Conditions: COPD Chronic Obstructive Pulmonary Disease Moderate to Very Severe COPD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3635
Healthy volunteers: no

Brief summary:
The Objectives of this study are to assess the safety of Aclidinium bromide on major adverse cardiovascular events (MACE), to assess the overall safety of Aclidinium bromide and to assess whether Aclidinium bromide reduces moderate or severe COPD exacerbations. This study is a double-blind, randomized, placebo controlled, parallel-group study to evaluate the effect of Aclidinium bromide on the cardiovascular safety and COPD exacerbations in patients with moderate to very severe COPD, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.

Detailed description:

Arms:
arm 1: Two-week washout/run-in period \[for patients on a long-acting muscarinic antagonist (LAMA)\] followed by a maximum of 36-month double-blind treatment period. arm 2: Two-week washout/run-in period \[for patients on a long-acting muscarinic antagonist (LAMA)\] followed by a maximum of 36-month double-blind treatment period.

Interventions: intervention 1: Aclidinium Bromide intervention 2: Placebo
Intervention descriptions: intervention 1: 400 μg, twice per day, oral administration via a multi-dose dry-powder inhaler (DPI) intervention 2: Dose matched placebo, twice per day, oral administration via a multi-dose dry-powder inhaler (DPI)

Protocol document:
Prot_000.pdf: 
Protocol: D6560C00002 
Confidential - Proprietary Information 
x Protocol number: D6560C00002 
x Document title: Double-blind, Randomized, Placebo-controlled, 
Parallel-group, Phase IV Study to Evaluate the Effect of Aclidinium 
Bromide on Long-term Cardiovascular Safety and COPD 
Exacerbations in Patients with Moderate to Very Severe COPD 
(ASCENT COPD) 
x Version number: 5 
x Date of the document: 30 August 2017 
x NCT number: NCT01966107 
 


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1.
TITLE PAGE
Sponsor: AstraZeneca AB, S-151 85 Södertälje, Sweden
Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase IV Study to 
Evaluate the Effect of Aclidinium Bromide on Long-term Cardiovascular Safety 
and COPD Exacerbations in Patients with Moderate to Very Severe COPD
(ASCENT COPD)
LAS-MD-45 (D6560C00002)
IND 068653
Original Protocol Date:
30 Nov 2012
Amended Protocol #1:
31 May 2013
Amended Protocol #2:
15 SEP 2015
Amended Protocol #3:
29 FEB 2016
Amended Protocol #4:
25 JAN 2017
Amended Protocol #5:
30 AUG 2017
Confidentiality Statement


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This submission document contains confidential commercial information, disclosure of which is prohibited without 
providing advance notice to AstraZeneca and opportunity to object. This Clinical Study Protocol has been subject to 
a peer review according to AstraZeneca Standard procedures. The clinical study protocol is publicly registered and 
the results are disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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2.
SYNOPSIS AND SCHEDULE OF EVALUATIONS
CLINICAL STUDY SYNOPSIS: Study LAS-MD-45 (D6560C00002)
Study Number
LAS-MD-45 (D6560C00002)
Title of Study
Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase IV Study to 
Evaluate the Effect of Aclidinium Bromide on Long-Term Cardiovascular Safety 
and COPD Exacerbations in Patients with Moderate to Very Severe COPD 
(ASCENT COPD)
Study Centers (Region)
~500 (North America)
Development Phase
4
Objective
1. To assess the safety of aclidinium bromide on major adverse cardiovascular 
events (MACE)
2. To assess the overall safety of aclidinium bromide
3. To assess whether aclidinium bromide reduces moderate or severe chronic 
obstructive pulmonary disease (COPD) exacerbations
Methodology
Double-blind, randomized, placebo-controlled, parallel-group
Number of Patients
4000 planned
Diagnosis and
Main Criteria for Inclusion
Male and female outpatients ≥ 40 years of age with moderate to very severe 
COPD (% predicted forced expiratory volume in 1 second (FEV1) < 80%) and a 
history of cardiovascular or cerebrovascular disease and/or significant 
cardiovascular risk factors. 
Test Product, Dosage, and Mode 
of Administration
Aclidinium bromide 400 μg administered BID, once in the morning and once in 
the evening, via a multi-dose dry-powder inhaler (DPI)
Study Duration 
Two-week washout/run-in period [for patients on a long-acting muscarinic 
antagonist (LAMA)] followed by a maximum of 36-month double-blind treatment 
period
Reference Therapy, Dosage, and
Mode of Administration
Placebo, inhalation administered BID, once in the morning and once in the 
evening, via a multi-dose DPI
Criteria for Evaluation
Pharmacokinetic Analysis
Not applicable
Primary Outcome Measure(s)
!
Time to first MACE
!
The rate of moderate or severe COPD exacerbations per patient per year 
during the first year of treatment
Secondary Outcome Measure(s)
!
Rate of hospitalizations due to COPD exacerbations per patient per year 
during the first year of treatment
!
Time to first MACE or other serious cardiovascular events of interest 
(i.e. standardized MedDRA query (SMQ) of cardiac disorders and SMQ of 
cerebrovascular disorders)


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Safety Measures
Physical examination, vital signs, adverse event (AE) monitoring, serious adverse 
event (SAE) reporting, electrocardiograms (ECGs), and vital status
Statistical Methods
The Full Analysis Set (FAS) is defined as any patient who was randomized in the 
trial and took at least one dose of treatment. Patients will be analyzed according to 
their randomized treatment. 
This study will be completed after 122 patients have an adjudicated MACE.
The primary safety endpoint of time to first MACE will be presented for the FAS 
Population and will be based on on-study analysis. The on-study analysis is 
defined as all events that occurred while the patients was in the study, irrespective 
of treatment exposure (i.e., this includes all events that occurred while a subject 
was on treatment or off treatment, including post treatment follow-up). The time 
to first MACE will be analyzed by means of Cox proportional hazards regression 
model including baseline cardiovascular (CV) severity, smoking status, and 
treatment group as factors. The CV severity at baseline will be defined as 
2 categories: 1) patients who had 2 CV risk factors, and 2) patients who had more 
than 2 CV risk factors or at least one non-fatal stroke or non-fatal myocardial 
infarction. The upper bound of the 95% confidence interval (based on Cox 
regression) for the hazard ratio (aclidinium relative to placebo) of time to first 
MACE will be used to rule out the null hypothesis. If the upper bound of the 95% 
confidence interval is less than the 1.8 margin of the hazard ratio, then the hazard 
ratio of 1.8 or higher will be ruled out. 
The primary efficacy endpoint of rate of moderate or severe COPD exacerbation 
per patient per year during the first year of treatment will be analyzed using 
Negative Binomial regression model. The model will include treatment group, 
baseline ICS use, baseline COPD severity, history of at least one exacerbation in 
the past year and smoking status as factors and the log exposure in years will be 
included as an offset variable. The rate ratio of moderate or severe COPD 
exacerbation per patient per year due to the effect of aclidinium bromide 400 μg 
BID relative to placebo will be estimated along with its confidence interval and 
the corresponding p-value. The two-sided p-value for aclidinium bromide 400 μg 
BID relative to placebo in reducing the rate of exacerbation will be compared to 
the 0.05 significance level.
For this study, a total of 122 MACE will be needed to have 90% power, at 
5% significance level, to rule out a hazard ratio of 1.8 in time to first MACE in 
aclidinium bromide treated patients relative to placebo.
The sample size of 4,000 patients after 1 year of treatment will have ~89% power 
to detect a reduction in the rate of moderate or severe COPD exacerbations per 
patient per year of 14% (rate ratio of 0.86 in aclidinium bromide relative to 
placebo) at 0.05 alpha level. The 89% power was calculated assuming a 
discontinuation rate of 30% during the first year, a placebo rate of 0.8 
exacerbation per patient per year (reduced from 1 to 0.8 as not all patients will 
have a history of exacerbation prior to randomization), and an over-dispersion 
factor of 0.67.


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SCHEDULE OF EVALUATIONS: Study LAS-MD-45 (D6560C00002)
Washout/
Run-in
Double-blind Treatment Period
Visit 0a
Visit 1A 
(Screening)
Visit 1B
(Baseline) Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7b Visit 8 Visit 9 b Visit 10 Visit 11b Visit 12 EOT
TCx
Study Month
-0.5
0
1
6
12
18
24
36
Study Week
-3
-1
0
4
16
28
40
52
65
78
91
104
130
156
N/A
N/A
Visit windowv
(days)
N/A
+7
±7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
N/A
N/A
Informed 
consentc
X
X
Access IWRS
X
X
X
X
X
X
X
X
X
X
X
Inclusion/ 
Exclusion 
criteria
X
X
X
Patient 
demographics
Xd
Xd
Medical and 
surgical history
Xe
Xe
Medication 
history
Xf
Xf
Smoking status 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
AEsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical 
laboratory 
assessmentsh
X
X
X
X
X
Vital signsi
X
X
X
X
X
X
X
X
X
X
ECGj
X
X
X
X
X
X
X
X
X
X
X
Physical 
examinationk
X
X
X
X
X
X
Pregnancy testl
X
X
X
X
X


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SCHEDULE OF EVALUATIONS: Study LAS-MD-45 (D6560C00002)
Washout/
Run-in
Double-blind Treatment Period
Visit 0a
Visit 1A 
(Screening)
Visit 1B
(Baseline) Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7b Visit 8 Visit 9 b Visit 10 Visit 11b Visit 12 EOT
TCx
Study Month
-0.5
0
1
6
12
18
24
36
Study Week
-3
-1
0
4
16
28
40
52
65
78
91
104
130
156
N/A
N/A
Visit windowv
(days)
N/A
+7
±7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
N/A
N/A
Pulmonary 
function 
testingm
X w
X n
X
X
X
X
X
X
X
X
X
X
Randomizationo
X
COPD 
Exacerbation 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CAT 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rescue
medication 
dispensing
X
as needed depending on frequency of use
Diary 
dispensing/ 
trainingu
X
X
X
X
X
X
X
X
X
X
Diary 
collection/
reviewp
X
X
X
X
X
X
X
X
X
IP trainingq/ IP 
dispensingr
X
X
X
X
X
X
X
IP dosing
X
X
X
X
X
X
X
X
X
IP collections/ 
compliancet
X
X
X
X
X
X
X
X
X


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a
For patients who require a washout, PFTs should be performed to assess patients COPD severity. Patients will then come back in 2 weeks to perform Visit 1A. Patients who 
do not require a washout will sign the ICF and begin the study at Visit 1A.
b
Visit 7, Visit 9, and Visit 11 will occur by telephone. Information regarding AEs, concomitant medications, smoking status, and COPD exacerbations will be collected. The
CAT will also be completed and mailed back to the study site.
c
ICF must be signed at the first visit for all patients prior to performing any study procedure. For patients requiring a washout, ICF must be signed at Visit 0, and then patients 
will return in 2 weeks to perform Visit 1A. ICF must be signed within the 30 days prior to Visit 1A. Rescue medication will only be dispensed after signing the ICF.
d
At Visit 0 for patients who require a washout or at Visit 1A for patients who do not require a washout, patient demographics will be collected to assess eligibility.
e
At Visit 0 for patients who require a washout or at Visit 1A for patients who do not require a washout, medical history will be collected to assess eligibility.
f
At Visit 0 for patients who require a washout or at Visit 1A for patients who do not require a washout, medication history will be collected to assess eligibility.
g
Any adverse event occurring from the time the ICF is signed until 15 days after the last dose of study drug must be recorded. AEs will be collected at Visit 1A for patients 
who completed a Visit 0.  For patients who prematurely discontinue IP, only SAEs (including MACE) will be collected until the last visit/end of study.
h
Although fasting is not required, the patient should be encouraged to fast prior to each visit.  The patient’s fasting condition should be consistent at all visits. For patients 
taking Theophylline, blood serum levels will be measured.
i
Vital signs will consist of pulse rate, systolic and diastolic BP. Pulse and BP will be taken after the patient has been sitting for 10 minutes. Height will only be measured at
Visit 1A and weight will be measured at Visit 1A and Visit 12 or EOT.
j
One ECG will be performed at Visit 1A, and a 2 hour post-dose ECG will be performed at Visit 1B. A 1 hour pre-dose and 2 hour post-dose ECG will be performed at Visits
2, 3, 4, 5, 6, 8, 10 and 12. Patients should be supine for at least 10 minutes before the test is performed. At EOT, only one ECG will be performed.
k
Genitourinary examinations are not required unless medically indicated.
l
For women of childbearing potential, a serum pregnancy test must be performed at Visit 1A and Visit 12 or EOT. A urine pregnancy test will be performed at Visits 6 and 10.
m
Two pre-dose measurements (30-45 mins apart) will be taken at Visits 1B prior to the first dose of IP. At all subsequent visits and EOT, only one measurement will be taken
n
At Visit 1A,  pre- and post-bronchodilator measurements will be performed to assess eligibility. The test will be performed using the rescue inhaler dispensed to the patient 
upon signature of the ICF.  Perform pre-bronchodilator test followed by administration of 4 puffs of bronchodilator (albuterol/salbutamol) with a spacer. Administration of 
bronchodilator can begin as soon as 10 minutes after the completion of the last pre-bronchodilator spirometric effort if the patient is rested and comfortable.
Post-bronchodilator maneuvers will be completed within 10-15 minutes after administration of bronchodilator. 
o
Randomization must occur in  IWRS at Visit 1B within the 3-5 day visit window. All tests/procedures including pre-dose PFTs must be performed, inclusion/exclusion 
verified, and laboratory results reviewed by the PI or medically qualified designee prior to randomization.
p
A paper diary will be used to record IP usage. The paper diary will be reviewed and used to primarily assess compliance at all indicated visits. 
q
Placebo inhaler devices are available for training and practice.
r
IP dispensing will be issued through  IWRS.  
s
IP will be collected at Visits 3, 4, 5, 6, 8, 10, and 12 or EOT.
t
IP compliance will also be measured by dose indicator assessment at Visits 2, 3, 4, 5, 6, 8, 10 and 12 or EOT.
u      Dispense rescue medication diary at Visit 0 for patients who require a washout or at Visit 1A for patients who do not require a washout.  Dispense IP diary at Visit 1B 
(randomization).
v
Visit 1B will be conducted within 3-5 days of Visit A upon receipt of clinical laboratory results. Patient Visit dates for the study will be based on the date of randomization.
w    At Visit 0 PFTs will be performed to assess COPD severity.
x
A telephone contact will be performed 15 days after the last known dose of IP is taken to assess any AEs that may have occurred since the last dose taken at the final visit and 
any changes to or new concomitant medications taken.
.
EOT = End of Treatment; TC = telephone contact


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3.
TABLE OF CONTENTS
1.
TITLE PAGE................................................................................................1
2.
SYNOPSIS AND SCHEDULE OF EVALUATIONS...................................3
3.
TABLE OF CONTENTS ..............................................................................8
3.1
List of In-Text Tables..................................................................................11
4.
LIST OF ABBREVIATIONS......................................................................12
5.
ETHICAL CONSIDERATIONS.................................................................14
5.1
Institutional Review Board and Independent Ethics Committee...................14
5.2
Ethical Conduct of the Study.......................................................................14
5.3
Patient Information and Informed Consent ..................................................14
6.
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE.....15
7.
INTRODUCTION ......................................................................................16
8.
STUDY OBJECTIVES...............................................................................17
9.
INVESTIGATIONAL PLAN......................................................................18
9.1
Overall Study Design and Plan: Description................................................18
9.2
Discussion of Study Design, Including the Choice of Control Groups .........18
9.3
Selection of Study Population......................................................................20
9.3.1
Inclusion Criteria.........................................................................................20
9.3.2
Exclusion Criteria .......................................................................................21
9.3.3
Removal of Patients from Treatment and Study Conduct.............................22
9.3.3.1
Removal of Patients from Investigational Product .......................................22
9.3.3.2
Removal of Patients from the Study ............................................................24
9.3.4
Patient Replacement Procedures..................................................................24
9.4
Treatments ..................................................................................................24
9.4.1
Treatments Administered ............................................................................24
9.4.2
Identity of Investigational Product(s)...........................................................26
9.4.3
Method of Assigning Patients to Treatment Groups.....................................27
9.4.4
Selection of Dosages in the Study................................................................27
9.4.5
Selection and Timing of Dose for Each Patient............................................27
9.4.6
Blinding ......................................................................................................28
9.4.7
Unblinding..................................................................................................28
9.4.8
Prior and Concomitant Therapy...................................................................28
9.4.9
Monitoring Treatment Compliance..............................................................28
9.4.10
Medication, Dietary, and Activity Restrictions Before Study Visits.............28
9.5
Efficacy and Safety Variables......................................................................29
9.5.1
Efficacy Assessment(s) ...............................................................................29
9.5.1.1
Primary and Secondary Efficacy Assessment(s) ..........................................29
9.5.1.2
Additional Efficacy Assessment(s)..............................................................30


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9.5.2
Safety Assessments.....................................................................................30
9.5.2.1
Adverse Events ...........................................................................................31
9.5.2.2
Causality Assessment..................................................................................31
9.5.2.3
Severity Assessment....................................................................................32
9.5.2.4
Serious Adverse Events...............................................................................32
9.5.2.5
Reporting Adverse Events and Serious Adverse Events...............................33
9.5.2.6
Immediate Reporting of Serious Adverse Events.........................................34
9.5.2.7
Overdose.....................................................................................................35
9.5.2.8
Exposure to Investigational Product During Pregnancy ...............................35
9.5.2.9
Potential Hy’s Law Cases............................................................................35
9.5.2.10
Major Adverse Cardiovascular Events.........................................................36
9.5.2.11
Clinical Laboratory Determinations.............................................................37
9.5.2.12
Vital Signs ..................................................................................................38
9.5.2.13
Electrocardiograms .....................................................................................38
9.5.2.14
Other Safety Assessments ...........................................................................38
9.5.2.15
Data Safety Monitoring Board.....................................................................38
9.5.2.16
Joint Advisory Committee...........................................................................38
9.5.3
Investigational Product Concentration Measurements..................................39
9.5.4
Health Economic and Outcomes Research Assessments..............................39
9.5.5
Schedule of Assessments.............................................................................39
9.5.5.1
Informed Consent........................................................................................39
9.5.5.2
Washout/Run-in (Visit 0) ............................................................................39
9.5.5.3
Screening (Visit 1A) ...................................................................................40
9.5.5.4
Baseline (Visit 1B)......................................................................................41
9.5.5.5
Visit 2 .........................................................................................................42
9.5.5.6
Visits 3, 4, 5, 6, 8, and 10............................................................................43
9.5.5.7
Visits 7, 9, and 11........................................................................................44
9.5.5.8
Visit 12 .......................................................................................................44
9.5.5.9
End of Treatment (EOT) Visit .....................................................................45
9.5.5.10
Contacts between treatment visits................................................................46
9.5.5.11
Vital Status Follow-up.................................................................................46
9.5.5.12
Completion of Study ...................................................................................47
9.6
Data Quality Assurance...............................................................................47
9.6.1
Data Monitoring..........................................................................................47
9.6.2
Data Recording and Documentation............................................................47
9.7
Statistical Methods and Determination of Sample Size................................48
9.7.1
Patient Populations......................................................................................48
9.7.1.1
Screened Population....................................................................................48
9.7.1.2
Randomized Population ..............................................................................48
9.7.1.3
Full Analysis Set Population .......................................................................48
9.7.2
Patient Disposition ......................................................................................48
9.7.3
Demographics and Other Baseline Characteristics.......................................49
9.7.4
Extent of Exposure and Treatment Compliance...........................................50
9.7.4.1
Extent of Exposure......................................................................................50
9.7.4.2
Measurement of Treatment Compliance ......................................................50
9.7.5
Efficacy Analyses .......................................................................................51


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9.7.5.1
Primary Efficacy Parameter.........................................................................51
9.7.5.2
Secondary Efficacy Parameter.....................................................................52
9.7.5.3
Additional Efficacy Parameters...................................................................52
9.7.6
Safety Analyses...........................................................................................54
9.7.6.1
Primary Safety Parameter............................................................................54
9.7.6.2
Secondary Safety Parameter........................................................................55
9.7.6.3
Additional Safety Parameters ......................................................................56
9.7.7
Health Economics and Outcomes Research Analyses..................................58
9.7.8
Interim Analysis..........................................................................................58
9.7.9
Determination of Sample Size .....................................................................58
9.7.9.1
Power for the Primary Safety Endpoint: Time to First MACE Event ...........58
9.7.9.2
Power for the Primary Efficacy Endpoint: Rate of Moderate or Severe 
Exacerbations Per Patient Per Year During First Year of Treatment ............59
9.7.10
Computer Methods......................................................................................60
9.8
Changes in the Conduct of the Study or Planned Analyses ..........................60
9.9
Protocol Deviations and Violations .............................................................60
10.
STUDY SPONSORSHIP............................................................................61
10.1
Study Termination.......................................................................................61
10.2
Reporting and Publication ...........................................................................61
11.
INVESTIGATOR OBLIGATIONS.............................................................62
11.1
Documentation............................................................................................62
11.2
Performance................................................................................................62
11.3
Use of Investigational Materials ..................................................................62
11.4
Case Report Forms......................................................................................63
11.5
Retention and Review of Records................................................................63
11.6
Patient Confidentiality.................................................................................63
12.
INVESTIGATOR’S STATEMENT............................................................64
13.
APPENDICES ............................................................................................65
APPENDIX I.
ELEMENTS OF INFORMED CONSENT........................................65
APPENDIX II.
CONCOMITANT MEDICATIONS.................................................67
APPENDIX III.
PULMONARY FUNCTION TESTS..............................................69
APPENDIX IV.
POWER COMPUTATION DETAILS............................................71
Appendix V.
COPD ASSESSMENT TEST - CAT ...................................................76
Appendix VI.
WAIST CIRCUMFERENCE MEASUREMENT INSTRUCTIONS ..77
14.
LITERATURE CITED................................................................................78


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3.1
List of In-Text Tables
Table 9.3.3–1. Schedule of Visits and Telephone Contacts for Patients in Post-treatment 
Follow Up......................................................................................23
Table 9.4.1–1.
Dispensing Schedule ......................................................................25
Table 9.7.9–1.
Summary of Statistical Power to Detect a Specific Rate Ratio 
(Aclidinium Over Placebo) as Statistically Significant for a Range of 
Rate Ratio: One Study with 4,000 Patients in Total to be Tested at 
0.05 Level ......................................................................................59
Table 13–1.
Summary of Moderate or Severe COPD Exacerbations and of 
Patients with Exacerbations Leading to Hospitalizations per Patient 
per Year in the Phase III Placebo Controlled Studies of Aclidinium 
(Studies LAS-MD-33, LAS-MD-38A, and M/34273/34 Pooled) 
Intent-to-treat Population................................................................71
Table 13–2.
Rate of Moderate or Severe COPD Exacerbations per Patient per 
Year based on the Pooled Phase III Placebo Controlled Studies of 
aclidinium (Studies LAS-MD-33, LAS-MD-38A, and M/34273/34 
Pooled) Intent-to-treat Population...................................................72
Table 13–3.
Exacerbation Outcomes (Benefit from Tiotropium Treatment in 
Handihaler®) from the UPLIFT trial...............................................72
Table 13–4.
Justification of the Selected Margin for Hazard Ratio for this Study 
Based on Benefit-Risk Approach: Risk Quantified using NNT for 1 
year to Harm with 1 MACE and Benefit Quantified Using NNT for 1 
Year to Reduce 1 Exacerbation.......................................................75


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4.
LIST OF ABBREVIATIONS
AE
adverse event
AZ                                      AstraZeneca
BID
twice a day (bis in die)
BP
blood pressure
BPH
benign prostatic hyperplasia
CAT
COPD Assessment Test
CEC
Clinical Events Committee
CFR
Code of Federal Regulations
COPD
chronic obstructive pulmonary disease
CV
cardiovascular
DSMB
Data Safety Monitoring Board
DHHS
Department of Health and Human Services
DPI
dry powder inhaler
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EOT
end of treatment
ET
early termination
FDA
Food and Drug Administration
FEV1
forced expiratory volume after one second
FR
Federal Register
FVC
forced vital capacity
GCP
Good Clinical Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HCG
human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act of 1996
HIV
human immunodeficiency virus
ICF
Informed Consent Form
ICH
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use
ICS
inhaled corticosteroid
IEC
Independent Ethics Committee
IP
investigational product
IRB
Institutional Review Board
ITT
intent to treat


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IWRS
interactive web response system
JAC
Joint Advisory Committee
LABA
long-acting β2-adrenergic agonists
LAMA
long-acting muscarinic antagonist
LAR
Legally Authorized Representative
MACE
major adverse cardiovascular event(s)
MDRD
modification of diet in renal disease
MI
myocardial infarction
MMRM
Mixed Model for Repeated Measures
NNH
Number Needed to Harm
NNT
number needed to treat 
PADAC
Pulmonary-Allergy Drug Advisory Committee
PCS
potentially clinically significant
PFT
pulmonary function test
PI
principal investigator
PID
patient identification
PRN
as needed (Pro Re Nata)
PT
preferred term
RSM
Regional Site Manager
SABA
short-acting β2-adrenergic agonists
SAE
serious adverse event
SAMA
short-acting inhaled anticholinergic
SAP
statistical analysis plan
SD
standard deviation
SMQ
standardized MedDRA query
Sponsor
AstraZeneca
TEAE
treatment-emergent adverse event


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5.
ETHICAL CONSIDERATIONS
5.1
Institutional Review Board and Independent Ethics Committee
Within the United States
Approval by the Institutional Review Board (IRB) before the start of the study will be the 
responsibility of the Principal Investigator (PI). A copy of the approval letter will be supplied to 
AstraZeneca (AZ), along with a roster of IRB members or the DHHS (US Department of Health 
and Human Services) general assurance number. During the course of the study, the PI will 
provide timely and accurate reports to the IRB on the progress of the study, at intervals not 
exceeding 1 year (or as appropriate), and will notify the IRB of serious adverse events (SAEs) or 
other significant safety findings. The study protocol, informed consent form (ICF), information 
sheet advertisements, and amendments (if any) will be approved by the IRBs at the study centers 
in conformance with Code of Federal Regulations (CFR), Title 21, Part 56.
Outside of the United States
This study will be carried out in full compliance with the guidelines of the independent ethics 
committee (IEC) and government agencies of each respective country, where applicable. Before 
the study begins, the study centers will require approval from an IEC and government agency. 
During the course of the study, the Sponsor or authorized representative will provide timely and 
accurate reports to the IEC on the progress of the study, at intervals not exceeding 1 year (or as 
appropriate) and will notify the IEC of SAEs or other significant safety findings. The study 
protocol, ICF, information sheet advertisements, and amendments (if any) will be approved by 
the IEC at the study centers in conformance with CFR, Title 21, Part 56, and local regulations.
5.2
Ethical Conduct of the Study
This clinical study will be conducted in accordance with the ethical principles that have their 
origins in the Declaration of Helsinki.
This clinical study will comply with the International Conference on Harmonisation (ICH) 
Guidances on General Considerations for Clinical Trials (ICH-E8; 62 FR 66113, December 17, 
1997) and Good Clinical Practice (ICH-E6; 62 FR 25692, May 9, 1997), as well as Part 312 of 
the Code of Federal Regulations (CFR).
5.3
Patient Information and Informed Consent
Patients, after being given an explanation of the study, will give voluntary and written informed 
consent and HIPAA (Health Insurance Portability and Accountability Act of 1996) authorization 
(in compliance with 21 CFR, Parts 50 and 312) or other appropriate form(s) before participating 
in any study-related procedures.
The informed consent statement contains all the elements of informed consent listed in Appendix 
I of this protocol. Signed copies of the ICF and the HIPAA or other locally applicable form will 
be given to the patient, and both documents will be placed in the PI’s study files.


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6.
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at approximately 500 study centers in North America
The PI is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, GCP guidelines, and applicable regulations; for 
protecting the rights, safety, and welfare of patients under the investigator’s care; and for the 
control of investigational products under investigation. An investigator shall, obtain the informed 
consent of each human patient prior to the patient enrolling in the study and/or submitted to any 
study related activity.
The PI at each study center must meet their obligations to the patients, ethics committee, sponsor 
and regulatory authorities by maintaining oversight and control of the study’s conduct and the 
study staff. It is the responsibility of the PI to ensure that any and all delegated duties be assigned 
to qualified staff; by education, experience and licensure (in accordance with local regulations) 
and that the PI oversight has to be documented and assessment of their capabilities and 
performance consistent with the study investigational plan. The PI at each study center will be
responsible for the management of the study, which will consist of maintaining the study file and 
the patient records, corresponding with the IRB, and completing the electronic case report forms 
(eCRFs).


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7.
INTRODUCTION
Aclidinium bromide is a long-acting muscarinic antagonist delivered by the Pressair® dry powder 
inhalation device (DPI) for the treatment of bronchospasm in patients with chronic obstructive 
pulmonary disease (COPD).
COPD is a major cause of morbidity and mortality with a high and increasing prevalence, a 
natural history of progressive deterioration, and a loss of pulmonary function characterized by 
incompletely reversible expiratory airflow limitation (Mannino, 2008; Rennard, 1998). The 
characteristic symptoms of COPD include cough, sputum production, and chronic and 
progressive dyspnea. Furthermore, although COPD is primarily a lung disease, it has also 
significant systemic manifestations, which include significant comorbidities such as diabetes, 
cardiovascular (CV) disease, muscle wasting, and bone loss (Global Initiative for Chronic 
Obstructive Lung Disease (GOLD), 2015; Huiart et al, 2005; Soriano et al, 2005; Wouters, 
2002).
Bronchodilators are central to the management of COPD and may be used on an as needed basis 
for acute symptomatic relief or as a maintenance treatment for prevention or reduction of 
symptoms. GOLD recommends regular use of one or more long-acting bronchodilators in 
patients with COPD of at least moderate severity. Currently used bronchodilators include β2-
agonists (short and long acting), anticholinergics (short and long acting), theophylline, or a 
combination of these drugs. The choice of bronchodilator therapy depends on availability and 
individual response in terms of symptom relief and tolerability.  Inhaled corticosteroids (ICS) are 
typically used in patients with more severe disease and/or frequent exacerbations.


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8.
STUDY OBJECTIVES
The objective(s) of this study are: 
!
To assess the safety of aclidinium bromide on major adverse cardiovascular events (MACE)
!
To assess the overall safety of aclidinium bromide
!
To assess whether aclidinium bromide reduces moderate or severe COPD exacerbations


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9.
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan: Description
This study will be a double-blind, randomized, placebo-controlled, parallel-group study to 
evaluate the effect of aclidinium bromide on cardiovascular safety and COPD exacerbations in 
patients with moderate to very severe COPD, as defined by the GOLD criteria (GOLD, 2015).
A total of 4000 patients will be enrolled across approximately 500 study centers. Patients 
meeting entry criteria will be randomized (1:1) to aclidinium bromide 400 μg twice a day (BID) 
or placebo BID with a background of standard of care treatment. Rescue medication 
(albuterol/salbutamol) will be provided for all patients.
The study will consist of a 2 week washout/run-in period followed by a maximum of 36-month 
double-blind treatment period.
Patients on a long-acting muscarinic antagonist (LAMA) (i.e. inhaled anticholinergics) must 
washout 2 weeks prior to randomization. During this time, the patient should be started on 
alternate therapy (e.g., long-acting β2-adrenergic agonist (LABA or LABA/inhaled corticosteroid 
(ICS)) and should be contacted by the PI during the washout period to assess COPD stability. 
AstraZeneca will allow for the reimbursement of background controller medication for patients 
switching their current treatment from a LAMA to an alternate controller medication for patients 
without any healthcare coverage or are not covered by their insurance plan, (e.g., long-acting β2-
adrenergic agonist (LABA or LABA/inhaled corticosteroid (ICS)) when entering the washout 
period and for the duration of the study. 
Patients on a combination of both LAMA and LABA/ICS therapies at washout or screening 
will not be eligible to participate (Section 9.3.2). 
Patients will be assessed according to the Schedule of Evaluations (Section 2).
Patients who prematurely discontinue investigational product (IP) will participate in a post-
treatment follow-up period. The follow-up period will include on-site visits and telephone visits 
to collect MACE, COPD exacerbations, concomitant medications, and SAEs for the remainder 
of the study duration.
This study will conclude when 122 patients have experienced an adjudicated MACE (Section 
9.5.2.10).
9.2
Discussion of Study Design, Including the Choice of Control 
Groups
Aclidinium bromide 400 μg in the Pressair® DPI is approved by the FDA for the long-term 
maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and 
emphysema. 


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During the Pulmonary-Allergy Drug Advisory Committee (PADAC) meeting held on February 
23, 2012, the expert panel noted that there is a large population of COPD patients with 
cardiovascular conditions and due to the small number of adverse events (AEs), the impact on 
cardiovascular safety could not be established. Subsequently, Forest Research Institute (IND 
holder when Tudorza® was approved) and the Food and Drug Administration (FDA) agreed that 
a separate study would be needed to conclusively answer the question of cardiovascular safety. 
This study will therefore evaluate MACE and other cardiovascular events of interest for up to 3 
years in patients with moderate to very severe COPD.
Results from the placebo-controlled studies of aclidinium bromide showed significant decreases 
in COPD exacerbations after three and six months of treatment. These data support the 
possibility that moderate to severe COPD exacerbations and associated hospitalizations may be 
reduced in COPD patients who receive longer term treatment with aclidinium bromide in the 
Pressair® DPI. This study is also designed to assess the effect of aclidinium bromide on the 
reduction of COPD exacerbations.
Moreover, this study will also include a health-related quality of life assessment, the COPD 
Assessment Test (CAT) (Jones, 2009).
To qualify for this study, patients must have a clinical diagnosis of moderate to very severe 
COPD, a history of cardiovascular or cerebrovascular disease or cardiovascular risk factors 
and may be treated per current standard of care, including treatment with β-blockers. 
Patients with COPD have a higher risk of acute myocardial infarction (MI), congestive heart 
failure, arrhythmia, and mortality secondary to hospitalization for cardiovascular disease when 
compared to an age- and sex-matched non-COPD population. Results of a longitudinal 
population based study indicate that COPD patients with poor lung function have the highest risk 
of cardiovascular mortality independent of smoking status (Sin et al, 2006). Moreover, it has 
been reported that even modest reductions in lung function increase the risk of ischemic heart 
disease, stroke, and sudden cardiac death 2 to 3 fold independent of other risk factors (Sin et al, 
2003). The patients selected for this study will have lung function < 80% predicted with no 
protocol-required lower limit. In addition, exacerbations have also been associated with 
increased cardiovascular events. Specifically, 1 to 5 days after an exacerbation the risk of MI 
increases 2.7-fold and the risk of stroke increases 1.26-fold 1 to 49 days after a COPD 
exacerbation (Donaldson et al, 2010). Therefore, inclusion of patients with severe to very severe 
lung disease will enrich the population for cardiovascular disease.
COPD is a complex disease involving more than airflow obstruction. The increased circulation
inflammatory mediators in response to inflammation and/or alterations in repair mechanisms 
may result in systemic manifestations or worsening of co-morbid diseases such as ischemic heart 
disease and heart failure (Barnes et al, 2009). Therefore, it is anticipated that the occurrence of 
MACE will be achieved in the proposed COPD patient population given the Inclusion/Exclusion 
Criteria (Section 9.3), specifically those patients with a history of cardiac disease/risk factors. 


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9.3
Selection of Study Population
9.3.1
Inclusion Criteria
To be eligible to participate in the study, patients must meet the following criteria:
1. Male or female outpatients ≥ 40 years of age
2. Current or former cigarette smokers with a smoking history of at least 10 pack-years
3. A diagnosis of stable, moderate to very severe COPD (GOLD, 2015) with a post-
bronchodilator FEV1 < 80% predicted and FEV1/forced vital capacity (FVC) ratio < 70% at 
Visit 1A
4. Must have at least one of the following 4 criteria:
a.
Documented cerebrovascular disease (stroke or transient ischemic attack, carotid 
stenosis)
b. Documented coronary artery disease (angina, MI, angioplasty/stent/bypass)
c.
Documented peripheral vascular disease or history of claudication
d. At least 2 of the following atherothrombotic risk factors as determined by the PI: 
∀
Male ≥ 65 years or female ≥ 70 years
∀
Diabetes
∀
Dyslipidemia
∀
Hypertension
∀
Waist circumference inches males ≥ 40 in or in females ≥ 38 inches
∀
Evidence of renal dysfunction (eGFR < 60) and micoralbuminuria (eGFR is based on 
modification of diet in renal disease [MDRD] equation, microalbuminuria is defined 
as >=30-300 mcg/mg creatinine on a spot urine or >=30 mg creatinine on a 24hr urine 
test)
5. Maintained stable respiratory medications for 2 weeks prior to randomization (Appendix II)
6. Able to perform pulmonary function test (PFT) maneuvers and follow study procedures
7. Women of childbearing potential must have a negative serum β-human chorionic 
gonadotropin (HCG) pregnancy test at Visit 1A and be practicing medically acceptable 
method of contraception. Otherwise, female patients should be at least 1 year 
postmenopausal, surgically sterile (defined as having a hysterectomy or tubal ligation).


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8. Should understand study procedures and be willing to participate in the study as indicated by 
signing the ICF
9.3.2
Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the study:
1. Significant diseases other than COPD or cardiovascular disease (e.g., metastatic cancer) 
which, in the opinion of the PI, may either put the patient at risk because of participation in 
the study or a disease which may influence the results of the study or the patient’s ability to 
participate in the study
2. Unstable or life threatening cardiovascular disease or COPD as determined by the PI
3. Patients with comorbid lung disease such as asthma, cystic fibrosis, bronchiectasis, 
interstitial lung disease, or pulmonary thromboembolic disease
4. Planned lung transplant or lung volume reduction surgery 
5. Currently treated with a combination of LAMA and LABA/ICS therapy.  
6. Malignancy for which patient has undergone resection, radiation therapy or chemotherapy 
within 5 years prior to screening. Patients with treated basal cell and squamous cell (skin) 
carcinoma are allowed
7. Respiratory infection or COPD exacerbation at Screening and/or within 4 weeks prior to
screening.  
NOTE: In the event of a Respiratory infection or COPD exacerbation four weeks prior to 
Screening and/or during the Screening period between (Visit 0 and 1B) the screening visit 
may be extended once only after the last increased additional dose of steroid burst and/or 
antibiotics is given to ensure patient has recovered from the exacerbation.
8. Uncontrolled infection resulting from human immunodeficiency virus (HIV) and/or active 
hepatitis
9. Reported history of drug or alcohol abuse within the past 12 months
10. History of hypersensitivity reaction to inhaled anticholinergics, sympathomimetic amines, or 
inhaled medication or any component thereof (including report of paradoxical 
bronchospasm)
11. History of acute urinary retention, treatment refractory benign prostatic hyperplasia (BPH), 
bladder neck obstruction, or narrow-angle glaucoma (Note: Patients with controlled, stable 
BPH are not excluded)
12. Patients unable to use a multidose DPI or a pressurized metered-dose inhaler
13. Treatment with any other investigational drug within 30 days (or 6 half-lives, whichever is 
longer) before Visit 1A


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14. Women who are pregnant or breastfeeding
15. Use of any prohibited medication listed in Appendix II
16. Employee or immediate relative of an employee of AstraZeneca, any of its affiliates or 
partners, or the study center
Only patients who meet all inclusion/exclusion criteria at Baseline (Visit 1B) as confirmed and 
documented by a medically qualified investigator will be randomized and allowed to continue to 
Visit 2. On a case-by-case basis and upon review by the AZ Study Physician and approval of the 
Sponsor, patients who do not meet all inclusion/exclusion criteria may repeat the full visit; 
however, whenever a patient is rescreened, a new patient identification (PID) number is to be 
assigned and the patient to be re-consented. 
Patients cannot participate in another clinical trial during treatment period and post-treatment 
follow-up period.
9.3.3
Removal of Patients from Treatment and Study Conduct  
9.3.3.1
Removal of Patients from Investigational Product
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/procedures for the full 36-months study period in 
order to support the final efficacy and safety analysis for aclidinium bromide. The reason for 
premature discontinuation of IP will be documented in the source documentation. It is essential 
to collect as much data as possible for all subjects throughout the study and especially all 
potential endpoint events. Complete withdrawal from the study (i.e., withdrawal of consent) has 
a direct negative impact on the potential validity of all study data and should be avoided 
wherever possible.
The post-treatment follow up period will include assessments at on-site visits and telephone 
visits to collect MACE, COPD exacerbations, concomitant medications, and SAEs for the 
remainder of the study duration.
After this period, the subjects will perform the EOT visit as described above. As per
Section 9.5.5.9, randomized patients who prematurely discontinue IP will enter into a post-
treatment follow-up period alternating telephone contacts and on-site visits (Table 9.3.3–1).
Patients who experience a MACE must be discontinued from IP and enter into the post-treatment 
follow-up period.
Patients can also be prematurely discontinued from IP and enter into the post-treatment follow-
up period for one of the following reasons:
!
Adverse event 
!
COPD exacerbation


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!
Insufficient therapeutic response
!
Other reasons, such as specified or pregnancy
If IP is temporarily suspended (for any reason) for more than 30 consecutive days or a total of 
60 aggregate days within the previous 6 months, the patient must be permanently discontinued 
from study drug and enter into the post-treatment follow-up period.
If the EOT visit occurs within 2 weeks of the next scheduled visit (TC or on-site), then the next 
visit can be skipped.
For unforeseen circumstances (e.g., patients move), post-treatment follow up period phone calls 
may be conducted in lieu of on-site visits, however, this must be pre-approved by the Sponsor.
Table 9.3.3–1. Schedule of Visits and Telephone Contacts for Patients in Post-treatment 
Follow Up
Patient Visit
Discontinued
Visit
1
2
3
4
5
6
7
8
9
10
11
12
Study Month
0
1
6
12
18
24
36
Study Week
0
4
16
28
40
52
65
78
91
104
130
156
At Visit 2
—
EOT
TCa
Xb
TCa
Xb
TCa
Xb
TCa
Xb
Xb
Xb
At Visit 3
—
—
EOT
TCa
Xb
TCa
Xb
TCa
Xb
TCa
Xb
Xb
At Visit 4
—
—
—
EOT
TCa
Xb
TCa
Xb
TCa
Xb
Xb
Xb
At Visit 5
—
—
—
—
EOT
TCa
Xb
TCa
Xb
TCa
Xb
Xb
At Visit 6
—
—
—
—
—
EOT
TCa
Xb
TCa
Xb
Xb
Xb
At Visit 7
—
—
—
—
—
—
EOT
TCa
Xb
TCa
Xb
Xb
At Visit 8
—
—
—
—
—
—
—
EOT
TCa
Xb
Xb
Xb
At Visit 9
—
—
—
—
—
—
—
—
EOT
TCa
Xb
Xb
At Visit 10
—
—
—
—
—
—
—
—
—
EOT
Xb
Xb
At Visit 11
—
—
—
—
—
—
—
—
—
—
EOT
Xb
a
Telephone contact (TC) to occur at designated time points to collect the following: MACE, COPD exacerbations, 
concomitant medications, SAEs, and arrange for provision of rescue medication as needed.
b
On-site patient visits to occur at designated time points to collect the following: MACE, COPD exacerbations, concomitant 
medications, SAEs, and arrange for provision of rescue medication as needed.  
AEs that occur from signing of ICF until 15 days after the last dose of study drug must be recorded.  
EOT = End of Treatment (discontinue IP); TC = telephone contact; X = on-site visit.


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9.3.3.2
Removal of Patients from the Study
Patients may withdraw from study participation for one of the following reasons:
!
Failure to meet inclusion/exclusion criteria (only for screen failures)
!
Adverse event (ex: death, long-term disability/hospitalization, etc.)
!
COPD exacerbation (ex: death, long-term disability/hospitalization, etc.)
!
Withdrawal of consent (a clear reason must be documented); patients who withdraw consent 
will not enter the post-treatment follow-up period
!
Lost to follow-up. Every effort must be made to contact the patient.  A certified letter must 
be sent after 2 documented unsuccessful attempts are made to contact the patient to come in 
for an EOT visit and to return any unused IP. All efforts to regain contact with the patient 
must be documented. In the event that contact is reestablished, the subject should not be 
considered lost to follow-up and post-treatment follow-up should resume according to Table 
9.3.3–1.
!
Study or site prematurely terminated by the Sponsor for any reason
9.3.4
Patient Replacement Procedures
Patients in this study who prematurely discontinue treatment will not be replaced.
9.4
Treatments
This clinical study will be a double-blind, randomized, placebo-controlled, parallel-group 
clinical trial of inhaled aclidinium bromide 400 μg and placebo via the Pressair™DPI.
9.4.1
Treatments Administered
Double-blind IP will be provided by AZ in the form of Pressair™DPIs containing 60 doses of 
aclidinium bromide 400 μg or placebo.
IP will be dispensed at Visits 1B, 3, 4, 5, 6, 8, and 10. Patients will be supplied enough IP until 
the next scheduled visit. Patients will also be instructed to bring the double-blind IP back to the 
study center at Visits 2, 3, 4, 5, 6, 8, 10, and 12 or EOT.
IP will be supplied individually as indicated below, with each IP inhaler enclosed in an 
aluminium pouch. Each study center will be provided with drug supplies corresponding to a 
sequence of randomization numbers.
Table 9.4.1–1 specifies the IP inhalers to be dispensed and returned at each visit.


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Table 9.4.1–1. Dispensing Schedule
Visit
0a
Washout/Run-in
No IP Drug Dispensed
1 Albuterol/Salbutamol Rescue Inhaler and 1 AeroChamber Plus
1A
Screening (If patient did not require a washout)
No IP Drug Dispensed
1 Albuterol/Salbutamol Rescue Inhaler and 1 AeroChamber Plus
Double-Blind Phase
Aclidinium Bromide 400μg 
Placebo
1B
1 kit containing 5 Aclidinium Bromide
400μg 60 Doses Inhalation Powder
Inhalers (5 inhalers)
3 Albuterol/Salbutamol Rescue Inhalers 
as needed
1 kit containing 5 Placebo 60 Doses Inhalation 
Powder Inhalers (5 inhalers)
3 Albuterol/Salbutamol Rescue Inhalers as 
needed
2
Continue dosing from Visit 1B Study Medication
3
1 kit containing 5 Aclidinium Bromide 
400μg 60 Doses Inhalation Powder 
Inhalers (5 inhalers)
3 Albuterol/Salbutamol Rescue Inhalers 
as needed
1 kit containing 5 Placebo 60 Doses Inhalation 
Powder Inhalers (5 inhalers)
3 Albuterol/Salbutamol Rescue Inhalers as 
needed
4
1 kit containing 5 Aclidinium Bromide 
400μg 60 Doses Inhalation Powder 
Inhalers (5 inhalers)
3 Albuterol/Salbutamol Rescue Inhalers 
as needed
1 kit containing 5 Placebo 60 Doses Inhalation 
Powder Inhalers (5 inhalers)
3 Albuterol/Salbutamol Rescue Inhalers as 
needed
5
1 kit containing 5 Aclidinium Bromide 
400μg 60 Doses Inhalation Powder 
Inhalers (5 inhalers)
3 Albuterol/Salbutamol Rescue Inhalers 
as needed
1 kit containing 5 Placebo 60 Doses Inhalation 
Powder Inhalers (5 inhalers)
3 Albuterol/Salbutamol Rescue Inhalers as 
needed
6
2 kits containing 5 Aclidinium Bromide 
400μg 60 Doses Inhalation Powder 
Inhalers (5 inhalers)
6 Albuterol/Salbutamol Rescue Inhalers 
as needed
2 kits containing 5 Placebo 60 Doses Inhalation 
Powder Inhalers (5 inhalers)
6 Albuterol/Salbutamol Rescue Inhalers as 
needed
7b
Telephone Visit No IP Drug Dispensed
8
2 kits containing 5 Aclidinium Bromide 
400μg 60 Doses Inhalation Powder 
Inhalers (5 inhalers)
6 Albuterol/Salbutamol Rescue Inhalers 
as needed
2 kits containing 5 Placebo 60 Doses Inhalation 
Powder Inhalers (5 inhalers)
6 Albuterol/Salbutamol Rescue Inhalers as 
needed
9b
Telephone Visit No IP Drug Dispensed
10
4 kits containing 5 Aclidinium Bromide 
400μg 60 Doses Inhalation Powder 
Inhalers (5 inhalers)
4 kits containing 5 Placebo 60 Doses Inhalation 
Powder Inhalers (5 inhalers)


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Table 9.4.1–1. Dispensing Schedule
Visit
12 Albuterol/Salbutamol Rescue Inhalers 
as needed
12 Albuterol/Salbutamol Rescue Inhalers as 
needed
11b
Telephone Visit No IP Drug Dispensed
12
ET
End of Treatment IP Collection
If IP dosing is interrupted (for any reason) for more than 30 consecutive days or a total of 
60 aggregate days within the previous 6 months, the patient must be discontinued from study 
drug and enter into the post-treatment follow-up period. 
Marketed albuterol (108 μg per puff) or salbutamol sulfate (100 μg/puff), supplied by AZ, will 
be the only rescue medication permitted during the IP treatment period of the study. The 
investigator or designee will provide the patient with this medication upon signing the ICF at 
Visit 0 or Visit 1B and at other visits as necessary according to use. Rescue medication will be 
provided by AZ during the study treatment period and the post-treatment follow-up period 
(Section 9.3.3.1). Rescue medication will be provided locally for all visits (except for visit 1A in 
the US where Albuterol for reversibility testing will be assigned to the patient via IWRS).
At Visit 1A (for patients who do not require a washout), 4 puffs of albuterol or salbutamol from 
the dispensed rescue inhaler should be given with a spacer device (AeroChamber Plus) to ensure 
proper inhalation. During the study, the use of spacers for albuterol/salbutamol administration is 
not required. If a spacer is used, it must be used consistently throughout the study at each visit.  
Albuterol/salbutamol should be discontinued at least 6 hours before all visits (including Visit 0 
and Visit 1A) and not used again until after the completion of the last study measurement of the 
visit. Rescue medication should only be used during a visit if absolutely necessary. 
9.4.2
Identity of Investigational Product(s)
IP will be identified with the protocol number, kit number, and inhaler number and labelled with 
storage information, warning language (“Caution: New Drug - Limited by Federal Law to 
Investigational Use”), space for the coordinator to write in the visit number, and instructions for 
using the inhaler as directed. Immediately before dispensing IP, the study coordinator will write 
on the label of the kit and the pouches the PID number, the patient’s initials, the visit number, 
and the date dispensed. Labelling will be provided in the local language, and specific language 
related to local laws will be included.
Double-blind IP will be prepared according to the randomization list. Each manufacturing 
process will be performed and documented in conformity with good manufacturing practices. 
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The IP should be stored at 25°C (77°F); in accordance with instructions given on the IP label, the 
range of 15°C to 30°C (59°F-86°F) should not be exceeded. All IP must be stored in an 
appropriate, secure area (e.g., a locked cabinet in a locked room).
The PI is responsible for recording the receipt and use of all IP supplied and for ensuring the 
supervision of the storage and allocation of these supplies. All unused IP must be returned; and, 
whenever IP is returned, unit counts must be performed. All IP must be accounted for. All 
unused IP and empty IP packages in US/Canada, following approval by AZ, should be destroyed 
unless otherwise instructed. 
9.4.3
Method of Assigning Patients to Treatment Groups
After a patient signs the ICF at the first screening visit, study personnel will register the patient 
in the interactive web response system (IWRS), and the system will assign the patient a 
sequential PID number. The first patient to sign the ICF at each site will be assigned the first 
number in the sequence by the system. The PID number will consist of nine digits: the first four 
will represent the study center (0101, 0202, etc), followed by the two digit study number (45) 
and a three digit screening number (001, 002, etc). As an example, at site number 0101, 
performing protocol number 45, the sequence of numbers for that site will be 
 
, etc. This PID number will be used to identify the patient throughout the 
study (i.e., at all study phases).
The study center must contact the IWRS at screening and at all subsequent study visits in order 
to obtain the kit number to be dispensed to the patient at that visit.
Confirmation of the IP and number will be faxed or e-mailed (per the study center’s preference) 
to the study center following each assignment. A detailed description of IWRS procedures is 
contained in the IWRS Manual in the Study Reference Binder.
9.4.4
Selection of Dosages in the Study
The aclidinium bromide dosage chosen for this study is based on the 400 μg BID dose currently
approved by the FDA for the long-term maintenance treatment of bronchospasm associated with 
COPD, including chronic bronchitis and emphysema. 
9.4.5
Selection and Timing of Dose for Each Patient
The first dose of IP will be administered at Visit 1B after pre-dose PFT measurements under the 
supervision of study staff. IP will continue to be taken twice daily approximately 12 hours apart. 
The morning dose of IP will be taken prior to 11:00 AM throughout the study. On visits where 
trough FEV1 is measured, the last dose of IP must be taken 12-14 hours prior to the study visit.  
At Visit 1B, following randomization, the PI, or a qualified designee, should make sure the 
patient understands the instructions and the correct use of the study medication IP inhaler. 
Patients will be provided with verbal and written instructions.
At each visit, the PI will ensure that the patient is properly using the study medication IP inhaler; 
reinstruction will follow when needed (the training device may be used again if appropriate).
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9.4.6
Blinding
A list of patient randomization codes will be generated by Statistical Programming at AZ and 
implemented by the IWRS vendor (an electronic version will be stored on a secure server). This 
list will identify each patient by randomization number and include the patient’s corresponding 
treatment assignment.
9.4.7
Unblinding
Any unblinding at the study site level should be done only in an emergency that requires the IP 
to be identified for the medical management of the patient. The PI has to notify the study 
physician immediately and a full written explanation will be provided if the blind is broken. 
Before IP is unblinded, every attempt should be made to discuss the case with the Study 
Physician. Breaking the code at the study center will immediately disqualify the patient from 
further participation in the study; however, the patient should enter into the post-treatment 
follow-up period.
Treatment codes may be broken by Global Patient Safety at AZ for regulatory reporting 
purposes. In such cases, the study staff will be kept blinded and the patient will not need to be 
disqualified from the study.
In an emergency, the PI can obtain the treatment assignment of any patient at his or her study 
center through the IWRS. In an emergency, the PI will access the IWRS to break the blind.
9.4.8
Prior and Concomitant Therapy
A list of medication classes that are allowed and not allowed as concomitant medications for 
either episodic or chronic use is provided in Appendix II. Medications taken during the previous 
15 days will be recorded at Screening (Visit 1A) and /Baseline (Visit 1B) in the eCRF. 
Thereafter, any changes in concomitant medications or new medications added will be recorded 
in the eCRF.
9.4.9
Monitoring Treatment Compliance
Compliance will be monitored primarily by paper diary review. Treatment compliance based on 
the diary will be recorded in the eCRF.
Dose counter indicator will act as a secondary measure of compliance. 
Before new IP is dispensed at each visit, every effort will be made to collect all unused IP.
9.4.10
Medication, Dietary, and Activity Restrictions Before Study Visits
The following are prohibited within the times indicated before any study visit:
!
Vigorous physical activity should be avoided for at least 20 minutes before each visit
!
Alcohol consumption should be avoided at least 4 hours before each visit
!
The intake of caffeinated products (e.g., coffee, tea, soda) will not permitted for at least 6 
hours before each visit until completion of all procedures on that day


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!
Smoking, prolonged exposure to cold air, dust or polluted air should be avoided for at least 1 
hour before each visit until the completion of all study procedures. For patients who cannot 
avoid smoking, smoking will be permitted during the visits; however, it should be stopped at 
least 1 hour before any spirometric testing is performed.
!
Large meals should be avoided for at least 2 hours before the visit. Patients should fast 
overnight before coming in for clinical laboratory assessments at Visits 1 (screening), Visit 6, 
Visit 10, and Visit 12 or EOT.
!
Supplemental oxygen must be discontinued at least 2 hours before any study visit
!
Albuterol must be discontinued at least 6 hours before the visit.
9.5
Efficacy and Safety Variables
9.5.1
Efficacy Assessment(s)
COPD exacerbations will be assessed in this study.
9.5.1.1
Primary and Secondary Efficacy Assessment(s)
The primary efficacy endpoint is the rate of moderate to severe COPD exacerbations per patient 
per year during the first year of treatment.
COPD exacerbations will be evaluated by the PI throughout the study.
The onset and end of an exacerbation is defined by the investigator in their assessment of patient 
symptoms and initiation/finalization of treatment (as defined below for the severity of 
exacerbation). 
The severity of a COPD exacerbation is to be assessed according to the following scale:
Mild:
Increase in COPD symptoms (e.g., dyspnea, cough, sputum volume, sputum 
purulence) during at least 2 consecutive days, managed by the patient at home by 
increasing short-acting bronchodilator and/or ICS use
Moderate:
Increase in COPD symptoms (e.g., dyspnea, cough, sputum volume, sputum 
purulence) during at least 2 consecutive days that does not lead to hospitalization 
but is treated with antibiotics and/or systemic corticosteroids
Severe:
Increase in COPD symptoms (e.g., dyspnea, cough, sputum volume, sputum 
purulence) during at least 2 consecutive days that leads to hospitalization 
(overnight stay at hospital or emergency room) or death
The interval between 2 consecutive COPD exacerbations must be at least 7 days. Therefore, if 2 
COPD exacerbations occur within 7 days of each other, it will be considered as 1 event.
Patients who experience a moderate COPD exacerbation may be treated with the addition of an 
allowed concomitant medication and remain on IP at the discretion of the PI.


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Patients who experience a severe or recurrent COPD exacerbation may be treated with the 
addition of an allowed concomitant medication and remain on IP at the discretion of the PI.
Patients who experience a severe or recurrent COPD exacerbation and require treatment with a 
LAMA, must be discontinued from IP and enter into the post-treatment follow-up period 
(Section 9.3.3.1).
The secondary efficacy endpoint is the rate of hospitalizations due to COPD exacerbations per 
patient per year during the first year of treatment.
9.5.1.2
Additional Efficacy Assessment(s)
a)
Spirometry
One pre-bronchodilator and one post-bronchodilator measurement will be taken at Visits 1A, and 
two pre-dose measurements at Visit 1B.  The assessment of morning pre-dose trough FEV1 will 
be obtained at Visits 2, 3, 4, 5, 6, 8, 10, and 12 or EOT.
Measurements to assess eligibility will be taken at Visit 1A. All spirometry results will be 
transferred via ndd Easy One Spirometer on a monthly basis. Data transfers (values will include: 
PFT assessment date, time, timepoint, the ATS/ERS criteria met or not, FEV1, percentage 
predicted FEV1, FVC, percentage predicted FVC, FEV1/FVC ratio, indication of the best effort 
evaluation per ndd Easy One Spirometer has met ATS/ERS grading) selected to assess Inclusion 
Criteria (Section 9.3.1)
All spirometry assessments (up to a maximum of 8 PFT maneuvers) will be performed, recorded 
locally, and will be read by a central vendor (see Appendix III).
The data for each visit must be entered into the electronic data capture system, including patient 
ID, date, time, visit number, whether spirometry was performed, whether the patient had a 
bronchodilator in the previous 6 hours, and the reason for visit, if it was unscheduled.
The values for the maneuvers using the sponsor provided ndd Easy One Spirometer will not be 
entered into the eCRF page anymore, this data will be collected via the ndd Easy One Spirometer 
and transmitted to the central vendor. 
The maneuvers must be reviewed by the PI or qualified designee to ensure ATS/ERS criteria for 
acceptability and repeatability have been met.  
b)
COPD Assessment Test (CAT)
Refer to Section 9.5.4, Health Economics and Outcomes.
9.5.2
Safety Assessments
Patients must be seen by a physician or an appropriately trained health professional at every visit 
and the evaluation must be documented. The procedures discussed below will be completed at 
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9.5.2.1
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), for example, symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product (ICH-E2A).
For the purpose of data collection for this study, any untoward event that was reported from the 
time the patient signed the ICF until 15 days after the last dose of treatment are to be considered 
AEs. For patients who prematurely discontinue study drug and enter post-treatment follow-up 
period, SAEs (including MACE) will be collected until end of study.
Examples of AEs are as follows:
!
Changes in the general condition of the patient
!
Subjective symptoms offered by or elicited from the patient
!
Objective signs observed by the PI or other study center personnel
!
All diseases that occur after signing ICF, including any change in severity or frequency of 
preexisting disease
!
All clinically relevant abnormalities in laboratory values or clinically relevant physical 
findings that occur during the study schedule
Please note medical procedures scheduled prior to consenting, but occurring during the study 
should not be captured as AEs, but should be listed in the medical history if related to a pre-
existing condition.
9.5.2.2
Causality Assessment
For all AEs, the PI must provide an assessment of causal relationship to the investigational 
product. The causality assessment must be recorded on the appropriate AE reporting page of the 
patient’s eCRF. Causal relationship must be assessed by answering the following question:
Is there a reasonable possibility the investigation product caused the event?
Yes:
There is evidence to suggest a causal relationship between the investigational product and 
adverse event; i.e.:
# There is a reasonable temporal relationship between the investigational product and the 
event, and
# The event is unlikely to be attributed to underlying/concurrent disease, other 
investigational products, or other factors, and/or


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# Positive dechallenge and/or rechallenge exist
No:
There is no evidence to suggest a causal relationship between the investigational product 
and adverse event; i.e.:
# There is no reasonable temporal relationship between the investigational product and the 
event, or
# The patient did not take the investigational product, or
# The event is likely to be attributed to underlying/concurrent disease, other investigational 
products, or other factors, or
# The event is commonly occurring in the (study) population independent of investigational 
product exposure
9.5.2.3
Severity Assessment
The PI will provide an assessment of the severity of each AE by recording a severity rating on 
the appropriate AE reporting page of the patient’s eCRF. Severity, which is a description of the 
intensity of manifestation of the AE, is distinct from seriousness, which implies a patient 
outcome or AE-required treatment measure associated with a threat to life or functionality 
(Section 9.5.2.4). Severity will be assessed according to the following scale:
Mild:
Minor awareness of signs or symptoms that are easily tolerated without specific 
medical intervention
Moderate:
Discomfort that interferes with usual activities and may require minimal 
intervention
Severe:
Significant signs or symptoms that are incapacitating with an inability to work or 
perform routine activities and/or that require medical intervention
9.5.2.4
Serious Adverse Events
A serious adverse event is any untoward medical occurrence that at any dose:
!
Results in death
!
Is life threatening
!
Requires inpatient hospitalization or prolongation of existing hospitalization
!
Results in persistent or significant disability/incapacity,
!
Is a congenital anomaly/birth defect, or
!
Important medical event


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Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in patient hospitalization, or the development of investigational 
product dependency or drug abuse.
Emergency room visits that do not result in hospitalization should be evaluated for one of the 
other serious outcomes to determine whether they qualify as SAEs.
Preplanned hospitalizations (e.g., elective procedures for preexisting conditions that did not 
worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE reporting.
The following events are captured as efficacy endpoints and are therefore excluded from 
AE/SAE reporting:
!
COPD exacerbation
!
Signs and symptoms associated with COPD exacerbation
!
COPD exacerbation resulting in hospitalization and/or death
For the purpose of data collection for this study, any SAE must be reported from the time the 
patient signed the ICF until 15 days after the last dose of study drug.
9.5.2.5
Reporting Adverse Events and Serious Adverse Events
Any untoward event that occurs in a patient from the time he or she signs the ICF for the trial 
until 15 days after the last dose of investigational product has to be collected. Thus, any 
untoward medical occurrences or unfavorable and unintended signs, symptoms, or diseases that 
occur in the pretreatment, in treatment, or post treatment period are to be considered AEs and/or 
SAEs, and consequently recorded and reported as such. For patients who prematurely 
discontinue study drug and enter post-treatment follow-up period, SAEs (including MACE) will 
be collected until end of study.
At each visit, patients are to be queried regarding any AEs or SAEs that have occurred since the 
previous visit. Patients will be asked to volunteer information with a nonleading question such 
as, “How do you feel since your last visit?” Study center personnel will then record all pertinent 
information in the patient’s eCRF. 
Follow-up of unresolved adverse events:
Any AEs that are unresolved at the patients last visit are followed up by the Investigator for as 
long as medically indicated, but without further recording in the CRF. AZ 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. 


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All AEs must be recorded on the appropriate AE reporting page of the patient’s eCRF whether or 
not they are considered causally related to the investigational product.
For every AE, the PI must:
!
Provide an assessment of the severity, causal relationship to the investigational product, and 
seriousness of the event (e.g., SAE)
!
Document all actions taken with regard to the investigational product
!
Detail any other treatment measures taken for the AE
Additional information regarding the immediate reporting required for SAEs is provided in 
Section 9.5.2.6.
9.5.2.6
Immediate Reporting of Serious Adverse Events
The Sponsor is required to inform worldwide regulatory authorities of SAEs that meet specific 
criteria. Therefore, the Sponsor must be notified immediately regarding any SAE that occurs 
after informed consent is obtained. All SAEs will be recorded in the eDC.
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the study center 
personnel must report the event to the appropriate AZ representative. The designated AZ 
representative works with the Investigator to ensure that all the necessary information is 
provided to the AZ 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 AZ 
representatives of any follow-up information on a previously reported SAE within one calendar 
day i.e., immediately but no later than 24 hours of when he or she becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the electronic data 
capture (eDC) system, an automated email alert is sent to the designated AZ representative.
If the eDC system is not available, then the Investigator or other study center personnel reports a 
SAE to the appropriate AZ representative by fax.
The AZ representative will advise the Investigator/study center personnel how to proceed. 
The AZ paper SAE Report Form should be faxed to the designated AZ representative using the 
country specific number below. 
For U.S: Fax number 
For Canada: Fax number 
The AstraZeneca representative will advise the Investigator/study center personnel how to 
proceed. As soon as the eDC is available data should be re-entered into the system. If, during 
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follow-up, any non-serious AE worsens and eventually meets the criteria for an SAE, that AE 
should be recorded as a new SAE. 
NOTE: For any follow up information pertaining to SAEs occurring prior to the implementation 
of the updated eDC the information must be faxed to an AZ representative using the process 
described above. No information should be entered into the eDC.
9.5.2.7
Overdose
Overdose only needs to be reported if leading to an Adverse Event. If the overdose leads to an
Adverse Event meeting the criteria of seriousness (SAE), the SAE module must be completed
within the same timeframe and following the same routing as for a SAE (see section 2.1 ). The
patient must be followed-up and the investigator will make every effort to obtain information on
how the overdose was managed, any treatment administered and the final outcome. This
information will be reported, following the same procedure and timeframes as for the initial 
report.
9.5.2.8
Exposure to Investigational Product During Pregnancy
Study center personnel must report every pregnancy from the time he or she signs the ICF for the 
trial until the patient’s last visit as soon as possible (within 24 hours of learning of the 
pregnancy) to the appropriate AZ representative. 
The designated AZ representative will work with the Investigator to ensure that all relevant 
information is provided to the AZ Patient Safety data entry site within 1 or 5 calendar days for 
SAEs (see Section 9.5.2.8) 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.
Pregnancy of the subject’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality), occurring from the date of the first dose until last visit, 
if possible, be followed up and documented.
9.5.2.9
Potential Hy’s Law Cases
Study center personnel must report every patient that meets potential Hy’s law criteria, i.e.:
!
ALT or AST ≥ 3xULN AND
!
Total Bilirubin ≥ 2xULN AND
!
Alkaline Phosphatase < 2xULN
Within a 24 hour period that occurs anytime from the time he or she signs the ICF for the trial 
until 15 days after the last dose of investigational product. A potential Hy’s law should be 
reported as an SAE using the most relevant SAE criteria, as judged by the Investigator (see 


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Section 9.5.2.5). Every effort to determine the cause of the liver enzyme abnormalities must be 
made, and close monitoring should be initiated in conjunction with the study physician.
Additionally, if a patient meets the above criteria, the presence or occurrence of any of the 
following will be collected in the eCRF:
!
Abnormal liver biochemistry risk factors (e.g. alcohol abuse, increased alcohol consumption 
within 1 month of a Hy’s Law event, IV drug use, tattoo, acupuncture, sexually transmitted 
disease, toxic/chemical agent exposure, travel to areas at risk, post-partum, parenteral 
nutrition, excessive physical exercise, changes in diet, fasting episode, weight loss, previous 
drug reaction associated with an elevation of liver tests, blood transfusion, exposure to 
anyone with known hepatitis, history of hypotension/shock, history of hepatitis C, history of 
hepatitis B, history of hepatitis A, history of hepatitis E, history of nonalcoholic 
steatohepatitis, Wilson’s disease, history of diabetes, hemochromatosis, history of α-
1antitrypsin disease, history of Gilbert’s disease, known hepatic congestion, cirrhosis, 
esophageal varices, GI bleeds, recent use of Tylenol/hepatotoxic drugs, and any other 
relevant abnormal liver biochemistry risk factors)
!
Liver disease signs and symptoms (e.g. anorexia, asthenia, pyrexia, pruritus, jaundice, 
arthralgia, abdominal pain, abdominal tenderness, nausea, vomiting, mucosal inflammation, 
purpura, hepatomegaly, hepatojugular reflux, splenomegaly, elevated jugular venous 
distension, ascites, confusional state/encephalopathy, coma, right upper quadrant pain, 
vascular cutaneous signs, and any other relevant signs and symptoms)
!
Liver diagnostic tests (e.g. ultrasound RUQ, abdomen CT, liver MRI/MRCP, endoscopic 
retrograde cholangiopancreatography/esophagogastroduodenoscopy, liver biopsy, x-ray, and 
paracentesis) 
9.5.2.10
Major Adverse Cardiovascular Events
The primary safety endpoint is time to first MACE.
MACE is a composite of the total of CV death, non-fatal MI and non-fatal stroke. 
A Clinical Events Committee (CEC) will be formed to assess and adjudicate all MACE. This 
committee will be blinded to treatment assignment and composed of independent cardiologists. 
A charter outlining the communication flow and the criteria to classify and adjudicate MACE 
will be established.
The committee will adjudicate:
!
All death cases 
!
Myocardial infarction defined as any non-fatal case that was coded to a preferred term (PT) 
in the standardized MedDRA query (SMQ) “myocardial infarction” 
!
Stroke defined as any non-fatal case that was coded to a PT in the SMQ “central nervous 
system hemorrhages and cerebrovascular conditions”


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Additionally, the SMQs of cardiac disorders and cerebrovascular disorders will also be assessed 
by the CEC.
Patients who experience a MACE must be discontinued from IP and enter into the post-treatment 
follow-up period (Section 9.3.3.1).
Rescue medication use will be collected in the patient diary to assist in the interpretation of 
patient level safety events, such as MACE or other cardiovascular events.  In the event of a 
MACE or other cardiovascular event, copies of the paper diary may be requested by the Sponsor.
9.5.2.11
Clinical Laboratory Determinations
Blood and urine samples for clinical laboratory tests will be collected at Visits 1A, 6, 10, and 12 
or EOT, for patients who prematurely discontinue IP. At Visit 1B, the PI will assess the clinical 
significance of any values outside the reference ranges provided by the local laboratory.
Although fasting is not required, the patient should be encouraged to fast prior to each visit.  The
patient’s fasting condition must be consistent at all visits.
Women of childbearing potential will be required to have a serum pregnancy test at Visit 1A and 
Visit 12 or EOT, for patients who prematurely discontinue IP. For Visits 6 and 10, a urine 
pregnancy test will be performed for women of childbearing potential.
The following clinical laboratory tests will be performed:
Hematology:
Absolute and differential blood count (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), white blood cell count, 
erythrocyte count, thrombocytes (platelets), hemoglobin, and hematocrit
Chemistry:
Sodium, potassium, calcium, chloride, glucose, blood urea nitrogen, 
creatinine, total protein, alkaline phosphatase, albumin, total bilirubin, 
aspartate aminotransferase, creatine kinase, inorganic phosphorus, alanine 
aminotransferase, total cholesterol, triglycerides, uric acid, 
gamma-glutamyl transferase, and lactate dehydrogenase
Urinalysis:
Dipstick analysis will be performed at the center and will include: pH, 
blood, leukocytes, protein, glucose, bilirubin, ketones, and nitrites. If urine 
dipstick is abnormal, a urine sample will be sent to local lab for analysis of 
the sediment
Theophylline:
Only if the patient is receiving theophylline
Local laboratories will be used to evaluate all urine and blood samples.
Clinically significant abnormalities in laboratory values as determined by the investigator should 
be reported as adverse events (Section 9.5.2.1).


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9.5.2.12
Vital Signs
Vital sign measurements will be documented at Visits 1A, 2, 3, 4, 5, 6, 8, 10, and 12 or EOT, for 
patients who prematurely discontinue IP. The parameters are pulse rate, sitting systolic and 
diastolic blood pressure (BP). Pulse and BP readings will be taken after the subject has been 
sitting for 10 minutes. Waist circumference will also be taken at Visit 1A according to guidance 
provided by the National Heart, Lung, and Blood Institute (NHLBI 2000) (See Appendix VI). 
9.5.2.13
Electrocardiograms
One 12-lead electrocardiogram (ECG) will be performed at Visit 1A, and 2 hour post-dose ECG 
will be performed at Visit 1B.
An ECG will be performed 1 hour pre-dose and 2 hours post-dose at Visits 2, 3, 4, 5, 6, 8, 10 and 
12.  For patients who prematurely discontinue IP (EOT Visit), one ECG assessment will be 
performed.  Patients should be in a supine position for at least 10 minutes prior to the test.  All 
ECGs will be read by a central vendor.  
If a clinically significant ECG abnormality persists, the PI must contact the study physician to 
determine whether the patients should be continued in the study. 
The time window for ECGs to be completed is ±10 minutes from the scheduled time point.
9.5.2.14
Other Safety Assessments
a)
Physical Examination
A physical examination will be done at Screening (Visit 1A) and Visits 4, 6, 10, and 12 or EOT 
by a professionally trained physician or health professional listed on Form FDA 1572 and 
licensed to perform physical examinations. Height will be collected only at Visit 1A. Body 
weight will be collected at Visit 1A and Visit 12 or EOT. If a clinically significant finding occurs 
at Visit 1A, it should be added to the Medical History and any changes thereafter considered 
AEs.
9.5.2.15
Data Safety Monitoring Board
An independent Data Safety Monitoring Board (DSMB) will be established for this study. The 
DSMB will periodically monitor and review relevant clinical safety data, including adjudicated 
MACE.
DSMB members comprise a multidisciplinary team, including experts in pulmonary disease, 
cardiovascular disease, and biostatistics. Ad hoc members from other disciplines may be 
appointed to the DSMB if deemed necessary by the DSMB Chair and the Sponsor.
Membership and responsibilities of the DSMB as well as meeting frequencies and other details 
(e.g. communication) will be defined in the DSMB charter.
9.5.2.16
Joint Advisory Committee   
The purpose of the ASCENT COPD Joint Advisory Committee (JAC) is to advise the Sponsor 
Study Team regarding issues related to the conduct of the study (e.g. global enrollment rate, 


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study patient compliance, screen failure rate, early termination rate), and to establish the 
scientific strategy, analyses and interpretation of study data and communication of that data.  The 
JAC is comprised of seven (7) expert members, 4 external (2 pulmonologist study investigators, 
1 cardiologist, 1 biostatistician), 3 sponsor representatives (2 clinicians and 1 biostatistician). 
9.5.3
Investigational Product Concentration Measurements
Not applicable.
9.5.4
Health Economic and Outcomes Research Assessments
The CAT is a validated, patient completed, questionnaire to measure the impact of COPD on a 
patient’s health status. It is comprised of 8 questions to be answered independently by patient via 
a paper questionnaire (See Appendix V). At Visits 1B, 3, 4, 5, 6, 8, 10 and 12 or EOT, the CAT 
will be completed at the study site prior to any other study procedures. At Visits 7, 9 and 11, the 
CAT will be completed at home by the patient during the telephone visit and mailed back to the 
study site.  All data captured on the CAT will be entered into EDC by site staff.
9.5.5
Schedule of Assessments
The schedule of study procedures and assessments is tabulated by visit in the Schedule of 
Evaluations in Section 2. 
The descriptions of the procedures to be performed at each visit are provided below. 
All procedures should be performed in the order listed. 
9.5.5.1
Informed Consent 
Patients must sign the ICF within 30 days prior to any procedures being performed, and before 
medication washouts are initiated. The following procedures will be performed upon obtaining 
consent:
!
Access IWRS. IWRS will assign Patient Identification Number (PID)
!
Obtain patient demographics, medical history, and medication history. Confirmatory 
documentation for cardiovascular history must be obtained prior to Visit 1B in the form of a 
historic record, or self-report accompanied by an appropriate treatment regimen as assessed 
and confirmed by a source (e.g. medically qualified investigator or patient’s treating 
physician).
!
If patient requires washout, proceed to Washout/Run-in (Visit 0). If a washout is not 
required, proceed to Visit 1A (Section 9.5.5.3)
9.5.5.2
Washout/Run-in (Visit 0)
Visit 0 will only occur for patients who are taking a prohibited medication and require a 
washout. At Visit 0 and prior to the start of the washout period, the following procedures will be 
performed: 


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!
Access IWRS 
!
Perform pre-bronchodilator FEV1 spirometry test (forced maneuver only) (see Section 
9.5.1.2 and Appendix III)
!
Schedule patient phone contacts during the washout period to assess COPD stability. Contact 
should be made once per week.
!
Dispense rescue medication and rescue medication diary and instructions. 
!
Schedule patients to return for Visit 1A in approximately 2 weeks
9.5.5.3
Screening (Visit 1A)
For patients who do not require a washout, the ICF must be signed within 30 days prior to Visit 
1A, prior to performing any procedures. On the day the ICF is signed, patients will be registered 
in IWRS, assigned a PID in sequential order (by the IWRS), and dispense albuterol/salbutamol
for reversibility testing and rescue medication diary and instructions. Rescue medication 
dispensing and specific rescue medication will be provided locally.
At Visit 1A, the following procedures will be performed:
!
For patients who required a washout, review rescue medication usage per diary.
!
Obtain patient demographics, medical history, and medication history. Confirmatory 
documentation for cardiovascular history must be obtained prior to Visit 1B in the form of a 
historic record, or self-report accompanied by an appropriate treatment regimen as assessed 
and confirmed by a source (e.g. medically qualified investigator or patient’s treating 
physician).
!
Assess smoking status
!
Assess COPD exacerbations (see Section 9.5.1.1)
!
Assess any AEs that have occurred since the patient signed the ICF 
!
Collect concomitant medications (see Appendix II)
!
Measure vital signs (see Section 9.5.2.12)
!
Perform ECG (see Section 9.5.2.13)
!
Perform physical examination (including height and weight) (see Section 9.5.2.14a))
!
Perform pre-bronchodilator FEV1 spirometry test (forced maneuver only) (See Section 
9.5.1.2 and Appendix III


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!
Reversibility test. Administer 4 puffs (~400 μg) of albuterol/salbutamol from the rescue 
inhaler within 30 mins of pre-bronchodilator spirometry. Perform qualifying 
post-bronchodilator assessment 10-15 mins after albuterol/salbutamol administration. 
!
Perform post-bronchodilator FEV1 spirometry test (forced maneuver only) and determine 
FEV1/FVC ratio (See Section 9.5.1.2 and Appendix III)
!
Collect blood and urine samples for local clinical laboratory determinations including serum 
pregnancy test for women of child bearing potential. Results must be reviewed prior to 
randomization (see Section 9.5.2.11)
!
Confirm patients meet inclusion/exclusion criteria (see Section 9.3) 
9.5.5.4
Baseline (Visit 1B)
Within 3-5 days following Visit 1A, upon receipt of clinical laboratory results, the following 
procedures should be completed at Visit 1B: 
!
Confirm patient continues to meet inclusion/exclusion criteria (See Section 9.3)
!
Administer the CAT (see Section 9.5.4) prior to any other study procedure
!
Assess COPD exacerbations (see Section 9.5.1.1). In the event of a Respiratory infection or 
COPD exacerbation prior to Screening and/or during the Screening period between (Visit 0 
and 1B) the screening visit may be extended once only after the last increased additional dose 
of steroid burst and/or antibiotics is given to ensure patient has recovered from the 
exacerbation. 
!
Assess any AEs that have occurred since the patient signed the ICF 
!
Collect concomitant medications (see Appendix II)
!
Perform two pre-dose FEV1 spirometry tests 30-45 minutes apart (forced maneuver only) 
(see Section 9.5.1.2 and Appendix III)
!
Randomize patients via IWRS
!
Dispense IP via IWRS
!
Provide and review DPI instructions and IP dosing instructions with patients
!
Provide and review diary and diary instructions for IP use with patients
!
First dose of IP should be taken in the office and documented in the diary under the 
supervision of study staff
!
Perform post-dose ECG (see Section 9.5.2.13)


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!
Provide the rescue medication locally if required
!
Schedule patients to return for Visit 2 in 1 month (±7 days) and remind patients not to take 
their dose of IP on the morning of the next visit
9.5.5.5
Visit 2
At Visit 2, the following procedures will be performed for patients continuing in the treatment 
period. For patients who discontinue IP, see Section 9.5.5.8 for End of Treatment procedures.
!
Confirm that morning dose of IP has not been taken.  If morning dose has been taken, the 
visit must be rescheduled. 
!
Assess smoking status
!
Assess COPD exacerbations (see Section 9.5.1.1)
!
Assess any AEs that have occurred since the previous visit
!
Assess concomitant medications (see Appendix II)
!
Review rescue medication usage per diary 
!
Measure vital signs (see Section 9.5.2.12)
!
Perform pre-dose ECG (see Section 9.5.2.13)
!
Perform FEV1 spirometry test (forced maneuver only) (see Section 9.5.1.2 and Appendix III)
!
Collect diary and assess compliance. Provide retraining if necessary (see Section 9.4.9)
!
Provide patients with diary and diary instructions for IP use 
!
Morning dose of IP should be taken in the office and documented in the diary under the 
supervision of study staff
!
Perform post-dose ECG (see Section 9.5.2.13)
!
Provide the rescue medication locally, if required
!
Schedule patients to return for Visit 3 and remind patients not to take their dose of IP on the 
morning of the next visit


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9.5.5.6
Visits 3, 4, 5, 6, 8, and 10
At Visits 3, 4, 5, 6, 8, and 10, the following procedures will be performed for patients continuing 
in the treatment period. For patients who discontinue IP, see Section 9.5.5.8 for End of 
Treatment procedures.
!
Confirm that morning dose of IP has not been taken. If morning dose has been taken, the visit 
must be rescheduled
!
Administer the CAT (see Section 9.5.4) prior to any other study procedures
!
Assess smoking status
!
Assess COPD exacerbations (see Section 9.5.1.1)
!
Assess any AEs that have occurred since the previous visit
!
Assess concomitant medications (see Appendix II)
!
Review rescue medication usage per diary 
!
Measure vital signs (see Section 9.5.2.12)
!
Perform pre-dose ECG (see Section 9.5.2.13)
!
Perform physical examination at Visits 4, 6, and 10 only (see Section 9.5.2.14a))
!
Perform FEV1 spirometry test (forced maneuver only) (see Section 9.5.1.2 and Appendix III)
!
Collect blood and urine samples for clinical laboratory determinations including urine 
pregnancy test for women of child bearing potential at Visits 6 and 10 only (see Section 
9.5.2.11)
!
Collect IP and diary and assess compliance. Provide retraining if necessary (see Section 
9.4.9)
!
Access IWRS
!
Dispense IP
!
Provide the rescue medication, if required
!
Review and provide patients with DPI instructions and IP dosing instructions
!
Provide patients with diary and diary instructions for IP use
!
First dose of IP should be taken in the office and documented in the diary under the 
supervision of study staff


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!
Perform post-dose ECG (see Section 9.5.2.13)
!
Provide CAT and mailing envelope at Visit 6, 8, and 10 for completion at next telephone 
visit (see Section 9.5.4)
!
Schedule patients to return for next visit according to Schedule of Evaluations and remind 
patients not to take their dose of IP on the morning of the all subsequent in-clinic visits
9.5.5.7
Visits 7, 9, and 11
Visits 7, 9, and 11 will be conducted by telephone for patients continuing in the treatment period. 
The following information will be collected at each telephone visit: 
!
Instruct patient to complete CAT (see Section 9.5.4) and remind patient to send CAT back to 
the site using the pre-addressed, pre-stamped mailing envelope
!
Assess smoking status
!
Assess COPD exacerbations (see Section 9.5.1.1)
!
Assess any AEs that have occurred since the previous visit
!
Assess concomitant medications (see Appendix II)
9.5.5.8
Visit 12
At the Final Visit (patients completing the treatment period only), the following procedures will 
be performed:
!
Confirm that morning dose of IP has not been taken. If morning dose has been taken, the visit 
must be rescheduled. 
!
Access IWRS
!
Administer the CAT (see Section 9.5.4)
!
Assess smoking status
!
Assess COPD exacerbations (see Section 9.5.1.1)
!
Assess any AEs that have occurred since the previous visit
!
Collect concomitant medications (see Appendix II)
!
Review rescue medication usage per diary 
!
Measure vital signs (see Section 9.5.2.12)
!
Perform pre-dose ECG (see Section 9.5.2.13)


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!
Complete physical examination (including weight) (see Section 9.5.2.14a))
!
Perform FEV1 spirometry test (forced maneuver only) (see Section 9.5.1.2 and Appendix III)
!
Collect blood and urine samples for clinical laboratory determinations including serum 
pregnancy test for women of child bearing potential (see Section 9.5.2.11)
!
Morning dose of IP should be taken in the office and documented in the diary under the 
supervision of study staff 
!
Perform post-dose ECG (See Section 9.5.2.13)
!
Collect IP and diary and assess compliance (see Section 9.4.9)
!
Collect rescue medication and assess usage via diary
!
Provide the rescue medication locally if required
Any clinically significant findings obtained during the final examination, including clinically 
significant laboratory abnormalities, will be documented. A telephone contact will be performed 
15 days after the last known dose of IP is taken to assess any AEs that may have occurred and 
changes to and/or new concomitant medications taken since the last dose taken at the final visit. 
Any SAEs that occur within 15 days of the last dose of IP, or that were identified during the 
telephone contact, will be followed up by the investigator for as long as medically indicated but 
after 30 days there will be no further recording in the CRF. AZ 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.
9.5.5.9
End of Treatment (EOT) Visit
Patients who prematurely discontinue IP will complete the following procedures:
!
Access IWRS
!
Administer the CAT (see Section 9.5.4)
!
Assess smoking status
!
Assess COPD exacerbations (see Section 9.5.1.1)
!
Assess any AEs that have occurred since the previous visit
!
Collect concomitant medications (see Appendix II)
!
Review rescue medication usage per diary 
!
Measure vital signs (see Section 9.5.2.12)


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!
Perform ECG (see Section 9.5.2.13)
!
Complete physical examination (including weight) (see Section 9.5.2.14a))
!
Perform FEV1 spirometry test (forced maneuver only) (see Section 9.5.1.2 and Appendix III)
!
Collect blood and urine samples for clinical laboratory determinations including serum 
pregnancy test for women of child bearing potential (see Section 9.5.2.11)
!
Collect IP and diary assess compliance (see Section 9.4.9)
!
Collect rescue medication inhaler(s) 
!
If patient discontinued trial medication before the end of the trial, the patient will be 
informed that he/she will be contacted every three months for the first two years and then 
every six months for the third year as per Table 9.3.3–1 via telephone calls, until the subject 
completes 36 months in the study.
!
Schedule next Post-Treatment Follow up Visit according to Table 9.3.3–1. If the EOT occurs 
within two weeks of the next scheduled visit (telephone contact or on-site) the next visit can
be skipped
Any clinically significant findings obtained during the final examination, including clinically 
significant laboratory abnormalities, will documented. A telephone contact will be performed 15 
days after the last known dose of IP is taken to assess any AEs that may have occurred and 
changes to and/or new concomitant medications taken since the last dose taken at the final visit. 
For patients who prematurely discontinue IP, only SAEs will be collected until the last visit/end 
of study. 
AZ 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.
9.5.5.10
Contacts between treatment visits
In the event of a patient missing a study visit, the patient will have a documented telephone 
contact initiated by the PI or designee in accordance with the Schedule of Evaluations (see pages 
4-6), approximately every 3 months for the first two years and once every six months for year 
three following each treatment visit starting after Visit 1B. The PI or designee will ask the 
patient about any new AEs, COPD exacerbations and concomitant medication changes since the 
last visit.
9.5.5.11
Vital Status Follow-up
Additionally, patients who discontinue trial medication early will be contacted in accordance 
with table 9.3.3-1, approximately every 3 months for the first two years and once every six 
months for year three to obtain vital status information: MACE events, COPD exacerbations, 
SAEs, and concomitant medications; until the sponsor-defined end of the trial.


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9.5.5.12
Completion of Study
The Ethical Committee (EC) / Competent Authority (CA) in the US and Canada needs to be 
notified about the end of the trial (last patient/patient out, unless specified differently or early 
termination of the trial.
Based on the number of MACE events, the sponsor will declare the end of the study date and 
give the study sites at least 3 months’ notice. After the announcement of the end of study, the 
following information will be collected for all patients (these visit procedures also apply for a 
patient who is discontinuing trial medication before the end of the trial):
!
Subjects active on study drug:
o
All assessments listed in Section 9.5.5.9(EOT).
o
Schedule a phone contact for 15 days from visit.
!
Subjects in post treatment follow up:
o
All assessments listed for V12 in Table 9.3.3-1
9.6
Data Quality Assurance
9.6.1
Data Monitoring
Before any patient enters the study, a representative of Sponsor, will meet with the PI and the 
study center staff to review the procedures to be followed during the study. Electronic data 
capture (EDC) functionality training is provided via computer-based training to train PIs and 
authorized designees on recording the data in the eCRFs using the electronic data capture EDC 
system. After the first patient is enrolled, the Sponsor representative, a Regional Site Manager 
(RSM) or designee, will periodically monitor the progress of the study by conducting on-site 
visits. This RSM or designee will review query statuses remotely, possibly warranting more 
frequent communication and/or site visits with the PI and the study center staff. The PI will make 
available to the RSM or designee source documents (written notes and medical records/ 
electronic medical records), signed consent forms, and all other study-related documents. The PI 
and the study center staff will be responsible for data entry of patient data into the eCRFs via the 
EDC system, resolving data queries generated via the EDC system and providing missing or 
corrected data. The PI or designee will be responsible for approving all changes performed on 
the data, and endorsing the patient data within the EDC system. This approval method will 
include applying an electronic signature linked to a uniquely assigned username and password 
that together will represent a traditional handwritten signature used in the past.
9.6.2
Data Recording and Documentation
Data collection will involve the use of the AZ EDC system, to which only authorized personnel 
will have access. Patient’s data are to be entered into the EDC system by the PI or designee using 
their assigned EDC user account. After data entry into the EDC system by the PI or designee, a 
combination of manual and programmatic edit checks will be used to review the data for 
completeness, logic, and adherence to study protocol. As a result of these edits checks, data 
monitoring and reviews; queries may be electronically issued to the study centers and should be 
answered electronically via the EDC system.


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Each query will carry identifying information (assigned username, date and time) to assist AZ 
and the PI on the origin of the data clarification request and the response provided by the PI. All 
data changes made to the patient’s data via a data query will be approved by the PI prior to final 
database lock.
After all data have been reviewed and all issues have been resolved, the database will be locked.
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee patient confidentiality in accordance with the legal 
stipulations applying to confidentiality of data. Study records (e.g., copies of eCRFs, laboratory 
reports, patient diaries, regulatory documents, etc.) will be retained at the study center, along 
with adequate source documentation, according to FDA and ICH requirements. All study records 
must be available for inspection by Sponsor; its authorized representatives; and the FDA or other 
health authorities.
9.7
Statistical Methods and Determination of Sample Size
9.7.1
Patient Populations
Three populations will be considered in the statistical analysis of the study.
9.7.1.1
Screened Population
The Screened Population will consist of all patients who signed a written informed consent form 
and received a screening number.
9.7.1.2
Randomized Population
The Randomized Population will consist of all patients in the Screened Population who were 
randomized to a treatment group in the study.
9.7.1.3
Full Analysis Set Population
The Full Analysis Set (FAS) population will consist of all patients in the Randomized Population 
who took at least one dose of double-blind investigational product. Patients will be analyzed 
according to their randomized treatment.  
The FAS will be used to carry out the primary analysis of both efficacy and safety data. Efficacy 
and safety data may be further investigated and sensitivity analyses may be performed using the 
Randomized Population if more than 1% of patients did not receive one dose of double-blind IP. 
9.7.2
Patient Disposition
The number of patients in Randomized, and FAS populations will be summarized by treatment 
group and study center; the Screened Population will only be summarized overall by study 
center.


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Screen failures (i.e., patients screened but not randomized) and the associated reasons for failure 
will be tabulated overall. The number and percentage of patients who complete the double-blind 
treatment period, who prematurely discontinue from IP, and who prematurely discontinue from 
the study during the same period will be presented for each treatment group and pooled across 
treatment groups for the FAS Population. The reasons for premature discontinuation as recorded 
on the termination pages of the eCRF will also be summarized (number and percentage) by 
treatment group for all randomized patients.
The percentage of premature discontinuations from the study treatment as well as from the study 
will be compared overall using Kaplan Meier and Log rank test. Each discontinuation reason will 
be summarized by treatment groups. Additional graphical presentation to illustrate patterns of 
missing data will be described in the Statistical Analysis Plan.
Handling professional/duplicate patients. Professional patients are individuals who, in 
violation of protocol entrance criteria enter into the same study more than once and/or enter into 
different studies at the same time. 
Unless otherwise stated, the first incidence of patient entering trial is used in analysis and 
summary. All data is listed for transparency, with flags for duplicate patients to ensure clarity on 
the records included/excluded from the analysis.
For handling of AEs, if a patient is randomized to same treatment arm, all data will be included 
into the analysis. If patient is randomized to a different treatment (i.e., different treatment 
received at the second incidence vs the first incidence), only the data from the first incidence will 
be used in analysis.
9.7.3
Demographics and Other Baseline Characteristics
Demographic parameters (including age, age group [≥ 40 and < 60, ≥ 60 and < 70, and ≥ 70 
years old], race, ethnicity, sex, weight, height, and body mass index) and other baseline 
characteristics (including duration of COPD in years; patient known to have either chronic 
bronchitis or emphysema; COPD exacerbation in the previous 12 months; number of COPD 
exacerbations in the previous 12 months; COPD severity according to degree of airway 
obstruction: grade I [mild], II [moderate], III [severe], or IV [very severe]; smoking status and 
history; smoking duration in years; number of cigarettes per day; total pack-years; FEV1, FEV1
% predicted, FVC, and FVC % predicted prebronchodilator test; FEV1, FEV1 % predicted, FVC, 
and FVC % predicted, and ratio of FEV1/FVC postbronchodilator tests; % bronchodilator 
reversibility; change from prebronchodilator FEV1 to postbronchodilator FEV1; reversibility and 
baseline FEV1) will be summarized by treatment group for the FAS populations. For continuous 
variables, the number of nonmissing observations, mean, SD, median, minimum, and maximum 
will be presented. No statistical tests will be performed.


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The World Health Organization Drug Dictionary, enhanced version of March 2011 or newer, 
will be used to classify prior and concomitant medications by therapeutic class. Prior medication 
is defined as any medication taken within the period from 15 days before Screening (V0/Visit 
1A) to the day before the first dose of double-blind IP. Concomitant medication is defined as any 
medication taken during the double-blind treatment period between the date of the first dose of 
IP and the date of the last dose of IP, inclusive.
Prior medications will be tabulated by Anatomical Therapeutic Chemical classification code, 
preferred name, and treatment group. In addition, the number and percentage of patients who 
used any prior medication for COPD will be presented by therapeutic categories (i.e., Long-
Acting β2-Agonists [LABA], Long-Acting Muscarinic Antagonist [LAMA], Short-Acting β2-
Agonists [SABA], Short-Acting Muscarinic Antagonist [SAMA], Inhaled Corticosteroids [ICS], 
LABA and ICS Combination, SABA and SAMA combination, leukotriene modifiers, oral 
phosphodiesterase type 4 [PDE4], systemic corticosteroid, oxygen, methylxanthines, and 
influenza vaccine) and by treatment groups. Prior medication in the reporting by therapeutic 
categories is defined as any medication taken within 15 days prior to Visit 0/1A before initiation 
of a washout period.
All concomitant medications will be classified for each one of the two following periods and 
listed by treatment groups: 1) medications that the patient started to take before the 
randomization and continued after the first IP administration, and 2) medications that the patient 
started to take during the treatment period (from the first IP administration to the last IP 
administration). Medications that were used between the last IP administration and to the study 
end will be summarized for the patients who discontinued IP. In addition, the overall number and 
percentage of patients taking no concomitant medications versus those taking any concomitant 
medications will be summarized for each of these two periods and by treatment group. 
Concomitant medications will be tabulated by the third level of the Anatomical Therapeutic 
Chemical code, preferred name, and treatment group.
The use of prior and concomitant medications will be summarized by the number and percentage 
of patients in each treatment group for the FAS Population. Multiple medication use by a patient 
will only be counted once.
9.7.4
Extent of Exposure and Treatment Compliance
9.7.4.1
Extent of Exposure
Exposure to double-blind IP for the FAS Population during the double-blind treatment period 
will be summarized for treatment duration, calculated as the number of days from the date of the 
first dose of double-blind IP taken to the date of the last dose taken, inclusive. Descriptive 
statistics (n, mean, standard deviation, minimum, median, and maximum) will be presented by 
treatment group.
9.7.4.2
Measurement of Treatment Compliance
Dosing compliance for the double-blind treatment period is defined as the total number of 
treatment applications (puffs) taken by a patient during that period divided by the number of 
puffs expected to be taken during that same period multiplied by 100.


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Descriptive statistics for IP compliance will be presented by treatment group for each 
scheduled visit and overall during the double-blind treatment period for the FAS Population. 
Further information on how to calculate the compliance will be provided in the statistical 
analysis plan (SAP).
9.7.5
Efficacy Analyses
Efficacy analyses will be based on the FAS Population. All statistical tests will be two-sided 
hypothesis tests performed at the 0.05 alpha level of significance for main effects. All 
confidence intervals will be two-sided 95% confidence intervals, unless stated otherwise.
To control for multiplicity, the primary and secondary efficacy variables will be tested 
sequentially, i.e., the secondary efficacy endpoint will be tested only when both primary and 
secondary analyses on the primary efficacy endpoint achieved statistical significance, and the 
secondary analysis on the primary efficacy endpoint will be tested only when the primary 
analyses on the primary efficacy endpoint achieved statistical significance. Otherwise, nominal 
p-values will be provided and should be interpreted descriptively.
9.7.5.1
Primary Efficacy Parameter
The primary efficacy parameter is the following:
!
Rate of moderate or severe COPD exacerbations during the first year of treatment per patient 
per year
The primary efficacy endpoint of rate of moderate or severe COPD exacerbation per patient per 
year during the first year of treatment will be presented for the FAS population. The rate ratio of 
moderate or severe COPD exacerbation per patient per year due to the effect of aclidinium 
bromide 400 μg BID relative to placebo will be estimated along with its confidence interval and 
the corresponding p-value. 
Exacerbation rate in aclidinium group will be compared to exacerbation rate in the placebo group 
using a Negative Binomial regression model. The response variable in the model will be the 
number of moderate or severe COPD exacerbations experienced by a patient during the first year 
of treatment. The model will include treatment group, baseline ICS use, baseline COPD severity, 
history of at least one exacerbation in the past year, and smoking status as factors. In order to 
adjust for the exposure for each patient, the natural logarithm of the exposure time (in years) 
during the first year of treatment will be used as an offset variable. When used as the offset 
variable, the exposure time will be adjusted by subtracting the time when a patient experienced 
COPD exacerbation(s) (i.e., not at risk during an exacerbation). If the Negative Binomial 
regression model does not converge, the Poisson regression model with robust variance estimate 
using sandwich method will be applied.


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The primary analysis on the primary efficacy endpoint will be based on on-treatment analysis, 
i.e. for those patients who prematurely discontinue during the first year of double-blind treatment 
period and have follow-up assessments, the primary analysis will be based on the data collected 
before treatment discontinuation. The secondary analysis of this endpoint will be based on on-
study analysis using the same model as for the primary analysis of the primary efficacy endpoint.
For those patients who prematurely discontinue IP during the first year of treatment and have 
follow-up assessments, the secondary analysis will include the events collected during the PTFU
period up to one year.
The rate ratio of moderate or severe COPD exacerbation per patient per year due to the effect of 
aclidinium bromide 400 μg BID relative to placebo will be estimated along with its confidence 
interval and the corresponding p-value. The two-sided p-value for aclidinium bromide 400 μg 
BID relative to placebo in reducing the rate of exacerbation will be compared to the 
0.05 significance level.
Sensitivity analyses 
To assess the robustness to variations of the data assumptions underlying the primary and 
secondary analysis of the primary efficacy endpoint, several sensitivity analyses will be 
conducted as follows:
!
Jump to reference (J2R) approach (see Appendix 1 for details) 
!
Copy reference (CR) approach (Keene et al, 2014; see Appendix 1 for details) 
!
Tipping point analysis (see Appendix 2 for details)
9.7.5.2
Secondary Efficacy Parameter
The secondary efficacy variable is rate of hospitalization due to COPD exacerbation per patient 
per year during the first year of treatment. This will be analysed (on-treatment analysis) using the 
same model as for the analyses of the primary efficacy endpoint, including on-study analysis as 
sensitivity analysis.
9.7.5.3
Additional Efficacy Parameters
The additional efficacy parameters are the following (on-treatment analysis):
!
COPD exacerbation parameters
○
Rate of moderate or severe COPD exacerbations per patient per year
○
Rate of mild, moderate, or severe COPD exacerbations per patient per year
○
Duration (days) of moderate or severe COPD exacerbations per patient per year 
○
Duration (days) of mild, moderate, or severe COPD exacerbations per patient per year 


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○
Number and percentage of patients with at least one COPD exacerbation (any, mild, 
moderate, severe, and moderate or severe)
○
Time (days) to first, second, and third COPD exacerbation (any, and moderate or severe)
○
Time (days) to withdrawal due to COPD exacerbation
○
Rate of hospitalizations due to COPD exacerbations per patient per year
○
Number of days hospitalized due to COPD exacerbations
○
Time (days) to first hospitalization due to COPD exacerbation
!
Spirometry 
o
Change from baseline in morning pre-dose trough FEV1 at visits 2, 3, 4, 5, 6, 8, 10, and 
12
COPD Exacerbations 
All additional efficacy parameters will be presented based on the FAS population. The details 
will be described in the SAP. 
The rate of COPD exacerbations per patient per year (any, and moderate or severe) will be 
analyzed using a Negative Binomial regression model similar the primary analysis of the primary 
efficacy parameter. For categories that Negative Binomial regression does not converge, the 
Poisson regression model with robust variance estimate using sandwich method will be applied. 
The details will be described in the SAP. The durations of all endpoints of COPD exacerbation
days will also be summarized for only the patients who had exacerbations during the double-blind
treatment period.
The number of patients with at least one COPD exacerbation (any, mild, moderate, severe, and 
moderate or severe) will be analyzed based on a logistic regression model with treatment group
and baseline COPD severity and smoking status as factors.
Time (days) to first COPD exacerbation (any, and moderate or severe) will be analyzed by 
means of Kaplan-Meier estimators and Cox Proportional Hazards model. The estimates of the 
hazard ratio comparing aclidinium bromide 400 μg with placebo will be derived using the Cox 
proportional hazard model for the time in terms of the number of days served as a response and 
treatment group, baseline ICS use, baseline COPD severity, history of at least one exacerbation 
in the past year, and smoking status as factors. 
Duration of COPD exacerbations per patient per year (any, and moderate or severe) will be 
summarized descriptively.


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Spirometry
The additional efficacy spirometry parameter, change from baseline in morning pre-dose trough 
FEV1 at visits 2, 3, 4, 5, 6, 8, 10, and 12, will be analyzed using a mixed model for repeated 
measures (MMRM). Treatment group will be fitted as the explanatory variable, and pre and 
post-bronchodilator (albuterol/salbutamol) FEV1 at screening visit (Visit 1A), and baseline FEV1
as covariates, and smoking status, baseline ICS use, visit, and treatment group-by-visit 
interaction as fixed effect factors. The within-patient correlation will be modeled using the 
unstructured covariance matrix. If the model does not converge, then the compound symmetry 
covariance structure will be used.
9.7.6
Safety Analyses
The safety analysis will be performed using the FAS Population. For the safety analysis, the 
safety parameters are AEs including COPD exacerbations, vital sign measurements, ECG 
parameters, and physical examination findings. For each safety parameter, the last assessment 
made before the first dose of double-blind IP will be used as the baseline for all analyses of 
that safety parameter.
9.7.6.1
Primary Safety Parameter
The primary safety parameter is time to first MACE.
The primary safety endpoint of time to first MACE will be presented for the FAS Population and 
will be based on on-study analysis. The on-study analysis will be used as it provides an overall 
evaluation of the effect of aclidinium or placebo, as well as reduces the potential bias caused by 
censoring events and patients as a result of differences in study drug adherence. We are defining 
on-study analysis as all events that occurred while the patients was in the study, irrespective of 
treatment exposure (i.e., this includes all events that occurred while a subject was on treatment or 
off treatment).   
In addition, to account for the relation of the occurrence of an event and treatment exposure, an 
on-treatment analysis will also be conducted and this will include only events that occurred while 
the patient was exposed to study treatment, i.e., events that occurred after the patient’s last 
treatment dose was censored. Two ascertainment windows, 0 and 15 days, will be evaluated in 
the on-treatment analyses. The on-treatment and on-treatment +15 days analyses will censor 
events that occur after and more than 15 days after, respectively, after the last treatment dose. 
While a primary method is pre-specified, patterns and timing of discontinuation from study 
treatment, as we as selected replacement therapy will be carefully evaluated between aclidinium 
bromide 400 μg BID and placebo. The impact of these explorations in the analysis methods (i.e., 
the on-study analysis and on-treatment analysis) will be thoroughly assessed. Since both 
approaches have limitations, the totality of evidence will be carefully weighed regarding the 
evaluation of MACE. 
The choice of on-study and on-treatment analyses (applying different censoring scheme) is 
consistent with the SAVOR-TIMI 53 trial [Scirica et al, 2013, Geiger et al, 2015] and the 
TIOSPIR trial assessing all-cause mortality [FDA Briefing Book for Pulmonary-Allergy Drugs 
Advisory Committee Meeting August 14, 2014 for NDA# 21936].


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The primary safety endpoint will be analyzed based on Cox-proportional hazards regression 
model including, baseline CV severity, smoking status, and treatment group as covariates. The 
assumption of proportional hazards will be assessed visually using log-cumulative hazard plots. 
The effect of any departures from proportional hazards will be discussed as part of the 
presentation of results of the analyses. The CV severity at baseline will be defined as 2 
categories: 1) patients who had 2 CV risk factors, and 2) patients who had more than 2 CV risk 
factors or at least one non-fatal stroke or non-fatal MI. This model will provide point estimate for 
the hazards ratio (aclidinium over placebo), as well as corresponding 95% confidence interval. 
The upper bound of the 95% confidence interval (based on Cox regression) for the hazard ratio 
(aclidinium relative to placebo) of time to first MACE will be used to rule out the null hypothesis 
of hazard ratio of 1.8 for the primary test on MACE. If the upper bound of the 95% confidence 
interval is less than the 1.8 margin of the hazard ratio, then the hazard ratio of 1.8 or higher will 
be ruled out (justification for the hazard ratio of 1.8 is provided in Appendix IV). In addition, the 
Kaplan-Meier survival curves will be displayed for each treatment group.
The results from the primary safety analysis will also be evaluated considering a superiority 
hypothesis.
Sensitivity analyses
To account for the relation of the occurrence of an event and treatment exposure, an on-treatment 
analysis will be conducted and this will include only events that occurred while the patient was 
exposed to study treatment, i.e., events that occurred after the patient’s last treatment dose will 
be censored. Two ascertainment windows, 0 and 15 days, will be evaluated in the on-treatment 
analyses. The on-treatment and on-treatment +15 days analyses will censor events that occur 
after and more than 15 days after, respectively, after the last treatment dose.
Sensitivity analysis of the primary composite endpoint will include analysis with CV death 
replaced with all-cause mortality. 
Sensitivity analysis will also be conducted to assess the impact of change in the inclusion 
criteria, by including in the model as factor a flag (1=Pre-/2=Post-) to account for the change 
in the inclusion criteria.
9.7.6.2
Secondary Safety Parameter
The secondary parameter is the following:
!
Time to first MACE or other serious cardiovascular events of interest (ie, SMQ of cardiac 
disorders and SMQ of cerebrovascular disorders)


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The analyses of the secondary safety endpoint of the time to first MACE or other serious 
cardiovascular events of interest and all additional endpoints will not be adjusted for multiple 
comparisons.
The secondary safety endpoint of time to first MACE or other serious cardiovascular events of 
interest (ie, SMQ of cardiac disorders and SMQ of cerebrovascular disorders) will be analyzed 
for the FAS Population using the same method as the primary safety endpoint using a confidence 
level of 95% and without statistical testing for non-inferiority (non-inferiority margin will not be 
used). Supportive listings will be provided for all adjudicated events with adjudication 
conclusions.
9.7.6.3
Additional Safety Parameters
a)
Adverse Events
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities, Version 15.0 or newer.
An AE (classified by preferred term) will be considered a treatment-emergent adverse event 
(TEAE) if it started on or after the date of the first dose of double-blind IP or it started before the 
date of the first dose of double-blind IP and continued during the double-blind treatment period 
with increased severity. An AE that occurs more than 15 days after the date of the last dose of 
double-blind IP will not be counted as a TEAE.
AEs will be collected only once with its maximum intensity, except when the AE started before 
first IP administration, persisted after it and worsened in intensity any time after first IP. In this 
latter case, the AE will be collected with each respective intensity. The AE term recorded must 
be exactly the same in the different intensities collected.
The number and percentage of patients reporting TEAEs in each treatment group will be 
tabulated by system organ class, high level term, and preferred term; by system organ class, high 
level term, preferred term, and severity; by system organ class, high level term, preferred term, 
and relationship to the IP; and by system organ class, high level term, preferred term, and 
outcome. If more than one AE is coded to the same preferred term for the same patient, the 
patient will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarization by severity and by causal relationship to the IP.
For the summary table by system organ class, high level term and preferred term, the distribution 
of TEAEs in each treatment group will be sorted in decreasing frequency by preferred term for 
aclidinium bromide 400 μg within each system organ class.
The incidence of common (e.g. ≥ 2% of patients in any treatment group) TEAEs will be 
summarized by preferred term.
All the incidences will be sorted by decreasing frequency for aclidinium bromide 400 μg.


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A SAE that occurs on or after the date of the first dose of double-blind IP and within 15 days of 
the date of the last dose of double-blind IP will be considered an on-therapy SAE. The number of 
percentages of patients with on-therapy SAEs, and AEs leading to premature discontinuation of 
the IP will be summarized by by SOC and PT, and treatment group and will be sorted by 
decreasing frequency for aclidinium bromide 400 μg. In addition, the incidence of fatal on-
therapy SAEs (i.e. events that caused death) will be summarized separately by preferred term, 
and treatment group.
For the Screened Population, separate listings will be presented for patients with SAEs, patients 
with AEs leading to discontinuation, and patients who die (if any).
b)
Vital Signs
Descriptive statistics for vital signs (pulse rate, sitting systolic and diastolic BP) and changes 
from baseline values at each visit and at end of study will be presented by treatment group.
Vital sign values will be PCS if they meet both the observed-value criteria and the change from 
baseline–value criteria. The criteria for PCS vital sign values will be detailed in the SAP. The 
percentages will be calculated relative to the number of patients with baseline values and at least 
one postbaseline assessment. The numerator will be the total number of patients with available 
baseline values and at least one PCS postbaseline value in the treatment period. The denominator 
will be the total number of patients with available non-PCS baseline values and at least one 
postbaseline assessment. A supportive listing of patients with PCS postbaseline values will be 
provided, including the PID number, study center number, and baseline and postbaseline values. 
A listing of all AEs occurring in patients who have PCS vital sign values will also be provided.
c)
Electrocardiogram
Descriptive statistics for ECG parameters (i.e. ventricular heart rate, RR interval, PR interval, 
QRS interval, QT interval, and QTc interval) and changes from baseline values at each 
assessment time point will be presented by treatment group. The QTc interval is calculated using 
both the Bazett (QTcB = QT/(RR)½) and Fridericia (QTcF = QT/(RR)⅓) corrections.
The number and percentage of patients with PCS postbaseline ECG values will be tabulated by 
treatment group. The criteria for PCS ECG values will be detailed in the SAP. The percentages 
will be calculated relative to the number of patients with available non-PCS baseline values and 
at least one postbaseline assessment. The numerator will be the total number of patients with 
available baseline values and at least one PCS postbaseline value in the treatment period. A 
supportive listing of patients with PCS postbaseline values will be provided, including the PID 
number, study center number, and baseline and postbaseline values. A listing of all AEs for 
patients with PCS ECG values will also be provided.


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d)
Other Safety Parameters
i) Physical Examination
A listing of physical examination findings at Screening (Visit 1A) will be provided by treatment 
group as a part of the medical history listing. Any new physical examination finding or change 
(worsening) since the previous physical examination will be recorded as an AE in the appropriate 
AE eCRF form. If any clinically significant change is observed after randomization (Visit 2), it 
should be recorded in the AE eCRF form.
ii) All-cause mortality
All-cause mortality based on patient’s vital status data will be analyzed using the same method 
as the primary safety endpoint using a 95% CI and without statistical testing for NI (NI margin 
will not be used).
9.7.7
Health Economics and Outcomes Research Analyses
CAT by Visits
The change from baseline of CAT score will be analyzed with MMRM models. The model may 
adjust for baseline CAT and history of at least one exacerbation in the past year as covariates, 
and treatment group, sex, smoking-status, visit, and treatment group-by-visit interaction as fixed 
effect factors. 
Descriptive statistics will also be provided.
In addition, changes from baseline in the CAT score will be evaluated in a responder analysis.
Further details for CAT calculation and analysis will be given in the SAP.
9.7.8
Interim Analysis
No interim analysis is planned for this study.
9.7.9
Determination of Sample Size
9.7.9.1
Power for the Primary Safety Endpoint: Time to First MACE Event
For this study, a total of 122 patients with MACE will be needed to have 90% power, at 5% 
significance level, to rule out a hazard ratio of 1.8 in time to first MACE in aclidinium bromide 
treated patients relative to placebo, assuming the hazard rate is 1.0 under the alternative 
hypothesis.  The justification for the hazard ratio of margin of 1.8 is provided in Appendix IV.
The study will be stopped when a total of 122 patients with MACE are observed.
The COPD safety database for the new drug application of roflumilast filing included a total of 
3,310 patient-years on roflumilast 500 μg and 3,448 patient-years on placebo. That is a total of 
6,758 patient years. Based on this exposure a total of 126 MACE were observed leading to ~1.9 
MACE per 100 patient years (out of the 126 MACE only 1 patient had 2 MACE). Also the 
majority of the patients in this program were recruited based on % predicted FEV1 below 50%.


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The placebo group in the UPLIFT study had 2.89 MACE per 100 patient-years while tiotropium 
group had 2.25 MACE. It should be noted that this was a 4-year study and therefore it is possible 
more events occurred in the last 2 years of treatment than in the first two years as the health 
status of the patients could be worse over time (Boehringer Ingelheim, 2009).
This ASCENT COPD study will be recruiting patients with an FEV1 below 80% and a planned 
maximum of 3 years double-blind treatment period.  The assumption of 1.9 MACE per 100 
patient years would be reasonable for this study. To obtain 122 MACE in this study with 1.9 
MACE per 100 patient years of treatment, a total of 6,500 patient years of treatment (aclidinium 
and placebo) would be needed. 
Assuming a treatment discontinuation rate of 40% and a study discontinuation rate of 20% at 
year 2, and following an exponential distributions for time to events and time to discontinuations, 
a sample size of 4000 is needed to ensure 90% power to observe 122 events applying the on-
study analysis, and an 80% power to observe 91 events applying the on-treatment analysis.
9.7.9.2
Power for the Primary Efficacy Endpoint: Rate of Moderate or Severe 
Exacerbations Per Patient Per Year During First Year of Treatment
The sample size of 4,000 patients after 1 year of treatment will have ~89% power to detect a 
reduction in the rate of moderate or severe COPD exacerbations per patient per year during the 
first year of treatment of 14% (rate ratio of 0.86 in aclidinium bromide relative to placebo) at 
0.05 alpha level (Table 9.7.9–1.). The 89% power was calculated assuming a discontinuation rate 
of 30% during the first year, a placebo rate of 0.8 exacerbation per patient per year (reduced 
from 1 to 0.8 as not all patients will have a history of exacerbation prior to randomization), and 
an over-dispersion factor k of 0.67 [Keene et al, 2007]. 
The clinical significance in reduction in the rate of exacerbation is not clearly defined for 
powering studies. Roflumilast was approved based on average reduction in exacerbation rate per 
patient per year of 17% relative to placebo averaged across the two pivotal studies. Tiotropium in 
the Handihaler® was approved for exacerbation based on UPLIFT trial along with another 6 
months trial. The hazard ratio for time to first moderate or severe COPD exacerbation in UPLIFT 
was 0.86 (tiotropium relative to placebo) and the rate ratio per patient per year in moderate or 
severe COPD exacerbation was 0.86, implying a reduction of 14% (Boehringer Ingelheim, 
2009). 
Table 9.7.9–1. Summary of Statistical Power to Detect a Specific Rate Ratio (Aclidinium 
Over Placebo) as Statistically Significant for a Range of Rate Ratio: One Study with 4,000 
Patients in Total to be Tested at 0.05 Level
Statistical Power (%)
Placebo Rate (event/pt-yr)
Expected Rate Ratio
(Aclidinium over placebo)
0.6
0.8
1.0
0.80
99
99.6
99.9
0.82
96
99
99


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Statistical Power (%)
Placebo Rate (event/pt-yr)
0.84
91
96
98
0.86
81
89
93
0.88
68
77
83
0.90
52
61
67
All calculations assume average exposure time of 0.85 years (30% discontinuation spread uniformly between Day 1 and 1 year) 
and overdispersion factor k of 0.67. Power was calculated using EAST version 6.3
9.7.10
Computer Methods
Statistical analyses will be performed using version 9.2 (or newer) of SAS on a UNIX operating 
system.
9.8
Changes in the Conduct of the Study or Planned Analyses
Any amendment to this protocol will be provided to the PI in writing by Sponsor. No protocol 
amendment may be implemented (with the exceptions noted below) before it has been approved 
by the IRB/IEC and the signature page, signed by the PI, has been received by Sponsor. If the 
protocol is amended to eliminate or reduce the risk to patients, the amendment may be 
implemented before IRB/independent ethics committee (IEC) review and approval. However, the 
IRB/IEC must be informed in writing of such an amendment, and approval must be obtained 
within reasonable time limits.
9.9
Protocol Deviations and Violations
A protocol deviation is any change, divergence, or departure from the study design or procedures 
that is under the PI’s responsibility and oversight (as defined by regulations) without prior 
written IRB/IEC approval or favorable opinion of an appropriate amendment and that does not 
have a major impact on the patient’s rights, safety, or well-being, or on the integrity and 
authenticity of the study data. Deviations may include, but are not limited to, departure from 
inclusion/exclusion criteria, dosing, duration of treatment, failure to perform the required 
assessments at specified time points, scheduling of visits not in accordance with specifications, 
or patient safety. Deviating from the protocol is permitted only if absolutely necessary for the 
safety or clinical management of the patients and must immediately be reported to Sponsor.
Protocol deviations must be reported to the Sponsor either verbally or electronically within 5 
working days from the day of discovery.
A protocol violation is a form of protocol deviation that has a major impact on the patient’s 
rights, safety, or well-being, or on the integrity and authenticity of the study data.
Protocol violations must be reported to the Sponsor within 24 hours, if possible. The IRB/IEC 
must be notified within the time period dictated by the IRB/IEC associated with this study.


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10.
STUDY SPONSORSHIP
This study is sponsored by AstraZeneca. 
10.1
Study Termination
The Sponsor reserves the right to terminate the study in its entirety or at a specific study center 
before study completion. 
10.2
Reporting and Publication
All data generated in this study will be the property of the Sponsor. An integrated clinical and 
statistical report will be prepared at the completion of the study.
Publication of the results by the PI will be subject to mutual agreement between the PI and 
Sponsor.


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11.
INVESTIGATOR OBLIGATIONS
11.1
Documentation
The PI must provide the following to the Sponsor, before the start of the study:
!
A completed and signed Form FDA 1572. If, during the course of the study, any changes are 
made that are not reflected on Form FDA 1572, a new Form FDA 1572 must be completed 
and returned to the Sponsor, for submission to the FDA
!
A fully executed contract
!
The curricula vitae for the PI and all Sub-Investigators listed on Form FDA 1572, including a 
copy of each physician’s license
!
A copy of the original IRB/EC approval for conducting the study. If the study is ongoing, 
renewals must be submitted at yearly intervals. All subsequent modifications must be 
submitted and approved by the IRB/IEC, as stated in Section 5.1
!
A copy of the IRB/EC-approved ICF
!
A copy of the HIPAA authorization form, or other local privacy applicable forms
!
A list of the IRB/EC members or the DHHS general assurance number
!
A copy of the laboratory certifications and reference ranges
!
The Investigator’s Statement page in this protocol signed and dated by the PI 
!
Financial disclosure agreement completed and signed by the PI and all Sub-Investigators 
listed on Form FDA 1572. The PI and all Sub-investigators will provide an updated financial 
disclosure agreement to the Sponsor 1 year after the completion of the study
11.2
Performance
The PI must demonstrate reasonable efforts to obtain qualified patients for the study.
11.3
Use of Investigational Materials
The PI will acknowledge that the investigational product supplies are investigational and as such 
must be used strictly in accordance with the protocol and only under the supervision of the PI or 
Sub-Investigators listed on Form FDA 1572. The investigational products must be stored in a 
safe and secure place. At study initiation, a representative from AZ, will inventory the 
investigational products at the study center. The PI must maintain adequate records documenting 
the receipt and disposition of all study supplies. The date investigational products were received 
and the date of dispensation to each patient will be recorded in IWRS. It is the PI’s responsibility 
to ensure that patients return their investigational product.  All unused IP and empty IP packages 
should be destroyed unless otherwise instructed by AZ.


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11.4
Case Report Forms
All patient data relating to the study will be recorded on eCRFs to be provided by AZ through 
the EDC system. The PI is responsible for verifying that all data entries in the eCRFs are 
accurate and correct by electronically signing the completed eCRF casebook submitted to AZ. 
The PI must maintain and retain accurate documentation that supports the information entered 
into the EDC system for source document verification and possible regulatory inspection.
11.5
Retention and Review of Records
Records and documents pertaining to the conduct of this study, including case report forms, 
source documents, consent forms, regulatory documents, clinical laboratory results or reports 
(including, but not limited to, all local laboratory results, spirometry reports and ECG reports), 
and medication inventory records in all formats (including, but not limited to, written, electronic, 
magnetic, and optical records, and scans, x-rays, and electrocardiograms) must be retained by the 
Investigator for a period of at least 15 years after study completion unless local regulations or 
institutional policies require a longer retention period or otherwise notified in writing by the 
Sponsor.
No study records shall be destroyed without notifying the Sponsor and providing the Sponsor the 
opportunity to arrange long-term storage for such study records or authorizing in writing the 
destruction of records after the required retention period.
The Principal Investigator must permit access to any documentation relating to the study upon 
request of the Sponsor or applicable regulatory authorities. If the Principal Investigator for the 
study retires, relocates, or for other reasons withdraws from the responsibility of keeping the 
study records, custody must be transferred to a suitable alternate custodian employee of the 
institution or to a suitably qualified and responsible third party. The Sponsor must be notified in 
writing of the name and address of the new custodian in advance of the transfer.
For Canadian study sites only: All records and documents pertaining to the conduct of the study 
must be retained for a 25-year period in accordance with the Canadian Food and Drugs Act and 
Regulations.
11.6
Patient Confidentiality
All patient records will only be identified by initials and PID number. Patients’ names are not to 
be transmitted to AZ. The PI will keep a master patient list on which the PID number and the full 
name, address, and telephone number of each patient are listed.


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12.
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with this protocol LAS-MD-45
(D6560C00002), dated 25 Jan 2017 and with all applicable government regulations 
and good clinical practice guidance.
_______________________________________
_____/_____/______
Principal Investigator’s Signature
Date
_______________________________________
Principal Investigator’s Name


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13.
APPENDICES
APPENDIX I.
ELEMENTS OF INFORMED CONSENT
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained from each patient participating in a clinical research study or from the patient’s Legally 
Authorized Representative (LAR). This consent must include the following items:
!
A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration of the patient’s participation
!
A description of any reasonably foreseeable risks or discomforts to the patient
!
A description of any benefits to the patient or to others that may reasonably be expected from 
the research. If the patient is to be paid for participating in the study, the consent form must 
state the amount that he/she will receive and the schedule of payment (to ensure neither 
coercion nor undue influence)
!
A disclosure of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the patient
!
A statement describing the extent, if any, to which confidentiality of records identifying the 
patient will be maintained and noting the possibility that the FDA; AZ the IRB; or an 
authorized contract research organization may inspect the records
!
For research involving more than minimal risk, an explanation of whether any medical 
treatment is available if injury occurs and, if so, what it consists of or where further 
information may be obtained
!
An explanation of whom to contact, including the relevant telephone number, for answers to 
pertinent questions about the research and the research patient’s rights and whom to contact 
in the event of a research-related injury to the patient. (Note: In some cases, it may be 
necessary to identify a person other than the PI as the contact. The guidance of the IRB/EC 
may be required)
!
A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the patient is otherwise entitled, and that the patient may 
discontinue participation at any time without penalty or loss of benefits to which the patient 
is otherwise entitled
!
A statement that the particular treatment or procedures may involve risks to the patient (or to 
the embryo or fetus if the patient is, or may become, pregnant) that are at present 
unforeseeable
!
The expected circumstances for which the patient’s participation may be terminated by the PI 
without regard to the patient’s consent


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!
Any additional costs to the patient that may result from participation in the research
!
The consequences of a patient’s decision to withdraw from the research and procedures for 
an orderly termination of the patient’s participation
!
A statement that significant new findings developed during the course of the research that 
may relate to the patient’s willingness to continue participation will be provided to the patient
!
The approximate number of patients involved in the study
!
A statement of consent (e.g., “I agree to participate...”)
!
A place for the patient’s signature and date of signing
!
A statement indicating that information about this study has been, or will be, entered into a 
databank that is publicly accessible at www.ClinicalTrials.gov
A copy of the signed consent form should be given to the patient.


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APPENDIX II.
CONCOMITANT MEDICATIONS
Drugs Allowed (Y) and Drugs Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions
Episodic 
(PRN)
Chronic
Long-acting β2-adrenergic 
agonists and Long-acting 
muscarinic 
antagonists (LABA/LAMA) 
fixed dose combination
N
N
Not allowed within 2 weeks prior to screening 
Visit 1A and throughout the study. For patients 
on (LAMA/LABA) fixed dose combination, 
alternate maintenance bronchodilator therapy 
should be initiated.
Long-acting muscarinic 
antagonists (i.e. inhaled 
anticholinergics) 
(e.g., tiotropium) and oral, 
intranasal or parenteral 
anticholinergics
N
N
Not allowed within 2 weeks prior to Visit 1A 
and throughout the study. For patients on 
LAMA, alternate maintenance bronchodilator 
therapy should be initiated.
Short-acting inhaled 
anticholinergics 
(e.g., ipratropium, 
oxitropium)
N
N
Not allowed within 24 hours prior to Visit 1A 
and throughout the study.
Short-acting β2-adrenergic 
agonists (e.g., fenoterol, 
terbutaline, albuterol, 
salbutamol)
Y
N
Episodic use of albuterol HFA or salbutamol 
sulfate is permitted, however, only Sponsor-
provided Albuterol/salbutamol should be used. 
Should be withheld for 6 hours prior to visits.
Long-acting β2-adrenergic 
agonists (e.g., salmeterol, 
formoterol)
N
Y
Must be stable for at least 2 weeks prior to 
Visit 1A.
Inhaled corticosteroids
Y
Y
Must be stable for at least 2 weeks prior to 
Visit 1A.
May be initiated or dose may be changed 
during the course of the study after a COPD 
exacerbation at the discretion of the 
investigator.
Must be a stable schedule at least 2 weeks prior 
to Visit 1A.


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Drugs Allowed (Y) and Drugs Not Allowed (N) as Concomitant Medications
Drug Class
Frequency of Use
Restrictions
Episodic 
(PRN)
Chronic
Oral or parenteral 
corticosteroids
Y
Y
May be initiated or dose may be changed 
during the course of the study after a COPD
exacerbation at the discretion of the
investigator.
LABA/ICS (e.g., Symbicort, 
Advair)
N
Y
Must be stable for at least 2 weeks prior to 
Visit 1A.
May also be initiated during the course of the 
study after a COPD exacerbation at the 
discretion of the investigator.
Roflumilast
N
Y
Must be stable for at least 2 weeks prior to 
Visit 1A.
May be initiated during the course of the study 
after a COPD exacerbation at the discretion of 
the investigator.
Methylxanthines
Y
Y
N/A
Supplemental oxygen
Y
Y
N/A
Leukotriene modifiers (e.g. 
montelukast, zafirlukast, 
zileuton)
Y
Y
N/A
Antihistamines
Y
Y
N/A
Vaccinations
Y
Y
N/A
Any other inhaled 
medications not listed above
N
N
Inhaled medications not listed above 
(e.g., medications used for nausea and/ or pain 
control) are prohibited throughout the study. 
Ingested forms of these medications may be 
allowed. Please contact the study physician 
with any questions.
Y = yes, allowed; N = not allowed; PRN = as needed; HFA = hydrofluoroalkane; N/A = not applicable.


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APPENDIX III.
PULMONARY FUNCTION TESTS
The Investigative site should have the spirometers and all necessary equipment (computer, 
calibration syringe, printer, paper, ink, etc.), and the proper training from American Association 
for Respiratory Care (AARC) (for qualification of all technicians in charge of conducting 
spirometry) is needed in order to conduct this clinical trial per the protocol requirements. 
Spirometers will measure FVC (maximal volume of air exhaled with maximally forced 
expiratory effort from a position of maximal inspiration) and FEV1 (volume of air expressed in 
liters exhaled during the first second of performance of the FVC) and will meet American 
Thoracic Society and European Respiratory Society recommendations for accuracy and precision 
(Miller et al, 2005).
Spirometer recommendations for the study provided devices should be followed to provide 
accurate and comparable spirometric data, and calibration should be performed every day the 
system is used. Daily calibration on the day of testing procedures should be conducted with a 3-
liter syringe which will allow validation of spirometer accuracy (GOLD, 2017. Spirometry must 
be performed at temperatures between 17°C and 40°C. Efforts should be made to perform all 
maneuvers at approximately the same temperature. A notebook must be maintained to document 
daily (at least for those days spirometric procedures have to be done) ambient temperature. In 
case of significant changes in temperature and/or barometric pressure within the same day, 
calibration must be repeated before any other spirometry is done. Daily equipment calibration for 
days where testing is conducted as well as appropriate staff training records should be kept in the 
site’s regulatory notebook.
Before the first spirometry is conducted for this clinical trial, the trained operator may 
demonstrate the procedure using a detached mouthpiece and then allow two practice attempts. A 
copy of the spirometry tracings should be printed and kept in the patient’s medical records as 
source documentation.
The technician performing the test must properly wash his/her hands or use gloves to avoid any 
possible contamination. Reusable mouthpieces, breathing tubes, valves, and manifolds should be 
properly disinfected or sterilized regularly in accordance to the recommendations of the 
American Thoracic Society and European Respiratory Society ATS/ERS (Miller et al, 2005).
Spirometry Maneuvers
Pulmonary function tests will be performed by highly experienced personnel. At each time point, 
3 technically adequate measurements should be performed according to the acceptability and 
repeatability criteria of the American Thoracic Society and European Respiratory Society 
ATS/ERS (Miller et al, 2005).
Patients should be able to produce repeatable pulmonary function testing (ie, the two best 
acceptable spirometry efforts must have FEV1 and FVC values that do not vary by more than 150 
mL). If both the acceptability and repeatability criteria are met, the test session may be 
concluded. If both of these criteria are not met, additional maneuvers should be performed until 
both criteria are met OR a total of 8 tests have been performed, unless the patient cannot 
continue. All maneuvers completed, whether deemed acceptable or not, must be retained and 
provided as source documentation.


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The data for each visit must be entered into the electronic data capture system, including patient 
ID, date, time, visit number, whether spirometry was performed, whether the patient had a
bronchodilator in the previous 6 hours, and the reason for visit, if it was unscheduled. The 
spirometry assessment results should be printed, signed by the technician and PI, and kept in the 
patient’s medical record as source documentation.
Throughout the study, the reading of spirometric values is to be performed by the PI, or 
appropriately trained designee, to ensure the values meet the American Thoracic Society and 
European Respiratory Society criteria for acceptability. At each time point, only the greatest 
acceptable FEV1 and FVC value will be used for all analyses.
The circumstances of the test should be similar on all occasions with respect to time of the day, 
temperature and pressure as well as the technician. Smoking and prolonged exposure to cold air, 
dust, and polluted air should be avoided for at least 1 hour before each visit until the completion 
of all study procedures. For patients having difficulty not smoking, nicotine gums or patches may 
be used.
Patients should be at rest for 15 minutes before the test and comfortable; tight or cumbersome 
clothing should be loosened to allow the thorax to move freely. Measurements are to be made 
with the patient seated in an upright posture and wearing a nose clip.
The procedure should be carefully described to the patient, with an emphasis on the need to 
avoid leaks around the mouthpiece. The following order of the spirometric maneuvers must
be followed for forced maneuvers for measuring FEV1 and FVC:
!
Breathe in as deeply and quickly as possible.
!
Immediately place the mouthpiece in your mouth and seal your lips tightly around it.
!
Blow out as hard and as fast as you can, remaining upright and keeping your lips sealed.
!
When your lungs are empty, remove the mouthpiece and breathe in normally.
At the time of forced maneuver, the technician performing the measurement should prompt the 
patient to blast, not just blow, the air from the lungs; continue to encourage him/her to fully 
exhale. Throughout all complete maneuvers, the technician should enthusiastically coach the 
patient by word and body language and attempt to obtain 3 acceptable and repeatable efforts with 
a maximum of 8 attempts for each assessment. The technician should provide the patient with 
ample time for the patient to rest between each maneuver.
Any bronchoconstriction that appears after consecutive measurements should be noted on the 
eCRF as an AE.


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APPENDIX IV.
POWER COMPUTATION DETAILS
ASSESSMENT OF BENEFIT-RISK RATIO AND JUSTIFICATION OF ACCEPTABLE 
INFERIORITY MARGIN OF HAZARD RATIO
A selected hazard ratio of 1.8 for time to first MACE for aclidinium relative to placebo that 
would need to be ruled out statistically is the subject of this appendix. The justification will be 
based on the NNH with 1 MACE per year of treatment compared to Number Needed to Treat 
(NNT) to reduce 1 exacerbation per patient per year and more importantly compared to NNT to 
reduce 1 hospitalization due to COPD exacerbation per patient per year. In COPD patients, the 
event of hospitalization due to COPD exacerbation may be considered comparable to a MACE. 
As can be seen from Table 13–1 and  Table 13–2 below, aclidinium 400 μg BID showed a 
reduction in the rate of moderate or severe COPD exacerbations of 26.4% across the three Phase 
III studies (3 to 6 months treatment period in these 3 studies). Also, the effect of aclidinium 400 
μg BID on hospitalization due to COPD exacerbation was also strong as can be seen in Table 
13–1. Approximately 12% of the moderate or severe exacerbations led to hospitalization. These 
data are being used to generate the exacerbation hypotheses proposed for this study and to 
estimate the benefit from aclidinium treatment in terms of reducing both COPD exacerbations 
and hospitalizations. In addition, the UPLIFT study showed that: tiotropium reduced the rate of 
moderate or severe COPD exacerbations by 14% over 4 years period; 27% of patients in the 
placebo group were hospitalized due to COPD exacerbation versus 25.4% of patients in the 
tiotropium group; the UPLIFT study showed that exacerbations are the largest cause of death in 
the population of COPD patients (Boehringer Ingelheim, 2009) (see Table 13–3).
Table 13–1.
Summary of Moderate or Severe COPD Exacerbations and of Patients with 
Exacerbations Leading to Hospitalizations per Patient per Year in the Phase 
III Placebo Controlled Studies of Aclidinium (Studies LAS-MD-33, LAS-
MD-38A, and M/34273/34 Pooled) Intent-to-treat Population
Placebo
(N = 640)
AB400
(N = 636)
Total Number of Moderate or severe
Exacerbations 
83
65
Number (%*) of Patients with ≥ 1 
Severe Exacerbations Leading to 
Hospitalization
13(2%)
5(0.8%)
N = number of patients in ITT Populations of the pooled 3 studies.
*(%) = percent is calculated based on number divided by N.
AB400 = Aclidinium Bromide 400 μg BID.


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Table 13–2.
Rate of Moderate or Severe COPD Exacerbations per Patient per Year 
based on the Pooled Phase III Placebo Controlled Studies of aclidinium 
(Studies LAS-MD-33, LAS-MD-38A, and M/34273/34 Pooled) Intent-to-treat 
Population
Statistics
Placebo
(N = 640)
Aclidinium 200 μg
(N = 643)
Aclidinium 400 μg
(N = 636)
Rate Ratio for 
Aclidinium 200 μg 
relative to Placebo
Rate Ratio for 
Aclidinium 400 μg 
relative to Placebo
Rate
0.461
0.319
0.339
0.692
0.736
95% C.I.
( 0.39, 0.54)
( 0.26, 0.39)
( 0.28, 0.41)
( 0.55, 0.88)
( 0.58, 0.93)
p-value 
0.0024
0.0098
Estimate of the rate ratio along with its 95% CI and p-value for comparing Aclidinium versus Placebo or comparing Aclidinium
400 μg versus Aclidinium 200 μg are derived using the Poisson regression model with overdispersion and with the total 
number of COPD exacerbations during the study as response and with study, sex, and baseline COPD severity as factors 
along with age as covariate, adjusting for the log of the corresponding total exposure time in years for a patient (as an offset 
variable in the model).
95% CI = 95% Wald Confidence Interval (lower limit, upper limit) for the rate ratio.
p-value of the rate ratio using the Wald test.
*A new exacerbation will be counted as a separate one only if the patient has been off systemic corticosteroids and antibiotics 
for ≥14 days since the prior exacerbation.
Table 13–3.
Exacerbation Outcomes (Benefit from Tiotropium Treatment in 
Handihaler®) from the UPLIFT trial
Placebo
(N = 3,006)
Tiotropium
(N = 2,986)
Difference in Number of events
(Placebo - tiotropium)
Rate of exacerbations per 
patient year
0.85
0.73
0.12 per patient year
(p-value < 0.001)
Number (%) of patients with 
hospitalization for COPD
811 (27.0)
759 (25.4)
52 hospitalized patients due to 
COPD
(p-value = 0.002 based on time 
to first hospitalization endpoint)
Number (%) of Death Due 
to COPD Exacerbation
121 (4.0)
103 (3.4)
18 Deaths
Approach of Benefit Assessment: Expected NNT with Aclidinium to Reduce 1 
Exacerbation or Hospitalization
For the purpose of assessing the benefit of reduction in exacerbation or hospitalization per year
we assume the placebo group to have a rate of 0.8 event per patient per year and the aclidinium 
group to have a rate of ~0.69 per patient per year (a reduction of 14%). Based on these 
assumptions, the aclidinium benefit can be measured by 9 NNT for 1 year to reduce 1 moderate 
or severe COPD exacerbations, calculated as 1/(1 - 0.89). The NNT to reduce 1 hospitalization 
due to COPD exacerbation can be predicted to be 42 (this calculation is based on the assumption 
of 12% of the moderate or severe exacerbation would be hospitalized as observed in Table 13–1, 
a rate of 0.12 per patient per year for placebo and 0.096 for aclidinium - a reduction of 20%).


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It is understood that the reduction in exacerbation of 14% is not known at this point in the 
planned population. However, since the hypothesis of hazard ratio margin for risk of MACE 
depends on the benefit magnitude of aclidinium we assume a reasonable expected benefit for the 
patients from aclidinium treatment for their COPD exacerbation and then compare that to the risk 
of MACE.
Approach of Risk Assessment: NNH with 1 MACE Per Year
This NNH with 1 MACE per year method for assessment of risk is an alternative approach to the 
hazard ratio. This is equivalent and easier to compare the benefit based on NNT to reduce 1 
exacerbation or hospitalization. The statistical test based on the upper bound of the confidence 
interval for the hazard ratio being lower than a null hazard ratio margin is the same as using a 
test based on the lower bound of the confidence interval for the NNH being greater than a null 
NNH margin. A lower NNH indicates that a product is associated with higher risk to the patient. 
Conversely, a higher NNH indicates a lower risk to the patient. Likewise a low margin of NNH 
corresponds to a high hazard ratio margin. These arguments are used to generate the margins for 
NNH that corresponds to the hazard ratio margins of 1.5, 1.7, 1.8, and 2.0 (See Table 13–4 below 
for details).
Table 13–4 provides NNT to reduce 1 exacerbation and the margin for NNH with 1 MACE that 
corresponds to the HR margin of 1.8 along with other useful information. Other important 
information from Table 13–4 is the maximum point estimate of the hazard ratio that can be 
observed to rule out the hazard ratio margin of 1.8, which is 1.262. The corresponding minimum 
point estimate of NNH to rule out the null NNH margin of 66 (with one MACE) is 201 patients 
per year. (See Table 13–4 for detailed calculations).
In the previously submitted study design, it was proposed to rule out a hazard ratio of 1.5. During 
the discussion at the aclidinium PADAC, the advisory board was asked to provide the Sponsor 
with advice on this preliminary study design. Two clear messages emerged:
!
The study results should be available as soon as possible, and the study design should be 
adjusted to allow for this
!
In evaluating the risk of MACE, the Sponsor should consider the potential benefit of 
reduction in exacerbations in addition to assessing risk of MACE, and we should consider 
adjusting the hazard ratio accordingly. Dr. Mauger pointed out a hazard ratio margin higher 
than 1.5 could be justified based on the NNH with 1 MACE.
He argued that for such an extremely rare event, you can have a hazard ratio of 1.5 and still be 
looking at a NNH of over 100, which may lead to accepting the null hypothesis in which the 
hazard ratio is set too low to be clinically meaningful. A complete discussion by Dr. Mauger and 
the chair of the PADAC regarding the HR margin is provided in Appendix 12.2. The NNH 
approach in this document (see Table 13–4) along with benefit-risk assessment was used to 
justify a HR margin of 1.8. 


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The calculations of risk are based on assuming 1.9 MACE per 100 patient years in the placebo 
group. A value of 201 for minimum point estimate of NNT in column 2 can be obtained as the 
minimum integer higher than 1 over ((1.262 × 0.019) – 0.019). This calculation assumes the 
hazard ratio is the same as the rate ratio and this is a valid assumption for low rates as 0.019.
It should be noted that the null hypothesis based on the hazard ratio margin of at least 1.8 is the 
same as the null hypothesis of at most 66 NNH margin with 1 MACE per year. Therefore, ruling 
out a hazard ratio of 1.8 or higher is the same as ruling out an NNH of 66 or lower.
The null NNH margin of 105 is calculated as 1/(0.0285 – 0.019) where the 0.019 is the assumed 
placebo mean rate of MACE per 1 patient per year which is the same as 1.9 events per 100 
patient years and the 0.0285 is the mean rate of MACE per 1 patient per year in the aclidinium 
group calculated under the null (the hazard ratio margin of 1.5 = 0.0285/0.019).
Benefit-Risk Ratio: Justification of Using 1.8 Hazard Ratio
The potential risk of treatment with aclidinium will be assessed in the context of the potential 
benefit to the patient through reduction of exacerbations and COPD-related hospitalizations. The 
NNH will define the risk of having a MACE, while the NNT will establish the potential benefit 
of avoiding an exacerbation or COPD-related hospitalization. This approach is consistent with 
the advice the Sponsor and the Agency were given at the PADAC. The established benefit of 
FEV1 bronchodilator effect of aclidinium bromide in the Pressair® DPI with supporting 
pulmonary function (ie, FVC, IC), SGRQ and other symptom data provide additional evidence in 
support of the reduction of exacerbations.
NNT: Reduction in Exacerbations and COPD-related Hospitalizations
The benefit from aclidinium treatment is predicted to be an NNT of 9 patients per year to reduce 
1 moderate to severe COPD exacerbation. Also, it can be seen above as an NNT of 42 patients 
would be expected to eliminate 1 hospitalization per year (Table 13–1 and Table 13–2).
NNH: MACE
The NNH for 1 MACE that will be compared to the above NNT to benefit in reducing 
1 exacerbation is the minimum point estimate of NNH of 201 patients with 1 MACE per year of 
treatment to rule out the null margin of 1.8 for the hazard ratio (or corresponding NNH of 66). 
The NNH of 201 for 1 MACE is the lowest number of patients needed to reject the null 
hypothesis (NNH margin of 66 or HR = 1.8 margin). In those 201 aclidinium treated patients, the 
benefit can be explained by the expected reduction of 22.3 events (201/9) of moderate or severe 
exacerbations and of those 22.3 events, 4.8 are expected to be COPD hospitalizations (201/42). 
Therefore, for each reduction of 4.8 hospitalizations due to COPD exacerbations at most 1 
additional MACE is allowed for the success of the study based on MACE.
It should be noted in addition to the assumed reduction in exacerbation/hospitalizations benefit, 
aclidinium has demonstrated robust efficacy as a bronchdilator in COPD, improvement in 
SGRQ, reduction in the use of rescue medication, and improvement in dyspnea. These benefits 
justify the selection of the hazard ratio margin of 1.8 for the null hypothesis of time to first 
MACE for aclidinium relative to placebo that needs to be ruled out statistically.


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Rationale for Change in Hazard Ratio Margin From Preliminary Study Synopsis
From Table 13–4, the NNH of 303 patients with 1 MACE is the most extreme point estimate of 
MACE risk for the study to be successful in ruling out the 1.5 margin of the hazard ratio (this 
corresponds to a null margin in NNH with 1 MACE of 105 patients). In this 303 aclidinium 
treated patients, the harm of 1 MACE is best compared to the expected reduction of 33.7 events 
(303/9) of moderate or severe exacerbations and of those 33.7 events 7.2 are expected to be 
COPD hospitalizations (303/42).
Based on the null margin of a hazard ratio of 1.5, the study is designed to be too strict with 
respect to the MACE margin of 1.5 for hazard ratio. The boundary for success is that for harm 
with 1 additional MACE and a benefit in the reduction of 34 exacerbations (7 of which are 
expected to be COPD hospitalizations) is required. It would not be appropriate to consider the 
study a failure if an increase beyond 1 MACE (such as 1.1) is observed despite the expected 
benefit in the reduction of 34 COPD exacerbations (7 of which are expected to be COPD 
hospitalizations.)
Table 13–4.
Justification of the Selected Margin for Hazard Ratio for this Study Based 
on Benefit-Risk Approach: Risk Quantified using NNT for 1 year to Harm 
with 1 MACE and Benefit Quantified Using NNT for 1 Year to Reduce 
1 Exacerbation 
Point 
Estimate of 
NNT† for
1 year to
Reduce 1
COPD 
Exacerbation
Minimum 
Point Estimate 
of NNH‡ with
1 MACE to Rule 
Out its Null 
Margin
Maximum Point 
Estimate of HR to 
Rule out the Null 
Margin of HR
Total MACE 
Needed for 90% 
Power to Rule 
Out the Null in 
the Right 
Columns at 5% 
Significance 
Level
Null Hypothesis¶:
Margin of 
NNH Per Year 
with 1 MACE:
1/(aclidinium -
placebo)
Null Hypothesis:
Hazard Ratio 
Margin for 
Increase of 
MACE: 
(aclidinium/
placebo)
9
303
1.174
256
105
1.5
9
225
1.234
150
75
1.7
9
201
1.262
122
66
1.8
9
167
1.317
88
53
2.0
†
Point estimate of NNT for 1 year to reduce 1 COPD exacerbation was calculated assuming 14% reduction in the rate of 
exacerbation per patient per year from an average rate of 0.8 event per patient per year in the placebo group.
‡
Minimum point estimate of NNH with 1 MACE to rule out the null margin was calculated by assuming 1.9 MACE per 100 
patient years in the placebo group and by using the maximum point estimate of HR to rule out the null margin of HR. For 
example the 303 value of minimum point estimate of NNT in column 2 can be obtained as the minimum integer higher than 
1 over ((1.174 x 0.019) - 0.019). This calculation assumes the hazard ratio is the same as the rate ratio and this is a valid 
assumption for low rates as 0.019.
It should be noted that the null hypothesis based on the hazard ratio corresponds to the null hypothesis based on NNH with 
1 MACE (For example the null hypothesis based on the hazard ratio of at least 1.8 is the same as the null hypothesis of at 
most 66 NNT with aclidinium to harm with 1 MACE. Therefore, ruling out a hazard ratio of 1.8 or higher is the same as 
ruling out an NNH of 66 or lower.)
# The NNH margin of 105 is calculated as 1/(0.0285 - 0.019) where the 0.019 is the assumed placebo mean rate of MACE per 1 
patient per year which is the same as 1.9 events per 100 patient years and the 0.0285 is the mean rate of MACE per 1 
patient per year in the aclidinium group calculated under the null (the hazard ration of 1.5 = 0.0285/0.019).


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APPENDIX V.
COPD ASSESSMENT TEST - CAT


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APPENDIX VI.
WAIST CIRCUMFERENCE MEASUREMENT INSTRUCTIONS
Figure and instructions sourced from:
The Practical Guide Identification, Evaluation, and Treatment of Overweight and Obesity in Adults
U.S. Department of Health and Human Services
Public Health Service
National Institutes of Health
National Heart, Lung, and Blood Institute
NIH Publication No. 00-4084
October 2000


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14.
LITERATURE CITED
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Mannino DM, Thorn D, Swensen A, et al. Prevalence and outcomes of diabetes, hypertension 
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Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005; 
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Scirica BM, Chatt DL, Braunwald E, et al. SAVOR-TIMI 53 Steering Committee and 
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Sin DD, Anthonisen NR, Soriano JB, et al. Mortality in COPD: role of comorbidities. Eur Respir 
J 2006, 28:1245-1257.
Sin DD, Man P. Why are patients with chronic obstructive pulmonary disease at increased risk of 
cardiovascular diseases?, the potential role of systemic inflammation in chronic obstructive 
pulmonary disease. Circulation 2003; 107:1514-1519.
Soriano JB, Visick GT, Muellerova H, et al. Patterns of comorbidities in newly diagnosed COPD 
and asthma in primary care. Chest 2005; 128:2099-107.
The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in 
Adults [NIH Publication No. 00-4084]. 2000 Oct. Available from: 
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Wouters EFM. Chronic obstructive pulmonary disease. 5: systemic effects of COPD. Thorax 
2002; 57:1067-70.

SAP_001.pdf: 
SAP: D6560C00002 
Confidential - Proprietary Information 
x Protocol number: D6560C00002 
x Document title: Double-blind, Randomized, Placebo-controlled, 
Parallel-group, Phase IV Study to Evaluate the Effect of Aclidinium 
Bromide on Long-term Cardiovascular Safety and COPD 
Exacerbations in Patients with Moderate to Very Severe COPD 
(ASCENT COPD) 
x Version number: 3 
x Date of the document: 23 October 2017 
x NCT number: NCT01966107 
 


 
Statistical Analysis Plan 
Study Code 
D6560C00002 
Edition Number 
Amendment 3.0 
Date 
23 October 2017  
Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase IV 
Study to Evaluate the Effect of Aclidinium Bromide on Long-term 
Cardiovascular Safety and COPD Exacerbations in Patients with Moderate 
to Very Severe COPD (ASCENT COPD) 
 
 


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
2 
 
 
 
 
 
 
 
 
Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase IV 
Study to Evaluate the Effect of Aclidinium Bromide on Long-term 
Cardiovascular Safety and COPD Exacerbations in Patients with Moderate 
to Very Severe COPD (ASCENT COPD) 
 
AZ Study Statistician 
 
 
Date 
 
 
 
 
 
 
 
 
PPD


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
3 
 
 
 
 
 
 
 
 
Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase IV 
Study to Evaluate the Effect of Aclidinium Bromide on Long-term 
Cardiovascular Safety and COPD Exacerbations in Patients with Moderate 
to Very Severe COPD (ASCENT COPD) 
 
PAREXEL Study Statistician 
 
 
Date 
 
 
 
 
 
 
 
 
PPD


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
4 
 
 
 
 
 
 
 
 
Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase IV 
Study to Evaluate the Effect of Aclidinium Bromide on Long-term 
Cardiovascular Safety and COPD Exacerbations in Patients with Moderate 
to Very Severe COPD (ASCENT COPD) 
 
Global Product Statistician 
 
 
Date 
 
 
 
 
 
 
 
 
PPD


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
5 
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1 
SIGNATURE OF STUDY STATISTICIAN .......................................................... 2 
SIGNATURE OF STUDY STATISTICIAN .......................................................... 3 
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN .................................... 4 
TABLE OF CONTENTS ......................................................................................... 5 
LIST OF ABBREVIATIONS .................................................................................. 8 
AMENDMENT HISTORY ................................................................................... 10 
1. 
STUDY DETAILS ................................................................................................. 11 
1.1 
Study objectives ..................................................................................................... 11 
1.2 
Study design ........................................................................................................... 12 
1.3 
Number of subjects ................................................................................................ 13 
1.3.1 
Power for the primary safety endpoint: time to first MACE event ........................ 13 
1.3.2 
Power for the primary efficacy endpoint: rate of moderate or severe 
exacerbations per patient per year during the first year of treatment..................... 13 
2. 
ANALYSIS SETS ................................................................................................. 13 
2.1 
Definition of analysis sets ...................................................................................... 13 
2.1.1 
Screened Population ............................................................................................... 13 
2.1.2 
Randomized Population ......................................................................................... 14 
2.1.3 
Full Analysis Set Population .................................................................................. 14 
2.2 
Violations and deviations ....................................................................................... 14 
2.2.1 
Protocol deviations ................................................................................................. 14 
2.2.2 
Visit window definitions ........................................................................................ 15 
3. 
PRIMARY AND SECONDARY VARIABLES ................................................... 15 
3.1 
General principles taken for analysis variables...................................................... 15 
3.1.1 
End of study date ................................................................................................... 15 
3.1.2 
Censoring rules in time-to-event analyses ............................................................. 15 
3.1.3 
Definition of baseline measurements ..................................................................... 16 
3.1.4 
Repeated or unscheduled assessments ................................................................... 17 
3.1.5 
Handling missing data ............................................................................................ 17 
3.1.5.1 
Data convention for FEV1 ...................................................................................... 17 
3.1.5.2 
Data convention for CAT ....................................................................................... 18 
3.1.5.3 
Missing end date of exacerbations ......................................................................... 18 
3.1.5.4 
Missing date of the last dose of the double-blind IP .............................................. 18 


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
6 
3.1.5.5 
Missing severity assessment for AEs ..................................................................... 18 
3.1.5.6 
Missing causal relationship to the double-blind IP for AEs .................................. 18 
3.1.5.7 
Missing date information for AEs .......................................................................... 18 
3.1.5.8 
Missing date information for prior and concomitant medications ......................... 19 
3.1.5.9 
Character Values of Clinical Laboratory Parameters ............................................ 21 
3.1.6 
Definition of COPD exacerbations ........................................................................ 21 
3.1.7 
Derived variables ................................................................................................... 22 
3.1.7.1 
Rate of event .......................................................................................................... 22 
3.1.7.2 
Duration of event ................................................................................................... 22 
3.1.7.3 
Time to first event .................................................................................................. 23 
3.1.7.4 
Other derived variables .......................................................................................... 23 
3.2 
Primary efficacy variable ....................................................................................... 24 
3.3 
Secondary efficacy variable ................................................................................... 24 
3.4 
Additional efficacy variables ................................................................................. 25 
3.4.1 
COPD exacerbation variables ................................................................................ 25 
3.4.1.1 
Rate of moderate or severe COPD exacerbations per patient per year .................. 25 
3.4.1.2 
Rate of mild, moderate, or severe COPD exacerbations per patient per year........ 25 
3.4.1.3 
Duration of moderate or severe COPD exacerbations per patient per year ........... 25 
3.4.1.4 
Duration of mild, moderate, or severe COPD exacerbations per patient per 
year ......................................................................................................................... 25 
3.4.1.5 
Proportion of patients with at least one COPD exacerbation................................. 25 
3.4.1.6 
Time to COPD exacerbation .................................................................................. 26 
3.4.1.7 
Time to Withdrawal from the double-blind IP due to COPD exacerbation .......... 27 
3.4.1.8 
Rate of hospitalization due to COPD exacerbations per patient per year .............. 27 
3.4.1.9 
Number of days hospitalized due to COPD exacerbations .................................... 27 
3.4.1.10 Time to first hospitalization due to COPD exacerbations ..................................... 28 
3.4.2 
Spirometry outcome variable ................................................................................. 28 
3.5 
Safety variables ...................................................................................................... 28 
3.5.1 
MACE and other serious CV events of interest ..................................................... 28 
3.5.1.1 
Adjudication of clinical endpoints ......................................................................... 29 
3.5.1.2 
Primary safety variable .......................................................................................... 30 
3.5.1.3 
Secondary safety variable ...................................................................................... 30 
3.5.2 
Adverse events ....................................................................................................... 30 
3.5.3 
Clinical laboratory variables .................................................................................. 31 
3.5.4 
Vital signs .............................................................................................................. 31 
3.5.5 
Electrocardiogram .................................................................................................. 31 
3.5.6 
Physical examination ............................................................................................. 32 
3.5.7 
All-cause mortality ................................................................................................. 32 
3.6 
Health economic and outcomes research assessments ........................................... 32 
4. 
ANALYSIS METHODS ....................................................................................... 33 
4.1 
General principles .................................................................................................. 33 
4.2 
Analysis methods ................................................................................................... 34 


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
7 
4.2.1 
Patient disposition .................................................................................................. 34 
4.2.2 
Demographics and other baseline characteristics .................................................. 36 
4.2.2.1 
Demography data ................................................................................................... 36 
4.2.2.2 
Other baseline characteristics................................................................................. 36 
4.2.2.3 
Prior and concomitant medications ........................................................................ 38 
4.2.3 
Extent of Exposure and Treatment Compliance .................................................... 40 
4.2.3.1 
Extent of Exposure ................................................................................................. 40 
4.2.3.2 
Measurement of Treatment Compliance ................................................................ 40 
4.2.4 
Efficacy analyses.................................................................................................... 40 
4.2.4.1 
Primary efficacy outcome variable ........................................................................ 41 
4.2.4.2 
Secondary efficacy variable ................................................................................... 43 
4.2.4.3 
Additional efficacy variables ................................................................................. 43 
4.2.5 
Safety analyses ....................................................................................................... 45 
4.2.5.1 
Primary safety variable .......................................................................................... 46 
4.2.5.2 
Secondary safety variable ...................................................................................... 47 
4.2.5.3 
Adverse Events ...................................................................................................... 47 
4.2.5.4 
Clinical laboratory variables .................................................................................. 49 
4.2.5.5 
Vital signs .............................................................................................................. 49 
4.2.5.6 
Electrocardiogram .................................................................................................. 50 
4.2.5.7 
Physical examination ............................................................................................. 50 
4.2.5.8 
All-cause mortality ................................................................................................. 50 
4.2.6 
Health economics and outcomes research analyses ............................................... 50 
4.2.6.1 
COPD assessment tests (CAT) by visit ................................................................. 50 
5. 
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 52 
6. 
REFERENCES ...................................................................................................... 52 
7. 
APPENDIX ............................................................................................................ 52 
Appendix 1: Imputation of unobserved exacerbations ........................................................... 53 
Appendix 2: Tipping point analysis ....................................................................................... 56 
 


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
8 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
adverse event 
AESI 
adverse event of special interest 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
AZ 
AstraZeneca 
BID 
twice a day (bis in die) 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minutes 
CAT 
COPD assessment test 
CEC 
Clinical Events Committee 
CI 
confidence interval 
COPD 
chronic obstructive pulmonary disease 
CR 
copy reference 
CSP 
clinical study protocol 
CSR 
clinical study report 
CV 
cardiovascular 
DB 
database 
DSMB 
Data Safety Monitoring Board 
DPI 
dry powder inhaler/inhalation 
ECG 
electrocardiogram, electrocardiographic 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EOT 
end of treatment  
FAS 
full analysis set 
FEV1 
forced expiratory volume after one second 
FVC 
forced vital capacity 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HLT 
high level term 
ICF 
informed consent form 
ICS 
inhaled corticosteroid 
IP 
investigational product 
IWRS 
interactive web response system 
J2R 
jump to reference 
KM 
Kaplan-Meier 


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
9 
Abbreviation or 
special term 
Explanation 
LABA 
long-acting β2-adrenergic agonists 
LAMA 
long-acting muscarinic antagonist 
LTFU 
lost to follow-up 
MACE 
major adverse cardiovascular event(s) 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MMRM 
mixed model for repeated measures 
NI 
non-inferior, non-inferiority 
OS 
overall survival 
PCS 
potentially clinically significant 
PDE4 
oral phosphodiesterase type 4 
PID 
patient identification number 
PT 
preferred term 
PTFU 
post treatment follow-up 
QTc 
QT Interval corrected for heart rate 
QTcB 
QT Interval corrected for heart rate using the Bazett formula 
(QTcB = QT/(RR)½) 
QTcF 
QT Interval corrected for heart rate using the Fredericia formula 
(QTcF = QT/(RR)⅓) 
SABA 
short-acting β2-adrenergic agonists 
SAE 
serious adverse event 
SAMA 
short-acting muscarinic antagonist 
SAP 
statistical analysis plan 
SD 
standard deviation 
SMQ 
standard MedDRA query 
SOC 
system organ class 
Sponsor 
AstraZeneca 
TEAE 
treatment-emergent adverse event 
WHO DD 
World Health Organization Drug Dictionary 
 


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
10 
AMENDMENT HISTORY 
Date 
Brief description of change 
30 Oct 2013 
Initial Approved SAP by Forest Lab 
26 May 2016 
Amend according to Amended Protocol #2 (15 Sep 2015), Amended Protocol #3 
(29 Feb 2016) and AstraZeneca (AZ) standard 
17 August 2017 
Amend according to FDA comments on the SAP amendment 1 (dated May 26, 
2016), JAC recommendations, and/or blind delivery reviews.  
23 October 2017 
Amend according to blind delivery reviews, particularly adding 2 subgroup 
analyses for LABA users and LABA/ICS users. 
 
 


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
11 
1. 
STUDY DETAILS 
1.1 
Study objectives 
Objectives: 
Outcome Measure*: 
To assess the safety of aclidinium 
bromide on major adverse 
cardiovascular events (MACE) 
Primary Outcome Measure: 
x Time to first MACE, where MACE for the analyses 
is defined as any adjudicated event which is a 
composite of the total of cardiovascular (CV) death, 
non-fatal myocardial infarction (MI), or non-fatal 
stroke 
Secondary Outcome Measure: 
x Time to first MACE or other serious CV events of 
interest (e.g., adjudicated serious adverse events 
[SAEs] based on standard MedDRA query [SMQ] of 
cardiac disorders [i.e. cardiac arrhythmias SMQ and 
cardiac failure SMQ] and of cerebrovascular 
disorders 
To assess the overall safety of 
aclidinium bromide 
Safety Outcome Measures: 
x Adverse events (AEs, includes SAEs) including 
chronic obstructive pulmonary disease (COPD) 
exacerbations 
x Vital sign measurements 
x Electrocardiograms (ECG) parameters 
x Physical examination findings 
To assess whether aclidinium 
bromide reduces moderate or 
severe COPD exacerbations 
Primary Outcome Measure: 
x Rate of moderate or severe COPD exacerbations per 
patient per year during the first year of treatment  
o Primary analysis: on-treatment analysis 
o Secondary analysis: on-study analysis 
Secondary Outcome Measure:  
x Rate of hospitalizations due to COPD exacerbations 
per patient per year during the first year of treatment   
* Only primary and secondary efficacy outcome measures and safety outcome measures are listed. The 
additional efficacy outcome measures and CAT assessment are described in Section 3.  


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
12 
1.2 
Study design 
This is a Phase IV, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study evaluating the effect of Aclidinium Bromide (a long-acting muscarinic antagonist 
delivered by the Pressair® dry powder inhalation [DPI] device) compared with placebo on 
long-term CV safety and COPD exacerbations in outpatients at least 40 years of age who have 
been diagnosed with moderate to very severe COPD (postbronchodilator % predicted forced 
expiratory volume in 1 second [FEV1] < 80% and FEV1/forced vital capacity [FVC] ratio 
< 70%) and a history of CV or cerebrovascular disease and/or significant CV risk factors.  
Note: in this document 
1. The term “double-blind treatment period” applies to the following 2 scenarios: 
x When used in “maximum of 36-months double-blind treatment period”  
x When used for patients who completed 36-months treatment (completer) 
2. The term “during the treatment period” refers to on-treatment period. 
3. The term “during the whole study period” refers to both on-treatment and off-treatment 
(post-treatment follow-up) periods. 
The study consists of two-week washout/run-in period (for patients on a long-acting 
muscarinic antagonist [LAMA]) followed by a maximum of 36-month double-blind treatment 
period. 
Signed informed consent form (ICF) from the patient or the patient’s legally authorized 
representative will be obtained before any study-related procedures are begun. All patients 
will be assigned a patient identification (PID) number via the interactive web response system 
(IWRS). Patients meeting the entry criteria for this study will be randomized (1:1) to 
aclidinium bromide 400 μg (abbreviated as aclidinium hereafter) twice a day (BID) or placebo 
BID. This study will conclude when 122 patients have experienced an adjudicated MACE. 
Patients who prematurely discontinue investigational product (IP) will participate in a 
post-treatment follow-up period. The follow-up period will include on-site visits and 
telephone visits to collect MACE, COPD exacerbations, concomitant medications, and SAEs 
for the remainder of the study duration. 
An independent Data Safety Monitoring Board (DSMB) will be established for this study. The 
DSMB will periodically monitor and review relevant clinical safety data, including 
adjudicated MACE.  
Patients will be assessed according to the Schedule of Evaluations (See Section 2 of the 
clinical study protocol [CSP]). 


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
13 
1.3 
Number of subjects 
1.3.1 
Power for the primary safety endpoint: time to first MACE event 
For this study, a total of 122 patients with MACE will be needed to have 90% power, at 5% 
significance level, to rule out a hazard ratio of 1.8 in time to first MACE in aclidinium 
bromide treated patients relative to placebo, assuming the hazard rate is 1.0 under the 
alternative hypothesis. The justification for the hazard ratio of margin of 1.8 is provided in 
Appendix IV of the CSP. 
This ASCENT COPD study will be recruiting patients with a FEV1 below 80% and a planned 
maximum of 36 months double-blind treatment period. The assumption of 1.9 MACE per 100 
patient years would be reasonable for this study (See Section 9.7.9.1 of the CSP for details). 
To obtain 122 MACE in this study with 1.9 MACE per 100 patient years of treatment, a total 
of 6,500 patient years of treatment (aclidinium bromide and placebo) would be needed. 
Assuming a treatment discontinuation rate of 40% and a study discontinuation rate of 20% at 
year 2, and following an exponential distributions for time to events and time to 
discontinuations, a sample size of 4000 is needed to ensure 90% power to observe 122 events 
applying the on-study analysis, and an 80% power to observe 91 events applying the 
on-treatment analysis.   
1.3.2 
Power for the primary efficacy endpoint: rate of moderate or severe 
exacerbations per patient per year during the first year of treatment  
The sample size of 4,000 patients after 1 year of treatment will have ~89% power to detect a 
reduction in the rate of moderate or severe COPD exacerbations per patient per year during 
the first year of treatment of 14% (rate ratio of 0.86 in aclidinium bromide relative to placebo) 
at 0.05 significance level. The 89% power was calculated assuming a treatment 
discontinuation rate of 30% during the first year, a placebo rate of 0.8 exacerbation per patient 
per year (reduced from 1 to 0.8 as not all patients will have a history of exacerbation prior to 
randomization), and an overdispersion factor k of 0.67 (Keene et al, 2007).  
See Section 9.7.9 of the CSP for detailed information on determination of sample size and 
power calculation.  
2. 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
Three populations will be considered in the statistical analysis of the study. 
2.1.1 
Screened Population 
The Screened Population will consist of all patients who signed a written ICF and received a 
screening number. 


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
14 
2.1.2 
Randomized Population   
The Randomized Population will consist of all patients in the Screened Population who were 
randomized to a treatment group in the study. 
2.1.3 
Full Analysis Set Population 
The Full Analysis Set (FAS) Population will consist of all patients in the Randomized 
Population who took at least one dose of the double-blind IP (aclidinium bromide or placebo). 
Patients will be analyzed according to their randomized treatment. 
The FAS will be used to carry out the primary analysis of both efficacy and safety data. 
Efficacy and safety data may be further investigated and sensitivity analyses may be 
performed using the Randomized Population if more than 1% of patients did not receive one 
dose of the double-blind IP.  Any important deviations from the randomized treatment 
assignment and any subjects who have received double-blind IP without being randomized 
will be listed and considered when interpreting the data. 
2.2 
Violations and deviations 
2.2.1 
Protocol deviations 
Only important protocol deviations (in the CSP referred to as protocol violations) will be 
listed and tabulated in the clinical study report (CSR). Protocol deviations that may greatly 
impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject’s rights, safety, or well-being, will be considered as important 
and will include the following: 
x Key eligibility criteria not fulfilled but randomized  
x Concomitant use of disallowed medications.  Patients who use one or more disallowed 
medication (for any reason, unless otherwise specified) on IP during the treatment 
period will be classified as protocol deviators after confirmation by an AZ physician 
x Patients who received the incorrect study treatment or study dose at any time during 
the treatment period  
x Patients who fulfilled withdrawal criteria during the study but were not withdrawn 
The final list of protocol deviations will be finalized and documented prior to unblinding the 
study data. 
All important protocol deviations will be programmatically derived. The programming 
produces a draft list of important protocol deviations for the medical/clinician review on an 
ongoing basis; a final list of important protocol deviations is determined before the database 
(DB) lock after a joint team review (the third bullet above is determined after the DB lock and 
unblinding) and include into the relevant dataset. 


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
15 
2.2.2 
Visit window definitions 
For exacerbation-related analyses and MACE-related analyses, no visit windows will be 
applied.  
For by-visit assessments (e.g., FEV1, CAT, vital signs, ECG, physical examinations, clinical 
laboratory), their baseline and post baseline visits may occur as per protocol at the indicated 
week ± 7 days throughout the treatment period. Unless otherwise specified, actual scheduled 
visits will be used for the summaries over time with no visit windows applied.  
3. 
PRIMARY AND SECONDARY VARIABLES 
3.1 
General principles taken for analysis variables  
3.1.1 
End of study date 
The study will be completed when a total of 122 patients with adjudicated MACE are 
observed. Based on the number of adjudicated MACE events, the sponsor will declare the end 
of the study date and give the study sites at least 3 months notice. At the conclusion of the 
treatment period, the following information will be collected for all patients (these visit 
procedures also apply for a patient who is discontinuing study medication before the end of 
the study): 
x All assessments listed for the EOT visit  
x Schedule a phone contact for 15 days from visit 
3.1.2 
Censoring rules in time-to-event analyses 
In time-to-event analyses, patients who have not had the event(s) in question will be censored 
at the following time points as applicable, depending on whether it is an on-study or 
on-treatment analysis (see Section 4.1 for definitions):  
For on-study analysis:  
x The last visit (in this case the EOT visit) for patients who completed the treatment or 
patients who are still on treatment at the end of study date   
x Last contact date for patients who pre-maturely discontinued IP and completed the 
study or patients who pre-maturely discontinued IP and are still in study at the end of 
study date  
x Any patient who is lost to follow-up (LTFU) at the end of the study will be censored at 
the last study contact where all elements of the endpoint in question were assessed 
x Patients who withdraw consent will be censored at date of withdrawal, except in the 
analysis of all-cause mortality as a single endpoint, when patients will be censored at 
the date of last known alive according to vital status data   


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
16 
For on-treatment analysis: 
x Patients will be censored on the date of IP discontinuation 
In analysis of time to CV death and composites including CV death, censoring will occur at 
date of death from non-CV causes. For endpoints not including death, all deaths are censoring 
events. 
3.1.3 
Definition of baseline measurements  
For each safety variable, the last assessment made before the first dose of the double-blind IP 
will be used as the baseline for all analyses of that safety variable. For physical examination 
and ECG, baseline is defined as Visit 1A assessment. 
Body mass index (BMI) is calculated as weight [kg]/(height [m])2, and will also be 
categorized as follows: 
x Underweight: BMI < 18.5 kg/m2 
x Normal range: BMI ≥ 18.5 kg/m2 and < 25 kg/m2 
x Overweight: BMI ≥ 25 kg/m2 and < 30 kg/m2 
x Obese: BMI ≥ 30 kg/m2 
Weight and height measured at Visit 1A will be used in calculation of baseline BMI. 
For pre-dose trough FEV1, the average of the two pre-dose values measured prior to the 
administration of the first dose of the double-blind IP at Visit 1B will be used as baseline. If 
one of the two measurements at Visit 1B is missing, then the available one will be used as 
baseline value. If both values at Visit 1B are missing, then the pre-bronchodilator value from 
Visit 1A will be used as baseline instead. 
Baseline COPD severity based on airflow obstruction is assessed using postbronchodilator 
FEV1 measured at Visit 1A or unscheduled visit prior to Visit 1B as follows: 
x GOLD Grade 1 (mild): FEV1 ≥ 80% predicted 
x GOLD Grade 2 (moderate): FEV1 ≥ 50% predicted and < 80% predicted 
x GOLD Grade 3 (severe): FEV1 ≥ 30% predicted and < 50% predicted 
x GOLD Grade 4 (very severe): FEV1 < 30% predicted 
Baseline COPD severity, when used as a factor in the statistical model, will be classified into 
3 levels above: moderate, severe, and very severe. In case any patient has baseline COPD 
severity as mild (a protocol deviation, and expected very limited), the value of mild will be 
pooled into the moderate to avoid convergence problem in the statistical model. 


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
17 
The COPD assessment test (CAT) assessments at Visit 1B will be used for calculating the 
respective baseline.  
The new Global Initiative for Chronic Obstructive Lung Disease (GOLD, 2017) for the 
assessment of COPD disease has been refined to separate spirometric grades from the ABCD 
groups. The assessment of airflow limitation is based on percent predicted FEV1 and is 
classified into 4 grades (see COPD severity classification above).  The assessment of 
symptoms/risk of exacerbations is classified into the 4 groups as shown in table below. 
 
Group 
Exacerbation history 
CAT at baseline 
A 
0 or 1 (not leading to hospital admission) 
<10 
B 
0 or 1 (not leading to hospital admission) 
≥10 
C 
≥2 or ≥1 leading to hospital admission  
<10 
D 
≥2 or ≥1 leading to hospital admission 
≥10 
 
Therefore, there are 16 potential categories with A, B, C and D phenotypes being further 
subdivided by 4 severities of airflow obstruction.   
 
3.1.4 
Repeated or unscheduled assessments 
Extra assessments (vital signs, or ECG parameters associated with non-protocol clinical visits 
or obtained in investigating or managing AEs) will be included in listings, but not summaries 
of the data.   
For summary tables, if repeated measurements are taken for either time point, then the last 
measurement will be used for the value for that time point.  If it is not possible to determine 
which is the last measurement due to missing times then the average of all measurements for 
that time point will be used for the value for that time point. 
However, all postbaseline assessments, including repeated or unscheduled visits, will be used 
for potentially clinically significant (PCS) value determinations. 
3.1.5 
Handling missing data  
3.1.5.1 
Data convention for FEV1  
For FEV1, refer to Section 3.1.3 for handling missing data in determination of baseline FEV1. 


Statistical Analysis Plan  
Study Code D6560C00002 
Edition Number Amendment 3.0  
Date 23 October 2017 
18 
3.1.5.2 
Data convention for CAT  
The CAT total score for each patient at each visit will be computed as the summation of 
scores for all 8 questions. If one or two responses are missing, then the average of the 
remaining non-missing responses will be used for missing values; if more than two responses 
are missing, then the total score will be treated as missing. 
3.1.5.3 
Missing end date of exacerbations  
For duration of COPD exacerbations, if end date of the exacerbation is completely missing, 
then the last contact date will be used as the end date of the event. If end date of the 
exacerbation is partially missing with month and year available, then the last day of that 
month will be used. 
3.1.5.4 
Missing date of the last dose of the double-blind IP 
When the date of the last dose of the double-blind IP during treatment period is missing for a 
patient in the FAS Population, all efforts should be made to obtain the date from the 
Investigator. If after all efforts are made it is still missing, then the last available dosing record 
date will be used as the last dose date in calculation of treatment duration. 
3.1.5.5 
Missing severity assessment for AEs 
If severity is missing for an AE that started before the date of the first dose of the double-blind 
IP, then an intensity of mild will be assigned. If severity is missing for an AE that started on 
or after the date of the first dose of the double-blind IP, then an intensity of severe will be 
assigned. The imputed values for severity assessment will be used for the incidence summary; 
the values will be shown as missing in the data listings. 
3.1.5.6 
Missing causal relationship to the double-blind IP for AEs 
If the causal relationship to the IP is missing for an AE that started on or after the date of the 
first dose of the double-blind IP, then a causality of Yes (reasonable possibility) will be 
assigned. The imputed values for causal relationship to the double-blind IP will be used for 
the incidence summary; the actual values will be presented in the data listings. 
3.1.5.7 
Missing date information for AEs  
The following imputation rules only apply to cases in which the start date for AEs is 
incomplete (i.e., partial missing). 
Missing Month and Day 
x If the year of the incomplete start date is the same as the year of the first dose of the 
double-blind IP, then the month and day of the first dose of the double-blind IP will be 
assigned to the missing fields. 
x If the year of the incomplete start date is before the year of the first dose of the 
double-blind IP, December 31 will be assigned to the missing fields. 


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x If the year of the incomplete start date is after the year of the first dose of double-blind 
IP, January 1 will be assigned to the missing fields. 
Missing Month Only 
x If only the month is missing, then the day will be treated as missing and both the 
month and the day will be replaced according to the procedure above. 
Missing Day Only 
x If the month and year of the incomplete start date are the same as the month and year 
of the first dose of the double-blind IP, then the day of the first dose of the 
double-blind IP will be assigned to the missing day. 
x If either the year of the incomplete start date is before the year of the date of the first 
dose of the double-blind IP or if both years are the same but the month of the 
incomplete start date is before the month of the date of the first dose of the 
double-blind IP, then the last day of the month will be assigned to the missing day. 
x If either the year of the incomplete start date is after the year of the date of the first 
dose of the double-blind IP or if both years are the same but the month of the 
incomplete start date is after the month of the date of the first dose of the double-blind 
IP, then the first day of the month will be assigned to the missing day. 
If the stop date is complete and the imputed start date as above is after the stop date, then the 
start date will be imputed by the stop date. 
If the start date is completely missing and the stop date is complete, then the following 
algorithm will be used to impute the start date: 
x If the stop date is after the date of the first dose of the double-blind IP, then the date of 
the first dose of the double-blind IP will be assigned to the missing start date. 
x If the stop date is before the date of the first dose of the double-blind IP, then the stop 
date will be assigned to the missing start date. 
3.1.5.8 
Missing date information for prior and concomitant medications 
For prior and concomitant medications, incomplete (i.e., partial missing) start dates and/or 
stop dates will be imputed. When the start date and the stop date are both incomplete for a 
patient, the start date will be imputed first. 
Incomplete start date 
The following rules will be applied to impute the missing numeric fields for an 
incomplete prior or concomitant medication start date. If the stop date is complete (or 
imputed) and the imputed start date is after the stop date, then the start date will be 
imputed using the stop date. 


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Missing Month and Day 
x If the year of the incomplete start date is the same as the year of the first dose of the 
double-blind IP, then the month and day of the first dose of the double-blind 
investigational product will be assigned to the missing fields. 
x If the year of the incomplete start date is before the year of the first dose of the 
double-blind IP, December 31 will be assigned to the missing fields. 
x If the year of the incomplete start date is after the year of the first dose of the 
double-blind IP, January 1 will be assigned to the missing fields. 
Missing Month Only 
x If only the month is missing, then the day will be treated as missing and both the 
month and the day will be replaced according to the procedure above. 
Missing Day Only 
x If the month and year of the incomplete start date are the same as the month and year 
of the first dose of the double-blind IP, then the day of the first dose of the 
double-blind IP will be assigned to the missing day. 
x If either the year of the incomplete start date is before the year of the date of the first 
dose of the double-blind IP or if both years are the same but the month of the 
incomplete start date is before the month of the date of the first dose of the 
double-blind IP, then the last day of the month will be assigned to the missing day. 
x If either the year of the incomplete start date is after the year of the date of the first 
dose of the double-blind IP or if both years are the same but the month of the 
incomplete start date is after the month of the date of the first dose of the double-blind 
IP, then the first day of the month will be assigned to the missing day. 
Incomplete stop date  
The following rules will be applied to impute the missing numeric fields for an incomplete 
prior or concomitant medication stop date. If the date of the last dose of the double-blind IP is 
missing, then replace it with the last visit date in the imputations described below. If the 
imputed stop date is before the start date (imputed or non-imputed start date), then the 
imputed stop date will be equal to the start date. 
Missing Month and Day 
x If the year of the incomplete stop date is the same as the year of the last dose of the 
double-blind IP, then the month and day of the last dose of the double-blind IP will be 
assigned to the missing fields. 


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x If the year of the incomplete stop date is before the year of the last dose of the 
double-blind IP, December 31 will be assigned to the missing fields. 
x If the year of the incomplete stop date is after the year of the last dose of the 
double-blind IP, January 1 will be assigned to the missing fields. 
Missing Month Only 
x If only the month is missing, then the day will be treated as missing and both the 
month and the day will be replaced according to the above procedure. 
Missing Day Only 
x If the month and year of the incomplete stop date are the same as the month and year 
of the last dose of the double-blind IP, then the day of the last dose of the double-blind 
IP will be assigned to the missing day. 
x If either the year of the incomplete stop date is before the year of the date of the last 
dose of the double-blind IP or if both years are the same but the month of the 
incomplete stop date is before the month of the date of the last dose of the 
double-blind IP, then the last day of the month will be assigned to the missing day. 
x If either the year of the incomplete stop date is after the year of the date of the last dose 
of the double-blind IP or if both years are the same but the month of the incomplete 
stop date is after the month of the date of the last dose of the double-blind IP, then the 
first day of the month will be assigned to the missing day. 
3.1.5.9 
Character Values of Clinical Laboratory Parameters 
Not applicable since there will be no report of the laboratory data. 
3.1.6 
Definition of COPD exacerbations  
The onset and end of a COPD exacerbation is defined by the investigators in their assessment 
of patient symptoms and initiation/finalization of treatment (as defined below for the severity 
of exacerbation), and recorded on COPD Exacerbation page of electronic case report forms 
(eCRFs). 
The severity of a COPD exacerbation is assessed according to the following scale: 
x Mild: Increase in COPD symptoms (e.g., dyspnea, cough, sputum volume, sputum 
purulence) during at least 2 consecutive days, managed by the patient at home by 
increasing short-acting bronchodilator and/or inhaled corticosteroid (ICS) use 
x Moderate: Increase in COPD symptoms (e.g., dyspnea, cough, sputum volume, sputum 
purulence) during at least 2 consecutive days that does not lead to hospitalization but is 
treated with antibiotics and/or systemic corticosteroids 


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x Severe: Increase in COPD symptoms (e.g., dyspnea, cough, sputum volume, sputum 
purulence) during at least 2 consecutive days that leads to hospitalization (overnight 
stay at hospital or emergency room) or death  
Definitions of New and/or Relapsed COPD exacerbations  
The interval between 2 consecutive COPD exacerbations must be at least 7 days. Therefore, if 
2 COPD exacerbations occur within 7 days of each other, then they will be considered as 1 
event (i.e., the second one is considered as a relapse). Inpatient hospitalization due to COPD 
occurring during an exacerbation should not be regarded as a new exacerbation. In order to be 
counted as a new exacerbation it must be preceded by at least 7 days in which none of the 
exacerbation criteria is fulfilled. 
A COPD exacerbation will be derived as a new COPD exacerbation if and only if either of the 
following conditions is met: 
x The exacerbation is the first episode, or 
x The start date of the exacerbation is greater than or equal to 7 days since the previous 
exacerbation 
All reported exacerbations will be combined with any reported relapses. Relapses will be 
considered as a continuation of the previous event. That is, the onset of exacerbation event 
will be the same as the onset of first exacerbation event with a resolution date being derived as 
the resolution date of last relapse. The severity of exacerbation event derived in this way will 
be the most severe of first exacerbation or any derived relapse. 
3.1.7 
Derived variables  
3.1.7.1 
Rate of event 
The rate of event per patient per year during a given period (e.g., during the first year of 
treatment) is calculated as the sum of all available events in that period divided by the sum of 
all patients follow-up time in that period, i.e., 
, where ei is the number of event in patient 
i and ti is the follow-up time in patient i. The follow-up time in patient i, ti, is calculated as 
, where di is the number of days patient i exposed, calculated as (follow-up date – 
randomization date + 1). 
3.1.7.2 
Duration of event  
For the production of summary statistics, the duration (in days) of event per patient per year 
during a given period is calculated as the sum of duration of all available events in that period 
divided by the sum of all patients follow-up time in that period, i.e., 
, where pi is the 
duration (in days) of all events in patient i. The duration of each event is calculated as (end 
date – onset date + 1).  
See Section 3.1.7.1 for calculation of the follow-up time in patient i, ti . 


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3.1.7.3 
Time to first event  
Time (in days) to first event in a given period is calculated as follows:  
Start date of first event in a given period − Date of randomization + 1.  
3.1.7.4 
Other derived variables 
Selection of spirometric measurements 
Spirometric measurements data for each maneuver attempt must be entered into the electronic 
data capture system. Throughout the study, the reading of spirometric values is to be 
performed by the PI, or appropriately trained designee, to ensure the values meet the 
American Thoracic Society and European Respiratory Society criteria for acceptability. At 
each time point, only the greatest acceptable FEV1 value and other corresponding spirometric 
measures (FVC, FEV1/FVC) will be used for all analyses. See Appendix III of the CSP for 
details.  
Reversible is defined as % bronchial reversibility ≥ 12% and change from pretest ≥ 200 mL in 
FEV1, where 
% bronchial reversibility = 100 × (postbronchodilator FEV1 – prebronchodilator FEV1)/ 
prebronchodilator FEV1 
Change from pretest (in liters) = postbronchodilator FEV1 – prebronchodilator FEV1 
Other variables 
Baseline ICS use, when used as a factor in statistical model, will be derived as follows: 
x ‘Yes’ if any ICS use was reported (as a monotherapy or in combination) within 15 
days prior the first dose of the double-blind IP. 
x ‘No’ otherwise 
The CV severity at baseline, when used as a factor in statistical model, will be defined as 2 
categories:  
x Patients who had 2 CV risk factors, and  
x Patients who had more than 2 CV risk factors or at least one documented 
cerebrovascular disease, coronary artery disease or peripheral vascular disease or 
history of claudication 
The CV risk factors will be defined as following atherothrombotic risk factors as determined 
by the PI: 
x Male ≥ 65 years or female ≥ 70 years 
x Diabetes 


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x Dyslipidemia 
x Hypertension 
x Waist circumference in males ≥ 40 inches or in females ≥ 38 inches. 
x Evidence of renal dysfunction (eGFR < 60) and micoralbuminuria (eGFR is based on 
modification of diet in renal disease equation, microalbuminuria is defined as ≥ 30-300 
mcg/mg creatinine on a spot urine or ≥ 30 mg creatinine on a 24hr urine test) 
Number of cigarettes per day is calculated as (20 * Total pack-years) / Smoking duration (in 
years). 
Age is also categorized as a categorical variable as follows:  
x ≥ 40 and < 60 years 
x ≥ 60 and < 70 years 
x ≥ 70 years old 
3.2 
Primary efficacy variable   
The primary efficacy variable is rate of moderate or severe COPD exacerbation per patient per 
year during the first year of treatment. COPD exacerbations are evaluated by the PI 
throughout the study.  
For the production of summary statistics, the rate of moderate or severe COPD exacerbation 
per patient per year during the first year of treatment is calculated by applying the following in 
the general formula defined in Section 3.1.7.1. 
x Event is moderate or severe COPD exacerbation 
x Period refers to the first year of treatment 
3.3 
Secondary efficacy variable   
The secondary efficacy variable is rate of hospitalization due to COPD exacerbation per 
patient per year during the first year of treatment.  
For the production of summary statistics, the rate of hospitalization due to COPD exacerbation 
per patient per year during the first year of treatment is calculated by applying the following in 
the general formula defined in Section 3.1.7.1. 
x Event is hospitalization due to COPD exacerbation 
x Period refers to the first year of treatment 


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3.4 
Additional efficacy variables  
3.4.1 
COPD exacerbation variables 
The following COPD exacerbation variables use data collected during the whole study period. 
Maximum follow-up time for a patient is approximately 36 months.  
3.4.1.1 
Rate of moderate or severe COPD exacerbations per patient per year  
For the production of summary statistics, the rate of moderate or severe COPD exacerbation 
per patient per year is calculated by applying the following in the general formula defined in 
Section 3.1.7.1. 
x Event is moderate or severe COPD exacerbation 
x Period refers to the whole study period 
3.4.1.2 
Rate of mild, moderate, or severe COPD exacerbations per patient per year  
For the production of summary statistics, the rate of mild, moderate, or severe COPD 
exacerbation per patient per year is calculated by applying the following in the general 
formula defined in Section 3.1.7.1. 
x Event is mild, moderate, or severe COPD exacerbation 
x Period refers to the whole study period 
3.4.1.3 
Duration of moderate or severe COPD exacerbations per patient per year  
For the production of summary statistics, the duration (in days) of moderate or severe COPD 
exacerbation per patient per year is calculated by applying the following in the general 
formula defined in Section 3.1.7.2. 
x Event is moderate or severe COPD exacerbation 
x Period refers to the whole study period 
3.4.1.4 
Duration of mild, moderate, or severe COPD exacerbations per patient per 
year  
For the production of summary statistics, the duration (in days) of mild, moderate, or severe 
COPD exacerbation per patient per year is calculated by applying the following in the general 
formula defined in Section 3.1.7.2. 
x Event is mild, moderate, or severe COPD exacerbation 
x Period refers to the whole study period 
3.4.1.5 
Proportion of patients with at least one COPD exacerbation  
x Number and percentage of patients with at least one COPD exacerbation 


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x Number and percentage of patients with at least one mild COPD exacerbation 
x Number and percentage of patients with at least one moderate COPD exacerbation  
x Number and percentage of patients with at least one severe COPD exacerbation  
x Number and percentage of patients with at least one moderate or severe COPD 
exacerbation 
3.4.1.6 
Time to COPD exacerbation  
x Time to first COPD exacerbation 
Time to first COPD exacerbation is calculated by applying the following in the general 
formula defined in Section 3.1.7.3. 
x Event is mild, moderate, or severe COPD exacerbation 
x Period refers to the whole study period 
For patients who do not experience a COPD exacerbation during the study, start date of the 
first COPD exacerbation will be censored per general censoring rules described in Section 
3.1.2, i.e., the event in question refers to a COPD exacerbation.  
x Time to first moderate or severe COPD exacerbation during the first year of treatment  
Time to first moderate or severe COPD exacerbation during the first year of treatment is 
similarly calculated and censored as time to first COPD exacerbation, by considering 
moderate or severe COPD during the first year of treatment only, i.e., patients will be 
censored on the date of IP discontinuation or at the end of the first year, whichever is earlier.    
x Time to first moderate or severe COPD exacerbation 
Time to first moderate or severe COPD exacerbation is similarly calculated and censored as 
time to first COPD exacerbation, by considering moderate or severe COPD only.   
x Time to second COPD exacerbation 
Time to second COPD exacerbation is calculated as follows:  
Start Date of the second COPD exacerbation − Date of randomization + 1.  
Time to second COPD exacerbation will be analyzed in patients who experience at least one 
COPD exacerbation. For patients who experience < 2 COPD exacerbations during the study, 
start date of the second COPD exacerbation will be censored per general censoring rules 
described in Section 3.1.2, i.e., the event in question refers to the second COPD exacerbation.  
x Time to second moderate or severe COPD exacerbation 


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Time to second moderate or severe COPD exacerbation is similarly calculated and censored as 
time to second COPD exacerbation, by considering moderate or severe COPD only.   
x Time to third COPD exacerbation 
Time to third COPD exacerbation is calculated as follows:  
Start Date of the third COPD exacerbation − Date of randomization + 1.  
Time to third COPD exacerbation will be analyzed in patients who experience at least two 
COPD exacerbations. For patients who experience < 3 COPD exacerbations during the study, 
date of the third COPD exacerbation will be censored per general censoring rules described in 
Section 3.1.2, i.e., the event in question refers to the third COPD exacerbation. 
x Time to third moderate or severe COPD exacerbation 
Time to third moderate or severe COPD exacerbation is similarly calculated and censored as 
time to third COPD exacerbation, by considering moderate or severe COPD only. 
3.4.1.7 
Time to Withdrawal from the double-blind IP due to COPD exacerbation  
Time (in days) to withdrawal from the double-blind IP due to COPD exacerbation is 
calculated as follows:  
Date of withdrawal from the double-blind IP due to COPD exacerbation − Date of 
randomization + 1.  
x For patients who do not withdraw from the double-blind IP, date of withdrawal from 
the double-blind IP due to COPD exacerbation will be censored at the last dose date.  
x For patients who withdraw from the double-blind IP due to reasons other than COPD 
exacerbation, patients will be censored at the date of withdrawal from the double-blind 
IP (due to reasons other than COPD exacerbation).  
 
3.4.1.8 
Rate of hospitalization due to COPD exacerbations per patient per year  
For the production of summary statistics, the rate of hospitalization due to COPD exacerbation 
per patient per year is calculated by applying the following in the general formula defined in 
Section 3.1.7.1. 
x Event is hospitalization due to COPD exacerbation 
x Period refers to the whole study period 
3.4.1.9 
Number of days hospitalized due to COPD exacerbations  
The number of days hospitalized due to COPD exacerbations is calculated as follows:  


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Number of days hospitalized due to COPD exacerbations = Sum of duration for all 
hospitalizations due to COPD exacerbations  
where  
Duration for each hospitalization due to COPD exacerbations = end date – onset date + 1  
Hospitalizations during the whole study period are counted in the calculation.  
3.4.1.10 Time to first hospitalization due to COPD exacerbations  
Time (in days) to first hospitalization due to COPD exacerbations is calculated by applying 
the following in the general formula defined in Section 3.1.7.3. 
x Event is hospitalization due to COPD exacerbation 
x Period refers to the whole study period 
For patients who do not experience a hospitalization during the study, date of first 
hospitalization due to COPD exacerbation will be censored at the last dose date (or study 
closure date for patients who did not discontinue from study treatment). For patients who 
experience a hospitalization due to reasons other than COPD exacerbation during the study, 
patients will be censored at the date of first hospitalization (due to reasons other than COPD 
exacerbation).  
3.4.2 
Spirometry outcome variable 
x Change from baseline in morning pre-dose trough FEV1 at visits 2, 3, 4, 5, 6, 8, 10, 
and 12 (on-treatment analysis) 
Changes from baseline in morning pre-dose FEV1 at a specified visit will be calculated as 
follows: 
Morning pre-dose FEV1 at a specified visit – baseline FEV1. 
3.5 
Safety variables   
The following safety data will be collected: AEs (including COPD exacerbations reported in 
the AE/SAE page of eCRFs), vital sign measurements, 12-lead ECGs, and physical 
examination findings.  
3.5.1 
MACE and other serious CV events of interest 
Major adverse cardiovascular event is a composite of the total of CV death, non-fatal MI and 
non-fatal stroke. 
Other serious CV events of interest are SAEs based on SMQs of cardiac disorders (i.e. cardiac 
arrhythmias SMQ and cardiac failure SMQ) and of cerebrovascular disorders, adjudicated to 


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‘Non-fatal other: Other cardiovascular event’.  See the Clinical Events Committee [CEC] 
charter for details. 
Adverse events based on SMQ for MACE and other serious CV events of interest (includes 
cardiac events and cerebrovascular events) are as follows: 
Events of interest 
Standard MedDRA Query Category plus additional High Level Terms or Preferred Term, 
if applicable 
Cardiac events  
Ischemic Heart Disease: 
 
    Myocardial infarction 
Narrow search SMQ 
    Other Ischemic Heart Disease Narrow search SMQ 
Tachyarrhythmias 
Tachyarrhythmias (narrow and broad search SMQ) plus 
additional PTs: tachycardia, heart rate increase and 
palpitation 
Cardiac failure 
Narrow search SMQ 
Bradycardia 
Bradyarrhythmia terms, non-specific (narrow search 
SMQ) plus additional PTs: sinus arrest and sinus 
bradycardia 
Conduction defects 
Narrow search SMQ 
 
Cerebrovascular 
events  
Hemorrhagic and Ischemic 
disorders 
Haemorrhagic central nervous system vascular 
conditions (narrow search SMQ) plus 
Ischaemic central nervous system vascular conditions 
(narrow search SMQ)  
Major adverse 
cardiovascular 
events (MACEs)  
All Adjudicated MACE  by CEC: cardiac death, non-fatal myocardial infarction and non-
fatal stroke 
 
3.5.1.1 
Adjudication of clinical endpoints 
A CEC will be formed to assess and adjudicate all MACE. This committee will be blinded to 
treatment assignment and composed of independent cardiologists. A charter outlining the 
communication flow and the criteria to classify and adjudicate MACE will be established. 
The committee will adjudicate the following events occurring from randomization to end of 
study (last contact visit): 
x All death cases 
x Myocardial infarction defined as any non-fatal case that was coded to a preferred term 
(PT) in the SMQ “myocardial infarction” 
x Stroke defined as any non-fatal case that was coded to a PT in the SMQ “central 
nervous system hemorrhages and cerebrovascular conditions” 
Additionally, the SMQs of cardiac disorders (i.e. cardiac arrhythmias SMQ and cardiac failure 
SMQ) and cerebrovascular disorders will also be assessed by the CEC. 


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3.5.1.2 
Primary safety variable 
The primary safety variable is time to first MACE event (i.e., time to first occurrence of any 
event from the composite of CV death, non-fatal MI, or non-fatal stroke) using only events 
adjudicated as such by the CEC. Time will be calculated as the number of days plus one 
between the date of randomization and date of the first occurrence of the MACE event, or, 
event free patients will be censored at the time as described in Section 3.1.2 for on-study 
analysis.  
A patient may suffer more than one event during the study. For composite endpoints only a 
patient’s first occurring event contributes to the analysis of the component. For example, if a 
stroke precedes an MI, only the stroke will be used for the analysis of the primary composite 
endpoint. However, the MI will be used in separate analysis of time to components of the 
composite endpoint. Multiple events for a patient will be included in tabulations at episode 
level, and may be included in exploratory analyses. 
When the first event is MI or stroke, the time of a composite endpoint will be the time of the 
MI or stroke, irrespective of whether or not the patient dies as a sequel of the event. Analysis 
of the individual components will include all MI/strokes at the time of the event. Thus, the 
qualifier ‘non-fatal’ used for MI and stroke throughout the composite endpoint definitions can 
be ignored. The qualifier was used to clarify that fatal MI and fatal strokes would not be 
counted twice (e.g., as an MI and as a CV death) in tallying the composite endpoint. 
The individual components (CV death, non-fatal MI, non-fatal stroke) of the primary endpoint 
will be examined in exploratory fashion.  
3.5.1.3 
Secondary safety variable 
The secondary safety variable is time to first MACE or other serious CV events of interest. 
3.5.2 
Adverse events  
Adverse events will be coded using the MedDRA version 18.0 or newer.  
Adverse event data will be categorized according to their onset date, as occurring during 
washout/run-in, during on treatment, or during off treatment.  
An AE will be considered a treatment-emergent adverse event (TEAE) if it started on or after 
the date of the first dose of double-blind IP or it started before the date of the first dose of 
double-blind IP and continued during the study with increased severity. An AE that occurs 
more than 15 days after the date of the last dose of double-blind IP will not be counted as a 
TEAE. 
A TEAE with cause Reasonable Possibility related to the double-blind IP as judged by the 
investigator is defined as a treatment related AE.   


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3.5.3 
Clinical laboratory variables  
Local laboratories will be used to evaluate all urine and blood samples. Any clinically 
significant abnormalities in laboratory values as determined by the investigator are reported as 
adverse events. 
Study center personnel must report every patient that meets potential Hy’s law criteria, i.e.:  
ALT or AST ≥ 3xULN and Total Bilirubin ≥ 2xULN and Alkaline Phosphatase < 2xULN. An 
event that potentially meets Hy’s law criteria should be reported as an SAE using the most 
relevant SAE criteria, as judged by the Investigator.  
 
3.5.4 
Vital signs  
Vital signs will be assessed including pulse rate (beats per minute [bpm]), systolic and 
diastolic blood pressure (BP; mmHg), and weight in accordance with the schedule of 
evaluations as specified in the CSP.  
Blood pressure (systolic and diastolic), pulse rate, and weight values meeting criteria for PCS 
vital signs will be considered with special attention. 
Criteria for Potentially Clinically Significant Vital Signs 
Vital sign 
Flag 
Criteria 
Systolic BP, mmHg 
High 
(≥ 180 and increase over baseline ≥ 20) or (≥ 200 
and baseline < 200) 
Low 
(≤ 90 and decrease over baseline ≥ 20) or (≤ 75 and 
baseline > 75) 
Diastolic BP, mmHg 
High 
(≥ 105 and increase over baseline ≥ 15) or (≥ 115 
and baseline < 115) 
Low 
(≤ 50 and decrease over baseline ≥ 15) or (≤ 40 and 
baseline > 40) 
Pulse rate, bpm 
High 
(≥ 110 bpm and increase over baseline ≥ 15%) or 
(≥ 120 bpm and baseline < 120 bpm) 
Low 
(≤ 50 bpm and decrease over baseline ≥ 15%) or 
(≤ 40 bpm and baseline > 40 bpm) 
Weight a, kg 
High 
Increase of ≥ 7% 
Low 
Decrease of ≥ 7% 
a Weight change is relative to Screening (Visit 1A).  
bpm = beats per minute. 
3.5.5 
Electrocardiogram 
ECG measurements include ventricular heart rate (bpm), RR interval (ms), PR interval (ms), 
QRS duration (ms), QT interval (ms), and QTc (ms).  QTc will be used for the data 
interpretation.  Commonly used techniques including Bazett’s (QTcB) and Fridericia’s 
(QTcF) methods are applied. 


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Categorical analyses of absolute QTc interval prolongation and change from baseline in QTc 
interval meeting criteria for PCS ECGs will be considered with special attention. 
Criteria for Potentially Clinically Significant Electrocardiograms 
ECG Parameter 
Criteria 1 
Criteria 2 
QTcB, and QTcF 
 
Absolute values 
> 480 ms 
> 500 ms 
Absolute change from 
baseline 
> 30 ms 
> 60 ms 
QRS duration 
≥ 100 ms and an increase 
of ≥ 25% over baseline 
value 
≥ 150 ms if baseline is  
< 150 ms 
PR interval 
≥ 200 ms and an increase 
of ≥ 25% over baseline 
value 
≥ 250 ms if baseline is  
< 250 ms 
Heart Rate 
 
Tachycardia event 
≥ 110 bpm and an 
increase of ≥ 15% over 
baseline value 
≥ 120 bpm if baseline is 
< 120 bpm 
Bradycardia event 
≤ 50 bpm and a decrease 
of ≥ 15% over baseline 
value 
≤ 40 bpm if baseline is > 40 
bmp 
bpm = beats per minute; ms = millisecond. 
QTcB = QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½);  
QTcF = QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓). 
3.5.6 
 Physical examination  
Clinically significant finding occurring at Visit 1A are considered Medical History and any 
changes thereafter considered AEs.  
3.5.7 
 All-cause mortality  
Patient’s vital status will be collected and used for all-cause mortality analysis. Death/alive 
status, date of death, and date last known to be alive will be collected at either 3 years post 
subject randomization date or study completion is announced.  The overall survival (OS) time 
is censored on the last date they were known to be alive.  
3.6 
Health economic and outcomes research assessments 
The CAT is a validated, patient completed, questionnaire to measure the impact of COPD on a 
patient’s health status. It is comprised of 8 questions to be answered independently by patient 


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via a paper questionnaire (See Appendix V of the CSP). Each question, except for total CAT 
score, ranges from 0 to 5 (5 indicates the worst health status). The total scores range from 0 to 
40 (40 indicates the worst health status). Refer to Section 3.1.5.2 for scoring the CAT total 
score.  
x Change from baseline in CAT score at visits 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 
Changes from baseline in CAT score at a specified visit will be calculated as follows: 
CAT score at a specified visit – baseline CAT. 
x Proportion of patients with an improvement of 2 or more units from baseline in CAT 
total score at visits 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 
4. 
ANALYSIS METHODS 
4.1 
General principles 
Unless otherwise stated, descriptive summaries will be presented by treatment group.  The 
treatment groups will be presented in the order of Aclidinium 400 μg and Placebo in tables.   
Continuous data will be summarized in terms of the number of nonmissing observations (n), 
mean, standard deviation (SD), median, minimum, and maximum, unless otherwise stated.  
Where data are collected over time, both the observed data and change from baseline (refer to 
Section 3.1.3 for baseline definitions) will be summarized at each time point.   
The minimum and maximum will be reported to the same number of decimal places as the 
raw data recorded in the database, unless a decision has been made to report the summary 
statistics to a lesser number of decimal places than the original data.  Unless otherwise 
specified in the actual table shells, the mean, SD, standard error of the mean (SEM), median, 
the upper and the lower limits of confidence interval (CI) will be displayed to the one more 
decimal place than the raw data in the database. In general, the maximum number of decimal 
places reported shall be three for any summary statistic. 
Categorical data will be summarized in terms of the number of patients providing data at the 
relevant time point (n), frequency counts and percentages.  Any planned collapsing of 
categories will be detailed in the SAP text and the data displays.   
Percentages will be presented to one decimal place.  A percentage of 100% will be reported as 
100%.  Percentages will not be presented for zero counts.  Unless otherwise stated, 
percentages will be calculated using n as the denominator.     
Changes from baseline in categorical data will be summarized using shift tables where 
appropriate. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places.   
P-values less than 0.001 will be presented as “<0.001”.  P-values greater than 0.999 will be 
presented as “>0.999”. 


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All report outputs will be produced using SAS® version 9.2 or a later version in a secure and 
validated environment.     
All statistical tests will be two-sided hypothesis tests performed at a 0.05 significance level for 
main effects. All CIs will be two-sided 95% CIs, unless otherwise stated. 
The on-study analysis is defined as all events that occurred while the patient was in the study, 
irrespective of treatment exposure (i.e., this includes all events that occurred during which the 
patient was on treatment or off treatment). The on-treatment analysis is defined as only events 
that occurred while the patient has received at least one dose of study double-blind IP during 
the treatment period excluding off treatment period/post treatment follow-up (PTFU) period. 
The status of patients off treatment during the study period is referred to as the PTFU period. 
Handling professional/duplicate patients. Professional patients are individuals who, in 
violation of protocol entrance criteria and enter into the same study more than once and/or 
enter into more than one study at the same or in close succession.  
Unless otherwise stated, the first incidence of patient entering trial is used in analysis and 
summary. All data is listed for transparency, with flags for duplicate patients to ensure clarity 
which records are in/out of the analysis. 
For handling of AEs, if a patient is on same treatment throughout (across all incidences), 
include all data in the analysis. If patient is on different treatments (i.e., different randomised 
treatment received at the second incidence vs the first incidence), the first incidence of patient 
entering trial is used in analysis.  
Handling data from patients with missing investigator signatures. These patients will be 
excluded from the FAS and would be included in screened and randomized patient population.  
 
4.2 
Analysis methods 
4.2.1 
 Patient disposition  
A clear accounting of the disposition of all patients who enter the study will be provided, from 
screening to study completion.  Summaries of patient disposition will be presented by 
treatment and overall (column), while summaries in the Screened Population (when 
applicable) will be presented only by overall (column).  The following patient disposition 
summaries will be provided:   
x Number and percentage of patients in the Screened, Randomized, and FAS populations 
by country and overall (row) (Analysis Population: Screened). 
x Number and percentage of screen-failure patients (i.e., patients screened but not 
randomized), further classified by reasons for screen failure (Analysis Population: 
Screened).  


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x Number and percentage of patients who complete the double-blind treatment period 
and who prematurely discontinue from the double-blind IP, further classified by 
reasons for premature discontinuation from the double-blind IP  (as recorded on 
Subject Status [IP Usage] page of the eCRFs); number and percentage of patients who 
prematurely discontinue from the double-blind IP and entered into post-treatment 
follow-up period and who prematurely discontinued from the double-blind IP and did 
not enter into post-treatment follow-up period will also be summarized (Analysis 
Population: FAS). 
x Number and percentage of patients who complete the study and who withdraw from 
the study, further classified by reasons for withdrawal from the study (as recorded on 
Termination/Death page of eCRFs). Patients who complete the study are those who by 
the time the study is stopped 1) complete the 36-months double-blind treatment period, 
2) prematurely discontinue the double-blind IP and complete the PTFU period, 3) are 
on treatment, or 4) prematurely discontinue the double-blind IP and are in the PTFU 
period. Number and percentage of patients who prematurely discontinued treatment, 
entered into PTFU, but prematurely discontinued the PTFU will also be summarized 
(Analysis Population: FAS).  
x Number and percentage of patients who complete the first year of treatment and who 
prematurely discontinue from the double-blind IP during the first year, further 
classified by reasons for premature discontinuation from the double-blind IP  during 
the first year  (as recorded on Subject Status [IP Usage] page of eCRFs); number and 
percentage of patients who prematurely discontinued from the double-blind IP during 
the first year  and entered into post-treatment follow-up period and who prematurely 
discontinued from the double-blind IP during the first year and did not enter into 
post-treatment follow-up period will also be summarized (Analysis Population: FAS). 
x Number and percentage of patients characterized at the key time point (e.g., one year) 
who remained on treatment through that time point, discontinued treatment but 
remained in study through that time point, withdrew from the study prior to that time 
point, or did not reach that time point due to study closure (Analysis Population: FAS). 
x Time (in days) to premature discontinuation from the double-blind IP based on 
Kaplan-Meier (KM) method and displayed graphically using KM curves. A log-rank 
test (two-sided) will be used to compare time to premature discontinuation from the 
double-blind IP between the two treatment groups (Analysis Population: FAS). 
Patients who did not discontinue from the double-blind IP will be censored at their last 
dose of IP.  
x Time (in days) to withdrawal from the study will be analyzed using the same methods 
as described above for analysing time to premature discontinuation from the 
double-blind IP (Analysis Population: FAS). Patients who did not discontinue from the 
study will be censored at their last visit date on the study. 
x A plot of time to discontinuation from the double-blind IP versus reasons for 
discontinuation form the double-blind IP will be presented to illustrate patterns of 


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missing data, with different symbols for treatment groups (Patients who discontinued 
from the double-blind IP).  
The following by-patients listings will be provided: 
x Patients who prematurely discontinued the double-blind IP during the first year of 
treatment will be listed, including, but not limited to, reason for premature 
discontinuation from the double-blind IP, exposure (days), day of last visit, and status 
of entering into post-treatment follow-up period (Analysis Population: FAS). Where 
Exposure (days) = Date of the last dose of the double-blind IP – Date of the first dose 
of the double-blind IP + 1. 
Day of last visit = Last visit date – Date of the first dose of the double-blind IP + 1. 
x Patients who prematurely discontinued the double-blind IP after the first year of 
treatment will be listed separately (Analysis Population: FAS). 
x Patients who withdraw from the study will be listed, including, but not limited to, 
reason for withdrawal from the study, exposure (days), and day of last visit (Analysis 
Population: FAS). 
4.2.2 
Demographics and other baseline characteristics  
4.2.2.1 
Demography data  
Demography data such as age (at informed consent), race, ethnicity, sex, waist 
circumference, weight, height, and BMI will be summarized by treatment group (Analysis 
Population: FAS).  
Demography data will also be summarized in a separate table before and after implementing 
the protocol amendment 2. 
4.2.2.2 
Other baseline characteristics  
Various baseline characteristics will also be summarized descriptively by treatment group 
(Analysis Population: FAS).  These include medical and surgical histories, COPD history, 
smoking status and history, pre-bronchodilator and post-bronchodilator tests at Screening, 
FEV1 at baseline, CAT score at baseline, prior medications, and COPD related prior 
medications. No statistical tests will be performed. 
Medical and surgical histories will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), version 18.0 or newer, and will be summarized by MedDRA SOC, 
HLT and PT. It will also be summarized in a separate table before and after implementing the 
protocol amendment 2. 
 COPD history will be summarized as follows:  
x Duration of COPD in years 


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x Patient known to have either chronic bronchitis or emphysema (Yes, No) 
x COPD exacerbation in the previous 12 months (Yes, No) 
x Number of COPD exacerbations in the previous 12 months 
x COPD severity based on airflow obstruction 
x Combined assessment of COPD per GOLD (see Section 3.1.3 for categories) 
COPD history will also be summarized in a separate table before and after implementing the 
protocol amendment 2 
Smoking status and history will be summarized as follows:  
x Smoking status 
x Smoking duration in years 
x Number of cigarettes per day 
x Total pack-years 
Smoking status and history will also be summarized in a separate table before and after 
implementing the protocol amendment 2. 
Pre-bronchodilator, post-bronchodilator tests, and reversibility at Screening will be 
summarized as follows: 
x Pre-bronchodilator tests: 
x FEV1 
x FEV1 % predicted 
x FVC 
x FVC % predicted  
x Post-bronchodilator tests: 
x FEV1 
x FEV1 % predicted 
x FVC 
x FVC % predicted  
x Ratio of FEV1/FVC  
x Change from pre-bronchodilator test: 


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x % bronchodilator reversibility 
x Change from pre-test FEV1 
x Reversible (Yes, No)  
Pre-bronchodilator, post-bronchodilator tests, and reversibility at Screening will also be 
summarized in a separate table before and after implementing the protocol amendment 2. 
FEV1 at baseline will be summarized descriptively. It will also be summarized in a separate 
table before and after implementing the protocol amendment 2. 
CV risk factors will be summarized descriptively. It will also be summarized in a separate 
table before and after implementing the protocol amendment 2. 
The CAT score at baseline will be summary descriptively by individual question and total 
CAT score. It will also be summarized in a separate table before and after implementing the 
protocol amendment 2. 
4.2.2.3 
Prior and concomitant medications  
The World Health Organization Drug Dictionary (WHO DD), enhanced version of March 
2011 or newer, will be used to classify prior and concomitant medications by therapeutic 
class.  
Prior medication is defined as any medication taken 15 days before signing ICF, regardless of 
stop date. Concomitant medication is defined as any medication taken during the treatment 
period between the date of the first dose of the double-blind IP and the date of the last dose of 
the double-blind IP, inclusive. 
Prior and concomitant medications will be tabulated by the third level of Anatomical 
Therapeutic Chemical (ATC) classification code, preferred name, and treatment group.  
All concomitant medications will be classified for each one of the two following periods and 
will be summarized by the third level of ATC classification code, preferred name, and 
treatment group (Analysis Population: FAS):  
1) Medications that the patient started to take before the randomization and continued 
after the first double-blind IP administration, and  
2) Medications that the patient started to take during the treatment period (from the first 
double-blind IP administration to the last double-blind IP administration).  
In addition, medications that were used between the last double-blind IP administration and to 
the study end will be summarized by the third level of ATC classification code, preferred 


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name, and treatment group (Analysis Population: patients who discontinued the double-blind 
IP and entered into post-treatment follow-up period). 
Number and percentage of patients who used any medication for COPD will be presented by 
therapeutic categories as follows (but not limited to) by treatment groups: 
x Long-Acting β2-Agonists (LABA) 
x LAMA 
x Short-Acting β2-Agonists (SABA) 
x Short-Acting Muscarinic Antagonist (SAMA) 
x ICS 
x LABA and ICS combination (free and fixed) 
x LABA and LAMA combination 
x SABA and SAMA combination 
x Leukotriene modifiers 
x Oral phosphodiesterase type 4 (PDE4) 
x Systemic corticosteroid 
x Oxygen 
x Methylxanthines 
x Influenza vaccine 
x Pneumococcal vaccine 
Specifically, medication in the reporting by therapeutic categories is presented for each of the 
two following periods: 
1) Prior medication for COPD the patient is taken at the time of signing ICF, regardless 
of the onset or stop date , and 
2) Concomitant medication for COPD that the patient started to take before the 
randomization and continued after the first double-blind IP administration. 
In addition, medications for COPD that were used between the last double-blind IP 
administration and to the study end will be summarized by therapeutic categories (Analysis 
Population: patients who discontinued the double-blind IP and entered into post-treatment 
follow-up period). 
Multiple medications used by a patient will only be counted once. 


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4.2.3 
 
Extent of Exposure and Treatment Compliance 
4.2.3.1 
Extent of Exposure 
Exposure to the double-blind IP will be summarized for treatment duration (in days), 
calculated as date of the last dose of the double-blind IP taken - date of the first dose of the 
double-blind IP taken + 1 (Analysis Population: FAS).  
Duration of exposure before and after implementing the CSP amendment 2 will also be 
summarized. 
4.2.3.2 
Measurement of Treatment Compliance 
Dosing compliance for a given period is calculated as follows: 
100 × (total number of treatment applications [puffs] of the double-blind IP actually taken / 
number of treatment applications [puffs] of the double-blind IP expected to be taken) by a 
patient during a given period. 
The number of puffs actually taken is obtained from “Double Blind Study Drug Record” page 
of eCRFs. 
The number of puffs expected to be taken in a given period is calculated as follows: 
2 × (End date - Start date + 1 for that period) 
 i.e., a patient is expected to inhale 2 puffs per day. For those patients who complete the study, 
1 puff is subtracted from the number of puffs expected to be taken since no evening dose is 
administered on the date of the last dose. 
A patient is defined as compliant with treatment if treatment compliance rate is at least 75%. 
Descriptive statistics for treatment compliance rate will be presented by treatment group for 
two periods (Analysis Population: FAS):  
x Treatment period, and  
x The first year of treatment.  
Number and percentage of patients compliant with treatment will also be presented by 
treatment group for two periods above (Analysis Population: FAS).  
4.2.4 
Efficacy analyses 
All efficacy analyses will be based on the FAS Population. All statistical tests will be 
two-sided hypothesis tests performed at the 0.05 significance level for main effects. All CIs 
will be two-sided 95% CIs. No multiplicity adjustment will be made to CIs as they will be 
interpreted descriptively and used as a measure of precision. All p-values will be unadjusted. 


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To control for multiplicity, the primary and secondary efficacy variables will be tested 
sequentially, i.e., the secondary efficacy endpoint will be tested only when both primary and 
secondary analyses on the primary efficacy endpoint achieved statistical significance, and the 
secondary analysis on the primary efficacy endpoint will be tested only when the primary 
analyses on the primary efficacy endpoint achieved statistical significance. Otherwise, 
nominal p-values will be provided and should be interpreted descriptively. 
Analyses on COPD exacerbations will be based on definitions as described in Section 3.1.6. 
4.2.4.1 
Primary efficacy outcome variable  
The primary efficacy variable is rate of moderate or severe COPD exacerbation per patient per 
year during the first year of treatment. The primary analysis (on-treatment analysis) is to 
compare rate of moderate or severe COPD exacerbation per patient per year during the first 
year of treatment between aclidinium and placebo in patients in the FAS. Patients will be 
analyzed according to randomized treatment.  
The null hypothesis is that the exacerbation rate on aclidinium is equal to the exacerbation rate 
on placebo. The alternative hypothesis is that the exacerbation rate on aclidinium is not equal 
to the exacerbation rate on placebo, i.e.:  
H0: Rate ratio (aclidinium over Placebo) = 1 
      versus 
Ha: Rate ratio (aclidinium over Placebo) ≠ 1 
Exacerbation rate in aclidinium group will be compared to exacerbation rate in the placebo 
group using a negative binomial regression model. The response variable in the model will be 
the number of moderate or severe COPD exacerbations experienced by a patient during the 
first year of treatment. The model will include treatment group, baseline ICS use, baseline 
COPD severity, history of at least one exacerbation in the past year, and smoking status as 
factors. In order to adjust for the exposure for each patient, the natural logarithm of the 
exposure time (in years) during the first year of treatment will be used as an offset variable. 
When used as the offset variable, the exposure time will be adjusted by subtracting the time 
when a patient experienced COPD exacerbation(s) (i.e., not at risk during an exacerbation). 
The model is as follows: 
Number of moderate or severe exacerbations during the first year of treatment = treatment 
group + baseline ICS use + baseline COPD severity + history of at least one exacerbation in 
the past year + smoking status 
The estimated treatment effect (i.e., the rate ratio of aclidinium over placebo), corresponding 
95% CI, and two-sided p-value for the rate ratio will be presented. In addition, the 
exacerbation rate and the corresponding 95% CI within each treatment group will be 
presented.  


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If the Negative Binomial regression model does not converge, the Poisson regression model 
with robust variance estimate using sandwich method will be applied. A scale parameter will 
be included to take overdispersion into account in fitting Poisson regression model. This 
would be a similar SAS GENMOD model to the one used for the Negative Binomial, but will 
specify Poisson as the distribution and include a scale parameter (DSCALE).  
The primary analysis on the primary efficacy endpoint will be based on on-treatment analysis. 
For those patients who prematurely discontinue IP during the first year of treatment and have 
follow-up assessments, the primary analysis described above will be based on the data 
(events) collected before treatment discontinuation. 
The secondary analysis on the primary efficacy endpoint will be based on on-study analysis 
using the same model as for the primary analyses of the primary efficacy endpoint. For those 
patients who prematurely discontinue IP during the first year of treatment and have follow-up 
assessments, the secondary analysis will include the events collected during the PTFU period 
up to one year. 
The individual exacerbation criteria (use of systemic corticosteroids, use of antibiotics, and 
inpatient hospitalization due to COPD) will also be analysed using the same method as the 
primary analysis for on-treatment analysis during the first year of treatment, and will be 
summarized descriptively for on-study analysis over the whole study period. 
The frequency of events and descriptive statistics of moderate or severe COPD exacerbations 
will also be provided by analysis method and period: 
x On-treatment analysis during the first year of treatment  
x On-study analysis during the first year of treatment 
x On-treatment analysis over the whole study period 
x On-study analysis over the whole study period.  
Sensitivity analyses  
To assess the robustness to variations of the data assumptions underlying the primary analysis 
on the primary efficacy endpoint, several sensitivity analyses will be conducted as follows: 
x Jump to reference (J2R) approach (see Appendix 1 for details)  
x Copy reference (CR) approach (Keene et al, 2014; see Appendix 1 for details)  
x Tipping point analysis (see Appendix 2 for details) 
Subgroup analyses  
To evaluate the consistency in the primary efficacy endpoint over demographics and baseline 
characteristics, subgroup analyses will be performed. The subgroups are described below:  


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x Age group (≥ 40 and < 60 years, ≥ 60 and < 70 years, ≥ 70 years old)  
x Sex (Female, Male) 
x Race (White, Other) 
x Smoking status (Current smoker, Ex-smoker) 
x Baseline ICS use (Yes, No) 
x Baseline COPD severity (moderate, severe, and very severe) 
x History of at least one exacerbation in the past year (0, ≥1)  
Exacerbation rate in aclidinium group will be compared to exacerbation rate in the placebo 
group for each subgroup (on-treatment analysis) using a negative binomial regression model. 
The response variable in the model will be the number of moderate or severe COPD 
exacerbations experienced by a patient during the first year of treatment. The model will 
include treatment group, each subgroup, and the interaction term. In order to adjust for the 
exposure for each patient, the natural logarithm of the exposure time (in years) during the first 
year of treatment (subtracting the time when a patient experienced COPD exacerbation) will 
be used as an offset variable.  
The estimated treatment effect (i.e., the rate ratio of aclidinium over placebo) and 
corresponding 95% CI will be presented graphically.  
In addition, the primary efficacy endpoint will be analyzed (on-treatment analysis) for the 
following 2 subgroups:  
x LABA users (with and without ICS): include patients who took LABA and/or 
LABA/ICS during the treatment period. 
x LABA/ICS users: include patients who took LABA/ICS during the treatment period. 
That is, data for each subgroup will be extracted first, then do analysis on each set of data 
using the same approach as the corresponding primary analysis. 
4.2.4.2 
Secondary efficacy variable  
The secondary efficacy endpoint of rate of hospitalizations due to COPD exacerbations per 
patient per year during the first year of treatment will be analyzed (on-treatment analysis) 
using the same model as for the analyses of the primary efficacy endpoint, including on-study 
analysis as sensitivity analysis.  
4.2.4.3 
Additional efficacy variables  
Unless otherwise specified, the following variables will use data collected during the whole 
study period using on-treatment analysis.  
Analyses for COPD Exacerbations  


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The rate of COPD exacerbations per patient per year (any, and moderate or severe) and rate of 
hospitalizations due to COPD exacerbations per patient per year will be analyzed using a 
Negative Binomial regression model (or Poisson regression model taking overdispersion into 
account for analyses that Negative Binomial regression does not converge) similar to the 
primary analysis of the primary efficacy variable. The exposure time will be re-calculated 
based on the last data collection during the whole study period.  
The number of patients with at least one COPD exacerbation (any, mild, moderate, severe, and 
moderate or severe) will be analyzed based on a logistic regression model with treatment 
group, baseline ICS use, baseline COPD severity, history of at least one exacerbation in the 
past year, and smoking status as factors.  The estimated treatment effect (i.e., the odds ratio of 
aclidinium over placebo), corresponding 95% CI, and two-sided p-value for the odds ratio will 
be presented. The model is as follows: 
Response (Yes=1/No=0) = treatment group + baseline ICS use + baseline COPD severity + 
history of at least one exacerbation in the past year + smoking status   
Time (in days) to first COPD exacerbation (any, and moderate or severe), time (in days) to 
second COPD exacerbation (any, and moderate or severe), time (in days) to third COPD 
exacerbation (any, and moderate or severe), time (in days) to first hospitalization due to 
COPD exacerbation, and time (in days) to withdrawal of the double-blind IP due to COPD 
exacerbation will be analyzed by means of Kaplan-Meier estimators and Cox Proportional 
Hazards model. The estimates of the hazard ratio comparing aclidinium with placebo will be 
derived using the Cox proportional hazard model for the time in terms of the number of days 
served as a response variable and treatment group, baseline ICS use, baseline COPD severity, 
history of at least one exacerbation in the past year, and smoking status as factors. The hazard 
ratio (aclidinium over placebo), corresponding 95% CI, and two-sided p-value for the hazard 
ratio will be presented. The model is as follows: 
 Survival time = treatment group + baseline ICS use + baseline COPD severity + history of at 
least one exacerbation in the past year + smoking status 
In addition, the Kaplan-Meier survival curves will be displayed for each treatment group 
along with p-value for differences (aclidinium over placebo) based on the Log-Rank test 
stratified by baseline COPD severity and smoking status.  
The durations of COPD exacerbation (any, and moderate or severe; in days) will be 
summarized descriptively for only the patients who had exacerbations during the treatment 
period. 
Number of days hospitalized due to COPD exacerbations will be summarized for only the 
patients who had exacerbations during the treatment period. The descriptive statistics of 
number of days hospitalization due to COPD exacerbations will be summarized by unit type 
(any, hospitalization unit, intensive care unit, emergency room). 
Analyses for spirometry variable  


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Change from baseline in morning pre-dose (trough) FEV1 by visit (on-treatment analysis) will 
be compared between aclidinium group and placebo using a MMRM model on patients with a 
baseline pre-dose/pre-bronchodilator FEV1 and at least one post-randomization pre-dose FEV1 
in the FAS Population.  The dependent variable will be the change from baseline in pre-dose 
FEV1 at postbaseline protocol-specified visits (up to Visit 12 or EOT visit). Treatment group 
will be fitted as the explanatory variable, and pre and post-bronchodilator 
(albuterol/salbutamol) FEV1 at screening visit (Visit 1A), and baseline FEV1 as covariates, and 
smoking status, baseline ICS use, visit, and treatment group-by-visit interaction as fixed effect 
factors. Visit will be fitted as a categorical variable, and the variance-covariance matrix will 
be assumed to be unstructured. Kenward Roger approximation will be used to estimate 
denominator degrees of freedom. If the procedure does not converge then a compound 
symmetric variance-covariance matrix will be used instead. The model is as follows:  
Change in FEV1=treatment group + pre-bronchodilator FEV1 at Screening + 
post-bronchodilator FEV1 at Screening + baseline FEV1 + smoking status + Baseline ICS 
use + visit + treatment*visit  
Each treatment effect and treatment difference between aclidinium and placebo at each visit 
will be estimated by their least squares (LS) means and the differences in LS means on the 
treatment-by-visit interaction, along with their standard errors (SEs), and 95% CIs and the p-
value corresponding to the between–treatment-group difference. In addition, the overall 
treatment effect and treatment difference over the treatment period will be estimated by the LS 
means and the difference in LS means on the treatment factor, along with the SEs, and 95% 
CIs and the p-value corresponding to the between treatment group difference. 
A longitudinal plot will be used to display the change from baseline in FEV1 at each visit by 
treatment group. 
In addition, change from baseline in morning pre-dose (trough) FEV1 by visit (on-treatment 
analysis) will be analyzed for the following 2 subgroups:  
x LABA users (with and without ICS) 
x LABA/ICS users 
That is, data for each subgroup will be extracted first, then do analysis on each set of data 
using the same approach as the corresponding primary analysis. 
 
4.2.5 
Safety analyses 
All safety analyses will be based on the FAS Population. No multiplicity adjustment will be 
made to CIs. All p-values will be unadjusted. The analyses of the secondary safety endpoint of 
the time to first MACE or other serious CV events of interest will not be adjusted for multiple 
comparisons. 


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4.2.5.1 
Primary safety variable 
The null hypothesis is that treatment with aclidinium is inferior to treatment with placebo with 
regard to the risk of developing a MACE for a non-inferior (NI) margin of 1.8, i.e.:  
H0: Hazard ratio (aclidinium over Placebo) ≥ 1.8  
      versus 
Ha: Hazard ratio (aclidinium over Placebo) < 1.8  
 
The primary safety variable of time to first MACE will be based on on-study analysis. Only 
events adjudicated by the Clinical Events Committee (CEC) will be included. 
The primary safety variable of time to first MACE will be analyzed based on 
Cox-proportional hazards regression model including baseline CV severity, smoking status, 
and treatment group as covariates. The model is as follows: 
Time to first MACE = treatment group + baseline CV severity + smoking status 
This model will provide point estimate for the hazards ratio (aclidinium over placebo), as well 
as corresponding 95% CI and two-sided p-value (p-value will be presented for composite 
MACE endpoint only). The upper bound of the 95% CI (based on Cox regression) for the 
hazard ratio (aclidinium over placebo) of time to first MACE will be used to rule out the null 
hypothesis of hazard ratio of 1.8 for the primary test on MACE. If the upper bound of the 95% 
CI is less than the 1.8 margin of the hazard ratio, then the hazard ratio of 1.8 or higher will be 
ruled out (justification for the hazard ratio of 1.8 is provided in Appendix IV of the CSP).  
In addition, the KM survival curves will be displayed for each treatment group.  
To examine the contribution of the components of the composite endpoint to the overall 
treatment effect, time to first non-fatal MI, non-fatal stroke and CV death will be analyzed 
individually and presented in the same way as for the primary endpoint.  
The results from the primary safety analysis will also be evaluated considering a superiority 
hypothesis. 
Model assumption checking  
The assumption of proportional hazards will be assessed visually using log-cumulative hazard 
plots. The effect of any departures from proportional hazards will be discussed as part of the 
presentation of results of the analyses. 
Sensitivity analysis  
To account for the relation of the occurrence of an event and treatment exposure, an 
on-treatment analysis will be conducted and this will include only events that occurred while 
the patient was exposed to study treatment, i.e., events that occurred after the patient’s last 


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treatment dose will be censored. Two ascertainment windows, 0 and 15 days, will be 
evaluated in the on-treatment analyses. The on-treatment and on-treatment +15 days analyses 
will censor events that occur after and more than 15 days after, respectively, after the last 
treatment dose (see Section 9.7.6.1 of the CSP for consideration on totality of evidence from 
on-study and on-treatment analyses in evaluation of MACE).  
To assess possible effects of informative censoring, sensitivity analysis (on-study analysis) 
will be done as follows: based on the missing follow-up time in drop-outs, i.e. the time from 
censoring to study closure, the expected number of events that might have been observed if 
the drop-outs had completed the study can be calculated using an event rate similar to that 
observed in the study. The test (aclidinium versus placebo) will be recalculated with these 
residual events allocated in different proportions to the treatment groups to assess the 
robustness of the results with regard to the censoring of drop-outs. 
Sensitivity analysis of the primary composite endpoint will also include analysis with CV 
death replaced with all-cause mortality.  
Subgroup analysis. To evaluate the consistency in the primary safety endpoint over selected 
baseline characteristics, subgroup analysis will be performed. The subgroup is described 
below:  
x History of at least one exacerbation in the past year (0, ≥1)  
The subgroup analysis on time to first adjudicated MACE will be analyzed using the same 
method as the primary analysis on the primary safety endpoint using a 95% CI and without 
statistical testing for NI (NI margin will not be used).  
 
4.2.5.2 
Secondary safety variable 
The secondary safety endpoint of time to first MACE or other serious CV events of interest 
will be analyzed using the same method as the primary safety endpoint using a 95% CI and 
without statistical testing for NI (NI margin will not be used).  
Supportive listings will be provided for all adjudicated events with adjudication conclusions. 
4.2.5.3 
Adverse Events 
High-level summaries of AEs and TEAEs will be presented separately.  The tables will 
include the number and percentage of patients for the following categories: 
x Any AE/TEAE 
x Any AE/TEAE with outcome = death 
x Any SAE/TESAE 
x Any AE/TEAE leading to discontinuation of IP 


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Summaries on event counts will also be presented by categories above. 
The number and percentage of patients reporting any TEAE will be summarized  
x by system organ class (SOC), high level term (HLT), and PT;  
x by SOC, HLT, PT, and severity;  
x by SOC, HLT, PT, and relationship to the IP 
If more than one AE is coded to the same PT for the same patient, the patient will be counted 
only once for that PT using the most severe and most related occurrence in the summarization 
by severity and by causal relationship to the IP. 
The incidence of common (≥ x% of patients in any treatment group, ‘x’ to be determined prior 
to the DB lock) TEAEs will be summarized by PT (sorted by decreasing frequency of PT 
[total]). 
All AEs will be provided in a by-patient listing which will include both the term reported on 
the eCRF (verbatim term) and the PT and SOC to which it is coded.  Relative start and stop 
days will be included along with the actual onset and resolution dates. 
Deaths, Serious Adverse Events, and Other Significant Adverse Events  
An SAE that occurs on or after the date of the first dose of double-blind IP and within 15 days 
of the date of the last dose of double-blind IP will be considered an on-treatment 
SAE/TESAE.  
An SAE that occurs after 15 days of the date of the last dose of double-blind IP will be 
considered an off-treatment SAE.  
The following summaries will be produced: 
x Number and percentage of patients with any SAEs by SOC, HLT, and PT 
x Number and percentage of patients with adverse events with outcome of  death by 
SOC and PT 
x Number and percentage of patients with off-treatment SAEs by SOC, HLT, and PT 
x Number and percentage of patients with AEs leading to premature discontinuation of 
the IP by SOC and PT 
In addition, separate listings will be provided for the following: 
x Deaths   
x SAEs   
x Permanent discontinuations of study treatment due to AEs 
Adjudicated MACEs and other serious CV events of interest will be summarized as follows: 


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x Number, percentage, and incidence (per 1000 patient-years of exposure to IP) of 
patients with adjudicated MACE by MACE category, adjudicated subcategory, and 
PT (on-study analysis and on-treatment analysis).  
x Number, percentage, and incidence (per 1000 patient-years of exposure to IP) of 
patients with adjudicated cardiac disorders (i.e. cardiac arrhythmias SMQ and cardiac 
failure SMQ) and cerebrovascular disorders by specific SMQ category and PT 
(on-study analysis and on-treatment analysis).  
x Number, percentage, and incidence (per 1000 patient-years of exposure to IP) of 
patients with adjudicated non-fatal other CV events by PT (on-study analysis). 
Supportive listings to summaries described above will be provided. 
Adverse events of special interest (AESI)  
The summaries on the following AESI will be produced by SOC and PT. 
Events of interest 
Standard MedDRA Query Category plus additional High Level Terms or Preferred Term, 
if applicable 
Anticholinergic 
events 
Anticholinergic syndrome (narrow and broad search SMQ)Glaucoma (narrow search 
SMQ) 
Additional PTs: sinus tachycardia, supraventricular tachycardia, ventricular tachycardia, 
heart rate increased, palpitations, pupillary reflex impaired, pupils unequal, visual 
disturbance, constipation, gastrointestinal obstruction, ileus paralytic, urinary tract 
infection, cystitis, urinary incontinence, incontinence, dysuria, urge incontinence, urine 
flow decreased, bladder irritation, oropharyngeal pain, dysphonia, laryngitis, pharyngitis, 
and throat irritation 
Pneumonia 
All PTs that contain the term pneumonia 
 
4.2.5.4 
Clinical laboratory variables 
There will be no report of the laboratory data.  
Patients who meet the potential Hy’s Law criteria from the first dose of double-blind IP to 
within 15 days after the last dose of double-blind IP will be summarized. A supportive listing 
will be provided. Related data collected in the eCRF (e.g., abnormal liver biochemistry risk 
factors, liver disease signs and symptoms, liver diagnostic tests) will be listed. 
4.2.5.5 
Vital signs 
Descriptive statistics for vital signs (pulse rate, systolic and diastolic BP, and weight) and 
changes from baseline values at each visit and at the end of study will be presented. 
The number and percentage of patients with PCS postbaseline values will be tabulated. The 
percentages will be calculated relative to the number of patients with available baseline values 
and at least one postbaseline assessment in the treatment period. The numerator will be the 
total number of patients with available baseline values and at least one PCS postbaseline value 
in the treatment period. A supportive tabular display of patients with PCS postbaseline values 


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will be provided, including the PID number and baseline and all postbaseline (including 
non-PCS) values. A tabular display of all AEs occurring in patients who have PCS 
postbaseline vital sign values will also be provided. 
 
4.2.5.6 
Electrocardiogram 
Descriptive statistics for ECG parameters (i.e., ventricular heart rate, RR interval, PR interval, 
QRS duration, QT interval, QTcB, and QTcF) and changes from baseline values at each 
assessment time point to the end of study will be presented. 
The number and percentage of patients with PCS postbaseline ECG values will be tabulated. 
The percentages will be calculated relative to the number of patients with available baseline 
values and at least one postbaseline assessment in the treatment period. The numerator will be 
the total number of patients with available baseline values and at least one PCS postbaseline 
value in the treatment period. A supportive tabular display of patients with PCS postbaseline 
values will be provided, including the PID number, baseline, all postbaseline (including 
non-PCS) values, and change from baseline. In addition, a tabular display showing all AEs 
that occurred in patients who had postbaseline PCS ECG values will be provided. 
A shift table from baseline to the end of study in the Investigator’s overall interpretation of the 
ECG will be presented for the following categories: normal; abnormal, not clinically 
significant (NCS); and abnormal, clinically significant (CS). 
Shift tables for ECG abnormal findings will be presented overall (in subjects with normal 
baselines and all subjects in FAS) and by visit. 
4.2.5.7 
Physical examination 
A listing of physical examination findings at Screening (Visit 1A) will be provided as a part of 
the medical and surgical history listing. Any new physical examination finding or change 
(worsening) since the previous physical examination during the treatment period will be 
provided as part of the AE listing. 
4.2.5.8 
All-cause mortality 
All-cause mortality based on patient’s vital status data will be analyzed using the same 
method as the primary safety endpoint using a 95% CI and without statistical testing for NI 
(NI margin will not be used).   
4.2.6 
Health economics and outcomes research analyses 
4.2.6.1 
COPD assessment tests (CAT) by visit 
Descriptive statistics will be provided at baseline (actual scores) and each postbaseline visit 
(actual and change from baseline scores).  
Change from baseline in CAT total score by visit will be compared between aclidinium group 
and placebo using a MMRM model on patients with a baseline CAT total score and at least 


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one post-randomization CAT total score in the FAS Population.  The dependent variable will 
be the change from baseline in CAT total score at postbaseline protocol-specified visits (up to 
Visit 12 or EOT visit). Treatment group will be fitted as the explanatory variable, and baseline 
CAT total score as covariate, and baseline ICS use, smoking status, visit, and treatment 
group-by-visit interaction as fixed effect factors. Visit will be fitted as a categorical variable, 
and the variance-covariance matrix will be assumed to be unstructured. Kenward Roger 
approximation will be used to estimate denominator degrees of freedom. If the procedure does 
not converge then a compound symmetric variance-covariance matrix will be used instead. 
The model is as follows:  
Change in CAT total score=treatment group + baseline CAT total score + baseline ICS use + 
smoking status + visit + treatment*visit  
Each treatment effect and treatment difference between aclidinium and placebo at each visit 
will be estimated by their LS means and the differences in LS means on the treatment-by-visit 
interaction, along with their SEs, and 95% CIs and the p-value corresponding to the between–
treatment-group difference. In addition, the overall treatment effect and treatment difference 
over the treatment period will be estimated by the LS means and the difference in LS means 
on the treatment factor, along with the SEs, and 95% CIs and the p-value corresponding to the 
between treatment group difference. 
A longitudinal plot will be used to display the change from baseline in CAT total score at each 
visit by treatment group. 
Change from baseline in CAT total score by visit will be analyzed for the following 2 
subgroups:  
x LABA users (with and without ICS) 
x LABA/ICS users 
That is, data for each subgroup will be extracted first, then do analysis on each set of data 
using the same approach as the primary analysis. 
In addition, the number (%) of patients experiencing response (improvement of 2 or more 
units from baseline in CAT total score) will be presented by visit. The number of patients who 
experience response will be analyzed based on a logistic random effect model with baseline 
CAT total score as covariate, and treatment group, baseline ICS use, smoking status, visit and 
treatment group-by-visit interaction as fixed effects and a random intercept to account for the 
variability between subjects.  The estimated treatment effect (i.e., the odds ratio of aclidinium 
over placebo), corresponding 95% CI, and two-sided p-value for the odds ratio will be 
presented. The model is as follows: 
Response (Yes=1/No=0) = treatment group + baseline CAT total score + baseline ICS use + 
smoking status + visit + treatment*visit 


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5. 
CHANGES OF ANALYSIS FROM PROTOCOL 
The primary efficacy endpoint, rate of moderate or severe COPD exacerbations per patient per 
year during the first year of treatment, will be analyzed using on-treatment analysis as primary 
analysis and on-study analysis as secondary analysis (per the CSP, on-treatment analysis as 
primary analysis and on-study analysis as sensitivity analysis). 
The covariates or factors included in the models are harmonized.  
The incidence of common (e.g. ≥ 2% of patients in any treatment group) TEAEs will be 
summarized by preferred term (per the CSP, by SOC and PT). 
Number (%) of patients with any SAEs is summarized by SOC, HLT, and PT (per the CSP, 
by PT). 
Number (%) of patients with adverse events with outcome of death is summarized by SOC 
and PT (per the CSP, by PT). 
Number (%) of patients with AEs leading to premature discontinuation of the IP is 
summarized by SOC and PT (per the CSP, by PT). 
The denominator and numerator for PCS vital sign and ECG values are re-defined. 
6. 
REFERENCES 
Global initiative for chronic obstructive lung disease (GOLD). Pocket guide to COPD 
diagnosis, management, and prevention. 2017 
Keene OH, Rogers JH, Hartley BF, Kenward MG. Missing data sensitivity analysis for 
recurrent event data using controlled imputation. Pharmaceutcal Statistics 2014 13(4): 
258-264.  
Keene ON, Jones MR, Lane PW, Anderson J. Analysis of exacerbation rates in asthma and 
chronic obstructive pulmonary disease: example from the Tristan Study. Pharmaceutical 
Statistics. 2007 6(2): 89 – 97.  
7. 
APPENDIX 
The changes in the appendices only will not need a SAP amendment, instead the revised appendix will 
be considered as an addendum of the SAP.  


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 Appendix 1: Imputation of unobserved exacerbations 
Assume a patient has y1 exacerbations during period 1 and then withdraws. We want to 
estimate y2, the number of unobserved exacerbations, given what we have actually seen. 
Numbers of events before and after withdrawal are seen as two periods with a joint negative 
multinomial distribution, with Y1 observed and Y2 unobserved. For a given patient, 
distribution Y2|Y1 is a function of:  
x Observed y1  
x Estimated dispersion (assumed same in both periods)  
x Estimated mean (model predicted) rate period 1  
x Imputed mean rate period 2 – options for this depends on the method: missing at 
random (MAR), CR, J2R chosen)  
In the CR approach, a patient’s expected event rate both before and after withdrawal is 
assumed to be the same as the reference group. This mimics the case where those withdrawing 
are in effect nonresponders. When a patient on test treatment has more events before 
withdrawal than expected for them if they had been in the reference arm, then this ‘positive 
residual’ will feed through into a higher than expected event rate in the postwithdrawal period. 
This is because their earlier observed higher than normal event rate suggests a personal high 
propensity to events. Postwithdrawal data in the reference arm are imputed under randomized 
arm MAR. 
In the J2R approach, dropouts on test treatment are assumed to have been on test treatment 
rather than the reference prior to dropout. In the FDA’s opinion, this may be more reasonable 
than the CR approach, given that the CR approach may carry forward a treatment effect (i.e., 
if a patient had a decreased rate while on treatment). The CR approach is likely inappropriate 
since effects of bronchodilators are expected to diminish within a few weeks of 
discontinuation and because such patients will not benefit from the drug in the long-term. 
Whichever imputation model is chosen, the subsequent procedure follows that of standard MI. 
For each imputation, a single set of data is created for each subject’s missing data conditional 
upon their observed data. After summing observed and imputed values for each subject, each 
imputed data set is analyzed using the model used for the primary analysis. At least 1000 
imputations are recommended and more should be considered, to provide sufficiently stable 
and reproducible results. 
Multiple imputation: 
x Take a random sample from Y2|Y1, add this to the y1 we observed for the patient 
x Analyse the data using PROC GENMOD as usual 
x Repeat analysis multiple times 
x Combine estimates using Rubin’s rules 


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Implementation in SAS:  
This approach to sensitivity analysis as described above can be implemented in the SAS 
system using the GENMOD procedure to derive and sample from the posterior distribution for 
k, β and the other covariate regression parameters. A sample can be drawn from the 
conditional distribution for the unobserved period using a DATA step. Results can be 
summarized using the MIANALYZE procedure, which applies Rubin’s formula.  
The following SAS code extracts samples from the posterior distribution of model parameters 
including the dispersion parameter using a Bayesian negative binomial log-link model with an 
offset variable which holds the log of the exposure time for each patient:  
Specifically for the sensitivity analysis using copy reference approach on the primary analysis 
of the primary efficacy endpoint in this study, using only the data from the placebo, run 
genmod using the primary analysis model (including all the covariates and offset) without 
treatment, and using Bayes statement with “coeffprior = normal”, output a posterior sample of 
the model parameters of size N. The rationale of using only the placebo’s group date is that 
when we explore the effect of the missing values we assume the missing values are treatment 
related. Therefore, when estimate the model parameters we do not want the missing values 
from the active group to contaminate the estimates. 
 
For each draw (after thinning) the expected number of events is calculated for the period 
before and after withdrawal for each subject. This depends upon the length of time before and 
after withdrawal. Denote these as y1_hat and y2_hat.  
The design matrices for an individual patient are modified to assign the withdrawing patient to 
the desired treatment arm for the observed or unobserved period (depending on the method: 
MAR, CR, J2R chosen).  
Then according to the derivation for the conditional distribution Y2|Y1, we can sample using 
the following statement:  
 
  
where invK_hat is the inverse of the sampled dispersion parameter, and y1 is the actual count 
before withdrawal.  
CCI
CCI
CCI


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The entire number of exacerbations (observed and unobserved) is then:  
 
  
These imputed numbers are then analyzed in a new series of further GENMOD runs (one for 
each draw), using the standard model (same covariates etc.) and a negative binomial model. 
However an offset will usually now not be required as the effective period at risk is the same 
for every patient. Derived parameters from the model such as least squares means for 
treatment and their differences are then combined across imputation data sets using Rubin’s 
formula, as implemented in the MIANALYZE procedure. These and their confidence interval 
limits are then exponentiated to derive relative rates.  
CCI
CCI


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Appendix 2: Tipping point analysis  
Missing counts for a subject will be imputed according to the mean of the arm that the subject 
belongs to, multiplied by a factor delta. The deltas for the two arms can be varied until the 
result crosses some relevant threshold (e.g., different statistical significance levels). That is, to 
do multiple imputation and apply the imputation to the unobserved period only. Since this will 
be computationally demanding a suggestion is to only multiply deltas to Aclidinium 400 μg 
group (to make it worse) and keep the placebo “delta” fixed to 1.