:

Improvements in TDI focal score at Weeks 4 and 12 and three component scores 
at Weeks 4, 12, 24, and over 24 weeks on treatment.

Number (%) of subjects who achieved a clinically meaningful difference in TDI 
focal score (improvement of ≥1 unit) at Weeks 4, 12, and 24.

Change from baseline in SGRQ total score at Weeks 4 and12 and three 
dimension scores at Weeks 4, 12, 24, and over 24 weeks on treatment.

Number (%) of subjects achieving a clinically meaningful improvement (≥4 
units) compared with baseline in SGRQ total score at Weeks 4, 12, and 24.


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
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
Change from baseline in the CAT score at Weeks 4, 12, 24, and over 24 weeks 
on treatment.

Number (%) of subjects achieving a clinically meaningful improvement (≥2 
units) in CAT score at Weeks 4, 12 and 24.
3.2.3.3
COPD Exacerbations
COPD exacerbations will be derived using the Health Care Resource Utilization (HCRU) 
and the EXACT tool. 
HCRU exacerbations are derived based on the information recorded in the Adverse Event 
module of the eCRF. The date of onset and date of resolution will be extracted from eCRF 
data.
EXACT questionnaire is completed by subjects every study day before bed and has 14 
questions. The EXACT Total score is computed across the 14 items and has a range of 0 
to 100, with higher values indicating a more severe condition  (Appendix 6). The onset 
date of a new EXACT exacerbation is the first day of the worsening of the baseline 
condition, where worsening is defined by an increase from baseline in the EXACT Daily 
Score of either ≥ 12 points for 2 consecutive days, or ≥ 9 points for 3 consecutive days. 
The date of onset and date of resolution for the exacerbation will be the dates started to 
meet these criteria and end to meeting them.
The following additional COPD exacerbation efficacy variables  are based on HCRU 
(worsening of symptoms requiring a change in COPD treatment and/or hospitalization 
and/or emergency room treatment):

Number (%) of subjects with at least 1 COPD exacerbation (any, mild, moderate, 
severe and moderate or severe).
Number of exacerbations will be set to zero for subjects with no exacerbations and 
further  categorizated as 0, 1, ≥ 2 exacerbations.

Total days of exacerbations (any, mild, moderate, severe and moderate or 
severe).
The duration of an exacerbation = date of recovery – date of onset +1.  For the summary
statistics, the duration will not be derived if either the date of onset or the date of 
recovery is completely or partially missing. The total days of exacerbation is the sum of 
all the durations of exacerbations experienced by the subject for a given severity. 

Time (days) to first COPD exacerbation (any, mild, moderate, severe and 
moderate or severe).
The time (in days) to the first exacerbation is derived as the time elapsed from the first IP 
dose date to the first exacerbation Onset Day (non-censored data) or the last IP dose date 
(censored data), whichever occurs first, + 1 day. 


Statistical Analysis Plan 
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
Total risk time in years (any, mild, moderate, severe and moderate or severe).
The total-risk time in years for each patient will be calculated separately for each 
exacerbation type (HCRU: any, mild, moderate, severe and moderate or severe). It is 
defined as the time that a patient is at risk of an exacerbation of that type. For example, 
for an analysis of moderate or severe HCRU exacerbations, a subject is not at risk of 
experiencing a moderate or severe exacerbation during a moderate or severe 
exacerbation (or the seven days afterwards), but is at risk during a mild exacerbation 
(except for when both are combined into one exacerbation). For the while on treatment 
analysis (see Section 4.1.1), the total-risk time will be defined as the treatment exposure 
deducting both the summed duration of exacerbations during treatment exposure and 
seven days for each exacerbation reported by the patient. For the treatment policy 
analysis, the total-risk time will be defined as the time-on-study deducting both the 
summed duration of exacerbations while on-study and seven days for each exacerbation 
reported by the patient. In general, seven days should be deducted from the total-risk 
time for each exacerbation of that type. However, for exacerbations that end less than 
seven days prior to the end of treatment/study, this duration should be deducted instead. 
When deriving the duration of exacerbations, partially or completely missing Onset and 
Recovery Days will be imputed. For all Recovery Days occurring after the end of 
treatment, the date will be curtailed to the date of the last IP dose. For a patient in any 
exacerbation analysis for which the time-at-risk is calculated as being less than 1 day, it 
will be set to 1. The total risk time will be converted to years. 

Rate of COPD exacerbations per patient/year (any, mild, moderate, severe and 
moderate or severe).
The annual crude rate of exacerbation for each type will be estimated as the number of 
exacerbations of that type divided by the total risk time.
Derived from the EXACT questionnaire:

Number (%) of subjects with at least 1 COPD exacerbation.
The derivation of number of subjects with at least 1 EXACT COPD exacerbation will be 
the same as for HCRU, as detailed above.

Total days of exacerbations.
For EXACT, the event duration calculation requires the identification of the following 
parameters: (i) Onset; (ii) 3-day rolling average; (iii) Maximum Observed Value; (iv) 
Threshold for improvement; (v) Recovery. Further details of these parameters can be
found in Appendix 7. The duration is calculated as the difference, in days, between the 
day of Onset and the day of Recovery. Recovery day is not included in the calculation 
of duration. 

Time (days) to first COPD exacerbation.


Statistical Analysis Plan 
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The derivation of time to first EXACT COPD exacerbation will be the same as for 
HCRU, as detailed above

Total risk time in years.
A similar approach to that given for HCRU above will be used to derive total risk time in 
years for EXACT COPD exacerbations.

Rate of COPD exacerbations per patient/year.
The annual crude rate will be calculated as the number of EXACT COPD exacerbations 
divided by the total risk time.
Appendix 7 provides further details on the derivation of both HCRU and EXACT 
exacerbation events.
For a COPD exacerbation to be counted as a separate event, it must be preceded by at 
least seven days in which no criteria for exacerbations is fulfilled. In case of relapse, the 
Recovery day for the resulting exacerbation is the Recovery day of the last episode and 
the onset day is the one from the first episode, and the severity of the resulting 
exacerbation will be that of the highest severity of the episodes.
For the while on treatment estimand, all exacerbations starting before the first IP dose or 
after the last IP dose will be excluded from the analysis and from the above calculations. 
For the policy estimand (on-study), all exacerbations starting before the first IP dose or 
after the last EOS visit date will be excluded from the analysis.
3.2.3.4
Daily COPD Symptoms (E-RS) and use of rescue medication
The E-RS scale is a part of the Exacerbations of Chronic Pulmonary Disease Tool
(EXACT) questionnaire, which is composed by the following three domains:
-
E-RS Breathlessness
-
E-RS Cough and Sputum 
-
E-RS Chest Symptoms 
The E-RS total score derived from 11 items of EXACT questionnaire (ranging from 0 to 
40), quantifies the overall severity of respiratory symptoms, and 3 domain scores assesses 
breathlessness (derived sum of 5 items); cough and sputum (derived sum of 3 items); and 
chest symptoms (derived sum of 3 items). 
The total E-RS score and the scores for the three domains are derived as detailed in 
Appendix 8. The higher scores of E-RS indicate a greater deterioration.
The additional COPD symptoms and use of recue medication variables are:

Change from baseline in EXACT-Respiratory Symptoms (E-RS) total score and 
its three domains (breathlessness, cough & sputum and chest) for each period 


Statistical Analysis Plan 
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comprised between two consecutive visits (Weeks 1, 4, 12, 18 and 24 and 
overall over 24 weeks).
The MCIDs for E-RS Breathlessness score, Cough and Sputum score and Chest 
Symptoms score are -1, -0.70, and -0.70, respectively. The MCID for the E-RS total 
score is based on a reduction from the baseline in at least 2 units. The following 
endpoint will be assessed:

Number (%) of subjects with a clinically meaningful improvement in E-RS total 
score, and by domains for each period comprised between two consecutive visits 
(Weeks 1, 4, 12, 18 and 24 and overall over 24 weeks).
All subjects are provided salbutamol (salbutamol pMDI 100 g/puff) as rescue 
medication. Subjects record every night the number of puffs of salbutamol taken within 
the last 24 hours by answering the question: How many puffs of relief medication 
(salbutamol) have you inhaled in the last 24 hours (from yesterday when you went to bed 
until now)?
The following endpoint will be assessed:

Change from baseline in the use of rescue medication for each period comprised 
between two consecutive visits (Weeks 1, 4, 12, 18 and 24 and overall over 24 
weeks).
The E-RS and the use of daily rescue medication are derived as the mean of all non-
missing daily entries recorded between two consecutive (non skipped) scheduled visits 
(ending the night before the scheduled visit), or between a visit and the last IP date 
(excluded), if a patient withdrawn. Overall period is defined as a period between first dose 
and last IP dose (excluded). Missing values in daily rescue medication will not be 
imputed. 
For E-RS and rescue medication, the baseline is defined as a 7-day interval before the 
first IP dose (ending the night before the first dose of IP), and will be calculated as the 
sum of scores/puffs divided by the total number of days with non-missing values reported 
that week. Baseline values will be computed only for those subjects recording at least 4 
diary entries during this period. Otherwise the baseline score will be set to missing.
3.3 Safety Variables
Extent of Exposure and Study Duration
The variables analysed are:

Duration of exposure to the IP calculated in days as: 
Date of the last IP dose - Date of the first IP dose +1. 

Categorised cumulative duration of exposure as: ≥ 1 day, ≥ 1 week, ≥ 4 weeks, ≥ 12 
weeks, ≥ 18 weeks, and ≥ 24 weeks.

Time in the study (duration of study) calculated in days as: 
Date of the last on-site visit - Date of randomisation +1.


Statistical Analysis Plan 
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
Categorised cumulative duration of study as: ≥ 1 day, ≥ 1 week, ≥ 4 weeks, ≥ 12 
weeks, ≥ 18 weeks, and ≥ 24 weeks.
See Section 4.6.2 for definition of the last IP dose date.
Adverse Events
Adverse events (AE) will be coded using the latest MedDRA dictionary (version 23.0 or 
higher). 
AEs will be categorised according to the following study periods:

Pre-treatment AEs: started before first IP dose date

Treatment-emergent AEs (TEAEs): AEs started on or after the date first IP dose until 
15 days from the last IP dose date.

Post-treatment AEs: AE started after 15 days from last dose
AEs with completely or partially missing start date/time and/or end date/time will be 
handled as detailed in Section 4.6.4 before flagging the AEs with the above 
categorisation. See Section 4.6.5 for imputation of missing severity and relationship to 
study drug.
The following durations will be derived as event date – first IP dose + 1:

Days from first dose to onset of AE

Days from last dose to onset of the AE

Days from first dose to death

Days from onset to resolution (duration of AE)

Days from first dose to becoming serious 
In case of the event date is prior to first IP dose, then the durations will be derived as 
event date – first IP dose.
Adverse Events of Special Interest (AESI) and Major Adverse Cardiovascular 
Events (MACE)
AEs of Special Interest (AESIs) will include cardiac, cerebrovascular, anticholinergic, 
pneumonia, and β2-adrenergic events. AESI will be identified based on the categorisation 
of Standardised MedDRA Query (SMQ), System organ class (SOC), High Level Terms 
(HLTs) or Preferred Terms (PTs) as per Table 3-2.  
The Cardiovascular Adjudication Committee (CVAC) is an independent external expert 
advisory panel responsible for applying a consistent and pre-specified set of criteria to 
determine if the reported potentially cardiovascular events are identified as Major 
Adverse Cardiovascular events (MACE). Adjudicated MACEs are composed by 
cardiovascular deaths (death due to acute myocardial infarction, sudden cardiac death, 
death due to heart failure or cardiogenic shock, death due to stroke, and death due to other 
cardiovascular cause), non-fatal myocardial infarction (MI) (Type 1: spontaneous; Type 
2: demand type and procedure-related MI), and non-fatal stroke (ischemic, hemorrhagic, 
and undetermined).






Statistical Analysis Plan 
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Please note that while the categories of New and Worsened are mutually exclusive, a 
notable PCS can be also new or worsened at the same time.






Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
 
 
 
 
 
 
 
 
 
 
 
The following increases in liver biochemistry observed in one active treatment group compared 
to the control group at any time during the study from first dose are signals of potential drug-
induced liver injury (DILI):

ALT/AST ≥ 3xULN and <5xULN

ALT/AST ≥5xULN and <10xULN

ALT/AST ≥10xULN and <20xULN

ALT/AST ≥20xULN
The presence of one of the above DILI signals together with TBL ≥ 2xULN in which the 
elevation in transaminases precede or coincide with (that is, on the same day as) the elevation 
in TBL and irrespective of an increase in ALP in one active treatment group compared to 
placebo may be a signal of Potential Hy´s Law (PHL) (FDA, 2009). 
For all the above DILI and PHL signals, the maximum value will be flagged.
Vital Signs
Systolic blood pressure (SBP) and diastolic blood pressure (DBP) are expected to be measured 
in millimeters of mercury (mmHg) as pre-morning dose and 1-hour post morning dose at each 
study visit except at Week 4. One single measurement will be also taken at the screening visit 
and at the last on-site visit (at week 24 [EOS] or EOT visit).
Changes from baseline will be calculated at each post-baseline visit and timepoint. The value 
recorded at morning pre-dose on Day 1 will be used as the baseline and if that value is missing 
Screening value will be used as the baseline. If both screening and Day 1 values are missing, 
then the baseline is considered as missing.
PCS abnormalities in blood pressure will be flagged if they meet either the high or low notable 
change criteria in Table 3-4. 






Statistical Analysis Plan 
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
Study drug disruption:  For each study drug-related disruption due to the pandemic, the 
start and stop date of the disruption will be collected in a new module added to the 
EDC for collecting information on the impact of the pandemic on administration of the 
study drug.

Discontinuation of treatment/Withdrawal from study due to COVID-19: A new page 
will be added to the EDC with two tickboxes for collecting information on the 
following: (i) Discontinuation of the study drug due to the pandemic; (ii) Study 
discontinuation due to the pandemic.
4
ANALYSIS METHODS
All primary, secondary and additional efficacy endpoints will be analysed using ITT (except for 
COPD exacerbations). In addition, per protocol (PP) analyses will be performed for the primary 
and secondary endpoints. Safety data and COPD exacerbations will be analysed in the SAF 
analysis. 
All personnel involved with the analysis of the study will remain blinded until DBL. Analyses 
will be performed by AstraZeneca. 
4.1 General Principles
Study Estimands
The estimand will be based on the while on treatment approach where treatment estimates are 
analysed while subjects are taking the study medication, i.e., on-treatment during the IP intake 
period. The following five attributes describe the estimand that will be used to define the 
treatment effect of interest for all efficacy and sefety analyses: 

Treatment Condition = Randomized IP.

Population = Patients with moderate to severe COPD, as per protocol-specified 
inclusion/exclusion criteria.

Patient-level outcome = Change from baseline in primary and secondary endpoints at 
Week 24.

Intercurrent event (IE) handling = While on treatment approach will be used to 
account for both intercurrent events by truncating at the time of the intercurrent event 
onset. Therefore, measurements of the endpoint until the time of the intercurrent 
events will be considered.

Summary measure = Adjusted LSMeans obtained from MMRM model.


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For COPD exacerbations, post treatment medications, and SAEs, in addition to the analysis 
based on while on treatment estimand, treatment policy estimand (on-study data) will be 
assessed. Treatment policy strategy considers events occurring during the IP intake and after 
the IP discontinuation. The while on treatment estimand will be the primary analysis for COPD 
exacerbations.
Generally, missing data are assumed to be Missing-At-Random (MAR). 
The robustness of the results to potential departures from the underlying assumptions will be 
assessed through sensitivity analysis (see Section 4.11).
Last IP Dose Date
Last IP dose date 
The date of the last IP dose is:

the date recorded as the last date of IP at EOT for prematurely discontinued subjects 

the date recorded as the last date of IP at EOS for completed subjects
If any of the above are missing, the latest date recorded on bedtime e-diary where the subject 
confirms to have taken the IP will be used as the date of last IP dose.
Descriptive Summary Statistics
All data will be summarised by treatment group, study visit (including over 24 weeks on 
treatment) and timepoint, where applicable. The visit called ‘over 24 weeks’ will be calculated 
at subject level as the mean values of all treatment visits. The number of subjects in each 
treatment group of the analysis set used will be given in the column/row header as “(N=xx)”. 
For the study population tables, the overall total summary column will be also reported.
The following standard descriptive statistics will be used:

Categorical data will be summarized with frequency counts and percentages over the 
corresponding treatment group total N [n (%)]
o Percentages will be rounded to one decimal place, unless the value is exactly equal 
to 100% (i.e. where the numerator is equal to the denominator), in which case there 
will be no decimal places
o The total of all categories will be always reported and the category “Missing” will 
be added in case of observations not falling in any of the pre-defined categories.
o Percentages for “Missing” will not be presented. 

Quantitative data will be summarized by the following statistics: number of non-missing 
values (n), arithmetic mean, standard deviation (SD), minimum (Min), first quartile 
(Q1), median, third quartile (Q3), and maximum (Max) 
o Except for tables of PFTs and lab data,minimum and maximum will be displayed 
with the same accuracy as the individual values


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o Except for tables of PFTs and lab data, all other statistics will be rounded to one 
additional decimal place compared to the Min and Max, unless otherwise specified
o For PFT tables, all summary statistics will be rounded to three decimal places
o For tables of lab data, all summary statistics will be rounded to two decimal places
Rounding should be the last operation in the treatment of data. There should be no rounding of 
intermediate results during the calculation of any derived value.
Visits Reported and Statistical Comparisons for Efficacy
Unless otherwise specified, all statistical comparisons will be done by treatment group.
Results of all visits will be reported in all efficacy tables by treatment group (no total column 
will be shown in tables). Also, results over 24 weeks on treatment will be reported for PFT 
endpoints as shown in Section 3.2.3.1., daily COPD symptoms (E-RS), and use of rescue 
medication. As an exception, COPD exacerbations are reported along the entire treatment 
period. 
All treatment effects will be estimated and presented in the tables. Primary and secondary 
treatment comparisons can be found in Table 4-1, and all remaining comparisons will be 
exploratory. Figures will only show the primary and secondary treatment comparisons.
All tests on treatment effects and all pairwise statistical comparisons will be two-sided 
superiority hypothesis tests presented along with their 95% Confidence Interval (CI) and p-
value. The significance level will be set at 0.05. The types of statistical test used to generate the 
CIs and p-values should be included in a footnote. 
All estimates and CIs will be presented to one more decimal place compared to the original 
individual data, if not otherwise specified. Actual p-values will be reported using three decimal 
places, or as ‘<0.001’ if they are less than 0.001.
Other Statistical Considerations
All statistical analyses described in this SAP will be performed by the sponsor using the 
software SAS® version 9.4 or higher, whichever available at the time of analysis.
Tables, figures and Listings (TFLs) will be compiled in an Appendix to the CSR: tables, and 
figures will be appended in CSR Section 14, subject-level data listings will be in CSR Section 
16.2. Every statistical inferential analysis on the primary and secondary endpoints (excluding 
sensitivity analyses) will be supported by the whole SAS output, which will be appended to 
Section 16.5 of the CSR. 
Relevant data collected on the eCRF will be provided in subject-data listings sorted by unique 
subject identification number and visit and timepoint where available. Any exclusion of data 
from the analyses will be flagged in the subject-data listings. 


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4.2 Summary of Study Populations 
Study population summaries will include subject dispositions, demographic and baseline 
characteristics, and treatment compliance. 
Subject Disposition 
Subjects will be counted for the Randomised Analysis Set, ITT and PP by randomised treatment  
and for SAF by treatment subjects actually received.
Number and percentage of subjects in each of the disposition categories of Section 3.1.1 will be 
tabulated by treatment group and overall for all subjects. Percentages will be calculated over 
the number of subjects randomised (with the exception of enrolment subjects for which only 
number will be shown). Enrolment, treatment completion status and study completion status 
will be summarised split into the following categories:

Subjects enrolled

Subjects randomised

Subjects who received treatment 

Subjects who completed treatment (based on EOT form for discontinued subjects and 
EOS form at Week 24 for completed subjects)

Subjects who completed study (based on EOS form) Subjects who made the follow-up 
contact 14 days after last dose 
All disposition events and dates will be listed in two subject-data listings, one for subjects 
withdrawing from study and one for subjects completing the study.
A frequency table (counts and percentages) will be produced for the randomised analysis set to 
show the subject recruitment by country and centre. Number of subjects in each treatment group 
will be used as the denominator in the calculation of percentages for country. Total number of 
subjects in each country will be used as the denominator in the calculation of percentages for 
centre. Number and percentage of subjects by IWRS stratification factors at randomization 
(country and smoking status) will be also tabulated by treatment group and overall for the total 
randomised analysis set in a separate table. The whole randomisation scheme and randomisation 
numbers will be listed for all randomised subjects along with their actual received treatment in 
case, if different to what they were assigned at randomization.
For Important Protocol Deviations (IPD), the following will be presented in a single summary 
table: number and percentage of subjects with at least one IPD, including COVID-19 related 
IPDs; number and percentage of subjects with at least one COVID-19 related IPD only and 
number and percentage of subjects with at least one IPD excluding COVID-19 related IPDs.  
Each of these will be presented by PD coded term (Eligibility criteria not fulfilled, prohibited 
concomitant medication taken during the study, received incorrect investigational 
treatment/dose, Protocol-required procedure not adhered to and Other reasons) for each 
treatment group and overall for the total randomised analysis set. All IPDs will be listed for 
each subject and the PDs leading to the exclusions from the PP analysis set will be highlighted. 


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A separate listing of  all COVID-19 related non-important PDs and other reported issues will 
also be produced. Other non-important PDs will not be included in the CSR.
Analysis sets defined in Section 2.1 and reasons for exclusion will be tabulated by treatment 
group and overall for the total randomized analysis set. Exclusions from each analysis set and 
related reasons will be also listed for each randomised subject.
Demography and Baseline Characteristics 
Summaries of all collected and derived demographic, subject and disease characteristics will be 
produced by treatment group and for the overall SAF and ITT using the standard descriptive 
statistics for categorical and quantitative data. The number of subjects with data will be used as 
the denominator for calculating percentages.

Demographic characteristics [age, age group, sex, race, ethnic population, and country]

Subject characteristics [height, weight, BMI, and BMI group] 

COPD characteristics at screening [COPD severity derived with the GOLD categories 
for airflow limitation and based on symptoms and risk of exacerbation, COPD duration, 
time since last COPD exacerbation, time since last hospitalization due to a COPD 
exacerbation, number of COPD exacerbations in the previous 12 months (as continuous 
variable and as categorised variable up to maximum), history of chronic bronchitis and 
emphysema]

Nicotine use at screening [smoking status, smoking consumption in pack-years, and 
smoking duration] 

Lung function data at screening [pre- and post-bronchodilator absolute (L) and percent 
predicted FEV1, FVC and post-bronchodilator FEV1/FVC Ratio (%), absolute (mL) and 
percent (%) bronchial reversibility and bronchial reversibility status] and at baseline 
[pre- and post-bronchodilator absolute (L) and percent predicted FEV1, FVC]. For 
baseline, use the average of the 2 pre-dose timepoints on Day 1.

BDI score (total score and scores of components), SGRQ score (total score and scores 
of dimensions) and CAT score at baseline
Demographic and subject characteristics will be listed together in a single subject-data listing.
Medical history and surgical history at screening will be summarised in two separate frequency 
tables in the SAF analysis set by treatment group and for the overall analysis set by SOC and 
PT. Results will be sorted alphabetically by SOC and PT. Medical and surgical history will be 
also presented together in a subject-data listing. The information about whether the condition is 
past or ongoing will be only listed. The version number of the MedDRA dictionary used will 
be shown as a footnote in every output.
Prior and Concomitant Medication
Prior medication (medication taken before ICF and medication taken after ICF and before first 
IP dose), prior COPD-related medication and all concomitant medication will be summarised 


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by treatment group in frequency tables produced in the Safety Analysis Set. The categorisation 
of medications given in Section 3.1.5 will be used for the summaries.
The number and percentage of subjects with prior COPD-related treatment will be tabulated by 
the AZBC SDG therapeutic categories of Section 3.1.5 (with the revised free- or fixed-dose 
combination). Prior and concomitant medication will be summarized by period, Anatomical 
Therapeutic Chemical 3 (ATC3) category and generic term. Results will be sorted 
alphabetically by ATC name and generic term. In all cases, if a patient uses more than 1 
medication in a generic term, that patient will be counted only once in that generic term. The 
version number of the WHO DRUG dictionary used will be shown as a footnote. 
Number and percentage of subjects taking prior, concomitant and post-treatment medications 
will be summarised overall, and by ATC3 text (or ATC2 if the ATC3 is missing), generic term, 
and treatment group for each period. 
In all cases, if a patient uses more than 1 medication in a generic term, that patient will be 
counted only once in that generic term.
Completely or partially missing start and end dates will be imputed as per the rules of Section 
4.3.4. See also the definition of last IP dose date in Section 4.1.2.
All prior and concomitant medications will be listed together in a subject-data listing. All tables 
and the subject-data listing will include medications taken for the treatment of COVID-19.
Study Compliance and Drug Accountability
The standard descriptive statistics will be presented for the compliance rates as continuous 
variable and for the compliance status for each inhaler and overall by treatment group and for 
ITT. Number and percentage of subject compliant with both devices will be also reported. The 
table will be produced with 3 subheadings: (i) Treatment compliance in all subjects; (ii) 
Treatment compliance in subjects not affected by COVID-19; (iii) Treatment compliance in 
subjects affected by COVID-19. This includes subjects with suspected/confirmed COVID-19 
infection, as recorded on the adverse events page of the eCRF. Such adverse events will be 
identified from a narrow and broad search of the SMQ ‘COVID-19’.
Drug accountability will be only listed as recorded on the eCRF.
4.3 Efficacy Analysis
For the analysis of efficacy endpoints, in order to avoid any possible instability in the  
statistical modelling, if one level of a given factor  represents only <5% of randomized 
subjects, the corresponding factor will be removed from all the inferential statistical models. 
However, this rule does not apply to randomization stratification factors.
Primary Efficacy Analysis 
All primary efficacy endpoints will be analysed, using the ITT and the PP, by means of a mixed 
model for repeated measures (MMRM) adjusted for pre and post bronchodilator (salbutamol) 


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FEV1 at screening visit, age, and baseline FEV1 as covariates, and treatment group, country,  
smoking-status, visit, and treatment group-by-visit interaction as fixed effect factors. 
The within-patient correlation will be modelled using the unstructured covariance matrix. The 
analysis will be performed based on all post baseline measurements using only the observed 
cases without imputation of missing values. If the model does not converge, then the compound 
symmetry covariance structure will be used. Restricted maximum likelihood method will be 
used. If the model still fails to converge, countries with too few subjects may be combined to 
address residual convergence issues. In this case, the country with smallest number of subjects 
in the analysis population will be merged with the next smaller country. This process will 
continue until the convergence is reached. If all the countries are to be merged to reach 
convergence, country term will be removed from the model.
Parameters will be estimated by means of the restricted maximum likelihood (REML) 
approach with the Newton-Raphson algorithm and using the Kenward-Roger approximation 
to estimate denominator degrees of freedom and adjust standard errors (Kenward and Roger, 
1997). Missing data will not be imputed but modelled using the direct likelihood approach 
under the missing-at-random (MAR) assumption.
From the MMRM model, the estimated mean (least squares mean: LSMean) for each treatment 
and the estimated mean difference for each pairwise treatment comparison at all study visit be 
extracted from treatment-by-visit interaction in the model along with their standard errors (SEs) 
and two-sided 95% CIs, and the p-values corresponding to the between-treatment group 
differences. The results at Week 24 will be based on the treatment-by-visit interaction at Week 
24 will be the primary efficacy results. Results over 24 weeks on treatment will also be reported, 
based on the treatment effect factor. Statistical comparisons will be two-sided hypothesis tests, 
and the overall significance level will set at 0.05. 
Primary efficacy data will be summarized by visit (and overall over the 24 weeks on treatment) 
and by treatment group. No total column will be shown in tables. 
Adjustment for multiplicity will be carried out for all primary endpoints as per Section 4.4.
Secondary Efficacy Analyses 
Secondary efficacy endpoints will be analysed using the ITT and the PP.
Secondary efficacy endpoints will be analysed and summarized using MMRM models like for 
the primary endpoints, i.e., using the same covariance matrix, convergence rules, parameter 
estimation, and reported outputs.
Change from baseline in peak FEV1 will be adjusted for pre and post bronchodilator 
(salbutamol) FEV1 at screening visit, age, and baseline FEV1 as covariates, and treatment group, 
country, smoking-status, visit, and treatment group-by-visit interaction as fixed effect factors. 
MMRM analysis for TDI focal score and change from baseline in SGRQ total score at Week 
24 will be adjusted by the corresponding baseline value (BDI or SGRQ at baseline) and age as 


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covariates, and treatment group, country, smoking-status, visit, and treatment group-by-visit 
interaction as fixed effect factors.
Adjustment for multiplicity will be carried out for all secondary endpoints as per Section 4.4.
Analysis of Additional Efficacy Endpoints
In addition to the primary and secondary efficacy analysis, the additional endpoints listed in 
Section 3.1.9 will also be analysed. 
All the data for additional efficacy endpoints will be summarised using the ITT population 
(except for COPD exacerbations).
4.3.3.1
Analysis of Additional PFT Endpoints
This section provides the statistical methodology used to analyse all the additional efficacy 
endpoints listed in Section 3.1.9.1.
Additional PFT endpoints will be analysed and summarized using MMRM models like for the 
primary endpoints, i.e., using the same covariance matrix, convergence rules, parameter 
estimation.
The MMRM analyses used for the primary analysis will be performed for the above exploratory 
parameters by adjusting for pre and post bronchodilator (salbutamol) FEV1 at screening visit, 
age, and baseline FEV1 as covariates, and treatment group, country, smoking-status, visit, and 
treatment group-by-visit interaction as fixed effect factors. 
For spirometric analysis by visit and timepoint, the statistical models will be specified as for the 
primary analysis, considering the specific time-point as the response. Note that for the ‘visit’ 
factor, only those visits whose timepoint was measured will be included.
4.3.3.2
Analysis of Signs and Symptoms and Health-related Quality of Life
This section provides the statistical methodology used to analyse all the additional efficacy 
endpoints listed in Section 3.1.9.2.
Change from baseline in TDI, SGRQ and CAT are analysed using the same MMRM model 
used for the secondary endpoints but using the appropriate baseline. All treatment effects and 
treatment comparisons will be estimated and 95% CIs and p-values will be presented.  
The responder analysis, i.e. the analysis of the proportion of subjects achieving a MCID, at each 
study visit, will be done using the random-effect logistic regression model with random 
intercept to account for the variability between subjects. The models will be adjusted for age 
and the baseline score of the endpoint as continuous covariate, and smoking status, country, 
treatment, visit and treatment-by-visit interaction as fixed effects. The within-subject correlation 
will be modelled using the unstructured covariance matrix. If the model fails to converge, the 
compound symmetry covariance structure will be used instead. If the model still fails to 
converge, due to the country factor then the same approach as for the primary variable will be 
applied.


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For each treatment arm, the odds will be presented along with the number of non-missing 
observations used in the estimation (n), the observed number and percentage of responders, and 
their two-sided 95% confidence intervals (CIs). ORs will be shown with their CIs and the two-
sided p-value.
At each of these visits the odds and the odds ratio (OR) along with 95% CI and the p-value will 
be estimated using the treatment-by-visit interaction. 
4.3.3.3
Analysis of COPD Exacerbations 
This section provides the statistical methodology used to analyse all the additional efficacy 
endpoints listed in Section 3.1.9.3.
COPD exacerbations are derived using HCRU and EXACT as detailed in Section 3.2.3.4 and 
summary results will be produced for each category by treatment group as given below. When 
using the HCRU analysis, any, mild, moderate, severe, moderate-to-severe COPD exacerbation 
severities will be summarized descriptively but only any and moderate-to-severe will be 
reported for modelling purposes.
For all models used in the analysis of COPD exacerbations, any countries where the planned 
number of randomised subjects is less than 5% of the overall number of randomised subjects
(equating to fewer than 13 subjects per treatment group) should be combined. If only one 
country meets this criteria, then it should be combined with the next smallest country.
While on treatment COPD Exacerbations:
The following analyses will be performed on the SAF for the COPD EXACT and HCRU 
exacerbation endpoints:

Rate of COPD exacerbations per patient/year will be estimated using the negative 
binomial (NB) regression model. 

Number and percentage of subjects with at least one COPD exacerbation will be 
estimated using the logistic regression model.

Time (days) to first COPD exacerbation through Week 24 will be analyzed using the 
Cox regression model. 
For each treatment arm, the annual crude rate of exacerbation of each type (EXACT and HCRU) 
will be estimated as the number of exacerbations of that type divided by the total risk time.The 
rate of COPD exacerbations per years of exposure will be analysed and by means of NB 
regression models including age as a covariate, and baseline ICS use (use/no use of ICS as 
monotherapy within 15 days prior to the first dose date of the IP and continued after 
randomization), baseline COPD severity (mild/moderate vs. severe/very severe), smoking 
status (current/former smokers), country, prior history of exacerbation over 12 months before 
randomization (yes/no), treatment group as factors, and the log risk time in years as an offset. 
Treatment effects and pairwise treatment comparisons will be estimated by the event rates per 
patient-year and the Rate Ratio (RR) on the treatment coefficient, respectively.


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For each treatment arm, estimated rates will be presented along with the number of non-missing 
observations used in the estimation (n), the number of events, the total risk time in years and 
their two-sided 95% Wald confidence intervals. RRs will be shown with their CIs and the two-
sided p-value.
In the case of non-convergence, then a modified Poisson regression model with robust variance 
estimate using the sandwich method will be used instead. A scale parameter will be included in 
the Poisson model in case of evidence of overdispersion. The same SAS code of the NB model 
can be used, by changing the distribution and by adding the DSCALE option [SAS code: dist = 
poisson dscale] and by including a repeated statement for each subject [SAS code: repeated 
subject=USUBJID]. 
If the model still fails to converge, countries with too few subjects may be combined to address 
residual convergence issues. In this case, the country with smallest number of subjects in 
analysis population will be merged with the next smaller country. This process will continue 
until the convergence is reached. If all the countries are to be merged to reach convergence, then 
instead, country term will be removed from the model.
The number of subjects with at least one COPD exacerbation will also be analysed using a 
logistic regression model including age as a covariate, and baseline ICS use (use/no use of ICS 
as monotherapy within 15 days prior to the first dose date of the IP and continued after 
randomization), baseline COPD severity (mild/moderate vs. severe/very severe), smoking 
status (current/former smokers), country, prior history of exacerbation over 12 months before 
randomization (yes/no), and treatment group as factors. Frequency distribution (number and 
percentage) will also be reported.
Time (days) to first COPD exacerbation will be analysed through Cox Proportional Hazard 
model including age as a covariate, and baseline ICS use (use of ICS [yes/no] as monotherapy 
within 15 days prior to the first dose date of the IP and continued after randomization), baseline 
COPD severity (mild/moderate vs. severe/very severe), smoking status (current/former 
smokers), country, prior history of exacerbation over 12 months before randomization (yes/no), 
and treatment group as factors. The Breslow approach will be used for handling ties. Kaplan-
Meier survival curves for any and moderate-to-severe exacerbations will be displayed for each 
treatment.
If a patient experiences a COPD exacerbation(s), the time to first event for while on treatment 
analysis will be derived as:
Time to event = date of onset of first exacerbation – date of first IP dose +1
Or if there are no exacerbations 
Time to event = date of last IP dose – date of first IP dose +1
For each treatment, the following will be presented: number of non-missing observations used 
in the estimation (n), the observed number and percentage of subjects with at least one 
exacerbation and the median time-to-event in days. Median time-to-event will be estimated 
from the Cox model as the time at which the predicted survival=0.5. It will be set to NE (Non-
estimable) if >50% of subjects are censored, and the median survival time cannot be determined. 


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Pairwise treatment comparisons will be estimated by Hazard Ratio (HR) and corresponding 
95% CI and p-value.
For the logistic regression and Cox Proportional Hazard models, if the models fail to converge, 
countries with too few subjects may be combined to address residual convergence issues. In this 
case, the country with smallest number of subjects in analysis population will be merged with 
the next smaller country. This process will continue until the convergence is reached. If all the 
countries are to be merged to reach convergence, then instead, country term will be removed 
from the model(s).
Treatment policy (on-study) COPD exacerbations:
COPD exacerbations (HCRU Exacerbations and EXACT exacerbations) recorded during the 
study (i.e. during the treatment period  and after discontinuation of study drug)  will be analysed 
using the same methodology used for the while on treatment exacerbations. 
For each type of exacerbation, all the analyses (the derivations of rate of exacerbations, the 
number (%) subjects with exacerbations, analysis of time to first exacerbation and estimation 
of odds and ORs) will be performed similarly and similar results will be presented. 
Note that last on-site visit date is used instead of the last IP dose date as reference date to impute 
recovery dates according to the treatment policy approach. Duration of on-going exacerbations 
at last visit will be curtailed to the last visit date. For subjects with zero exacerbations, the time 
to the first exacerbation will be censored at the last on-site visit date.
4.3.3.4
Analysis of daily COPD Symptoms (EXACT-Respiratory Symptoms [E-RS]) 
This section provides the statistical methodology used to analyse all the additional efficacy 
endpoints listed in Section 3.1.9.4.
Change from baseline in E-RS score between two consecutive visits (Weeks 1, 4, 12, 18 and 
24 and overall over 24 weeks) will be analysed using the same MMRM model used for the 
primary endpoints using the appropriate baseline and removing pre and post bronchodilator 
covariates. All treatment effect and treatment comparisons will be estimated and 95% CIs and 
p-values will be presented.
The responder analyses for the E-RS will be performed like the analyses performed for TDI, 
SGRQ and CAT (Section 4.3.3.2) and the results will be presented similarly. 
4.3.3.5
Analysis of use of Rescue Medication
Subjects may be taking either salbutamol as rescue medications during the study period. Use 
of rescue medication is calculated as in Section 3.2.3.4.
Change from baseline in rescue medication (salbutamol) between two consecutive visits 
(Weeks 1, 4, 12, 18 and 24 and overall over 24 weeks) will be analysed using the same 
MMRM model used for the primary endpoints using the appropriate baseline and removing 
pre and post bronchodilator covariates. All treatment effect and treatment comparisons will be 
estimated and 95% CIs and p-values will be presented.


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4.4 Multiplicity Adjustment Strategy
Hierarchical Strategy for Adjusting for Multiplicity:
Due to the presence of multiple study objectives and multiple comparisons (multiplicity), to 
control the family-wise type I error, the pre-specified sequence of testing of Table 4-1 will be 
carried out for all primary and secondary efficacy objectives (multiplicity hierarchical 
approach). 
Any endpoint in the hierarchy following a non-statistically significant result at the 5% 
significance level will be reported for exploratory purposes and p-values will be only nominal 
and should be interpreted descriptively. Note that both primary variables for AB/FF 400/12 
should overcome the statistical hierarchy (i.e., should be statistically significant) to meet the 
primary bronchodilator objective of the FDC.




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
Pre-treatment AEs: started before first IP dose date

Treatment-emergent AEs (TEAEs): AEs started on or after the date first IP dose until 
15 days from the last IP dose date.

Post-treatment AEs: AE started after 15 days from last dose.
Pre-treatment AEs:
The pre-treatment AEs will be flagged in the AE listings.
Treatment-emergent AEs (TEAEs):
The following frequency distribution (subject counts and percentages, and number of events) 
tables of TEAEs will be produced by treatment group, SOC and PT, as appropriate. Subjects 
with multiple events in the same category are counted only once in that category and subjects 
with events belonging to multiple categories are counted in each of those categories. Multiple 
events in the same category are counted multiple times in that category. Multiple events 
belonging to more than 1 category are counted multiple times in each of those categories.

TEAEs in any category:
Frequency distribution of the following TEAE categories: “Any AE”, “Any TEAE”, 
“Any TEAE with outcome of death”, “Any SAE)”, “Any treatment-emergent SAE 
(TESAE)”, “Any TEAE leading to treatment discontinuation”, “Any treatment-
emergent AESI”, “Any significant cardiac and cerebrovascular TEAE”, “Any 
anticholinergic TEAE”, “Any β2 adrenergic TEAE”, “Any pneumonia TEAE”, “Any 
MACE”.  

Most common TEAEs (frequency of >1%):
Frequency distribution by PT of all the TEAEs with a total frequency of >1% (in any 
treatment group). PTs will be sorted by the descending frequency of the total column 
(even if not reported). The number of subjects with at least one TEAE will be reported 
in the top row of the table.

TEAEs by SOC and PT: 
Frequency distribution (patient counts and percentages, and event counts and incidence 
rates) of the below groups of TEAEs (one table for each grouping) sorted by 
international order for SOC and  alphabetically for PT. The number of subjects with at 
least one AE in the below categories and the number of related events will be reported 
as top row of the table.
o
Any TEAE
o
Any TEAE with outcome of death
o
Any TESAE
o
Any TEAE leading to discontinuation of IP
Event rates per 1,000 patient-years of exposure is calculated as the number of subjects 
with at least one TEAE divided by the total number of years at risk for that TEAE 
multiplied by 1000. The number of years at risk is derived as the sum of the individual 


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durations of exposure as defined in Section 3.3.1, divided by 365.25. To each duration 
15 days of follow-up will be added.

TEAEs by SOC, PT and maximum reported intensity:
Frequency distribution of the below groups of TEAEs (one table for each grouping) 
sorted by international order for SOC and alphabetical order for PT and “mild”, 
“moderate”, “severe” for intensity. The number of subjects with at least one TEAE in 
the category will be reported in the top row of the table.
o
Any TEAE
o
Any TESAE

TEAEs by SOC, PT and investigator's causality assessment:
Frequency distribution of the below groups of TEAEs (one table for each grouping) 
sorted by international order for SOC and alphabetical order for PT and “Not related and 
“Possibly Related” for causality. Each subject will be represented by the maximum 
reported causality for each PT. The number of subjects with at least one AE in each of 
the below category will be reported as top row of the table. 
o
Any TEAE
o
Any TESAE

TEAEs by SOC, PT and outcome:
Frequency distribution of TEAE by SOC, PT and outcome, sorted by international order 
for 
SOC 
and 
alphabetical 
order 
for 
PT 
and 
“recovered/resolved”, 
“recovering/resolving”, “recovered/resolved with sequelae”, “not recovered/not 
resolved”, “fatal” for outcome. Each subject will be represented by the worst outcome 
for each PT. The number of subjects with at least one TEAE will be reported as top row 
of the table. 

Key subject information in listings:
The following key information will be reported for each individual subject: treatment 
group, subject identifier, sex, age at screening visit, SOC, PT, term as reported by the 
investigator, treatment period (pre-, on-, or post-treatment) days from first dose to onset 
of AE, days from last dose to onset of the AE, whether subject received treatment for 
the AE, whether there is a reasonable possibility as assessed by the investigator that the 
AE is causally related to the IP. 
The output will be generated for the following AE groups:
o
Any AE with outcome of death (includes days from first dose to death)
o
Any TESAE (includes days from first dose to becoming serious, outcome, and 
action taken with IP. SAEs which are not TEAEs will be flagged)


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o
Any TEAE leading to discontinuation of IP (includes seriousness, outcome)

Non-serious TEAEs occurring in greater than 5% of subjects:
Frequency distribution by SOC and PT of all the TEAEs with a total frequency of >5% 
(in any treatment group) sorted by international order for SOC and alphabetically for 
PT. The number of subjects with at least one TEAE, the number of subjects with at least 
one non-serious TEAE and the number of subjects with at least one non-serious TEAE 
at the threshold cut-off greater than 5% will be reported in the top rows of the table.

AESIs and MACE by SMQ, SOC and PT: 
Frequency distribution (patient counts, percentages and event rates) of the below groups 
of AEs (one table for each grouping) sorted by alphabetical order for SMQ, international 
order for SOC and alphabetically for PT. The number of subjects with at least one AE 
in the below categories will be reported as top row of the table. 
o
Any treatment-emergent cardiac and cerebrovascular AESI
o
Any treatment-emergent anticholinergic AESI
o
Any treatment-emergent β2 adrenergic AESI
o
Any treatment-emergent pneumonia AESI
o
Any treatment-emergent MACE 

Key AESI and MACE information in listings:
The following information will be reported for each individual subject: treatment group, 
subject identifier, sex, age at screening visit, SMQ, SOC, PT, Adjudication Conclusion 
from Cardiovascular Adjudication Committee (CVAC), treatment period (pre-, on-, or 
post-treatment), treatment period (pre-, on-, or post-treatment), seriousness, intensity, 
whether there is a reasonable possibility as assessed by the investigator that the AE is 
causally related to the IP, outcome and action taken with IP . The output will be repeated 
for the following AE groups:
o
Any treatment-emergent cardiac and cerebrovascular AESI
o
Any treatment-emergent MACE 
Treatment policy (on-study) SAEs:
The following summaries will be produced using a format similar to the corresponding TEAE 
summary:

Any post-treatment SAE by SOC and PT

Any post-treatment SAE by SOC, PT and maximum reported intensity

Any post-treatment SAE by SOC, PT and investigator’s causality assessment
All AEs and SAEs (including TEAEs and post-treatment AEs) will be listed and events flagged, 
as required. For all displays, the MedDRA version used will be shown as footnote.


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Laboratory Data, Vital Signs and ECG 
Absolute values and changes from baseline of all laboratory (haematology and biochemistry), 
vital signs and ECG parameters will be tabulated for each study visit and timepoint (if 
applicable) by treatment group using the standards descriptive statistics. For baseline, only 
absolute values will be summarized.
The number and percentage of ECG abnormal findings not present at baseline (rhythm, ectopy, 
conduction, morphology, myocardial infarction, ST segment, T wave and U wave observations) 
will be reported by finding, parameter, timepoint for each treatment group. Denominator for 
percentages will be the number of subjects with available baseline and at least one post-baseline 
assessment at a specific visit.
Contingency tables of the treatment-emergent potentially clinically significant abnormalities in 
haematology, biochemistry, vital signs and ECG will be produced: the number and incidence of 
subjects with at least one PCS shift from baseline will be summarised at each post-baseline 
study visit/timepoint and at any visit (i.e. at least once from start of treatment). Incidence rates 
will be calculated as the number of subjects in a specific PCS shift category over the number of 
subjects with a baseline value and an assessment made at the specific visit. For the laboratory 
parameters the shift categories will be: New / Decrease, New / Increase, Total New, Worsening 
/ Decrease, Worsening / Increase, Total Worsening, Notable < Lower Limit, Notable > Upper 
Limit, Total Notable. The shift categories will be high and low for vital signs, and criterion 1 or 
criterion 2 for ECG.
Moreover, for each subject with a treatment-emergent PCS abnormality in haematology or 
biochemistry, the following key information will be tabulated: treatment group, subject 
identifier, sex, age at screening visit, study visit, abnormal laboratory variable name and SI unit, 
value, whether it is low (L) or high (H) according to the ENR, whether it is new or worsened, 
whether it is notable, and the related ENR, notable abnormalities range. For laboratory 
variables, values classified as clinically significant, as assessed by the investigator, will be 
flagged.
Listings of all TEAEs for subjects with PCS values for laboratory data; vital signs and ECG 
will also be provided. For laboratory data, the number and percentage of subjects with a result 
classified as abnormally clinically relevant by the investigator will be tabulated by study visit 
and treatment group for each parameter. In addition, a listing of TEAEs for subjects with 
abnormal clinically relevant results will be provided.  For labs, the high and low alerts flagged 
by the investigator will not be listed, although they are collected on the eCRF.
For ECG, the distribution of the Global evaluation from the cardiologist (interpretation 
variable) will be summarised by visit and timepoint (where applicable) with counts and 
percentages by treatment group. The number and percentage of patients with any ECG 
(performed within a visit) classified as abnormal clinically relevant by the investigator will be 
tabulated by visit, timepont, and treatment group. In addition, a listing of TEAEs for those 
patients included in the previous table will be provided.


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Drug Induced Liver Injury (DILI) and Possible Hy’s Law (PHL)
A contingency frequency table for the maximum treatment-emergent liver biochemistry value 
will be presented to assess the DILI and PHL criteria comparing ALT and AST categories (< 
3xULN, ≥3xULN - <5xULN, ≥5xULN - <10xULN, ≥10xULN - <20xULN. ≥20xULN) versus 
the TBL categories (< 2xULN and ≥ 2xULN).
Furthermore, two scatter plots will be produced (one for ALT and one for AST) plotting the 
maximum post-baseline ALT/AST versus the maximum post-baseline TBL values, all 
expressed as xULN and on a log scale.  Reference line will be added as dotted lines at 3xULN 
of ALT/AST and 2xULN of TBL, which will be explained in a footnote.
For subjects with ALT/AST ≥3xULN together with TBL ≥ 2xULN (regardless of the time-
relationship between transaminases and TBL), the following key information will be tabulated: 
treatment group, subject identifier, sex, age at screening visit, study visit, treatment 
discontinuation day, ALT, AST, TBL, and ALP values, all expressed both in their SI-units and 
as xULN.
Pregnancy test data will be only listed and not summarized. 
4.6 Statistical Considerations for Analyses
Graphical Representations and Plots
Graphical displays will be presented for primary and secondary endpoints  in addition to the 
corresponding summary/analysis tables.
For example, the adjusted by-visit LS means of the primary and secondary variables will be 
plotted over time (in weeks) along with their 95% CIs. A reference horizontal line on zero will 
be also plotted to show the point of no change from baseline. 
When plots are to be compared, the same scale (minimum and maximum axis values) will be 
used. 
Selection of Spirometry Data (Best Test Review)
For all spirometric parameters, the Best Test Review (BTR) process done by a eResearch 
Technology clinical specialist will be utilized. Unacceptable values after BTR coded as 
BF410=”YES” for FEV1 and FVC will be treated as missing.
Repeated and unscheduled assessments or visits
Efficacy analysis:
Repeated assessments/visits will be used for analysis. With the exception of COPD 
exacerbations, efficacy data obtained during unscheduled and premature discontinuation visits 
(at EOT or EOS visits) will not be statistically analysed, since they are aimed to patient 
monitoring purposes only. However, these data will be listed.

For repeated assessments/visits, the spirometry observation from the last repeated 
assessment/visit will be used in statistical analyses (both pre and post IP intake). 


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
Questionnaires: In case of repeated questionnaires (SGRQ, TDI, CAT, E-RS,  and 
rescue medication), the first one will be used for analysis.
Safety analysis:
Repeated assessments/visits will be used for analysis as follow:

Before treatment intake: the last observation will be used in statistical analyses

After treatment intake: the first observation will be used in statistical analyses

Aberrant / non-interpretable values: the value will be excluded from the analyses

For presentations that select a single ‘at any visit’ observation per subject (e.g., 
abnormal lab values over the course of the trial), scheduled and unscheduled visit data 
will be included in any table and plot. 
Repeated, unscheduled, and early termination visits (EOT/EOS) assessments will be listed.
Imputing Missing Event Dates
Imputed dates will not be shown in subject-data listings and will not be used to calculate 
durations of events. The only purpose will be to categorise whether an event, such as an AE or 
a medication or an exacerbation, is treatment-emergent. 
The following rules will be applied:

When the start date and the end date are both incomplete, the imputation of the start date 
will be the first step.

If the imputed start date is after the complete end date (or the date the AE becomes 
serious), then the start date will be set to the end date (or the date when the AE becomes 
serious). 

If the imputed end date is before the start date (imputed or non-imputed), then the end 
date will be set to the start date. If the end date is after the AE becomes serious (if 
applies), then the end date will be set to the date when the AE becomes serious.
Imputation rules for an event start date based on the first IP dose date 

If the start date is completely missing or only the year is missing, it will be imputed with 
the event end date/year or the first dose date/year, whichever occurs earlier. If the event 
start date is completely missing, the event end date is partially missing (only info of the 
month and year is available), and the first IP date is completely known (i.e., 
day/month/year):
o
If the first IP occurs on the same month and year than the event end date, then, 
use the first IP date to impute the event start date.
o
If the month of the event end date occurs firstly, then use the event end date 
considering the last day of that month (i.e. usually 30 or 31th) to impute the event 
start date.

If the start year is not missing but the month is missing, then the following will be 
imputed:


Statistical Analysis Plan 
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o
if the start year is prior to the year of first dose, then December 31 will be used
o
if the start year is equal to the year of first dose, then the month and day of first 
dose will be assigned 
o
otherwise, January 1 will be assigned to the missing fields

If only the start day is missing, then the following will be imputed: 
o if month and year are the same as the first dose, then the day of the first dose will be 
assigned. 
o if the year is prior to the year of the first dose or the years are the same but the 
month is prior to first dose, then last day of the month will be used. 
o If the year is after the first dose date or the years are the same but the month is after 
to first dose, then first day of the month will be used.
Imputation rules for an event end date based on the last IP dose date

If the end date is completely missing or only the year is missing, it will be imputed with 
the last dose date/year or the event start date/year, whichever occurs later. If the one 
which occurs later results to be the event start date but this date is partially missing, we 
will use this event start date with day = 1 (when only the day is missing) or January 1rst 
(when month and day are missing) to impute the event end date.

If the end year is not missing but the month is missing, then the following will be 
imputed: 
o if the end year is prior to the year of last dose, then December 31 will be used 
o if the end year is equal to the year of last dose then the month and day of the last 
dose will be assigned
o otherwise, January 1 will be assigned to the missing fields

If only the end day is missing, then the following will be imputed: 
o if month and year are the same as the last dose, then the day of the last dose will be 
assigned
o if the year is prior to of last dose or the years are the same but the month is prior to 
last dose, then last day of the month will be used 
o If the year is after last dose date or the years are the same but the month is after to 
last dose, then first day of the month will be used
If an analysis needs to be done using a treatment policy (on-study) approach (i.e. by including 
post-treatment data), the imputation of the end dates will be based on the last on-site visit date 
instead.
Imputation of Missing Data 
In general, missing values in the efficacy endpoints will not be imputed (direct likelihood 
approach will be used). For the derivation of endpoints for summary tables and analysis, existing 
missing data will be imputed using the given methods below. Imputed values will not be shown 
in the subject-data listings.
Sensitivity analysis is given in Section 4.8.


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Pre and Post- FEV1 and FVC at Screening.
Screening FEV1 pre- and post-bronchodilator will be imputed as follows:

If pre-bronchodilator value (at screening visit) is missing, then the baseline value will 
be used as the pre-bronchodilator value. 

If post-bronchodilator value (at screening visit) is missing, it will be imputed after 
imputation is performed for pre-bronchodilator value. Missing post-bronchodilator 
value will be imputed by the pre-bronchodilator of the ith patient plus the mean 
absolute reversibility of all subjects (whole sample).
The same approach will be used for screening FVC pre- and post-bronchodilator.
Where it is necessary to impute the screening FEV1 pre- and/or post-bronchodilator, the 
following PFT quantities at Screening will be imputed:

FEV1/FVC ratio pre-bronchodilator (%) derived as:
100 x FEV1 (pre-bronchodilator) / FVC (pre-bronchodilator)

FEV1/FVC ratio post-bronchodilator (%) derived as:
100 x FEV1 (post-bronchodilator) / FVC (post -bronchodilator)

Screening absolute FEV1 bronchial reversibility (mL) derived as: 
FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator)

Screening percentage of FEV1 bronchial reversibility (%) derived as: 
100 x [absolute FEV1 bronchial reversibility / FEV1 (pre-bronchodilator)]
Questionnaire Data

Imputation methods for missing responses for the SGRQ are handled as described in 
Appendix 4.

Details about how to handle the BDI and TDI scores are described in Appendix 3.
No other questionnaire data will be imputed.
Safety and Exacerbation Data
The following imputation will be done on AE data as well as on the HCRU COPD exacerbations 
for the summary statistics and inferential analyses:

events with missing intensity will be imputed as severe. 

events with missing relationship to study drug will be deemed as definitely related. 
The following imputation will be done on laboratory data (haematology and biochemistry) for 
the summary statistics and for the PCS categorisation:

Any parameter value reported as ‘< xx.x’ or ‘≤ xx.x’ will be imputed with half of xx.x


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
Any laboratory values reported as ‘> xx.x’ or ‘≥xx.x’ will be imputed with 1.5 times 
xx.x
Professional duplicate subjects
Professional subjects are individuals who, in violation of protocol entrance criteria, enter into 
the study more than once at the same or in close succession.
During the trial, a Centralized Statistical Monitoring (CSM) Analysis Plan will be performed 
analyses performed. One of the objectives of the CSM analysis plan is to detect professional 
subjects. 
Unless otherwise stated, data from the first instance of the patient entering the trial is used in 
analyses and summary tables. All data is listed for transparency, with flags for duplicate subjects 
to ensure clarity which records are in/out of the analysis. 
For AEs, if a subject is on the same treatment throughout (across all instances), include all 
data in the analysis. If the patient is on different randomised treatments, the first instance of 
the subject entering the trial is used in analyses.
4.7 Subgroup Analyses
To explore the homogeneity of these results efficacy of AB/FF 400/12 and AB 400 over placebo 
across subgroups all the primary and secondary analyses will be carried out by the following 
subgroups:

Sub-population (China and non-China)

Sex (Male, Female)

Age Group (< 65, ≥ 65 years old)

Smoking Status (Current smoker, Former smoker)

Screening Bronchodilator Reversibility (Reversible, Non-reversible)

Baseline COPD Severity based on airflow limitation (mild-moderate, severe-very 
severe)

Baseline ICS Use (Yes, No)
Information on how to derive the above categorisations can be found in Section 3. If less than 
5% of subjects are included in a pre-specified subgroup category, categories may be combined 
or removed for a meaningful analysis. Subjects with missing values for the subgroup variables 
will be excluded from the subgroup analyses.
The descriptive and inferential analyses will be repeated by subgroup for the following main 
endpoints:

Change from baseline in 1-h morning post-dose FEV1 at Week 24

Change from baseline in morning pre-dose FEV1 at Week 24

Change from baseline in peak FEV1 at Week 24


Statistical Analysis Plan 
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
TDI focal score at Week 24

Change from baseline in SGRQ total score at Week 24
For each endpoints, analysis will be performed using the same MMRM model described  for 
the main analysis including the subgroup as a factor in the statistical model, if not already 
included. Also, in addition to the treatment-by-visit interaction term which is already included 
in the original model, treatment-by-subgroup, visit-by-subgroup, and treatment-by-visit-by-
subgroup interactions will be added as fixed effect factors. 
In addition, the estimate, 95% CI and p-value of testing the homogeneity between subgroup 
levels of AB/FF 400/12 vs. placebo, and AB 400 vs. placebo at Week 24, will be obtained 
through contrasts of hypothesis by using lsmestimate statement in PROC MIXED. The 
resulting SAS code and LSMESTIMATE statement for the comparisons between AB/FF 
400/12 and AB 400 and placebo are provided in Appendix 9.
For each level of a subgroup, estimate of treatment effect and 95% CI and, for and the 
pairwise comparisons of AB/FF 400/12 versus placebo and AB 400 versus placebo the 
estimate of difference, 95% CI and p-value will be reported from the treatment-by-visit-by-
subgroup interaction at Week 24. For the comparison between the two levels of each 
subgroup, estimate, 95% CI and p-value will be presented.
The adjusted LS Mean differences between AB/FF 400/12 versus Placebo and AB 400 versus 
Placebo at Week 24 in all subgroups will be shown in a single forest plot along with their 95% 
CIs. Values for the LS mean differences and 95% CI will be presented to the right of the plot. 
Within each forest plot, all the subgroup results will be compared to the results produced for the 
whole population (all subjects) which is extracted from the main analysis, that will be shown 
on the top of the plot. Number of subjects in each subgroup for a given treatment group, along 
with the corresponding change from baseline LS mean estimate at Week 24, will be presented 
to the left of the plot. The plot will show a reference vertical line on zero for the point of no 
treatment differences, with effect estimates on the right hand of the reference line favouring the 
fixed-dose combination. For the SGRQ total score, the interpretation of the results will be the 
opposite, with negative values on the left hand of the reference line favouring the active 
treatment.
All the above subgroup analyses are exploratory, and thus any statistically significant effect will 
be interpreted as nominally significant.
4.8 Sensitivity Analyses
Sensitivity analyses will be performed to assess the robustness of the analysis of primary and 
secondary continuous endpoints to the assumptions made when defining the while on treatment 
estimands for the study. 
All sensitivity analyses will be performed on the ITT and performed using the multiple 
imputation (MI) model. The results of these analyses will provide information whether or not 
these assumptions have an impact on the main study conclusions.


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Multiple Imputation Models
The missing values will be imputed for the sensitivity analyses on primary and secondary 
endpoints using MI.
The MI method can be summarised in three steps, imputation phase, analysis phase and pooling 
phase: 

Imputation phase 
By means of the MI SAS procedure PROC MI, 25 copies of the original dataset will be 
simulated with random seed= 54321, where missing continuous endpoint values will be 
replaced with a 2-step imputation process. 
The first step will be to impute non-monotone missing data (‘holes’ while on treatment) by 
treatment group. These will be imputed under the MAR assumption by means of a 
multivariate joint Gaussian imputation model using the stochastic Markov Chain Monte Carlo 
(MCMC) method. In the VAR statement of the PROC MI, screening and baseline variables 
should be ordered in such a way as to create a dataset with monotone missing values only 
following MCMC imputation. If there are no missing values for screening and baseline 
variables, then the suggested order is: pre-bronchodilator FEV1 at screening; post-
bronchodilator FEV1 at screening; age; country; smoking status and then baseline value for 
PFT endpoints and age; country; smoking status and then baseline value for TDI and SGRQ 
endpoints.The second step is impute the remaining post-treatment discontinuation monotone 
missing values using a sequential (visit-by-visit) regression model based on the Copy 
Reference (CR) approach (Section 4.8.2) that assume that data are Missing-Not-At-Random 
(MNAR) (O´Kelly M, Ratitch B).
All imputation models should be at least as complex as the analysis model. All fixed effects 
used to adjust the analysis model will be therefore be included in the MCMC model and the 
sequential regression models. Since the MCMC method models all variables as continuous, it 
will be necessary to code all factors as numerical.  

Analysis phase 
After the imputation phase, the same MMRM of the main analysis will be applied to the 25 fully 
imputed datasets to estimate the LS means and LS mean differences, one set of estimates for 
each imputed dataset.

Pooling phase 
The treatment effects and treatment differences for each visit from the results from 25 datasets 
will be combined to produce the study results, using the SAS procedure PROC MIANALYZE.
SAS code will be provided to the programmers for the MI algorithms.


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Copy Reference (CR) Approach
The CR approach is a conditional sequential regression method based on the MNAR assumption 
that, after discontinuation, subjects in the experimental arm will no longer benefit from 
treatment and will be assumed to continue as if they were on the reference arm. 
According to this approach, missing data in the treatment arm of interest at a certain visit will 
be imputed using the estimated means in the reference arm. For change from baseline at 1h post-
dose FEV1, the treatment arm of interest is AB/FF 400/12 and the reference arm will be AB 
400. For change from baseline in trough FEV1., the treatment arms of interest will be AB/FF 
400/12 and AB 400 using reference arms of FF 12 and Placebo respectively. For change from 
baseline in peak FEV1, the treatment arm of interest will be AB 400, using Placebo as the 
reference arm. For TDI and SGRQ, the treatment arms of interest will be AB/FF 400/12 and 
AB 400, using Placebo as the reference arm for both. Imputation at each visit will be conditional 
on the subjects’ outcomes observed or imputed at previous visit. 
4.9 COVID-19 Analyses
For subjects in China, any date before 09 January 2020 is considered prior to the start of the 
COVID-19 pandemic, and any date on or following this time is considered post start of 
COVID-19 pandemic. For subjects in all other countries, any date before 11 March 2020 is 
considered prior to the start of the COVID-19 pandemic, and any date on or following this 
time is considered post start of COVID-19 pandemic.
Disruption due to the COVID-19 Pandemic
A summary table of disruptions due to COVID-19 will be produced for the Randomised 
Analysis Set and will display the number and percentage of subjects randomised prior to the 
start of the COVID-19 pandemic and post start of the COVID-19 pandemic by treatment 
group and for the overall total. For those randomised prior to the start of the pandemic, 
additional rows will be included to summarise the number and percentage no longer in the 
study at the start of the pandemic and the number and percentage still ongoing at the start of 
the pandemic.
Also included in this summary table will be the number and percentage of subjects with at 
least 1 disruption (i.e. visit impacted, study drug disrupted or discontinued, withdrawal from 
study) due to the COVID-19 pandemic by treatment group and for the overall total. For 
subjects with at least 1 disruption, the number and percentage will be additionally split by the 
following disruption categories:

Scheduled visit impacted

Study drug impacted 

Discontinued treatment due to COVID-19

Withdrew from study due to COVID-19






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7
REFERENCES
Beunckens C, Molenberghs G and Kenward MG. Direct likelihood analysis versus simple 
forms of imputation for missing data in randomized clinical trials. Clinical Trials 2005; 2: 
379–86.
EXACT-RS Initiative, Evidera; E-RS (EXACT-Respiratory Symptoms) User Manual, 
Version 3.0; October 2014. Available at: http://www.ema.europa.eu.
FDA; Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation; 
2009. Available at: https://www.fda.gov/downloads/Guidances/UCM174090.pdf
GOLD 2015, Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global 
strategy for the diagnosis, management and prevention of chronic obstructive pulmonary 
disease. Medical Communications Resources, Inc; 2015. Available at: 
http://www.goldcopd.org.
Jones P W, Forde Y; St George’s Respiratory Questionnaire Manual, Version 2.3; June 2009. 
Available at: http://www.healthstatus.sgul.ac.uk.
O´Kelly M, Ratitch B; Clinical Trial with Missing Data: A Guide for Practitioners, Wiley; 
March 2014.








Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
80
8.2 Appendix  2: All Important Protocol deviations (IPDs) with those 
leading to exclusion from the Per Protocol analysis
There are 7 ‘PD Coded terms’ for classifying IPDs:
- Inc/Excl criteria
- Disallowed medications
- IP admin/Study treat
- Procedures/Tests
- Developed discontinuation criteria but continued
- Informed Consent
- Other
Within each ‘PD Coded Term’ there is a detailed list of all ‘IPD Terms’ and the corresponding 
‘Description’. This classification can be found in the Protocol Deviations Specifications. In 
addition, the following table shows the criterion used to exclude terms ‘Yes/No’ from  PP 
population. PP exclusion terms will be also applied to IPDs related with the COVID-19 
outbreak (IPD terms PD082a, PD099a and PD118a in the table below).


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
 
 
 
 
 
 
 
 
 
 
 
PD Coded Term
IPD Term
Description
PP Exclusion
Inc/Excl criteria
PD001
Subject Randomized 
without fulfilling the 
inclusion criteria #1: 
Adult male or non-
pregnant, non-lactating 
female patients aged ≥40
No
PD002
Subject Randomized 
without fulfilling the 
inclusion criteria #2: 
Patients with a diagnosis 
of COPD (GOLD 
guidelines, 2015) prior to 
Visit 1 (screening)
Yes
PD003
Subject Randomized 
without fulfilling the 
inclusion criteria #3: 
Moderate to severe stable 
COPD (Stage II or Stage 
III) at Visit 1: post-
bronchodilator FEV1
≥30% and < 80% and 
FEV1/FVC < 70%
Yes
PD004
Subject Randomized 
without fulfilling the 
inclusion criteria #4: 
Current or former 
smokers with a smoking 
history of ≥ 10 pack-years
No
PD005
Subject Randomized 
without fulfilling the 
inclusion criteria #5: Able 
to perform repeatable 
pulmonary function 
testing for FEV1 at Visit 
1(screening)
Yes
PD006
Subject Randomized 
without fulfilling the 
inclusion criteria #6: 
Patients who understand 
the study procedures and 
are willing to participate 
in the study as indicated 
No


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
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Date: 06 May 2022
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by signing the informed 
consent
PD008
Subject Randomized 
fulfilling the exclusion 
criteria #24: Patients 
unable to give consent, or 
patients of consenting age 
but under guardianship, or 
vulnerable patients
No
PD009, 
PD010, 
PD011,
PD014, 
PD015, 
PD016, 
PD017, 
PD018, 
PD019, 
PD020, 
PD021, 
PD025, 
PD027, 
PD030, 
PD134
Subject Randomized 
fulfilling the exclusion 
criteria #23: Patient did 
not undergo the required 
washout prior to V1 for 
different medications as 
specified in the Protocol 
Deviation Specification 
Form
No
PD012, 
PD013, 
PD023, 
PD024, 
PD124, 
PD125, 
PD126
Subject Randomized 
fulfilling the exclusion 
criteria #23: Patient did 
not undergo the required 
washout prior to V1 for 
different medications as 
specified in the Protocol 
Deviation Specification 
Form
Yes
PD031
Subject Randomized 
fulfilling the exclusion 
criteria #22: Patients 
treated with any 
investigational drug 
within 30 days (or 6 half-
lives, whichever is longer) 
prior to screening
No
PD034
Subject Randomized 
fulfilling the exclusion 
criteria #19: Any other 
No


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
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Date: 06 May 2022
83
serious or uncontrolled 
physical or mental 
dysfunction
PD035
Subject Randomized 
fulfilling the exclusion 
criteria #18: History of 
malignancy of any organ 
system (including lung 
cancer) within the past 5 
years, other than basal or 
squamous cell skin cancer
No
PD036
Subject Randomized 
fulfilling the exclusion 
criteria #17: Known 
narrow-angle glaucoma, 
symptomatic bladder neck 
obstruction, acute urinary 
retention, symptomatic 
non-stable prostatic 
hypertrophy
No
PD037
Subject Randomized 
fulfilling the exclusion 
criteria #16: History of 
hypersensitivity reaction 
to inhaled anticholinergic 
drugs, sympathomimetic 
amines, inhaled 
medication or any 
component
No
PD038
Subject Randomized 
fulfilling the exclusion 
criteria #15: Patient with 
known non-controlled 
history of infection with 
human immunodeficiency 
virus and/or active 
hepatitis  
No
PD039
Subject Randomized 
fulfilling the exclusion 
criteria #14: Abnormal 
liver function tests 
defined as AST, ALT, or 
total bilirubin ≥ 2.5 times 
No


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
84
upper limit of normal 
ranges at screening
PD041
Subject Randomized 
fulfilling the exclusion 
criteria #12: QT corrected 
interval (QTc) using 
Fridericia formula (QTcF) 
(QTc=QT/RR1/3) >470 
msec at Screening (Visit 
1)
No
PD042
Subject Randomized 
fulfilling exclusion 
criteria #11: Type I or 
uncontrolled Type II 
diabetes, uncontrolled 
hypo-or hyperthyroidism, 
hypokalaemia, 
hyperadrenergic state, 
uncontrolled or untreated 
hypertension
No
PD043
Subject Randomized 
fulfilling the exclusion 
criteria #10: Clinically 
significant cardiovascular 
conditions
No
PD046
Subject Randomized 
fulfilling the exclusion 
criteria #7: Patients who 
in the Investigator’s 
opinion may need to start 
a pulmonary rehabilitation 
program during the study 
and/or patients who 
started/finished it within 3 
months prior to screening
Yes
PD047
Subject Randomized 
fulfilling the exclusion 
criteria #6: Clinically 
significant respiratory 
conditions other than 
COPD
Yes
PD048
Subject Randomized 
fulfilling the exclusion 
Yes


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
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Date: 06 May 2022
85
criteria #5: Patients 
hospitalized for COPD 
exacerbation within 3 
months prior to screening 
and during the run-in 
period
PD049
Subject Randomized 
fulfilling the exclusion 
criteria #4: Any 
respiratory tract infection 
or COPD exacerbation 
within 6 weeks prior to 
screening or during the 
run-in period
Yes
PD050
Subject Randomized 
fulfilling the exclusion 
criteria #3: History or 
current diagnosis of 
asthma
Yes
PD051
Subject Randomized 
fulfilling the exclusion 
criteria #2: Previous 
enrolment or 
randomisation in the 
present study
No
Disallowed 
medications
PD053a
Subject took prohibited 
medication at V2 or V7: 
Medication X  YYYY*, 
Dose XX, Frequency XX 
taken between DD-
MMM-YYYY and DD-
MMM-YYYY
Yes
PD129
Subject receiving a 
restricted medication X 
YYYY*, changed either 
daily dose, dosing 
schedule, formulation or 
treatment during the 
course of the trial with 
reason other than COPD 
exacerbation
Yes
IP admin/Study treat
PD054
The subject did not follow 
the dose regimen for the 
No


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
86
IMP according to the 
protocol taking more IMP 
doses than expected: >125 
% of expected doses taken
PD055
Patient received expired 
IMP kit
Yes
PD056
The IMP was not stored 
according to the 
temperature conditions 
stated in the protocol and 
the IMP manuals, AND 
This IMP was given to a 
subject
Yes
PD058
The subject did not follow 
the dose regimen for the 
IMP according to the 
protocol: <70 % 
compliance
Yes
PD059
Subject was 
dispensed/administered 
the wrong kit of 
medication (kit xx 
dispensed instead of kit 
yy)
Yes
PD060
Patient is a screening 
failure, however patient 
received study drug
Yes
Procedures/Tests
PD070
SAE was not reported 
within 24 hours as per the 
protocol requirement
No
PD073
ECG assessments were 
not performed at Visit 1 
and not available in 
source document but 
patient was randomized
No
PD074
Pre-dose ECG 
assessments were not 
performed at Visit 2 and 
not available in source 
document
No


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
87
PD077
Blood pressure 
assessments were not 
performed at Visit 1 and 
not available in source 
document but patient was 
randomised
No
PD078
Pre-dose Blood pressure 
assessments were not 
performed at Visit 2 and 
not available in source 
document but patient was 
randomised
No
PD082, 
PD082a
Patient is randomised but 
the Pregnancy Test was 
not done at Visit X for a 
female patient of 
childbearing potential
No
PD083
Pre dose Spirometry was 
not done at Visit 1 but 
patient was randomised
No
PD084
Pre dose Spirometry was 
not done at Visit 2 but 
patient was randomised
No
PD087
The Laboratory analysis 
(haematology and/or 
biochemistry) was not 
done at Visit 1 but patient 
was randomised
No
PD091
Physical exam not done at 
Visit 1 but patient was 
randomised
No
PD092
Bronchodilator test not 
done at Visit 1 but patient 
was randomised
No
PD098
Patient relief medication 
is not dispensed according 
to the protocol (upon ICF 
signature and as needed 
during the whole duration 
of the trial)
No


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
88
PD099, 
PD099a
Test xx was not 
performed according to 
the instructions given in 
the standard guidelines or 
per protocol requirements
No
PD107
There is no baseline FEV1
result available for a 
randomised patient
Yes
PD108
There is no baseline FVC 
result available for a 
randomised patient
No
PD109
There is no post -baseline 
FEV1 result available for 
a randomised patient
Yes
PD110
There is no post-baseline 
FVC result available for a 
randomised patient
No
PD111
Visit 3/4/5/6 performed 
while patient was affected 
by any mild COPD 
exacerbation or within 2 
weeks after mild COPD 
exacerbations recovery
No
PD112
Visit 3/4/5/6 performed 
while patient was affected 
by any moderate or severe 
COPD exacerbation or 
within 4 weeks after 
moderate/severe COPD 
exacerbations recovery
No
PD113
Patient performed Visit 7 
(efficacy assessments) 
while affected by a COPD 
exacerbation
Yes
PD115
Patient randomized in the 
wrong stratus strata (data 
from RTSM)
No
PD118, 
PD118a
Visit 7 is missing for a 
patient completing the 
treatment
No


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
89
Developed 
discontinuation 
criteria but continued
PD123
The pregnancy Test at 
Visit X was positive and 
patient was not withdrawn 
from the study
No
Informed Consent
PD128
Subject started study 
related procedures before 
signing the ICF: More 
than 1-day between 
stopping medications and 
ICF signature date
No
Other
PD120
GCP breach: any critical 
issue that may jeopardize 
the data reliability such as 
evidences of bad use of 
users credentials to access 
the electronic data 
collection tools, missing 
source documents or 
medical notes, clear 
evidences of 
data/documents/signatures 
falsification, etc
No
PD121
GCP breach: any critical 
issue related to the 
patients confidentiality 
(i.e. full name of the 
patient included in the 
databases)
No
PD122
GCP issue: poor quality 
of medical notes, a lot of 
missing data in medical 
notes, investigator did not 
review/sign tests results, 
investigator did not check 
treatment compliance or 
did not complete drug 
accountability, 
investigator did not 
follow-up a clinically 
significant abnormality to 
guarantee the patient 
safety, etc
No




Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
91
8.4 Appendix 4: SGRQ questionnaire 
As per the Note to File dated 21 October 2019, while the original UK English version of 
the SGRQ is attached to the CSP (Appendix G), the version used in the study database 
and described in this section is the US English version.
The SGRQ is composed of 50 items split into 17 parts, from which the following 
dimension scores will be derived:

Symptoms Score: derived from questions 1-8

Activity Score: derived from questions 11, 15

Impact Score: derived from questions 9-10, 12-14, 16-17
For each of the above SGRQ dimensions, the score is derived in the below 4 steps:

Sum up the weights for all questions with a response (sum of weights of positive 
items).

Sum up the weights for all questions with a missing response (sum of weights of 
missing items)

Deduct the possible maximum sum of weights from the sum of weights of missing 
items obtained at bullet point 2), where the maximum sum of weights for each 
dimension is:
o
Symptoms: 662.5
o
Activity: 1209.1
o
Impacts: 2117.8

Divide the sum of weights of positive items derived at bullet point 1) by the 
adjusted sum of weights for all items derived at bullet point 3):
7
8 = 1009
7: 
; <=ℎ? ;
8 @
?A :?  B:?

BC?B ?: 
; <=ℎ? ;
8 		 :?  B:

The SGRQ total score is calculated in a similar way:
7
8 = 1009
7: 
; <=ℎ? ;
8 @
?A :?  ℎ D?
8
BC?B ?: 
; <=ℎ? ;
8 		 :?  ℎ D?
8
The maximum sum of weights for the questionnaire (total) is: 3989.4
SGRQ total score summarizes the overall impact of COPD on patients’ quality of life. If 
any of the component scores is missing, total score will not be derived.
SGRQ scores range from 0 to 100, with higher SGRQ scores indicating a higher 
deterioration in patients’ health status.
Missing items will not be imputed except for the following cases and imputation will be 
performed before the derivation of scores:

If the response of question 6 is missing and the answer of question 5 is “no attacks”, 
then the question 6 response will be imputed to “less than a day”.


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
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
If the four items of question 14 are missing, their responses will be imputed to 
“false”.

If more than 2 items of the Symptoms dimension have missing response, the 
Symptom Score will be set to missing. 

If more than 4 items of the Activity dimension have missing response, the Activity 
Score will be set to missing. 

If more than 6 items of the Impacts dimension have missing response, the Impacts 
Score will be set to missing.
NOTES:
[1] If the response of question 6 is missing and the answer of question 5 is “no attacks”, 
then the question 6 response will be imputed to “less than a day”.
[2] If the four items of Section 5 are missing, their responses will be imputed to “false”.










Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
97
SGRQ Questionnaire (US English Version)


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
98


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
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Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
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Statistical Analysis Plan 
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Edition Number 3.0
Date: 06 May 2022
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Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
102


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
103
8.5 Appendix 5: COPD Assessment Test (CAT)
Patient-completed questionnaire assessing globally the impact of COPD (cough, sputum, 
dysnea, chest tighteness) on health status. The questionnaire has 8 item (one question 
assessing impact on sleep). 
Range of CAT scores from 0–40. Higher scores denote a more severe impact of COPD 
on a patient’s life. The difference between stable and exacerbation patients was five units. 
No target score represents the best achievable outcome.
In case of one (or more) question is missing, the CAT will be kept as missing and not 
calculated.










Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
108
8.7 Appendix 7: Derivation of COPD Exacerbations
Health Care Resource Utilization (HCRU) Exacerbations
HCRU exacerbations are evaluated by the investigator and recorded in the AE form of 
the EDC system at each protocol visit based on the information provided in the patients´ 
electronic and paper diaries. 
The intensity will be based on the following actions taken as recorded on the eCRF:
-
Mild: Increase of COPD symptoms during at least 2 consecutive days, self-managed 
by the patient at home by increasing usual COPD medication (short-acting and/or 
inhaled corticosteroid used.
-
Moderate: Increase of COPD symptoms during at least 2 consecutive days, which 
does not lead to hospitalization but is treated with antibiotics and/or systemic 
corticosteroids or an increase in dose of systemic corticosteroids.
-
Severe: Increase in COPD symptoms during at least 2 consecutive days, which leads 
to hospitalization (overnight stay at hospital or emergency room) or death.
If the above severity classes cannot be derived, intensity will be imputed as severe.
The Onset Day and the Recovery Day are the AE start and stop dates recorded on the 
eCRF.
For a COPD exacerbation to be counted as a separate event, it must be preceded by at 
least seven days in which no criteria for exacerbations is fulfilled. In case of relapse, the 
Recovery day for the resulting exacerbation is the Recovery day of the last episode and 
the onset day is the one from the first episode, and the severity of the resulting 
exacerbation will be that of the highest severity of the episodes.
Exacerbations of Chronic Pulmonary Disease Tool (EXACT) 
EXACT exacerbations are symptom-based exacerbations derived using the daily EXACT 
questionnaire. 
The following parameters must be derived:

EXACT Daily Scores
From the first IP dose date onwards.

EXACT Baseline Score
The mean of the EXACT Daily Scores recorded 7 days before the first IP dose 
day (excluded). If fewer than 4 days of data are available, the score will be set 
to missing. 

Onset Day
The first day (Day 1) of the worsening of the baseline condition, where 
worsening is defined by an increase from baseline in the EXACT Daily Score 
of either ≥12 points for 2 consecutive days, or ≥9 points for 3 consecutive 
days. 


Statistical Analysis Plan 
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
EXACT Rolling Scores
3-day (Dayx-1, Dayx, and Dayx+1) rolling averages of the EXACT Daily Scores 
from the Onset Day until last possible day. Only one of the 3 data points need 
to be present for this computation and therefore, a rolling average can still be 
calculated on days where EXACT Daily Scores are missing.  The rolling mean 
for the Onset Day will only include Day 1 and Day 2.

Maximum Observed Value (MOV)
The highest EXACT Rolling Score within 14 days from the Onset Day.

Recovery Day
The first day of the 7-day recovery period, where recovery is defined by a decrease from 
the MOV in the EXACT Rolling Score ≥9 points for 7 consecutive days. It is permitted 
for days where an EXACT Daily Score is missing, but an Exact Rolling Score is 
calculable, to be considered as the recovery day if the criteria for recovery, based on the 
MOV and EXACT Rolling Score, is met. 
The occurring of a score increase meeting the onset definition of point 3) identifies an 
EXACT exacerbation. 
For a COPD exacerbation to be counted as a separate event, it must be preceded by at 
least seven days in which no criteria for exacerbations is fulfilled. In case of relapse, the 
Recovery day for the resulting exacerbation is the Recovery day of the last episode and 
the onset day is the one from the first episode, and the severity of the resulting 
exacerbation will be that of the highest severity of the episodes.
The patient EXACT Baseline Score is reset following each exacerbation as the mean of 
the EXACT Daily Scores during the 4th week following recovery (22-28 days after the 
Recovery Day), with a required of minimum of 4 days of data. If the subject 
experiences new events (i.e. score increases meeting the onset criteria) during this 4-
week period, the EXACT Baseline Score will be calculated during the 4th week 
following the recovery from that last event. If no exacerbations occur, the EXACT 
Baseline Score will be reset every 28 exacerbation-free days. If less than 4 days data are 
available the baseline will not be re-established and the previous baseline will be used 
instead.


Statistical Analysis Plan 
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Edition Number 3.0
Date: 06 May 2022
110
8.8 Appendix 8: Annotated E-RS for Raw Score Assignment
The following domain scores will be derived:

E-RS Breathlessness score: sum the raw scores of questions 7-11 (ranging 0-17)

E-RS Cough and Sputum score: sum the raw scores of questions 2-4 (ranging 0-
11)

E-RS Chest Symptoms score: sum the raw scores of questions 1, 5-6 (ranging 0-
12)

E-RS Total Score: sum the raw scores of all questions 1-14 of the three domain 
scores. The E-RS total score ranges from 0 to 40, with higher scores indicating a 
higher symptom worsening
The following annotates the raw score values associated with each response category for the E-
RS items:
1. Did your chest feel congested today?
0. Not at all
1. Slightly
2. Moderately
3. Severely
4. Extremely
2. How often did you cough today?
0. Not at all
1. Rarely
2. Occasionally
3. Frequently
4. Almost constantly
3. How much mucus (phlegm) did you bring up when coughing today?


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0. None at all
1. A little
1. Some
2. A great deal
3. A very great deal
NOTE: Score “a little” and “some” the same.
4. How difficult was it to bring up mucus (phlegm) today?
0. Not at all
1. Slightly
2. Moderately
3. Quite a bit
4. Extremely
5. Did you have chest discomfort today?
0. Not at all
1. Slightly
2. Moderate
3. Severe
4. Extreme
6. Did your chest feel tight today?
0. Not at all
1. Slightly
2. Moderately
3. Severely
4. Extremely
7. Were you breathless today?
0. Not at all
1. Slightly
2. Moderately
3. Severely
4. Extremely
8. Describe how breathless you were today:
0. Unaware of breathlessness
1. Breathless during strenuous activity
2. Breathless during light activity
3. Breathless when washing or dressing
3. Present when resting
NOTE: Score “Breathless when washing or dressing” and “Present when resting” the same.
9. Were you short of breath today when performing your usual personal care activities like 
washing or dressing?
0. Not at all
1. Slightly
2. Moderately
3. Severely
3. Extremely
4. Too breathless to do these
NOTE: Score “severely” and “extremely” the same


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10. Were you short of breath today when performing your usual indoor activities like cleaning or 
household work?
0. Not at all
1. Slightly
2. Moderately
3. Severely
3. Extremely
3. Too breathless to do these
NOTE: Score “severely”, “extremely”, and “too breathless to do these” the same
11. Were you short of breath today when performing your usual activities outside the home such 
as yard work or errands?
0. Not at all
1. Slightly
2. Moderately
3. Severely
3. Extremely
3. Too breathless to do these
NOTE: Score “severely”, “extremely”, and “Too breathless to do these” the same.
Importantly, this simple summation is an entirely different measurement scale from that used in the EXACT, which 
includes three additional items and focuses on measuring the frequency, duration and severity of acute exacerbations. 
Given that the domains contained with the E-RS are nearly identical to that of the EXACT, it is critical that these 
domains are clearly distinguished from one another in studies using both scoring algorithms.


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0 
Date: 06 May 2022
 
 
 
 
 
 
 
 
 
 
 
8.9 Appendix 9: SAS code for subgroup analysis including contrasts of hypothesis
Subgroups:

Sub-population (China and non-China)

Sex (Male, Female)

Age Group (< 65, ≥ 65 years old)

Smoking Status (Current smoker, Former smoker)

Screening Bronchodilator Reversibility (Reversible, Non-reversible)

Baseline COPD Severity based on airflow limitation (mild-moderate, severe-very severe)

Baseline ICS Use (Yes, No)
Note that all subgroups have 2 Levels, Level 1, and Level 2.
Note1: subgroup factor must be included in the class statement in SAS unless it is already in the “by default” stats model
Note2: TRTPN, AVISITN, and SUBGROUP must be in this order in the class statement
1. Differences between Level 1 and Level 2 in change from baseline in 1-h morning post-dose FEV1 at week 24 
We consider 4 levels for the treatment in this order (A): AB/FF 400/12, AB 400, FF 12, placebo; 2 levels for the <<SUBGROUP>>
(B): Level 1, Level 2; and 6 levels for visits (C): day 1, week 1, week 4, week 12, week 18, and week 24. 
To compare AB/FF 400/12 versus placebo:
proc mixed data = <<dataset>> method=reml;
  class usubjid trt01pn <<subgroup>> smokstat country avisitn;
  model chg = base trt01pn <<pre>> <<post>> age <<subgroup>> smokstat country avisitn      
              trt01pn*avisitn trt01pn*<<subgroup>> avisitn*<<subgroup>>
              trt01pn*<<subgroup>>*avisitn
              / ddfm=kr;
  repeated avisitn / type=un subject=usubjid(trt01pn);
  lsmeans trt01pn*<<subgroup>>*avisitn / diff=all cl;
  lsmestimate trt01pn*<<subgroup>>*avisitn “Change from baseline in 1-h post-dose FEV1  
              of AB/FF 400/12 vs. placebo between <<Level 1>> and <<Level 2>> at week 24”


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
114
              0 0 0 0 0 1 0 0 0 0 0 -1 
              0 0 0 0 0 0 0 0 0 0 0 0  
              0 0 0 0 0 0 0 0 0 0 0 0  
              0 0 0 0 0 -1 0 0 0 0 0 1 
              / cl;
run;
To compare AB 400 versus placebo:
proc mixed data = <<dataset>> method=reml;
  class usubjid trt01pn <<subgroup>> smokstat country avisitn;
  model chg = base trt01pn <<pre>> <<post>> age <<subgroup>> smokstat country avisitn      
              trt01pn*avisitn trt01pn*<<subgroup>> avisitn*<<subgroup>>
              trt01pn*<<subgroup>>*avisitn
              / ddfm=kr;
  repeated avisitn / type=un subject=usubjid(trt01pn);
  lsmeans trt01pn*<<subgroup>>*avisitn / diff=all cl;
  lsmestimate trt01pn*<<subgroup>>*avisitn “Change from baseline in 1-h post-dose FEV1  
              of AB 400 vs. placebo between <<Level 1>> and <<Level 2>> at week 24”
              0 0 0 0 0 0 0 0 0 0 0 0 
              0 0 0 0 0 1 0 0 0 0 0 -1                     
              0 0 0 0 0 0 0 0 0 0 0 0  
              0 0 0 0 0 -1 0 0 0 0 0 1 
              / cl;
run;
2. Differences between Level 1 and Level 2 in change from baseline in trough FEV1 at week 24 
We consider 4 levels for the treatment in this order (A): AB/FF 400/12, AB 400, FF 12, placebo; 2 levels for the <<SUBGROUP>> 
(B): Level 1, Level 2; and 5 levels for visits (C): Week 1, Week 4, Week 12, Week 18, Week 24. 
To compare AB/FF 400/12 versus placebo:
proc mixed data = <<dataset>> method=reml;
  class usubjid trt01pn <<subgroup>> smokstat country avisitn;
  model chg = base trt01pn <<pre>> <<post>> age <<subgroup>> smokstat country avisitn      
              trt01pn*avisitn trt01pn*<<subgroup>> avisitn*<<subgroup>>
              trt01pn*<<subgroup>>*avisitn


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
115
              / ddfm=kr;
  repeated avisitn / type=un subject=usubjid(trt01pn);
  lsmeans trt01pn*<<subgroup>>*avisitn / diff=all cl;
  lsmestimate trt01pn*<<subgroup>>*avisitn “Change from baseline in trough FEV1 of AB/FF 400/12 vs. placebo between  
              <<Level 1>> and <<Level 2>> at week 24”
              0 0 0 0 1 0 0 0 0 -1  
              0 0 0 0 0 0 0 0 0 0   
              0 0 0 0 0 0 0 0 0 0   
              0 0 0 0 -1 0 0 0 0 1 
              / cl;
run;
To compare AB 400 versus placebo:
proc mixed data = <<dataset>> method=reml; 
  class usubjid trt01pn <<subgroup>> smokstat country avisitn;
  model chg = base trt01pn <<pre>> <<post>> age <<subgroup>> smokstat country avisitn      
              trt01pn*avisitn trt01pn*<<subgroup>> avisitn*<<subgroup>>
              trt01pn*<<subgroup>>*avisitn
              / ddfm=kr;
  repeated avisitn / type=un subject=usubjid(trt01pn);
  lsmeans trt01pn*<<subgroup>>*avisitn / diff=all cl;
  lsmestimate trt01pn*<<subgroup>>*avisitn “Change from baseline in trough FEV1  
              of AB 400 vs. placebo between <<Level 1>> and <<Level 2>> at week 24”
              0 0 0 0 0 0 0 0 0 0  
              0 0 0 0 1 0 0 0 0 -1   
              0 0 0 0 0 0 0 0 0 0   
              0 0 0 0 -1 0 0 0 0 1 
              / cl;
run;
3. Differences between Level 1 and Level 2 in change from baseline in peak FEV1 at week 24 
We consider 4 levels for the treatment in this order (A): AB/FF 400/12, AB 400, FF 12, placebo; 2 levels for the <<SUBGROUP>> 
(B): Level 1, Level 2; and 2 levels for visits (C): day 1, and week 24.


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
116
To compare AB/FF 400/12 versus placebo:
proc mixed data = <<dataset>> method=reml;
  class usubjid trt01pn <<subgroup>> smokstat country avisitn;
  model chg = base trt01pn <<pre>> <<post>> age <<subgroup>> smokstat country avisitn      
              trt01pn*avisitn trt01pn*<<subgroup>> avisitn*<<subgroup>>
              trt01pn*<<subgroup>>*avisitn
              / ddfm=kr;
  repeated avisitn / type=un subject=usubjid(trt01pn);
  lsmeans trt01pn*<<subgroup>>*avisitn / diff=all cl;
  lsmestimate trt01pn*<<subgroup>>*avisitn “Change from baseline in peak FEV1 of AB/FF 400/12 vs. placebo between  
              <<Level 1>> and <<Level 2>> at week 24”
              0 1 0 -1 
              0 0 0 0 
              0 0 0 0 
              0 -1 0 1 
              / cl;
run;
To compare AB 400 versus placebo:
proc mixed data = <<dataset>> method=reml;
  class usubjid trt01pn <<subgroup>> smokstat country avisitn;
  model chg = base trt01pn <<pre>> <<post>> age <<subgroup>> smokstat country avisitn      
              trt01pn*avisitn trt01pn*<<subgroup>> avisitn*<<subgroup>>
              trt01pn*<<subgroup>>*avisitn
              / ddfm=kr;
  repeated avisitn / type=un subject=usubjid(trt01pn);
  lsmeans trt01pn*<<subgroup>>*avisitn / diff=all cl;
  lsmestimate trt01pn*<<subgroup>>*avisitn “Change from baseline in peak FEV1  
              of AB 400 vs. placebo between <<Level 1>> and <<Level 2>> at week 24”
              0 0 0 0 
              0 1 0 -1 
              0 0 0 0 
              0 -1 0 1
              / cl;
run;


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
117
4. Differences between Level 1 and Level 2 in TDI focal score at week 24 
TDI and SGRQ main analyses are change from baseline. Therefore, the same MMRM model will be used. Except for that the baseline 
to use is the BDI and that pre and post bronchodilator covariates must not be included as covariates of adjustment
We consider 4 levels for the treatment in this order (A): AB/FF 400/12, AB 400, FF 12, placebo; 2 levels for the <<SUBGROUP>> 
(B): Level 1, Level 2; and 3 levels for visits (C): Week 4, Week 12, Week 24. 
To compare AB/FF 400/12 versus placebo:
proc mixed data = <<dataset>> method=reml;
  class usubjid trt01pn <<subgroup>> smokstat country avisitn;
  model aval = bdi trt01pn age <<subgroup>> smokstat country avisitn      
              trt01pn*avisitn trt01pn*<<subgroup>> avisitn*<<subgroup>>
              trt01pn*<<subgroup>>*avisitn
              / ddfm=kr;
  repeated avisitn / type=un subject=usubjid(trt01pn);
  lsmeans trt01pn*<<subgroup>>*avisitn / diff=all cl;
  lsmestimate trt01pn*<<subgroup>>*avisitn “TDI focal score of AB/FF 400/12 vs. placebo between  
              <<Level 1>> and <<Level 2>> at week 24”
              0 0 1 0 0 -1 
              0 0 0 0 0 0 
              0 0 0 0 0 0 
              0 0 -1 0 0 1 
              / cl;
run;
To compare AB 400 versus placebo:
proc mixed data = <<dataset>> method=reml;
  class usubjid trt01pn <<subgroup>> smokstat country avisitn;
  model aval = bdi trt01pn age <<subgroup>> smokstat country avisitn      
              trt01pn*avisitn trt01pn*<<subgroup>> avisitn*<<subgroup>>
              trt01pn*<<subgroup>>*avisitn
              / ddfm=kr;
  repeated avisitn / type=un subject=usubjid(trt01pn);
  lsmeans trt01pn*<<subgroup>>*avisitn / diff=all cl;


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
118
  lsmestimate trt01pn*<<subgroup>>*avisitn “TDI focal score of AB 400 vs. placebo between  
              <<Level 1>> and <<Level 2>> at week 24”
              0 0 0 0 0 0 
              0 0 1 0 0 -1 
              0 0 0 0 0 0 
              0 0 -1 0 0 1 
              / cl;
run;
5. Differences between Level 1 and Level 2 in change from baseline SGRQ total score at week 24 
We consider 4 levels for the treatment in this order (A): AB/FF 400/12, AB 400, FF 12, placebo; 2 levels for the <<SUBGROUP>> 
(B): Level 1, Level 2; and 3 levels for visits (C): Week 4, Week 12, Week 24. 
To compare AB/FF 400/12 versus placebo:
proc mixed data = <<dataset>> method=reml;
  class usubjid trt01pn <<subgroup>> smokstat country avisitn;
  model chg = base trt01pn age <<subgroup>> smokstat country avisitn      
              trt01pn*avisitn trt01pn*<<subgroup>> avisitn*<<subgroup>>
              trt01pn*<<subgroup>>*avisitn
              / ddfm=kr;
  repeated avisitn / type=un subject=usubjid(trt01pn);
  lsmeans trt01pn*<<subgroup>>*avisitn / diff=all cl;
  lsmestimate trt01pn*<<subgroup>>*avisitn “Change from baseline in SGRQ total score of AB/FF 400/12 vs. placebo  
              between <<Level 1>> and <<Level 2>> at week 24”
              0 0 1 0 0 -1 
              0 0 0 0 0 0 
              0 0 0 0 0 0 
              0 0 -1 0 0 1 
              / cl;
run;
To compare AB 400 versus placebo:


Statistical Analysis Plan 
Study Code D6570C00002 (M-AS464-30)
Edition Number 3.0
Date: 06 May 2022
119
proc mixed data = <<dataset>> method=reml;
  class usubjid trt01pn <<subgroup>> smokstat country avisitn;
  model chg = base trt01pn age <<subgroup>> smokstat country avisitn      
              trt01pn*avisitn trt01pn*<<subgroup>> avisitn*<<subgroup>>
              trt01pn*<<subgroup>>*avisitn
              / ddfm=kr;
  repeated avisitn / type=un subject=usubjid(trt01pn);
  lsmeans trt01pn*<<subgroup>>*avisitn / diff=all cl;
  lsmestimate trt01pn*<<subgroup>>*avisitn “Change from baseline in SGRQ total score of AB 400 vs. placebo  
              between <<Level 1>> and <<Level 2>> at week 24”
              0 0 0 0 0 0 
              0 0 1 0 0 -1 
              0 0 0 0 0 0 
              0 0 -1 0 0 1 
              / cl;
run;


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Document Name: d6570c00002-sap-ed-3
Document Title:
D6570C00002 Statistical Analysis Plan Edition 3
Document ID:
Doc ID-004867477
Version Label:
1.0 CURRENT LATEST APPROVED
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(dd-MMM-yyyy HH:mm ‘UTC’Z)
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Meaning of Signature
09-May-2022 16:20 UTC
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11-May-2022 09:34 UTC
Author Approval
09-May-2022 16:52 UTC
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