Clinical trial NCT03276078
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: COPD
Sponsor: AstraZeneca
Start date: 2017-11-23; Completion date: 2018-06-12
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase IIa, open-label, repeat-dose trial to investigate the pharmacokinetics (PK), safety and tolerability of single and multiple twice daily doses of inhaled Aclidinium Bromide/Formoterol Fumarate 400/12 μg in 20 Chinese male and female patients with stable moderate to severe COPD.

Detailed description:
Screening will be performed within 21 days of dosing on Day 1 at visit 2. Eligible participants will be admitted to the trial center the day preceding the first dosing (day -1).

Participants will receive Aclidinium Bromide/Formoterol Fumarate 400/12 μg twice-daily (morning and evening) on Days 1 to 4. On Day 5 patients will receive the morning dose only. PK and safety assessments will be conducted at specific timepoints on Day 1 to Day 7.

Participants will be discharged 48 h after the last administration of investigational product and completion of the 48-h PK sample collection and safety assessments on Day 7.

A follow-up visit will be performed within 5 days of the last PK sample collection on Day 7.

Arms: arm 1: Aclidinium bromide/Formoterol Fumarate 400/12μg inhalation powder twice-daily. Oral inhalation via Genuair® dry powder inhaler (DPI).
Interventions: intervention 1: Aclidinium Bromide/Formoterol Fumarate 400/12μg BID
Intervention descriptions: intervention 1: Aclidinium bromide/formoterol fumarate 400/12μg administered by inhalation via the Genuair® multidose dry powder inhaler, twice daily (morning and evening) for 5 days

Protocol documents:
Prot_001.pdf: 
1 (85)
This document contains confidential commercial information, disclosure of which is 
prohibited without providing advance notice to AstraZeneca and opportunity to object.
Clinical Study Protocol D6572C00001
Drug Substance
Aclidinium bromide 
/Formoterol fumarate
Study Code
D6572C00001
M-AS464-01
Version
1.0
Date
24 March 2017
A Phase IIa, Open-Label, Repeat-Dose Clinical Trial to Evaluate the 
Pharmacokinetics, Safety and Tolerability of Aclidinium Bromide / 
Formoterol Fumarate Fixed Dose Combination Administered Twice-Daily 
by Inhalation in Chinese Patients With Moderate to Severe Chronic 
Obstructive Pulmonary Disease
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


2 (85)
VERSION HISTORY
Version 1.0, 23 March 2017
Initial Creation 
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 patient 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.


3 (85)
PROTOCOL SYNOPSIS
A Phase IIa, Open-Label, Repeat-Dose Clinical Trial to Evaluate the 
Pharmacokinetics, Safety and Tolerability of Aclidinium Bromide / 
Formoterol Fumarate Fixed Dose Combination Administered Twice-Daily 
by Inhalation in Chinese Patients With Moderate to Severe Chronic 
Obstructive Pulmonary Disease (COPD)
Principal Investigator
 
Study site(s) and number of patients planned
Twenty (20) Chinese male and female patients with stable moderate to severe COPD will be 
dosed.
Study period
Phase of development
Estimated date of first patient enrolled
Q3-Q4 2017
Phase IIa
Estimated date of last patient completed
Q1-Q2 2018
Study design
This is a Phase IIa, open-label, repeat-dose trial to investigate the pharmacokinetics (PK), 
safety and tolerability of single and multiple twice daily doses of inhaled aclidinium 
bromide/formoterol fumarate 400/12 μg in Chinese male and female patients with stable 
moderate to severe COPD.
Twenty COPD Chinese patients of at least 40 years of age or older, will participate in the 
study.
Patients will be admitted to the trial center on Day -1 and will be discharged on Day 7, 48
hours after last IP administration on Day 5 and after the completion of the 48-hour PK sample 
collection and safety assessment on Day 7. A follow up visit that will be performed within 5 
days of the final PK sample collection on Day 7.
PPD


Clinical Study Protocol Synopsis
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01 / D6572C00001
Version 1.0
Date 24 March 2017
4 (85)
Safety measurements and blood samples for PK assessments will be collected at 
predetermined time points on Days 1 through 7.
Objectives
Primary Objective:
Outcome Measure:
To evaluate the pharmacokinetics (PK) of 
aclidinium bromide, its metabolites 
LAS34850 and LAS34823 and formoterol 
after administration of aclidinium 
bromide/formoterol 400/12 μg twice-daily 
(BID) for 5 days in Chinese patients with 
stable moderate to severe COPD.
The following pharmacokinetic parameters will 
be calculated when applicable for aclidinium 
bromide, its metabolites and formoterol 
fumarate:
Day 1: Cmax, tmax, AUClast, AUC!, Cmin
Day 5: Css,max, tss,max, λz, t½λz, AUCss,!, CL/F*, 
Vz/F*, Cav, %Fluctuation, Css,min, Rac(Cmax)
Rac(AUC!) and Rac(Cmin).
Additional parameters may be determined where 
appropriate 
*Only for Aclidinium bromide and formoterol
Secondary Objective:
Outcome Measure:
To evaluate the safety and tolerability of 
aclidinium bromide/ formoterol 400/12 μg 
twice-daily (BID) administered for 5 days 
in Chinese patients with stable moderate to 
severe COPD.
AEs/SAEs
Blood pressure
Clinical laboratory parameters (haematology, 
serum biochemistry and urinalysis)
12-lead ECG parameters
Procedures and assessments
After obtaining written informed consent, all patients will be screened within 21 days prior to 
the first investigational product (IP) dose administration on Day 1 at Visit 2. Eligibility 
screening will consist of inclusion and exclusion criteria evaluation; complete medical and 
surgical history/COPD history; prior and concomitant medications; demographics; inhaler 
training; physical examination, body weight and height; blood pressure; 12-lead 
electrocardiogram (ECG); spirometry and reversibility test; clinical laboratory tests 
(haematology, serum biochemistry and urinalysis); serum pregnancy test for women of 
childbearing potential; serology (anti-hepatitis C virus, hepatitis B surface antigen and anti-
human immunodeficiency virus [HIV] type 1); urine drugs of abuse and alcohol screen; and 
adverse event (AE) monitoring. Relief medication is to be provided to the patient at Visit 1 
(Screening visit) as necessary.


Clinical Study Protocol Synopsis
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01 / D6572C00001
Version 1.0
Date 24 March 2017
5 (85)
Spirometry will be conducted at Visit 1 (Screening) to confirm eligibility criteria and COPD 
severity stage (post-bronchodilator forced expiratory volume in 1 second [FEV1] according to 
the Global Initiative for Chronic Obstructive Lung Disease [GOLD] guidelines 2016).
Upon admission to the trial center on Day -1 of Visit 2 (the day preceding the first day of IP 
administration [Day 1]), the following procedures are to be performed: review of inclusion 
and exclusion criteria; prior and concomitant medications; inhaler training; blood pressure; 
12-lead ECG; clinical laboratory tests (haematology, serum biochemistry and urinalysis); 
physical examination; serum pregnancy test for women of childbearing potential; urine drugs 
of abuse and alcohol screen; and AE monitoring.
Each eligible patient will be dosed on Day 1. On Day 1 through Day 4, patients will receive 
one inhalation of aclidinium bromide/formoterol 400/12 μg BID (morning and evening) via 
the Genuair® multidose dry powder inhaler (DPI). On Day 5 patients will receive only the 
morning dose of one inhalation of aclidinium bromide/formoterol 400/12 μg via the Genuair® 
multidose DPI. Patients will be discharged on Day 7, 48 hours after last IP administration and 
completion of the 48-hour PK sample collection and safety assessments. Relief medication is 
to be provided to the patient during the treatment period as necessary.
From Day 1 through Day 7 at Visit 2, safety measurements (blood pressure, 12-lead ECG and 
AE monitoring) and blood samples for PK assessments will be collected at predetermined 
time points.
A follow-up Visit will be performed within 5 days of the final PK sample collection on Day 7. 
The following procedures are to be performed at the Follow up Visit: recording of 
concomitant medications; physical examination; blood pressure; clinical laboratory tests, 12-
lead ECG; serum pregnancy test for women of childbearing potential and AE monitoring.
Patients who prematurely discontinue from the study (withdrawal) will participate in a 
Premature Discontinuation Visit that will include physical examination, clinical laboratory 
test, 12-lead ECG, blood pressure, serum pregnancy test for women of childbearing potential,
and assessment of AEs and concomitant medications to ensure patient´s safety.
The total amount of blood to be collected for safety assessments will be 29 mL. For female 
patients of childbearing potential an additional 9 mL will be collected for serum pregnancy 
test.
Blood samples for serum pregnancy tests will be sent to the site local laboratory for analysis. 
Test for drugs of abuse and alcohol screen will also be performed at the site. All other blood 
and urine specimens will be sent to a central laboratory (Covance) in China for analysis.
AE and recording of concomitant medications will be monitored starting after the time the 
informed consent is signed through the completion of the follow-up; should any AEs or 
serious adverse events (SAEs) be ongoing at that time, they will be followed up until 
resolution, stabilization, or the PI and the Sponsor agree that follow-up is no longer necessary.


Clinical Study Protocol Synopsis
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01 / D6572C00001
Version 1.0
Date 24 March 2017
6 (85)
Relief medication (salbutamol pMDI 100 μg/puff) will be permitted as needed throughout the 
study, for all participating patients. 
Pharmacokinetic Assessments
Serial blood samples will be collected for PK assessments of aclidinium bromide and its 
metabolites (LAS34823 and LAS34850) and formoterol in plasma at the following time 
points:
•
Day 1: pre-dose, 5, 15, 30 min and 1h, 1,5h, 2, 3, 4, 6, 8 and 12h. (12 time points)
•
Day 2-4: pre- morning and evening dose (6 time points)
•
Day 5: pre-dose, 5, 15, 30 min and 1h, 1,5h, 2,3,4,6,8,12, 24, 36 and 48 h (15 time
points)
The total amount of blood to be collected for the PK assessments will be 264 mL (33 time
points x 8 mL).  All PK plasma specimens will be sent to Covance in China for analysis. 
Aclidinium bromide undergoes rapid hydrolysis in human plasma to its acid (LAS34850) and 
alcohol metabolites (LAS34823). Therefore, blood samples generated in study must be 
stabilized with 4-(2-aminoethyl) benzene sulfonyl fluoride hydrochloride (AEBSF) and 
temperature control to guarantee that these samples are not altered between the collection time 
and the time they are stored frozen (at –70°C). The time from blood draw to freezing of 
plasma samples should be completed as quickly as possible and should not exceed 30 minutes. 
Laboratory kits containing additives and AEBSF will be provided by the Covance Central 
Services.
Target patient population
Twenty (20) Chinese male and female patients who are aged ≥ 40, current or former smokers 
with a smoking history of ≥ 10 pack-years, and with stable, moderate to severe COPD (GOLD 
guidelines 2016). Patient must have screening post-bronchodilator test FEV1/FVC < 70% and 
FEV1 ≥30 and < 80% of the predicted normal value.
Duration of treatment
The total duration of the trial for each patient will be approximately 5 weeks. There will be a 
run-in period of up to 21 days followed by treatment period of 8 days (including admission 
Day -1, 5 treatment days, and 2 days for PK sampling after last IP dose), and a follow up visit 
that will be performed within 5 days of the final PK sample collection on Day 7.
Investigational product, dosage and mode of administration
The IP consists of a fixed-dose combination (FDC) of a long-acting anticholinergic drug, 
namely aclidinium bromide, combined with the long-acting β2-agonist formoterol fumarate 
(aclidinium bromide 400 μg/formoterol fumarate 12 μg inhalation powder)


Clinical Study Protocol Synopsis
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01 / D6572C00001
Version 1.0
Date 24 March 2017
7 (85)
The aclidinium bromide/formoterol 400/12 μg FDC inhalation powder will be administered 
via the Genuair® device (dry powder inhaler, DPI) via oral inhalation.
Statistical methods
Analysis will be done using the safety and PK populations. All patients who complete the 
treatment period (Days 1-5) and have evaluable PK parameters will be defined as the PK 
population. All patients who receive at least 1 dose of aclidinium bromide/formoterol will be 
defined as the safety population.
PK Parameters will be summarized descriptively by compound/study day separately using 
appropriate descriptive statistics including tables, listings and graphs, as appropriate. 
Descriptive statistics for demographics and other baseline characteristics will be provided.
Safety Outcomes: The incidence of TEAEs will be presented by system organ class and 
preferred term; by relationship to investigational product, by severity, seriousness, and action 
taken with IP. Clinical laboratory parameters, vital signs, and 12-lead ECG will be analysed 
for both absolute values and change from baseline by means of descriptive statistics. Shift 
tables will be performed when applicable. An outlier analysis of the appropriate ECG 
parameters and potentially clinical significant laboratory values will also be presented.


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
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TABLE OF CONTENTS
PAGE
TITLE PAGE............................................................................................................................1
VERSION HISTORY ..............................................................................................................2
PROTOCOL SYNOPSIS .........................................................................................................3
TABLE OF CONTENTS .........................................................................................................8
1.
INTRODUCTION .................................................................................................18
1.1
Background and rationale for conducting this study .............................................18
1.2
Rationale for study design, doses and control groups............................................19
1.3
Benefit/risk and ethical assessment........................................................................19
1.4
Study Design..........................................................................................................21
2.
STUDY OBJECTIVES..........................................................................................23
2.1
Primary objective...................................................................................................23
2.2
Secondary objectives .............................................................................................23
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................23
3.1
Inclusion criteria ....................................................................................................24
3.2
Exclusion criteria ...................................................................................................25
3.3
Patient enrolment ...................................................................................................28
3.4
Procedures for handling incorrectly enrolled patients ...........................................28
3.5
Methods for assigning treatment groups................................................................29
3.6
Methods for ensuring blinding...............................................................................29
3.7
Methods for unblinding..........................................................................................29
3.8
Restrictions ............................................................................................................29
3.8.1
Dietary and Fluid Restrictions ...............................................................................29
3.8.2
Other Restrictions ..................................................................................................30
3.9
Discontinuation of investigational product and study withdrawal ........................30
3.9.1
Procedures for discontinuation of a patient from investigational product 
and from the study. ................................................................................................31
3.10
Criteria for withdrawal...........................................................................................32
3.10.1
Screen failures........................................................................................................32
3.11
Premature Discontinuation of the study.................................................................32


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
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4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................33
4.1
Enrolment/screening period...................................................................................36
4.2
Treatment period (Visit 2: from Day -1 to Day 7).................................................37
4.2.2
Day 1......................................................................................................................38
4.2.3
Day 2 to Day 5 .......................................................................................................39
4.2.4
Day 6 and Day 7 ....................................................................................................40
4.3
Follow-up period (Visit 3) .....................................................................................40
4.4
Premature discontinuation visit..............................................................................41
5.
STUDY ASSESSMENTS .....................................................................................41
5.1
Safety assessments.................................................................................................41
5.1.1
Laboratory safety assessments...............................................................................41
5.1.1.1
Urinalysis ...............................................................................................................44
5.1.1.2
Pregnancy Test.......................................................................................................44
5.1.1.3
Drugs of Abuse Screen ..........................................................................................44
5.1.2
Medical History/Physical examination..................................................................44
5.1.3
Spirometry..............................................................................................................44
5.1.4
ECG........................................................................................................................45
5.1.4.1
Resting 12-lead ECG .............................................................................................45
5.1.5
Vital signs ..............................................................................................................47
5.1.5.1
Blood pressure .......................................................................................................47
5.1.6
Adverse Events ......................................................................................................47
5.1.7
Repeated Tests (Re-Test).......................................................................................47
5.1.8
Unscheduled Tests .................................................................................................48
5.2
Pharmacokinetics ...................................................................................................48
5.2.1
Collection of samples.............................................................................................48
5.2.2
Determination of drug concentration.....................................................................49
5.2.3
Storage and destruction of pharmacokinetic samples............................................49
5.3
Pharmacodynamics ................................................................................................49
5.3.1
Collection of samples.............................................................................................49
5.4
Pharmacogenetics ..................................................................................................49
5.5
Biomarker analysis.................................................................................................49
5.6
Total Blood Volume ..............................................................................................50
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................52
6.1
Definition of adverse events ..................................................................................52
6.2
Definitions of serious adverse event......................................................................52
6.3
Recording of adverse events ..................................................................................53
6.3.1
Time period for collection of adverse events.........................................................53
6.3.2
Follow-up of unresolved adverse events................................................................53
6.3.3
Variables ................................................................................................................53


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
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6.3.4
Causality collection................................................................................................54
6.3.5
Adverse events based on signs and symptoms.......................................................55
6.3.6
Adverse events based on examinations and tests...................................................55
6.3.7
Hy’s Law................................................................................................................55
6.4
Reporting of serious adverse events.......................................................................55
6.5
Overdose ................................................................................................................56
6.6
Pregnancy...............................................................................................................57
6.6.1
Maternal exposure..................................................................................................57
6.6.2
Paternal exposure...................................................................................................57
6.7
Medication errors...................................................................................................58
6.8
Management of IP related toxicities ......................................................................58
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................58
7.1
Identity of investigational product(s).....................................................................58
7.2
Additional Drug .....................................................................................................58
7.3
Dose and treatment regimens.................................................................................59
7.4
Labelling ................................................................................................................59
7.5
Training on DPI inhaler use...................................................................................60
7.6
Storage ...................................................................................................................60
7.7
Compliance ............................................................................................................60
7.8
Accountability........................................................................................................60
7.9
Prior and Concomitant medications.......................................................................61
7.9.1
Other concomitant treatment..................................................................................65
8.
STATISTICAL ANALYSES ................................................................................65
8.1
Statistical considerations........................................................................................65
8.2
Sample size estimate..............................................................................................66
8.3
Definitions of analysis sets ....................................................................................66
8.3.1
Safety analysis set..................................................................................................66
8.3.2
PK analysis set .......................................................................................................66
8.3.3
Protocol deviations.................................................................................................66
8.4
Outcome measures for analyses.............................................................................67
8.4.1
Pharmacokinetics Variables...................................................................................67
8.4.2
Safety and Tolerability Outcomes..........................................................................68
8.5
Methods for statistical analyses .............................................................................69
8.5.1
Analysis of the Pharmacokinetic variables............................................................69
8.5.1.1
Calculation or derivation of the pharmacokinetic parameters ...............................69
8.5.1.2
Statistical analysis of the Pharmacokinetic Parameters.........................................70


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
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8.5.2
Analysis of safety data...........................................................................................70
8.5.2.1
Adverse events.......................................................................................................71
8.5.2.2
Blood Pressure .......................................................................................................71
8.5.2.3
Resting (safety) 12-lead electrocardiogram...........................................................72
8.5.2.4
Physical examination .............................................................................................72
8.5.2.5
Laboratory assessments .........................................................................................72
9.
STUDY AND DATA MANAGEMENT...............................................................72
9.1
Training of study site personnel.............................................................................72
9.2
Monitoring of the study .........................................................................................72
9.2.1
Source data.............................................................................................................73
9.2.2
Study agreements...................................................................................................73
9.2.3
Archiving of study documents...............................................................................73
9.3
Study timetable and end of study...........................................................................73
9.4
Data management...................................................................................................74
10.
ETHICAL AND REGULATORY REQUIREMENTS.........................................75
10.1
Ethical conduct of the study...................................................................................75
10.2
Patient data protection............................................................................................75
10.3
Ethics and regulatory review..................................................................................75
10.4
Informed consent ...................................................................................................76
10.5
Changes to the protocol and informed consent form.............................................76
10.6
Audits and inspections ...........................................................................................77
11.
LIST OF REFERENCES.......................................................................................77
LIST OF TABLES
Table 1
Schedule of Assessments..........................................................................34
Table 2
Laboratory Safety Variables.....................................................................43
Table 3
Number and Volume of Blood Samples and Total Blood Volume 
Collected per Patient.................................................................................51
Table 4
Allowed Concomitant Medications..........................................................62
Table 5
Prohibited Medications.............................................................................63
Table 6 
Relief Medication .....................................................................................64
Table 7
CYP P450 Inhibitors.................................................................................64
Table 8
CYP P450 Inducers ..................................................................................65


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
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LIST OF FIGURES
Figure 1
Study flow chart ......................................................................................22
LIST OF APPENDICES
Appendix A
Additional Safety Information..................................................................79
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document .................................................................................81
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law............................................................................82


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse Event
ALT
Alanine Aminotransferase 
AM
Morning (antemeridian)
AST
Aspartate Aminotransferase 
ATC
Anatomical Therapeutic Chemical 
ATS
American Thoracic Society
AUC
Area Under the Curve
AUCex
Percentage of AUC obtained by extrapolation, calculated as 
[(Clast(pred)/λz)/AUC * 100]
AUClast
Area under the plasma concentration-curve from time zero to the time of 
last quantifiable concentration
AUC/D
Area under the concentration-time curve from time zero extrapolated to 
infinity divided by the dose
AUCss,τ/D
Area under the concentration-time curve zero to 12 h divided by the dose
AUC!
Area under the plasma concentration-curve from time zero to 12 hours post 
dose
AUC!/D
Area under the concentration-time curve zero to 12 h divided by the dose
AUMC
Area Under the First Moment Curve
BLQ
Below the lower limit of quantification
β-hCG
β-human chorionic gonadotropin 
BID
Twice daily
BMI
Body Mass Index
BP
Blood Pressure
bpm
Beats per minute
CFDA
China Food and Drug Administration
Cav
Average steady state concentration
CI
Confidence Interval
CK
Creatine kinase
CL/F
Apparent clearance for parent drug estimated as dose divided by AUC


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
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Abbreviation or 
special term
Explanation
Cmax
Observed maximum concentration
Cmax/D
Observed maximum concentration divided by dose
Cmin
Observed minimum concentration within a dosing interval
Css,av
Average plasma concentration during a dosing interval, estimated as 
AUCss,τ/12
Css,max
Observed maximum concentration, taken directly from the individual 
concentration-time curve on Day 5
Css,min
Observed minimum concentration, taken directly from the individual 
concentration-time curve on Day 5
Css,max /D
Observed maximum concentration divided by dose
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CRO
Clinical Research Organisation
CSA
Clinical Study Agreement
CSR
Clinical Study Report
DAE
Discontinuation of Investigational Product due to Adverse Event
DBP
Diastolic Blood Pressure
DES
Data Entry Site
DILI
Drug-Induced Liver Injury
DMP
Data Management Plan
DPI
Dry Powder Inhaler
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
electronic Case Report Form 
EDC
Electronic Data Capture
E-R
Exposure-response
ERS
European Respiratory Society
EU
European Union
FDA
Food and Drug Administration
FDC
Fixed Dose Combination
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
15 (85)
Abbreviation or 
special term
Explanation
GGT
Gamma-glutamyl transferase
GMP
Good Manufacturing Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HBsAg
hepatitis B surface antigen
HIV
Human immunodeficiency virus
HL
Hy’s Law
HR
Heart Rate
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IP
Investigational Product
λz
Terminal rate constant
LABA
Long-Acting β2-agonist
LAMA
Long-Acting Muscarinic Antagonist
LLOQ
Lower Limit of Quantification
LS
Least Square
LSLV
Last Subject Last Visit
MedDRA
Medical Dictionary for Regulatory Activities
mmHg
Millimeters of mercury
msec
Milliseconds
MRT
Mean residence time calculated by AUMC/AUC, where AUMC is the area 
under the first moment-time curve
NA
Not applicable
ND
Not determined
N obs
Number of data points included in the log-linear regression analysis
OTC
Over-the-counter medicine
PD
Pharmacodynamic
PHL
Potential Hy’s Law
PI
Principal Investigator
PK
Pharmacokinetics
PM
Evening (Post meridiem)


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
16 (85)
Abbreviation or 
special term
Explanation
PP
Per-Protocol
PR(PQ)
Period that extends from the beginning of the P wave (the onset of atrial
depolarization) until the beginning of the QRS complex (the onset of 
ventricular depolarization)
PR interval
Duration in milliseconds from the beginning of wave P to onset of 
ventricular depolarisation (Q and R)
PT
Preferred Term
QRS
Onset of ventricular depolarization
QT interval
Duration in milliseconds from the beginning of Q wave to the end of the T 
wave
QTc interval
QT interval corrected by heart rate
QTcB interval
QT interval corrected, Bazett formulae (QT/RR1/2)
QTcF interval
QT interval corrected, Fredericia formulae (QT/RR1/3)
Rac(Cmax)
Accumulation ratio for Cmax estimated as ratio of Css,max on Day 5/Cmax on 
Day 1
Rac(Cmin)
Accumulation ratio for Cmin estimated as ratio of Css,min on Day 5/Cmin on 
Day 1
Rac(AUC!)
Accumulation ratio for AUC! estimated as ratio of AUCss,!on Day 5/AUC!
on Day 1
RR
Respiratory rate
RSq adj
Adjusted coefficient of determination for calculation of λz
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard Deviation
SE
Standard error
SOC
System Organ Class
SOP
Standard Operating Procedure
TBL
Total Bilirubin
TCS
Tata Consultancy Services
TEAE
Treatment-Emergent Adverse Event
TMF
Trial Master File
t½λz
Terminal half-life
tmax
Time to reach maximum concentration


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Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
17 (85)
Abbreviation or 
special term
Explanation
Tss, max
Time to reach maximum concentration, taken directly from the individual 
concentration-time curve
ULN
Upper Limit of Normal
US
United States
Vz/F
Apparent volume of distribution for parent drug at terminal phase 
(extravascular administration)
WBDC
Web Based Data Capture
%AUCex
Percentage of AUC obtained by extrapolation
%Fluctuation
Fluctuation index during a dosing interval estimated as 100*(Cmax-
Cmin)/Cavg (%)


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
18 (85)
1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Chronic Obstructive Pulmonary Disease (COPD), a common preventable and treatable 
disease, is characterized by airflow limitation that is usually progressive and associated with 
an enhanced chronic inflammatory response in the airways and the lungs to noxious particles 
or gases. Cigarette smoking is the most common risk factor for COPD. Exacerbation and 
comorbidities contribute to the overall severity in individual patients. COPD is a major cause 
of morbidity and mortality worldwide and results in an economic and social burden which is 
both substantial and increasing. 
In a study of the burden of obstructive lung disease (BOLD Study), the crude prevalence of 
COPD, all stages, among the study populations ranged from 11.4% in Guangzhou, China to 
26.1% in Salzburg, Austria (Buist et al 2007). The prevalence of COPD in China is 8.2% in 
those aged over 40 years old (Zhong et al 2007).
COPD is characterized by structural changes in the airways resulting from repeated injury and 
repair and by bronchoconstriction, which is an important target for pharmacologic 
interventions (GOLD 2016). Dyspnoea, chronic cough and sputum production are the most 
common clinical symptoms. Adrenergic and cholinergic pathways mediate 
bronchoconstriction in COPD.
Anticholinergic compounds such as ipratropium, oxitropium, tiotropium, aclidinium 
glycopyrronium or umeclidinium have been shown to provide clinical benefit in the treatment 
of COPD. These therapeutic agents block the muscarinic acetylcholine receptors in the 
bronchial smooth muscle and thus decreasing the cholinergic tone (muscarinic antagonism). 
β2-adrenergic agonists such as albuterol, formoterol, salmeterol or indacaterol stimulate β2-
receptors in the bronchial smooth muscle resulting in similar effects to those of 
anticholinergics. Both anticholinergic drugs and β2-adrenergic agonists decrease 
bronchoconstriction (increased FEV1) and thereby reduce dyspnoea and COPD exacerbations, 
increase exercise tolerance, and improve quality of life.
As a result of their differing mechanisms of action and similar pharmacodynamic effects, β2-
agonists and muscarinic antagonists have been used simultaneously in the same inhalation 
device for the treatment of COPD. 
Several combinations of LABA and LAMAs have been recently approved worldwide for the 
treatment of COPD, i.e. Ultibro (indacaterol/glycopyrronium) and Anoro 
(vilanterol/umeclidinium). The clinical studies have shown that the combined use of a LABA 
and a LAMA results in greater improvement of bronchodilation as well as a better symptoms 
control compared with monotherapies (Pelaia et al 2014, Maltais et al 2014, Maleki-Yazdi et 
al 2014).


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Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
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Duaklir® Genuair® is a combination product of LAMA (aclidinium bromide) and LABA 
(formoterol fumarate) approved in Europe for the treatment of COPD at a dose of 400/12 μg 
(delivered as 340/12 μg) twice daily in 2014 (Duaklir® Genuair® SmPC 2015). Since then, 
aclidinium/formoterol has been approved in more than 35 countries and is marketed in more 
than 21 countries globally. Additional studies are to be initiated to support the regulatory 
registration in other territories, including China.
Results from the current trial will characterize the pharmacokinetic (PK) profile of 
aclidinium/formoterol fumarate in Chinese COPD patients.
The Investigator Brochure (IB) of aclidinium bromide/formoterol fumarate contains relevant 
preclinical and clinical findings with the product.
1.2
Rationale for study design, doses and control groups
The current trial aims to characterize the pharmacokinetics (PK) and safety profile of 
aclidinium bromide/formoterol 400/12 μg BID after multiple doses in Chinese patients with 
stable moderate to severe COPD.
The present agent has been developed as a long-term control drug for COPD treatment. When 
aclidinium bromide/formoterol was repeatedly administered twice a day for five days in the 
LAC-PK-01 study, it was confirmed that the drug concentration of plasma aclidinium bromide 
and its metabolites, and the concentration of plasma formoterol, reached a steady state in five 
days, and it is considered that the concentration of plasma aclidinium bromide reached a 
steady state in five days in the KRPAB1102-D202 study in Japan; therefore, five-day repeated 
administration was set for the present trial. Moreover, we set the dosage (aclidinium 
bromide/formoterol 400/12μg) and the subjects (COPD patients) taking into account the fact 
that it will be possible to compare pharmacokinetic data from aclidinium bromide /formoterol
administration to Chinese patients.
In addition, the dose strength selected for this study corresponds to the currently registered 
product.
Twenty (20) patients with stable moderate to severe COPD are to be enrolled in this study and 
are considered to be a sufficient number to meet the objective of the study.
1.3
Benefit/risk and ethical assessment
Aclidinium bromide /formoterol 400/12 μg is currently approved in Europe as a maintenance 
bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive 
pulmonary disease (COPD).
The clinical development programme for aclidinium bromide/formoterol 400 μg/12 μg has 
shown to provide additional efficacy benefits compared to those associated with aclidinium or 
formoterol fumarate monotherapies (as assessed by measures of lung function, COPD 
symptoms and disease-specific health status) and yet the safety and tolerability of aclidinium 


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
20 (85)
400 μg/formoterol fumarate 12μg is generally comparable to that of the component 
monotherapies (D’Urzo et al. 2014, Singh et al. 2014).
The safety profile for aclidinium bromide /formoterol 400/12 μg is based on the clinical 
experience after exposure at the recommended therapeutic dose for up to 12 months. The type 
and severity of adverse reactions associated with aclidinium bromide /formoterol 400/12 μg is 
comparable to each of the monocomponents.
The most frequently reported adverse reactions with aclidinium bromide/formoterol 400/12 μg 
were nasopharyngitis (7.9%) and headache (6.8%).
Other commonly reported adverse reactions with aclidinium bromide/formoterol 400/12 μg 
are urinary tract infection, sinusitis, tooth abscess, insomnia, anxiety, headache, dizziness, 
tremor, cough, diarrhoea, nausea, dry mouth, myalgia, muscle spasms, oedema peripheral and 
blood creatine phosphokinase increased.
Hypokalaemia, hyperglycaemia, agitation, dysgeusia, tachycardia, electrocardiogram QTc 
prolonged, palpitations, rash, pruritus, blurred vision, dysphonia, throat irritation, urinary 
retention, stomatitis and blood pressure increased are uncommon adverse reactions that could 
be observed with the aclidinium bromide/formoterol 400/12 μg.
The major metabolic pathways of aclidinium bromide in humans are nonenzymatic and 
enzymatic hydrolysis of its carboxylester moiety leading to two inactive metabolites, 
LAS34823 and LAS34850.  Although the genetic locus of the enzyme responsible for the 
hydrolysis (butyrylcholinesterase) contains polymorphisms, the incidence of the variants 
reported in Asians and Caucasians are low and it is inferred that there is no great difference in 
the distribution of enzymatic activity between races. Moreover, since aclidinium bromide 
undergoes non enzymatic hydrolysis (its half-life at physiological pH, 1.2 hours), it is 
considered that ethnicity differences are unlikely to affect the metabolism of aclidinium 
bromide.  
The pharmacokinetic parameters related to the absorption, distribution and elimination of 
aclidinium/formoterol, obtained in Japanese COPD patients (Study KRP-AB1102F-D302) 
were broadly comparable to the pharmacokinetic data obtained for aclidinium/formoterol in 
Western subjects. In addition, no differences in systemic exposure were seen for aclidinium 
bromide or formoterol fumarate when administered as a fixed dose combination or as 
monotherapies in clinical study LAC-PK-02.
Therefore, on the basis of the available pharmacokinetic data in Asian and Caucasian 
population and the lack of drug-drug interactions between aclidinium and formoterol, similar 
exposure is expected in Chinese COPD patients than in Japanese or Caucasian patients. 
Based on the study drug safety profile, no specific risk is anticipated with the dose and the 
dose regimen proposed in this trial. Still, investigators will ensure adequate medical care of 
the trial participants at all times throughout the course of the study.


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
21 (85)
1.4
Study Design 
This is a Phase IIa, single centre, open-label, repeat-dose study to investigate
pharmacokinetics (PK), safety and tolerability of aclidinium/formoterol 400/12 μg 
administered twice-daily by inhalation in Chinese male and female patients with stable 
moderate to severe COPD.
All patients will sign an ICF before starting any study related procedure.
The study will consist of a Screening Visit (Visit 1) conducted after signature of the ICF and 
maximum 21 days before the first dose of investigational product (IP) administration on Day 1 
at Visit 2. Eligibility screening will consist of inclusion and exclusion criteria evaluation; 
complete medical and surgical history/COPD history; prior and concomitant medications; 
demographics; inhaler training; physical examination; blood pressure assessment; 12-lead 
electrocardiogram (ECG); spirometry and reversibility test; clinical laboratory tests; serum 
pregnancy test for women of childbearing potential; serology (anti-hepatitis C virus, hepatitis 
B surface antigen, and anti-human immunodeficiency virus [HIV] type 1); urine drugs of 
abuse and alcohol screen; and adverse event (AE) monitoring. Relief medication is to be 
provided to the patient at Visit 1 (Screening).
All patients fulfilling inclusion/exclusion criteria will be admitted to the clinical unit the day 
preceding the 1st IP dose. On Day 1 through Day 4, patients will receive one inhalation of 
aclidinium bromide/formoterol 400/12 μg BID (morning and evening) via the Genuair® DPI. 
On Day 5 patients will receive only the morning dose of one inhalation of aclidinium 
bromide/formoterol 400/12 μg via the Genuair® DPI. Patients will be discharged on Day 7, 48 
hours after last IP administration. 
Pharmacokinetics and safety assessments will be conducted at specific time points in the 
clinical unit during the residential period (from Day -1 to Day 7 at Visit 2).
A follow-up visit will be performed within 5 days from patient’s discharge after last PK 
sample collection on Day 7. 
Patients who prematurely discontinue from the study (withdrawal) will participate in a 
Premature Discontinuation Visit that will include physical examination, clinical laboratory 
test, 12-lead ECG, blood pressure, serum pregnancy test for women of childbearing potential, 
and assessment of AEs and concomitant medication to ensure patient´s safety.
A complete list of all procedures and assessments is provided in the Schedule of Assessments 
in Table 1.
The study flow chart for each treatment sequence is shown in Figure 1.


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
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Figure 1
Study flow chart
Visit 1
Screening
Visit 2
Treatment period 1
Residential Period
Follow-up Visit or 
Premature 
Discontinuation
Informed 
consent
Admission to 
study unit
               Multiple Dose administration
Discharge from 
study unit
7-day washout
Screening 
period
Day -21 
to Day -2
Day -1
Day 1
Day 5
Day 7
Day 8 to Day 12


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
23 (85)
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To evaluate the pharmacokinetics (PK) of 
aclidinium bromide, its metabolites 
LAS34850 and LAS34823 and formoterol 
after administration of aclidinium 
bromide/formoterol 400/12 μg twice-daily 
(BID) for 5 days in Chinese patients with 
stable moderate to severe COPD.
The following pharmacokinetic parameters will 
be calculated when applicable for aclidinium 
bromide, its metabolites and formoterol 
fumarate:
Day 1: Cmax, tmax, AUClast, AUC!, Cmin
Day 5: Css,max, tss,max, λz, t½λz, AUCss,!, CL/F*, 
Vz/F*, Cav, %Fluctuation, Css,min, Rac(Cmax)
Rac(AUC!) and Rac(Cmin).
Additional parameters may be determined where 
appropriate 
*Only for Aclidinium bromide and formoterol
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To evaluate the safety and tolerability of 
aclidinium bromide/ formoterol 400/12 μg 
twice-daily (BID) administered for 5 days 
in Chinese patients with stable moderate to 
severe COPD.
AEs/SAEs
Blood pressure
Clinical laboratory parameters (haematology, 
serum biochemistry and urinalysis)
12-lead ECG parameters
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
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3.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1. Ability to communicate with medical team and staff, willing to participate in the trial, 
willing to give written informed consent, and comply with the trial procedures and 
restrictions. 
2. Chinese men or non-pregnant, non-lactating women, aged ≥40 years old at Visit 1 
(Screening).
Explanatory note: A female is considered to be of childbearing potential unless is at 
least one year post-menopausal or permanently sterilised (e.g. tubal occlusion, 
hysterectomy, bilateral salpingectomy). Women of childbearing potential are allowed 
to enter the trial if they have a negative serum pregnancy test at the Visit 1 (Screening) 
and a negative serum pregnancy test at Day -1 and are using, during the last two 
months before the Visit 1 (Screening) and during the whole duration of the trial, at 
least one medically approved and highly effective method of birth control defined as 
those, alone or in combination, which result in a low failure rate (i.e less than 1% per 
year) when used consistently and correctly. Male participants are not requested to use 
contraception methods during their participation on the trial. 
3. Patients with a diagnosis of COPD (GOLD guidelines, 2016) for a period of at least 6 
months prior to Visit 1 (screening).
4. Current or former smokers with a smoking history of ≥ 10 pack-years.
Explanatory notes: 
a. Former smoker condition defined as having quit smoking ≥ 6 months before 
Visit 1 (Screening).
b. Pack-years is calculated by dividing the number of cigarettes smoked per 
day by 20 (the number of cigarettes in a pack) and multiplying this figure by 
the number of years a person has smoked. For example, a person who smokes 
40 cigarettes a day and has smoked for 10 years would have a 20 pack-year 
smoking history (40 cigarettes per day ÷ 20 cigarettes per pack = 2; 2 x 10 
years of smoking = 20 pack-year history). In case of intermittent smoking/non-
smoking periods, pack-years is calculated by summing all periods pack-years.
c. Patients smoking other tobacco types will not be allowed, unless they meet 
the cigarette criterion as well.
5. Patients with moderate to severe stable COPD (Stage II or Stage III, according to 
GOLD Guidelines 2016) at Visit 1: post-bronchodilator FEV1 ≥30% and < 80% and 
post-bronchodilator FEV1/FVC < 70%.


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Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
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Explanatory note: “post” means FEV1 and FVC between 10 to 15 minutes after 
inhalation of 400 μg of salbutamol from acceptable and repeatable pulmonary function 
testing according to the American Thoracic Society (ATS)/European Respiratory 
Society (ERS) 2005 criteria. Predicted normal values to be used for calculation 
purposes are based on European Community for Steel and Coal predicted values 
(Quanjer et al. 1993).
6. Must be able to perform repeatable pulmonary function testing for FEV1 according to 
ATS/ERS 2005 criteria at Visit 1 (Screening).
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff 
and/or site staff) or patients employed by or relatives of the employees of the site or 
sponsor.
2. Previous enrolment or randomisation in the present study.
3. History or current diagnosis of asthma.
4. Any respiratory tract infection (including the upper respiratory tract) or COPD 
exacerbation (including the mild COPD exacerbation) within 6 weeks prior to 
screening or during the run-in period. 
5. Patients hospitalized for COPD exacerbation (an emergency room visit for longer than 
24 hours will be considered a hospitalization) within 3 months prior to screening and 
during the run-in period.
6. Use of long-term oxygen therapy ≥ 15 hours per day.
7. Patient with a history of hypersensitivity reaction to inhaled anticholinergics, 
sympathomimetic amines, inhaled medication, or any component thereof.
8. Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, 
acute urinary retention, or patients with symptomatic nonstable prostatic hypertrophy. 
Explanatory note: Patients with well-controlled, stable, asymptomatic benign prostatic 
hyperplasia (BPH) may be eligible to participate in the trial.
9. Patients with Type I or uncontrolled Type II diabetes, uncontrolled hypothyroidism or 
hyperthyroidism, hypokalaemia, hyperadrenergic state, or uncontrolled or untreated 
hypertension.
10. Clinically significant cardiovascular conditions.


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Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
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Explanatory note: The following are examples of clinically significant cardiovascular 
conditions:
∀
Myocardial infarction within the 6 months prior to Visit 1 (Screening).
∀
Thoracic surgery within 12 months prior to Visit 1 (Screening)
∀
Unstable angina or unstable arrhythmia, which has required changes in the 
pharmacological therapy or other intervention within 12 months prior to Visit 1 
(Screening) or newly diagnosed arrhythmia within the previous 3 months prior 
to Visit 1 (Screening).
∀
Hospitalization within 12 months prior to Visit 1 (Screening) for heart failure 
functional class III (marked limitation of activity and only comfortable at rest) 
and class IV (need of complete rest, confinement to bed or chair, discomfort at 
any physical activity, and presence of symptoms at rest) as per the New York 
Heart Association.
11. Patient with resting systolic blood pressure ≥ 160 mmHg, a resting diastolic blood 
pressure ≥ 100 mmHg, or a resting heart rate ≤ 50 bpm or ≥ 100 bpm at Visit 1 
(Screening) or/and at Visit 2 (Day-1 to Day 7).
Explanatory note: Patient can be with or without pharmacological therapy.
12. Have a body mass index (BMI) ≥ 40 kg/m2
Explanatory note: [BMI (kg/m2) = Body weight (kg)/Height2 (m2)]
13. Electrocardiogram (ECG) at Screening or Day -1 showing corrected QT interval (QTc) 
using Fridericia's correction (QTcF) > 470 msec.
14. Patients with clinically relevant abnormalities in the results of the laboratory tests, 
ECG parameters (other than QTcF), or in the physical examination at Visit 1, except 
those related to COPD.
15. Positive results for drugs of abuse in the urine at Visit 1 (Screening).
Explanatory note: Drugs of abuse include alcohol, benzoylecgonine (cocaine), 
methadone, barbiturates, amphetamines, benzodiazepines, cannabinoids, opiates, and 
phencyclidine.
16. Positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody and/or 
human immunodeficiency virus (HIV) I antibodies at Visit 1 (Screening).
17. History of malignancy of any organ system (including lung cancer), treated or 
untreated, within the past 5 years other than basal or squamous cell skin cancer.


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
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Version 1.0
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Explanatory note: Patients are excluded whether or not there is evidence of local 
recurrence or metastases.
18. Any other serious or uncontrolled physical or mental condition/disease.
Explanatory note: As judged by the investigator, the dysfunction could place the 
patient at a higher risk as a result of his/her participation in the trial, or confound the 
results of the trial, or would be likely to prevent the patient from complying with the 
requirements of the trial or completing the trial.
19. Patient with a history (within 2 years prior to Visit 1 [Screening]) of drug and/or 
alcohol abuse that may prevent trial compliance based on investigator judgment.
20. Taken any medication within 14 days before the first dose of IP, or hormonal drug 
products and traditional Chinese medicines within 30 days before the first dose of IP, 
with the exception of allowed medications listed in Section 7.9.
Explanatory note: Medications include any prescription or over-the-counter medicinal 
products, health supplements and herbal remedies.
21. Participation in any other clinical investigation using an experimental drug requiring 
repeated blood or plasma drawn within 60 days of Day 1 at Visit 2.
22. Have participated in a blood/plasma donation or blood loss greater than 400 mL within 
90 days or greater than 200 mL within 30 days prior to Visit 1 (Screening).
23. Have any clinical condition that might affect the absorption, distribution, 
biotransformation, or excretion of aclidinium bromide/formoterol fumarate.
24. Have consumed caffeine or any grapefruit-containing products within 48 hours or 
alcohol within 72 hours before Day -1 at Visit 2.
Explanatory note: Examples include coffee, tea, cola, chocolate, diet pills, "energy 
drinks”.
25. Inability to be venipunctured or tolerate venous access as determined by the 
investigator or designee.
26. Inability to use a multidose DPI.
27. Subjects unable to give their consent, or subjects of consenting age but under 
guardianship, or vulnerable subjects.
28. In the opinion of the PI, subjects who are unlikely to comply with the protocol
requirements, instructions, and trial-related restrictions. 


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
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Explanatory note: Examples include uncooperative attitude, inability to return for 
follow-up visits, and improbability of completing the clinical trial. This also includes 
subjects who have problems understanding the protocol requirements; instructions and 
trial-related restrictions; the nature, scope and possible consequences of the clinical 
trial.
29. Previously taken aclidinium or previously participated in an investigational study of 
aclidinium within 6 months of Day 1
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment 
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening. 
Patient numbers will be assigned at Visit 1 (Screening) or at informed consent form (ICF) 
signature, consecutively starting with the lowest number available.
The Investigator(s) will:
1.
Obtain signed ICF from the potential subject before any study specific procedures 
are performed.
2.
Assign a unique Patient Identification number. This number will be composed of 
two parts: the first 4 digits (fixed) representing the site identifier. The next 3 digits 
(ascending) which will be assigned sequentially within each site, starting with 001. 
The subject identification number will be used to identify the subject throughout the 
study and will be recorded in the electronic Case Report Form (eCRF).
3.
At Screening and Day -1 (Visit 2), the investigator will determine patient’s
eligibility. See Sections 3.1and 3.2. Patients not meeting inclusion and/ or meeting 
exclusion criteria will be marked as “screen failures” and should have the final 
evaluation eCRFs completed.
If a patient withdraws from participation in the study, then his/her Patient ID code cannot be 
reused.
3.4
Procedures for handling incorrectly enrolled patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule. Patients who 
are enrolled, but subsequently found not to meet all the eligibility criteria must not be initiated 
on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is enrolled in error, or incorrectly 
started on treatment, the Investigator should inform the AstraZeneca study physician 


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Drug Substance Aclidinium bromide /Formoterol fumarate
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Version 1.0
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immediately, and a discussion should occur between the AstraZeneca study physician and the 
investigator regarding whether to continue or discontinue the patient from treatment. The 
AstraZeneca study physician must ensure all decisions are appropriately documented.
3.5
Methods for assigning treatment groups
Not applicable
3.6
Methods for ensuring blinding
This is an open-label trial.
3.7
Methods for unblinding 
Not applicable.
3.8
Restrictions
3.8.1
Dietary and Fluid Restrictions
On treatment days, breakfast will be served approximately 2 hours prior to IP, lunch at
approximately 4.5h after IP, dinner approximately 2 hours prior IP and snack approximately 
2h after IP. Time window allowance for each meal is ± 1 hour, except on Day 1 and Day 5 
where breakfast will not be served.
Water is allowed as desired except for 1 hour before and 1 hour after IP administration. 
Patients will be instructed to consume the entire contents of each meal and snack, if possible. 
Trial center personnel will document the percentage or the amount of unconsumed food for 
each subject, at least on Day 1 and Day 5.
Standard low fat (< 20 g) meals and snacks during trial confinement will be provided 
according to the trial center SOPs and in accordance with this protocol. Meals should not 
include any xanthine-containing beverages or food (eg, coffee, tea, cola, chocolate, diet pills, 
"energy drinks"), or caffeine.
On days that serum biochemistry samples will be drawn (Visit 1 [Screening], Day -1 at Visit 2 
and Follow Up Visit), a fast of at least 8 hours will be observed.
Patients must abstain from caffeine, and xanthine-containing beverages or food (eg, coffee, 
tea, cola, chocolate, diet pills, "energy drinks"), grapefruit, grapefruit juice, Seville oranges or 
other products containing grapefruit or Seville oranges from 48 hours (2 days) prior to entry in 
the trial center on Day -1 at Visit 2 until discharge from the trial center.
Abstain from alcohol from 72 hours (3 days) prior to entry in the trial center on Day -1 at Visit 
2 until discharge from the trial center.


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3.8.2
Other Restrictions
All patients will have to comply with the following general requirements:
∀
Strenuous activity, sunbathing, and contact sports are prohibited within 
96 hours (4 days) prior to admission into the trial center on Day -1 at 
Visit 2, and for the duration of the trial.
∀
Smoking and exposure to cold air, dust, or polluted air should be avoided 
for at least 1 hour before Visit 1 (Screening) until the completion of all 
Screening procedures.
∀
Blood or plasma donation until 3 months after the Follow-up Visit.
Any event likely to interfere with the objectives of the trial will be communicated to the 
investigator and reported without delay to AstraZeneca.
3.9
Discontinuation of investigational product and study withdrawal
If a patient is discontinued from IP, the patient will be withdrawn from further study 
procedures.
Any patient may withdraw from the trial at any time during the trial at the discretion of the 
Investigator or at the request of the patient. The main reason for such a premature 
discontinuation must be documented in the eCRF.
Patients may be prematurely discontinued from the trial by the Investigator for any of the 
following reasons:
∀
Adverse Event: if a patient experiences an AE (including COPD 
exacerbations), their premature discontinuation will be considered at the 
discretion of either the investigator or the patient regardless of the causal 
relationship to the IP. AE should be indicated as the reason for 
discontinuation in the eCRF, and the appropriate AE eCRF form must be 
completed.
∀
Protocol deviation: After enrolment, any protocol deviations detected 
should be corrected when possible and the patient should be allowed to 
continue.  The following will lead to discontinuation of treatment: 
protocol deviations that could affect patient’s safety (eg, illness requiring 
treatment(s) which in the clinical judgement of the Investigator [or after 
discussion with the trial monitor] might invalidate the trial by interfering 
with the IP); deviations due to patient non-compliance with the study 
protocol.
∀
Failure to meet randomisation criteria: Violations of inclusion and/or 
exclusion criteria detected after enrollment. See Section 3.4 for patients 
not fulfilling inclusion/exclusion criteria but detected after enrollment.


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∀
Lost to follow-up: Non-attendance. In these cases, the Investigator should 
make every effort to ascertain the whereabouts, reason for lack of 
attendance, the health of the patient, and to assure patient attendance as 
soon as possible. Every effort (at least 3 documented attempts in the 
medical records) should be made to contact the patient. A registered mail 
letter will be sent to the subject and documented in the medical records.
∀
Withdrawal by subject: The patient is permitted to stop his/her 
participation at any time during the trial without incurring any loss in 
his/her medical care. The Investigator should ensure that such withdrawal 
is not due to AEs, in which case this reason should be selected.
∀
Pregnancy: In case of pregnancy, the female patient will be immediately 
discontinued from the trial.
∀
"Other": at the Investigator’s request, study cancellation or any other 
reason not described above.
∀
Patient withdrawal due to death.
All dosed patients who prematurely discontinue from the trial, regardless of cause, will be 
seen for a premature discontinuation visit. Procedures/assessments for the premature 
discontinuation are indicated in the Schedule of Assessments (Table 1).
If there is a medical reason for withdrawal, the patient will remain under the supervision of the 
Investigator until satisfactory health has returned.
Patients prematurely discontinued from the trial will not be replaced. A minimum of 10 COPD 
patients completed are required in this trial.
3.9.1
Procedures for discontinuation of a patient from investigational product and 
from the study.
At any time, patients are free to discontinue investigational product or withdraw from the 
study (i.e., investigational product and assessments – see Section 3.9), without prejudice to 
further treatment.  A patient that decides to discontinue investigational will always be asked 
about the reason(s) and the presence of any adverse events.  If possible, they will be seen and 
assessed by an Investigator(s).  Adverse events will be followed up (See Section 6); and all 
study drugs should be returned by the patient.
For any patient who withdraws from the IP, the investigator will:
1.
Ask the subject to undergo the Premature Discontinuation Visit AS SOON AS 
POSSIBLE after discontinuation of IP.
The date and the main reason for such a premature discontinuation must be documented in the
eCRF.


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3.10
Criteria for withdrawal
3.10.1
Screen failures
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised.  These patients should have the reason for study withdrawal 
recorded as ‘Screen Failure’ (ie, patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures (not randomised 
patients).
3.11
Premature Discontinuation of the study
The “end of trial” is defined as the date when all patients enrolled in the trial performed the 
last contact (either Visit 3 Follow-up or Premature Discontinuation Visit) and will be 
communicated to Regulatory Authorities and Ethics Committees on due time according to 
local regulations.
The Sponsor reserves the right to prematurely terminate (i.e., suspend) the trial for reasons 
such as:
∀
The principal investigator and the sponsor feel that the type, number and 
/or severity of AEs justify discontinuation of the trial.
∀
Data not known before become available and raise concern about the 
safety of the study drug so that continuation would pose potential risks to 
the patient.
∀
The Sponsor decides to discontinue the trial.
If the trial is terminated or suspended, the Sponsor will promptly inform the Investigator/trial 
center and the Regulatory Authorities. The EC should be promptly informed and provided the 
reason(s) for the termination or suspension by the PI/Sponsor, as specified by the applicable 
regulatory requirement(s).
The Investigator will inform the patients and will collect and keep all the data up to the date of 
discontinuation. Samples retrieved up to the date of trial termination will be analyzed as per 
protocol.
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented.
If the trial is terminated or suspended, trial results will be reported according to the 
requirements outlined in this protocol as far as applicable.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.


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4.
STUDY PLAN AND TIMING OF PROCEDURES 


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Table 1
Schedule of Assessments
Screening period
Treatment period
Follow-up period
Visit 11
Visit 2
Procedure
Screening 
Day -21 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Follow-Up Visit Days 8-
12c or Premature 
Discontinuation2
Informed consent
X
Demographics 
X
Inclusion/Exclusion criteria
X
X
Medical/surgical and COPD
history
X
Prior and Concomitant 
Medications3
X
X
X
X
X
X
X
X
X
X
Spirometry12
X
Inhaler Training
X
X
Admission to Trial Center
X
Meals (provided by trial 
center)13
X
X
X
X
X
X
X
X
Discharge from the Trial 
Center4
X
Outpatient Visit
X
X
Physical examination5
X
X
X
12-lead ECG and blood 
pressure 6
X
X
X
X
X
X
X
X
Laboratory Tests7
X
X
X
Pregnancy Test8
X
X
X
Serology9
X
Drug-of-abuse and Alcohol 
Screen
X
X
Dosing of IP10
X
X
X
X
X
PK Blood samples11
X
X
X
X
X
X
X
Adverse Event review
X
X
X
X
X
X
X
X
X
X
AE = adverse event; AM = morning; BMI = body mass index; COPD= Chronic Obstructive Pulmonary Disease; DPI = dry powder inhaler; ECG = electrocardiogram; eC
form; HIV = human immunodeficiency virus; ICF = Informed Consent Form; IP = investigational product; PK = pharmacokinetic; PM = evening


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1. If the patient needs additional time to washout any prior medications, the ICF must be provided before Visit 1. Patients must discontinue medications after informed c
2. The premature discontinuation visit/assessments will be performed as soon as possible after patient discontinuation.
3. Any treatment administered during the 2 weeks before the ICF signature and during the Run-in Period must be recorded into the eCRF to ensure a proper washout of a
From Visit 1 (Screening) onwards, any new treatments taken or any change to the ongoing medications during the participation in the study, apart from the IP, will be reg
investigator or designee.
4. Patients will be discharged from the trial center after the completion of the PK blood sample collection and safety assessments.
5. Height and weight will be measured and BMI will be calculated at Visit 1 (Screening) only. 
6. Safety ECGs (including heart rate) and blood pressure will be collected at Visit 1 (Screening), at Visit 2 ( from Days -1 on admission to Day 5) and at the Follow-up V
Discontinuation Visit. On Visit 2 (from Day 1 to Day 5) the standard 12-lead ECG will be performed at 0h morning pre-dose and at 2 hours (± 15 min) post morning dos
after the patient has rested quietly in a seated position for at least 5 minutes. If blood sampling, blood pressure assessments, and ECG recordings are scheduled at the sam
sequence will be followed: 1) ECG recording; 2) blood pressure assessments; and 3) blood sampling, assuring that PK blood sampling occurs on the time point. If an EC
time as a meal, the ECG must be obtained first. 
7. Includes blood, serum, and urine samples. Patients are required to fast for at least 8 hours prior to the collection of specimens.
8. For women of childbearing potential, a serum pregnancy test will be done at visit 1 (Screening); on Day -1 (Visit 2), and at the Follow-up visit or Premature Discontin
must be available and reviewed prior to dosing on Day 1 on Visit 2.
9. Serum for anti-hepatitis C virus, hepatitis B surface antigen and anti-HIV type 1. Results must be available and reviewed prior to dosing on Day 1 (Visit 2)
10. On Day 5, only the morning dose of aclidinium bromide/formoterol 400/12 μg will be administered; no evening dose will be administered. At approximately 08:00 h
receive one inhalation of aclidinium bromide/formoterol 400/12 μg via the Genuair® multidose DPI. 
11. PK blood samples will be collected on Day 1 of Visit 2 at 0 hour (approximately 15 minutes prior to the morning dose), 5 minutes, 15 minutes, 30 minutes, 1 hour, 1
hours, 6 hours, 8 hours, and 12 hours post the morning dose (the 12-hour sample will be collected 5 minutes before the evening dose).
On Days 2-4 of Visit 2, PK blood samples will be collected at 0 hour (approximately 5 minutes prior to the morning and evening dose).
On Day 5 of Visit 2, PK blood samples will be collected at 0 hour (approximately 5 minutes prior to the morning dose), 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 h
hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours and 48 hours post morning dose. Time window allowance for all PK time points are indicated in section 5.2.1
12. Administer inhaled salbutamol (100 μg x 4 puffs) through a spacer device at a minimum of 10 minutes after the previous spirometry test. Ten (10) to 15 minutes afte
perform the 1 set of spirometry forced manoeuvres again.
13. No breakfast will be served on Day 1 and Day 5.


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4.1
Enrolment/screening period
This period will start with the signature of the Informed Consent Form (ICF), will follow with 
Visit 1 (Screening) when Chinese male and female COPD patients will be screened for 
participation in this trial within 21 days before Day 1 dosing, and will end at completion of all 
tests and procedures on Day -1. Eligible patients will be admitted to the trial center on Day -1.
Prior to ICF signing, investigators will evaluate suitability of patients for entry in the trial by 
comparing past and current medical status, as documented in the patient's medical records, to 
the inclusion/exclusion criteria of this study protocol.
Patients’ ICF signature must be obtained before performing any procedure related to the trial. 
ICF must be signed after the patient has received sufficient information about the trial, after 
he/she has had the opportunity to ask any questions related to the study and considered the 
options.
Patients who require a washout period from prohibited concomitant treatments after ICF 
signature, Visit 2 will be scheduled later according to the wash-out length required for the 
specific medication stopped prior to Day -1 (Visit 2) (see section 7.9). Trial assessments will 
be performed at Visit 1 and patient will be dispensed one inhaler of relief medication and 
trained on its use.
At Screening, to verify the eligibility of subjects, the following evaluations will be performed:
∀
Obtain informed consent.
∀
Assess inclusion/exclusion criteria. 
∀
Complete medical/surgical history, COPD history, smoking history and 
demographic (age, sex, race, and BMI).
∀
Perform a complete physical examination including body weight (in light 
indoor clothes, without shoes) and height.
∀
Collect blood pressure.
∀
Perform the 12-lead ECG.
∀
Collect blood and urine samples for the safety laboratory tests (including 
serology, haematology, biochemistry and urinalysis tests).
∀
Test for drugs of abuse and alcohol screen.
∀
Collect blood sample for serum β-human chorionic gonadotropin (β-
hCG) pregnancy test only for women of childbearing potential.
∀
Adverse event (AE) monitoring and assessment.


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∀
Record in the eCRF all medications the patient is currently taking and has 
taken during the previous 14 days before signature of the ICF. Remind 
the subject to avoid prohibited medications (see Section 7.9for details). 
∀
Train the patient on the Genuair ® DPI user instructions.  The 
investigator/designee will evaluate proper use of the device by the patient 
and provide additional training if needed. (See section 7.5)
∀
Provide relief medication to the patient as necessary and train patient on 
using the pressurized metered-dose inhaler, if necessary.
∀
Provide a patient diary to record relief medication use and AEs during the 
screening period until Visit 2.
∀
Spirometry Forced manoeuvre test (FEV1 and FVC measurement): Three 
technically adequate measurements will be performed according to 
acceptability and repeatability criteria that meet ATS/ERS guidelines.
∀
Bronchodilator test (Reversibility test): administer inhaled salbutamol 
(100 μg x 4 puffs) through a spacer device at least 10 minutes after 
previous spirometry test. Three technically adequate measurements will 
be performed 10-15 minutes after inhalation of albuterol according to the 
ATS/ERS acceptability & repeatability criteria. Record each 
measurement.
∀
Document participation in the study into the subject's medical records.
Only patients who meet all inclusion/exclusion criteria will be allowed to continue to Visit 2.  
4.2
Treatment period (Visit 2: from Day -1 to Day 7)
The sequence of evaluations in each day is recommended, but the specific order will depend 
on the site logistics provided the time-points referred to the IP administration (pre-dose and 
post-dose) are respected.
All patients will remain in the trial center from Day -1 at Visit 2 until the completion of the 
48-hour PK sample collection and safety assessments on Day 7. Patients will be discharged 
from the trial center on Day 7 after all safety assessments and PK collections are completed. 
If blood sampling, blood pressure assessments, and ECG recordings are scheduled at the same 
time points, the following sequence will be followed: 1) ECG recording; 2) blood pressure
assessments; and 3) blood sampling, assuring that PK blood sampling occurs on the time 
point. If an ECG is scheduled at the same time as a meal, the ECG must be obtained first.
4.2.1
Day -1
The following procedures will be performed:


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∀
Reassess the inclusion/exclusion criteria to confirm the eligibility of the 
patient before being dosed on Day 1.
∀
Review with patient if any AEs occurred or any prior and/or concomitant 
medication that may have been taken since last visit.
∀
Assess relief medication use as documented in the patient diary.
∀
Perform the 12-lead ECG
∀
Blood pressure assessment.  The BP should be determined in sitting 
position after 5 minutes.
∀
Blood and urine sample collection for the safety laboratory tests
(haematology, biochemistry and urinalysis).  Patients should be fasting a 
minimum of 8 hours prior to safety laboratory test collection.
∀
Perform a complete physical examination.
∀
Test for drug of abuse and alcohol screen
∀
Collect blood sample for serum β-human chorionic gonadotropin (β-
hCG) pregnancy test only for women of childbearing potential.
∀
Train the patient on how to use the Genuair ® DPI device.  The 
investigator/designee will evaluate proper use of the device by the patient
and provide additional training if needed.
∀
Relief medication is to be provided to the patient during the treatment 
period as necessary.
∀
Provide meals according to Section 3.8.1
∀
Have the patient remain in the study center overnight.
4.2.2
Day 1
∀
Perform 12-lead ECG before morning (AM) IP administration (pre AM 
dose). 
∀
Blood pressure assessment before IP administration (pre AM dose). The 
BP should be determined in sitting position after 5 minutes.
∀
Collect PK blood samples at morning pre-dose (approximately 15 
minutes before the IP administration). Time window allowance in section 
5.2.1


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∀
Administer the 1st dose of AM IP approximately at 8:00 hours by 
inhalation from the Genuair ® DPI. The investigator or study personnel 
should check that the patient has used the inhaler correctly.  Window 
allowance deviation for IP will be ± 1h.
∀
Collect PK blood samples at 5, 15, 30 min and 1h, 1.5h, 2, 3, 4, 6, 8, 12 h 
post IP AM administration. Time window allowance in section 5.2.1
∀
Perform 12-lead ECG at 2 hours (± 15 min) post IP administration. (post 
AM dose)
∀
Blood pressure assessment at 2 hours (± 30 min) post IP administration
(post AM dose). The BP should be determined in sitting position after 5 
minutes.
∀
Administer the evening (PM) dose of IP at approximately 20:00 hours 
(12 hours after AM dose) by inhalation from the DPI on Day 1. The 
investigator or study personnel should check that the subject has used the 
inhaler correctly. Window allowance deviation for IP will be ±1h in 
either AM dose or PM dose.
∀
Review with patient if any AEs occurred
∀
Assess relief and allowed concomitant medication use.
∀
Provide meals according to section 3.8.1. No breakfast will be served on 
Day 1.
∀
Have the patient remain the study center overnight.
4.2.3
Day 2 to Day 5
∀
Perform 12-lead ECG before IP administration (pre AM dose). 
∀
Blood pressure assessment before IP administration (pre AM dose). The 
BP should be determined in sitting position after 5 minutes.
∀
From Day 2 to Day 4 administer AM IP aprox. at 8:00 hours and IP 
evening (PM) dose at approximately 20:00 hours (12 hours after AM 
dose).  On Day 5, only the AM dose (aprox. at 8:00 hours) will be 
administered. No PM dose will be administered. Window allowance 
deviation for IP will be ±1h in either AM dose or PM dose 
∀
On Days 2, 3 and 4 collect PK blood samples at pre-dose (approximately 
5 minutes before the IP AM and PM administration). Time window 
allowance in section 5.2.1


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∀
On Day 5 collect PK blood samples at pre-dose (approximately 5 minutes 
before the IP administration) and at 5, 15, 30 min and 1h, 1.5h, 2, 3, 4, 6, 
8, 12 h post IP administration. Time window allowance in section 5.2.1
∀
Perform 12-lead ECG at 2 hours (± 15 min) post IP administration (post
AM dose). 
∀
Blood pressure assessment at 2 hours (± 30 min) post IP administration
(post AM dose). The BP should be determined in sitting position after 5 
minutes.
∀
Review with subject if any AEs occurred
∀
Assess relief and allowed concomitant medication use.
∀
Provide meals according to section 3.8.1. No breakfast will be served on 
Day 5.
∀
Have the patient remain in the study center overnight.
4.2.4
Day 6 and Day 7
∀
Collect PK blood samples at 24h, 36h and 48h post IP administration on
Day 5. Time window allowance in section 5.2.1
∀
Review with subject if any AEs occurred.
∀
Assess relief and allowed concomitant medication use.
∀
Have the patient remain in the study center overnight on Day 6.
∀
Provide meals according to section 3.8.1.
∀
Discharge the subject on Day 7 after all safety and PK assessments are 
completed.
4.3
Follow-up period (Visit 3)
Patients are required to return to the trial centre for a Follow-up Visit (performed within 5 
days of the final PK sample collection on Day 7 of Visit 2).
The following procedures are to be performed at the Follow-up Visit: 
∀
Assessment of AEs and concomitant medications.
∀
Perform physical examination.
∀
Perform 12-lead ECG.


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∀
Blood pressure assessment.
∀
Clinical laboratory tests (haematology, serum biochemistry and urinalysis).
∀
Serum pregnancy test for women of childbearing potential.
4.4
Premature discontinuation visit
If the patient is agreeable, the following procedures should be performed at this visit as soon 
as the subject has been discontinued from the trial: 
∀
Assessment of AEs and concomitant medications.
∀
Perform physical examination.
∀
Perform 12-lead ECG.
∀
Blood pressure assessment.
∀
Clinical laboratory tests (haematology, serum biochemistry and urinalysis).
∀
Serum pregnancy test for women of childbearing potential.
5.
STUDY ASSESSMENTS
The Electronic Data Capture (EDC) system will be used for data collection and query 
handling. The investigator will ensure that data are recorded on the electronic Case Report 
Forms (eCRF) as specified in the study protocol and in accordance with the instructions 
provided.
The investigator ensures the accuracy, completeness and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRF. A copy of the completed eCRFs will be archived 
at the study site.
5.1
Safety assessments
5.1.1
Laboratory safety assessments
Blood samples and urine samples for determination of clinical biochemistry, haematology and 
urinalysis will be taken at the times indicated in the Study Plan (see Section 4).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF page.


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The clinical chemistry, haematology, serology and urinalysis will be performed by Covance 
laboratory services which will provide the report to the site. Covance will provide the trial 
center with blood sampling kits and shipment supplies. A specific manual will be distributed 
by Covance. Serum pregnancy test will be performed by the site local laboratory.
Complete routine laboratory assessments will be performed under fasting conditions. Patients 
are required to fast for at least 8 hours prior to the collection of specimens.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables. 
Throughout the trial, new clinically relevant findings or worsening of a pre-existing finding in 
the laboratory results must be considered an AE and must be recorded on the AE eCRF form. 
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 6.3
In case of technical problems, or if the Investigator considers a result is clinically relevant or 
doubtful, additional blood samples may be collected within a reasonable time and will be sent 
to the central laboratory for analysis (see Sections 5.1.7and 5.1.8 for Repeated and 
Unscheduled test criteria)
The following laboratory variables will be measured:


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Table 2
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Creatinine
B-Hematocrit
S/P-Bilirubin, total
B-Erythrocytes count
S/P-Alkaline phosphatise (ALP)
B-Leukocyte count
S/P-Aspartate transaminase (AST)
B-Leukocyte differential count (absolute count)
S/P-Alanine transaminase (ALT)
B-Platelet (thrombocytes) count
S/P- Gamma-glutamyl transferase (GGT)
S/P- Lactate dehydrogenase
S/P-Creatine kinase (CK)
Serology (serum or plasma)
S/P-Albumin
S/P-HBsAg
S/P-Potassium
S/P- anti-HCV
S/P-Calcium, total
S/P- anti-HIV type 1 
S/P-Sodium
S/P- Chloride
S/P- Inorganic phosphorous
Urinalysis
S/P-Glucose
U-Hb/Erythrocytes/Blood 
S/P-Total cholesterol
U-Leukocytes
S/P- Triglycerides
U-Glucose 
S/P- Total protein
U-pH
S/P- Uric acid
U-Protein/Albumin 
S/P- Urea Nitrogen
U-Bilirubin
U-Urobilinogen
U-Ketones
U-Nitrites
NB. In case a patient shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer 
to Appendix C‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions. 
During the course of the trial, the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the trial.
Hy’s Law guidance for the Investigator is included in Section 6.3.7and Appendix C.


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5.1.1.1
Urinalysis
The urine sample will be sent to Covance central laboratory in China for analysis.
5.1.1.2
Pregnancy Test
For women of childbearing potential only, a serum pregnancy test will be done at Visit 1 
(Screening); on Day -1 at Visit 2 and at the Follow up or Premature Discontinuation Visit.
If pregnancy occurs during participation in the trial, the patient must immediately discontinue 
from the trial. The pregnancy should be reported as described in Section 6.6.
5.1.1.3
Drugs of Abuse Screen
Drugs of abuse and alcohol screen will be performed at Screening (Visit 1) and on Day -1 
(Visit 2) at the site.
Urine will be collected for the assessment of the following drugs of abuse: benzoylecgonine 
(cocaine), methadone, barbiturates, amphetamines, benzodiazepines, cannabinoids, opiates
and phencyclidine. Alcohol screen will be performed using a breath test. 
5.1.2
Medical History/Physical examination
A medical history of screened patients will be obtained at Visit 1 (Screening) (see Table 2), 
recording only the relevant demographic and medical data, as required in the Medical 
History/Physical examination electronic data capture (EDC) form.
A complete physical examination will be performed at Visit 1 (Screening), and at the Follow-
Up Visit or Premature Discontinuation Visit (see Table 2). At Visit 1 (Screening), only 
relevant findings will be recorded in the Medical History/Physical examination eCRF form. 
On Day -1 or at Follow-up visit or premature discontinuation, new physical examination 
findings or physical examination findings that have worsened from previously known 
conditions will be recorded on the AE form. For information on how AEs based on physical 
examination should be recorded and reported, see Section 6.3
Body weight and height will be measured only at Visit 1 (Screening) (see Table 2), allowing 
the calculation of BMI. Patients should be in light indoor clothes without shoes.
5.1.3
Spirometry
Spirometry will be conducted at Visit 1 (Screening) to confirm eligibility criteria and COPD 
severity stage (post-bronchodilator forced expiratory volume in 1 second [FEV1] according to 
the Global Initiative for Chronic Obstructive Lung Disease [GOLD] guidelines 2016). 
All spirometry equipment will be calibrated on the day it is to be used for trial purposes and 
the calibration will be documented in a log maintained at the trial center. Spirometers will 
measure the following:


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∀
FVC (maximal volume of air exhaled with maximally forced expiratory 
effort from a position of maximal inspiration).
∀
FEV1 (volume of air expressed in liters exhaled during the first second of 
performance of the FVC).
European Community for Steel and Coal predicted values (Quanjer et al., 1993) will be used 
to calculate the percentage predicted for FEV1/FVC.
The local spirometers that will be used for the pulmonary function tests at the trial center must 
be in agreement with the standardization stated by the American Thoracic Society (ATS) and 
European Respiratory Society (ERS) guidelines. Spirometry will be conducted by qualified & 
experienced personnel. The circumstances of patient’s tests should be similar, as much as 
possible, on all occasions with respect to time of the day, temperature, as well as the 
technician conducting the test.
5.1.4
ECG
5.1.4.1
Resting 12-lead ECG
Standard 12-lead ECGs will be performed at time points detailed in Table 2 and evaluations 
will be recorded after approximately 5 minutes resting in a supine position before any blood 
sampling. Preferably, 12-lead ECGs will always be recorded by the same technician for each 
patient.
At Visit 1 (Screening), the 12-lead ECG should be recorded at a similar time to the one that 
will be obtained at pre-dose during the course of the trial. Investigator will assess subject’s 
eligibility according to the centralized reading report (manual reading) of Visit 1. At following 
visits, 12-lead ECG will be recorded pre morning dose and 2 hours (± 15 min) post morning 
dose as indicated in Table 2.
ERT, as the responsible company for the centralized electrocardiographic assessments, will 
provide the site with the 12-lead ECG equipment and supplies, specific training and written 
instructions.
Following an acquisition of a quality ECG tracing, the investigator or designee will manually 
read the ECG tracing and will electronically transfer the data to ERT.
Any finding in the ECG tracing will be evaluated by the ERT cardiologist. An overall 
assessment will be reported by ERT cardiologist as well as the Investigator, both overall 
assessment evaluations will be reported in the study database. In case of discrepancies, the 
investigator opinion/judgement will not be questioned and this will be specifically 
documented in the subject’s medical notes. 
When any 12-lead ECG result exceeds normal ranges, alert reports will be immediately sent 
by ERT by e-mail to the investigator. 


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The investigator will review the “manual reading” reports to assess the clinical relevance of 
any abnormal finding and/or to decide if the subject is or remains eligible for the study.
However, the responsibility for inclusion or continuation of the subject in the study will lie 
within the investigator in consultancy with the sponsor.
The 12-lead ECG will be recorded at 25 mm/sec and will consist of a recording of leads I, II, 
III, aVR, aVL, aVF and V1 to V6 and 10 seconds recording of lead II (rhythm strip). At least 
3 complete evaluable complexes per lead will be recorded. The following ECG parameters 
will be determined:
∀
Heart rate 
∀
RR interval: Duration in milliseconds between two R peaks of two 
consecutive QRS complexes.
∀
PR interval: Duration in milliseconds from the beginning of wave P to 
onset of ventricular depolarization (Q and R).
∀
QRS interval: Duration in milliseconds of the QRS complex.
∀
QT interval: Duration in milliseconds from the beginning of Q wave to 
the end of the T wave
∀
QTc interval: QTc by heart rate:
∀
QTcB interval: QTcB (QT[msec]/RR[sec]1/2).
∀
QTc using Fridericia’s formula (QTcF): QTcF 
(QT[msec]/RR[sec]1/3).
Any abnormal finding in the ECG tracing will be evaluated by the Investigator and will be 
specifically documented on the eCRF.
Throughout the trial, new clinically relevant findings or worsening of a pre-existing finding in 
the ECGs (parameters or abnormal findings in the tracing) must be considered as an AE and 
must be recorded on the AE eCRF form. For information on how AEs based on ECG results 
should be recorded and reported, see Section 6.3.
In case of technical problems, if the PI considers any result to be clinically relevant or 
doubtful, additional 12-lead ECGs may be performed using the same equipment and within a 
reasonable time (see Sections.5.1.7 and 5.1.8).
For information on how AEs based on ECG results should be recorded and reported, see 
Section 6.3.


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5.1.5
Vital signs
5.1.5.1
Blood pressure
Both systolic blood pressure and diastolic blood pressure (in mmHg) will be measured after at 
least 5 minutes resting, at time points indicated in Table 2, and also before taking any blood 
samples. Measurements will be carried out with patient in the sitting position and preferably
always on the same arm. Data will be recorded on the eCRF.
If there is any suspicion of an unreliable measurement, blood pressure will be measured again. 
The value obtained on the second measurement will be considered as definitive and will be the 
one recorded on the eCRF.
For information on how AEs based on vital signs should be recorded and reported, see Section 
6.3
5.1.6
Adverse Events
Adverse events will be recorded throughout the trial, see Table 2. Procedures for recording 
and assessing AEs are included in Section 6.3.
5.1.7
Repeated Tests (Re-Test)
Any test may be repeated at the investigator’s discretion in any of the following situations:
At Visit 1 (screening) and on Day -1 at Visit 2 any individual test(s) might be repeated before 
dosing e.g., in case of impaired results (e.g., blood sample haemolysed) or results requiring 
confirmation (to ensure patient eligibility or results inconsistent with patient’s known past 
medical conditions, etc…). Patients who do not meet the eligibility criteria (despite the 
repeated tests) will be screen failed.  Repetition of the entire screening visit (Visit 1) is not 
allowed. 
If any of the specific tests of the Screening Visit needs to be repeated, and more than 28 days 
has elapsed since first test date, the patient will be screen failed.
As deemed necessary by the investigator, ECGs and laboratory test can be repeated at any 
time during the study in order to follow-up the progress of any clinically relevant abnormal 
finding, investigate any potential new adverse event, etc. 
Before starting any procedure at Visit 2, research personnel will ask the patient about his/her 
overall status. The following rules with respect to postponing the visit will be adhered to: 
•
The intake of any prohibited medication, the visit will be postponed (no assessment 
performed) according to the wash-out length required for the specific prohibited medication 
taken as long as delay fits the protocol allowed time window. 
•
For logistic reasons: Patient or Investigator are not able to perform the visit on the 
scheduled date due to technical or personal issues by site/patient. 


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The repeated tests will be called “re-test” and will be identified with the same visit identifier 
as the first attempt.
5.1.8
Unscheduled Tests
As deemed necessary by the investigator, additional safety test(s) can be performed at any 
time during the trial in order to follow-up on the progress of any clinically relevant abnormal 
finding, investigate any potential new AE, etc. These additional test(s) out of the initial trial 
schedule will be called "Unscheduled test" and will not be associated to any trial visit
5.2
Pharmacokinetics
5.2.1
Collection of samples
Blood samples for determination aclidinium bromide and its metabolites LAS34850 and 
LAS34823 and formoterol fumarate in plasma will be taken at the following time points: 
Day 1:
0 hour (pre-dose; approximately 15 minutes prior to the morning dose), 5 
minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hour, 2 hours, 3 hours, 4 hours, 6 
hours, 8 hours and 12 hours (12 time points).
Days 2-4:
0 hour (pre-dose; approximately 5 minutes prior to the morning and evening 
dose) (6 time points).
Day 5:
0 hour (pre-dose; approximately 5 minutes prior to the morning dose), 5 
minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hour, 2 hours, 3 hours, 4 hours, 6 
hours, 8 hours, 12 hours, 24 hours, 36 hours and 48 hours post the morning
dose (15 time points).
The recommended time window allowance for PK blood collection is the following:
Day 1 and Day 5:
∀
Pre-dose: ± 10 min
∀
5-30 min: ± 1 min
∀
1-6 hours: ± 5 min
∀
8-12 hours: ± 10 min
∀
24-48 hours: ± 30 min
Days 2 to 4:
∀
Pre-dose: ± 10 min


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At each time-point, approximately 4 mL of blood will be drawn for the determination of 
aclidinium bromide and its metabolites and 4 mL for the determination of formoterol 
fumarate. 
The total amount of blood to be collected for the PK assessments will be 264 mL (33 time
points x 8 mL). 
Samples will be collected, labelled, handled, stored and shipped as detailed in the Laboratory 
Manual.
5.2.2
Determination of drug concentration
Samples for determination of drug concentration in plasma will be analysed by Covance 
Laboratories on behalf of AstraZeneca, using validated bioanalytical methods. 
Full details of the analytical method used will be described in a separate Bioanalytical report. 
Results will be only reported for samples shipped within a timeframe for which the stability of 
aclidinium bromide or formoterol in the samples has been validated and shown to be 
acceptable.
5.2.3
Storage and destruction of pharmacokinetic samples
Pharmacokinetic (PK) samples will be disposed of after the Bioanalytical Report finalization 
or six months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
requested for future analyses.
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling. 
Additional analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.
Incurred sample reproducibility analysis, will be performed alongside the bioanalysis of the 
test samples.  The results from the evaluation will not be reported in the Clinical Study Report 
but separately in a Bioanalytical Report.
5.3
Pharmacodynamics
5.3.1
Collection of samples
Pharmacodynamic samples will not be taken during the study.
5.4
Pharmacogenetics
Pharmacogenetic samples will not be taken during the study
5.5
Biomarker analysis 
Biological samples for biomarker analysis will not be taken during the study


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5.6
Total Blood Volume
Table 3 presents the number and volume of blood samples and the total volume of blood that 
will be collected per patient in the trial.


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Table 3
Number and Volume of Blood Samples and Total Blood Volume Collected per Patient
Test
Visit 1
Visit 2
Follow-up Visit 
or Premature 
Discontinuation
Number of 
Samples
Approximate 
mL/sample
Total mL of 
Blood
Screening
Day 
-1
Day 
1
Day 2
to 4
Day 5 
to 7
Day 8 – Day 12
Hematology
1
1
1
3
3
9
Fasting Serum 
Biochemistry
1
1
1
3
5
15
Serology
1
1
5
5
Serum 
Pregnancy Test
1
1
1
3
3
9
PK Collections
12
6
15
33
8
264
Approximate total per subjecta
302
PK= Pharmacokinetic
a
This total does not include any additional tests that might be required because of AEs or retesting because of abnormal results or unschedule
b
Only for women of childbearing potential.


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6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The Investigator will closely monitor any AE and will adopt the necessary clinical measures 
to ensure the safety of the patients.
6.1
Definition of adverse events
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:
∀
Results in death
∀
Is immediately life-threatening
∀
Requires in-patient hospitalisation or prolongation of existing 
hospitalisation 
∀
Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions
∀
Is a congenital abnormality or birth defect
∀
Is an important medical event that may jeopardise the patient or may 
require medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol.


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6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events will be collected from time of signature of informed consent throughout the 
treatment period and including the follow-up period (i.e. follow-up visit or premature 
discontinuation visit).
In case an SAE is notified to the investigator after last follow up contact as per protocol, this 
SAE should be proactively reported to AstraZeneca for recording in the Safety Database, but 
without further recording in the eCRF.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last AE assessment in the study are 
followed up by the Investigator for as long as medically indicated, but without 
further recording in the eCRF. AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
6.3.3
Variables 
The following variables will be collect for each AE;
∀
AE (verbatim)
∀
The date and time when the AE started and stopped
∀
Maximum intensity 
∀
Whether the AE is serious or not
∀
Investigator causality rating against the Investigational Product (yes or 
no)
∀
Action taken with regards to investigational product
∀
Outcome.
In addition, the following variables will be collected for SAEs:
∀
Date AE met criteria for serious AE
∀
Date Investigator became aware of serious AE
∀
AE is serious due to
∀
Date of hospitalisation


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∀
Date of discharge
∀
Probable cause of death
∀
Date of death
∀
Autopsy performed
∀
Causality assessment in relation to Study procedure(s)
∀
Description of AE.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
For grading the intensity of an AE the following 3 categories will be considered:
∀
Mild: means awareness of symptoms or signs, but easily tolerated 
(acceptable).
∀
Moderate: means enough discomfort to interfere with usual activity 
(disturbing).
∀
Severe: means incapacity to work or to perform usual activities 
(unacceptable).
AEs will be collected only once with its maximum intensity.
6.3.4
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol.


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6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: ‘Have you/the child had any health problems since the previous 
visit/you were last asked?’, or revealed by observation will be collected and recorded in the 
eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms.  However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests, ECGs, physical examination and vital 
signs will be summarised in the clinical study report (CSR).
Medical disorders present at the time of signing the ICF that are part of the patient’s medical 
history will only be considered AEs if they worsen after this time.
Relevant abnormalities detected before IP administration in physical exam, laboratory 
value/vital sign, ECGs will not be considered AEs if already known as part of the medical 
history or in relation to prior medical conditions, and will be recorded on the eCRF Medical 
History/physical examination form/page.
Abnormalities detected in screening/run-in/baseline tests, thought to be due to a study 
procedure, will be considered AEs.
During the trial, abnormalities (newly occurring or worsening of previously known 
abnormalities) detected in laboratory values, vital signs, ECGs and physical examination 
which are considered clinically relevant by the investigator or which require an intervention or 
a diagnosis test, or may result in the IP discontinuation, should be reported as AEs.
In addition, when an AE meets the criteria of seriousness (SAE), it must also be recorded on 
the SAE form and reported following the defined timelines (section 6.4).
6.3.7
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to 
be reported as SAEs. Please refer to Appendix C for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.


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If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
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 EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the Investigator or other study site personnel reports a 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed.
SAEs not considered to be reported to AstraZeneca will be:
-
Hospitalisation for a treatment/surgical procedure which was elective or pre-planned 
for a pre-existing condition that did not worsen during the participation in the study
-
Hospitalisation or prolongation of an existing hospitalisation for respite care (eg, 
patient lives too far from the hospital or has no caregiver at home)
A regulatory report of the SAE (depending on the local requirements) will be produced by 
AstraZeneca and submitted to the Regulatory Authorities, EC and/or Investigators when 
applicable according to local regulations.
6.5
Overdose
As patients are admitted to the site unit during the treatment phase, it is very unlikely overdose 
may occur, however in the accidental case of an overdose please refer to the IB.
∀
An overdose with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the CRF and on the 
Overdose CRF module.
∀
An overdose without associated symptoms is only reported on the 
Overdose CRF module.


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If an overdose with associated AE on an AstraZeneca study drug occurs in the course of the 
study, then the Investigator or other site personnel inform appropriate AstraZeneca 
representatives immediately, or no later than 24 hours of when he or she becomes aware of 
it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
6.6.2
Paternal exposure 
Provided that nonclinical data with aclidinium and formoterol fumarate based on conventional 
studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic 
potential and toxicity to reproduction and development do not reveal special hazard for 
humans, male participants are not requested to use contraception methods during their 
participation on the trial.


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In case of pregnancy of the patient’s partners, the participant will not be necessarily 
discontinued from the trial but the partner’s pregnancy should be reported on the Pregnancy 
form following the same timeframe and routing as described for any participant’s pregnancy. 
These pregnancies will be also followed up, and the outcome of the pregnancy (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should if possible be obtained and documented.
6.7
Management of IP related toxicities 
There will be no dose reductions in this study.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Investigational product
Dosage form and strength
Manufacturer
Aclidinium bromide/formoterol 
fumarate
Inhalation powder in a 
multidose DPI (Genuair ®).
Every puff of the inhaler 
administers 400 μg of 
aclidinium bromide and 12 μg 
of formoterol (metered dose), 
via oral inhalation.
Industrias Farmacéuticas 
Almirall, S.A. (IFA)
Sant Feliu de Llobregat, 
Barcelona, Spain
The IP (Aclidinium Bromide 400 μg/Formoterol Fumarate 12 μg inhalation powder) consists 
of a fixed dose combination of long-acting anticholinergic drug, namely aclidinium bromide, 
combined with the long-acting β2-agonist formoterol fumarate.
The drug product is an inhalation powder comprising of micronized aclidinium bromide and 
micronized Formoterol fumarate with α-lactose monohydrate as the carrier.
IP manufacturing, labelling, packaging and release will be conducted following Good 
Manufacturing Practice (GMP).  Each Genuair® DPI will be packed in an Alu-Pouch.
Batch numbers will be indicated in the CSR.
For training purposes, each subject will receive an empty Genuair® DPI that will be used on 
Visit 1 (Screening) and on Day -1 at Visit 2.
7.2
Additional Drug
Relief medication Salbutamol pMDI (100 μg/puff) is considered as additional study drug and 
the accepted standard brand available in the country will be sourced. 


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Relief medication is to be provided by the investigator to the patient at the Visit 1 (screening)
and re-supplied throughout the study as necessary according to use. When administered for 
the reversibility test at the study center (screening visit), salbutamol should be given through a 
spacer device to be certain it has been inhaled properly. During the study, the use of spacers 
for the salbutamol administration will be permitted, provided they were used routinely by the 
patient prior to study entry.
Marketed salbutamol pMDI (100 mcg per puff) provided by the Sponsor will ONLY be 
permitted as relief medication during the participation in the trial to be used on an as-needed 
basis but it is mandatory that the patient does not intake salbutamol at least 6 hours prior to 
performing the first spirometry maneuver at Screening. If salbutamol is taken within 6 hours 
of the scheduled spirometry measurement at Screening, the visit should be rescheduled for the 
next day.
7.3
Dose and treatment regimens
Before taking the first dose the IP the patient will be instructed by the study personnel on how 
to use the Genuair® DPI. Subject will practice inhalation technique with empty training 
devices provided for this purpose. Instructions on how to use the Genuair® DPI will be 
provided to the subjects in local language. 
Further information regarding IP preparation at site will be provided in the investigator drug 
manual.
From Day 1 to Day 4, at approximately 08:00 hours, patients will receive one inhalation of 
aclidinium bromide/ formoterol 400/12 μg via the Genuair® multidose DPI. The PM dose (12 
hours after the AM dose, at approximately 20:00 hours) will be administered after the 12-hour 
PK sample collection; patients will receive one inhalation of aclidinium bromide/formoterol 
400/12 μg via the Genuair® multidose DPI.
On Day 5, at approximately 08:00 hours, patients will receive one inhalation of aclidinium 
bromide/ formoterol 400/12 μg via the Genuair® multidose DPI. There will be no PM dose 
administered.
7.4
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language.
IP will be supplied in the form of medication kits (medication box). Every medication kit will 
contain one Genuair® inhaler, inserted in an aluminium pouch along with a desiccant and 
placed in a box.
In order to allow drug reconciliation and dispensation control, research personnel will record 
the Patient ID number on the labels of every kit dispensed, as well as on the bags label and 
inhalers labels.  


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Training DPI will be provided with the appropriate labelling but the patient number 
information will be completed by the investigator. All Genuair® DPIs for training will be 
clearly identified as TRAINING.
7.5
Training on DPI inhaler use
Training for the use of the DPI will be done at Visit 1 (Screening) and on Day -1 at Visit 2; 
the patient will receive an empty Genuair® inhaler device for training. All patients will be 
trained on the use of the inhaler. As many practices as needed to learn the correct technique 
for use of the device will be allowed. The Investigator should ensure the comprehension of the 
instructions by the patient and the correct use of the inhaler training devices. Patients will be 
provided written instructions on the use of the inhaler device.
7.6
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the pack specifies the appropriate storage.
The person responsible for the IP at the drug distribution centre and hospital pharmacy (or any 
facility at the research site) will inventory and acknowledge receipt of all IP supplies received 
as well as its dispensation.
Further information regarding IP storage at site will be provided in the investigator drug 
manual.
7.7
Compliance
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the eCRF.
Patients will receive all IP doses under the direct supervision of trial center personnel which 
will guarantee compliance. The Investigator is responsible for ensuring that dosing is 
administered in compliance with the protocol. Delegation of this task must be clearly 
documented and approved by the Investigator.
Investigational product compliance will be assumed to be 100% when dosing has been 
recorded in the eCRF.
The trial center will keep an accurate drug disposition record that specifies the amount of IP 
administered to each patient and the date of administration.
No IP will be administered out of the unit, therefore no extra compliance method will be 
needed.
7.8
Accountability
The study drug provided for this study will be used only as directed in the study protocol.


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The Investigator is responsible for the control of the IP (aclidinium bromide/formoterol 
400/12 μg) under investigation. Adequate records of the receipt (eg, Drug Receipt Record) 
and disposition (e.g. Drug Dispensing Log) of the IP must be maintained. The Drug 
Dispensing Log must be kept current and should contain the following information:
∀
Identification of the patient to whom the IP was dispensed 
∀
Date(s) and quantity of the IP administered to the patient.
The study personnel will account for all study drugs dispensed to the patient.
Study site personnel, if applicable, or the AstraZeneca monitor will account for all study drugs 
received at the site, unused study drugs and for appropriate destruction.  Certificates of 
delivery, destruction and return should be signed. 
All records and drug supplies must be available for inspection by the site monitor at every 
monitoring visit. At the end of the trial, after final IP accountability is performed, all unused 
IP and relief medication will be destroyed according to appropriate SOPs. If unused IP will be 
disposed, the disposal will be conducted according to appropriate SOPs after final 
accountability is performed by the site monitor.  The completed Drug Dispensing Log and 
Drug Return Record(s) will be sent to the trial master file (TMF).
7.9
Prior and Concomitant medications
Any medication taken by the patient within 14 days prior to signature of Informed Consent 
will be collected in the electronic case report form (eCRF).
The use of the following medications is not allowed during the trial: anticholinesterases, 
anticholinergics (long and short acting), inhaled ß2 agonists (long and short acting agents, 
except salbutamol used as relief medication), methylxanthines, continuous oral corticosteroids 
used at a dose in excess of the equivalent of 10 mg prednisone per day or 20 mg every other 
day, mast-cell stabilizers, leukotriene modifiers, and nonselective ß1- blocking agents. See 
Table 4 for a list of concomitant medications that are allowed and not allowed during the trial.
Relief medication (salbutamol pMDI 100 μg/puff) is permitted as needed throughout the trial 
duration for all patients. In addition, several background medications for the treatment of 
COPD (inhaled corticosteroids; oral corticosteroids up to a maximum of 10 mg of 
prednisone/day or 20 mg every other day are permitted if the dose is stable for at least 4 weeks 
prior to Visit 1 (Screening)). Relief and background therapies will be allowed to help 
minimize the risk of COPD exacerbations. Use of relief medication will be recorded on a 
separate medication log by site staff during inpatient stay and recorded on a patient diary 
during the wash-out period. All relief medication use will be recorded on a specific eCRF 
page.
No hormonal drug products or traditional Chinese medicines will be allowed 30 days before 
Day 1 at Visit 2 and throughout the study, except for hormonal IUDs.


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No new concomitant medications will be allowed during the trial unless they are approved by 
the Sponsor or prescribed in response to an AEs. In the event medication is used, it will be 
recorded in the appropriate section of the eCRF and in the source documents.
Table 4
Allowed Concomitant Medications
Allowed Medication/Class of 
drug:
Restrictions
Stabilization 
period
Inhaled corticosteroids*
Patients who were following a stable regimen of a 
LABA/ICS combination for at least 4 weeks can 
be switched to the same inhaled corticosteroid (at 
the same dose and dose regimen) as monotherapy. 
In this case no stabilisation period is needed.
If treatment is switched to a different inhaled 
corticosteroid as monotherapy at an equivalent 
therapeutic dose to the one used for the fixed
inhaled combination, a stabilisation period of at 
least 14 days or longer, until patient is considered 
stabilised, should occur before Screening (Visit 
1). The patient will be considered stabilised if, 
according to the Investigator's judgement, during 
the second week of observation there are no 
changes in symptoms beyond the day to day 
variation, or symptoms experienced remain at a 
similar level of those existing before medication 
change
4 weeks
Continuous oral or parenteral 
corticosteroids*
Dose equivalent of 10 mg of prednisone per day 
or 20 mg every other day or lower than this.
4 weeks
Selective β-blocking agents (eg. 
Atenolol, metoprolol, nebivolol)
-
2 weeks
Oxygen therapy*
< 15 hours a day
4 weeks
Oral sustained-release 
theophyllines *
Theophylline should be avoided the morning of 
study visits and begin after visit completion.
4 weeks
*Change in daily dose, dosing schedule, formulation or treatment is unlikely during the course of the trial (the exception being the treatment of a COPD exacerbation).


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Version 1.0
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Table 5
Prohibited Medications
Prohibited Medication/Class of drug:
Wash-out 
before Day -1 
(Visit 2) and 
during the 
trial
Oral, intra-nasal or parenteral anticholinergic agents such as atropine, 
glycopyrrolate or biperiden
14 days
Twice daily long-acting inhaled anticholinergics, LAMAs (e.g. aclidinium 
bromide)
14 days
Once daily long-acting inhaled anticholinergics, LAMAs (e.g. umeclidinium, 
tiotropium bromide, glycopyrrolate)
14 days
Short-acting inhaled anticholinergics, SAMAs
12h
Inhaled and short acting β2-agonists, SABAs  (eg, fenoterol or albuterol, except 
for albuterol/salbutamol)
6h
Oral* and twice-daily long acting β2-agonists, LABAs (eg, terbutaline*, 
formoterol or salmeterol)
14h
Once daily long-acting β2- agonists (LABAs) (eg, indacaterol, oladaterol) and 
once daily combination of LABAs+ICS (eg vilanterol/fluticasone)
14 days
Twice daily LABAs (eg, formoterol, salmeterol) and twice daily combination of 
LABAs+ICS (eg fluticasone/salmeterol, budesonide/formoterol)
Note: Patients can be switched to the same or a different inhaled corticosteroid as 
monotherapy (see restricted medication section for stabilization period) 
14 days
Combination of SABAs+SAMA (eg ipratropium/salbutamol)
12h
Combination of LABA+LAMA (eg indacaterol/glycopyrronium, 
umeclidinium/vilanterol, tiotropium/olodaterol)
14 days
Methyl-xanthines (eg. Theophylline, theobromine tablets)
14 days
Leukotriene modifiers (eg montellukast)
14 days
PDE IV inhibitors (eg, roflumilast)
14 days
Continuous oral or parenteral corticosteroids used at a dose in excess of the 
equivalent of 10 mg of prednisone per day or 20 mg every other day
Note: can be switched to dose equivalent of 10 mg of prednisone per day or 20 mg 
every other day as long as they are at stable dose for at least 4 weeks prior to V1
14 days
Non-selective β-blocking agents (eg. Carvedilol, alprenolol, nadolol, propranolol, 
sotalol, timolol)
Note: can be switched to selective β1-blocking agents, as long as they are at stable 
dose for at least 2 weeks prior to V1
14 days
Herbal/Traditional Chinese Medicine
30 days


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Table 6
Relief Medication
Relief/Wash-out and Run-in 
Medication/Class of drug:
Usage:
Salbutamol pMDI (100 #g/puff)
Note: marketed salbutamol available in the 
participating countries will be supplied in their 
original box and with its original instructions 
leaflet (local languages). Where needed 
according to local regulations, salbutamol 
boxes will be provided labelled for the 
purposes of this trial.   
Administration should be on “as needed” basis, as per 
the investigator’s instructions from the ICF signature 
until the end of the trial
6h of wash-out is needed before spirometry test at 
Visit 1.
Cytochrome P450 (CYP) isozymes 2C9, 2C19, and 2D6, are involved in the metabolism of 
formoterol fumarate. Patients need to be washed out for a minimum of 14 days prior to dosing 
and throughout the clinical conduct of this trial of the following medications:
Table 7
CYP P450 Inhibitors
2C9
2C19
2D6
Fluconazole
Amiodarone
Fenofibrate
Fluvastatin
Fluvoxamine
Isoniazid
Lovastatin
Phenylbutazone
Probenicid
Sertraline
Sulfamethoxazole
Sulfaphenazole
Teniposide
Voriconazole
Zafirlukast
Proton Pump Inhibitors:
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole
Chloramphenicol
Cimetidine
Felbamate
Fluoxetine
Fluvoxamine
Indomethacin
Ketoconazole
Modafinil
Oxcarbazepine
Probenicid
Ticlopidine
Topiramate
Bupropion
Fluoxetine
Paroxetine
Quinidine
Duloxetine
Terbinafine
Amiodarone
Cimetidine
Sertraline
Celecoxib
Chlorpheniramine
Chlorpromazine
Citalopram
Clemastine
Clomipramine
Cocaine
Diphenhydramine
Doxepin
Doxorubicin
Escitalopram
Halofantrine
Hydroxyzine
Levomepromazine
Methadone
Metoclopramide
Mibefradil
Midodrine
Moclobemide
Perphenazine
Ranitidine
Red-Haloperidol
Ritonavir
Ticlopidine
Tripelennamine


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Version 1.0
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Table 8
CYP P450 Inducers
2C9
2C19
2D6
Rifampin
Secobarbital
Carbamazepine
Norethindrone
NOT Pentobarbital
Prednisone
Rifampin
Dexamethasone
Rifampin
7.9.1
Other concomitant treatment
Medications other than that described above, which is considered necessary for the subject’s 
safety and well-being, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the Case Report Form.
8.
STATISTICAL ANALYSES
8.1
Statistical considerations
All data analyses will be performed by Parexel except the derivation of the PK parameters, 
which will be performed by Covance. 
A comprehensive Statistical Analysis Plan (SAP) will be prepared by Parexel prior to first 
subject rendomised and any subsequent amendments will be documented, with final 
amendments completed prior to the database lock. 
All results will be presented by treatment with descriptive statistics appropriate to the nature 
of the variables. Demographic and baseline characteristics will be presented. For continuous 
variables, the number of non-missing observations, mean, standard deviation, standard error of 
the mean, 95% CI of the mean (except safety data), median, first and third quartiles, minimum 
and maximum will be presented. For categorical variables: counts (n) and percentages (%) 
will be presented. These summaries will be provided by time-point of assessment as 
appropriate. 
The SAS® version 9.3 or later will be used for the data analysis. A complete set of raw data 
listings will be appended to the final CSR. 
In general, there will be no imputation of missing data for the safety analyses. Additional 
details will be provided in the SAP.


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8.2
Sample size estimate
A total of 20 patients are deemed sufficient to ensure appropriate characterization of the PK of 
aclidinium bromide, LAS34823, LAS34850 and formoterol.
8.3
Definitions of analysis sets
Analysis will be done using the safety and PK populations. Descriptive statistics for 
demographics and other baseline characteristics will be provided.
The number and percentage of patients enrolled, patients who complete the treatment period, 
and those patients included in the PK and Safety populations will be tabulated. Patients who 
prematurely discontinue along with the reasons as recorded on the termination pages of the 
eCRFs will be summarized using the Safety population. Additionally, the cause of screening 
failure should be tabulated for Screening population.
8.3.1
Safety analysis set
All patients who receive at least 1 dose of aclidinium bromide/formoterol will be included in 
the safety population.
8.3.2
PK analysis set
The PK analysis set is defined as all patients who took at least one dose of IP and have at least 
one of the parameters (Cmax, Css,max, AUC, AUClast or AUCss,!) evaluable and are assumed not 
to be affected by factors such as protocol deviations (e.g., disallowed medication, or incorrect 
study medication received). All protocol deviations that occur during the study will be 
considered for their severity/impact and will be taken into consideration when patients are 
assigned to the PK analysis sets.
The exclusion of any patients or time points from the calculation of the PK parameters will be 
documented by the PK scientist including the reason(s) for exclusion. The available 
concentration data and PK parameter data for any patients excluded from the PK analysis set 
will be listed only, and presented in the individual figures of concentration time plots.
8.3.3
Protocol deviations.
The criteria for the assessment and reporting of protocol deviations will be stipulated in a 
separate study specific protocol deviation specification document.  Safety measurements and 
PK sample collections performed within the time window allowances recommended in this 
protocol will not be considered as protocol deviations and will not be reported.
Deviations from the protocol will be assessed as “important” in conjunction with the sponsor.  
Important deviations from the protocol may lead to the exclusion of subjects from the PK 
analysis set. 
Important deviations and analysis sets will be defined before database hard lock at the data 
review meeting.


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Important deviations will include the following:
•
Violation of inclusion and/or exclusion criteria that may influence PK analysis;
•
Time window deviations for PK and safety assessments;
•
Administration of prohibited concomitant medications that are expected to influence 
the measurement of the PK endpoints;
•
Missing IP administration.
All protocol deviations will be listed by subject for all randomised subjects.  Further details 
will be described in the statistical analysis plan (SAP).
8.4
Outcome measures for analyses
8.4.1
Pharmacokinetics Variables
Where possible, the following PK parameters will be assessed for aclidinium bromide, its 
metabolites (LAS34850 and LAS34823) and formoterol on plasma concentrations:
Day 1
Cmax
Observed maximum concentration, taken directly from the individual 
concentration-time curve (first dose)
tmax
Time to maximum concentration (h), taken directly from the individual
concentration-time curve (first dose)
Cmin
minimum plasma drug concentration at the end of the dosing interval (first 
dose)
AUClast
Area under the plasma concentration-curve from time zero to the time of last 
quantifiable analyte concentration
AUC!
area under the plasma concentration curve during the first
dosing interval, τ (first dose)
Day 5
Css,max
Observed maximum concentration, taken directly from the individual 
concentration-time curve at steady state
Css,min
Observed minimum concentration, taken directly from the individual 
concentration-time curve within a dosing interval on Day 5
tss,max
Time to maximum concentration (h), taken directly from the individual
concentration-time curve at steady state
∃z 
Terminal rate constant, estimated by log-linear least square regression of the 
terminal part of the concentration-time curve. 


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t½∃z
Terminal half-life (h), estimated as (ln2)/∃z.
AUCss,!
area under the plasma concentration curve during the dosing interval,τ at 
steady state 
CL/F
Apparent plasma clearance for parent drug estimated as dose divided by 
AUCss,!
Vz/F
Apparent volume of distribution for parent drug at terminal phase, estimated 
by dividing the apparent clearance (CL/F) by λz
Cav
Average plasma concentration during a dosing interval, estimated as
AUCss,!/12
%Fluctuation
Fluctuation index during a dosing interval estimated as 100*(Cmax-Cmin)/Cav 
(%)
Rac (Cmax)
Accumulation ratio for Cmax estimated as Css,max on Day 5/ Cmax on Day 1
Rac (Cmin)
Accumulation ratio for Cmin estimated as Css,min on Day 5/ Cmin on Day 1
Rac (AUC!)
Accumulation ratio for AUC! estimated as AUCss,! on Day 5/AUC! on Day 1
The following diagnostic parameters of the plasma PK analysis will be listed, but not 
summarised:
λz interval
Lower and upper limit of the time interval (h) of the log-linear regression to 
determine λz
Rsq adj
Adjusted coefficient of determination for calculation of λz
n
Number of data points included in the log-linear regression analysis
%AUCex
Percentage 
of 
AUC 
obtained 
by 
extrapolation, 
calculated 
as 
[(Clast(obs)/λz)/AUC * 100]
Additional parameters may be determined as appropriate.
8.4.2
Safety and Tolerability Outcomes
∀
AEs
∀
Clinical laboratory parameters (hematology, serum biochemistry and 
urinalysis)
∀
Blood pressure


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∀
12-lead ECG parameters
8.5
Methods for statistical analyses
8.5.1
Analysis of the Pharmacokinetic variables
8.5.1.1
Calculation or derivation of the pharmacokinetic parameters
The PK analyses will be performed by Covance on behalf of AstraZeneca. The actual 
sampling times (calculated based on the start time of dosing) will be used in the PK parameter 
calculations. PK parameters will be determined using standard non-compartmental methods 
with Phoenix® Winnonlin® (Version 6.2 or higher). Graphics may be prepared with SAS®
Version 9.3 or higher). Pharmacokinetic analyses will be conducted according to AstraZeneca 
SOPs for PK analyses, if not otherwise indicated.
Plasma concentrations below the lower limit of quantification (BLQ) from the time of pre-
dose sampling (t=0) up to the time of the first quantifiable concentration will be set to a value 
of 0. After this point, BLQ plasma concentrations will be set to missing for all concentration 
profiles. Also, if 2 or more consecutive below the lower limit of quantification concentrations 
are followed by quantifiable concentrations in the terminal portion of the concentration curve, 
the profile will be deemed to have terminated and therefore these quantifiable values will be 
set to missing for the calculation of the PK parameters unless there is a scientific rationale not 
to do so, this is documented in the PK analysis notes. 
If an entire concentration-time profile is BLQ, the profile is excluded from the PK analysis. 
The choice of data points used to estimate ∃z should follow the general guidelines: 
∀
If there is more than 1 phase, use only observations from the terminal 
phase.
∀
In general, the minimum data requirements are 3 measured 
concentrations spanning 3 half-lives. Where t½ is estimated over less than 
three half-lives, the values will be flagged in the data listings.
∀
Should include the last measurable concentration.
∀
Include only observations after Cmax.
∀
The adjusted correlation coefficient (Rsq adj) should be ≥0.80.
Area under the plasma concentration-curve will be calculated using trapezoidal methods when 
concentration is increasing and logarithmic trapezoidal method when concentrations are 
decreasing.
Three concentrations higher than the lower limit of quantification (LLOQ) are required as a 
minimum for the AUC parameter to be summarised. 


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8.5.1.2
Statistical analysis of the Pharmacokinetic Parameters
All analyses of the PK parameters will be performed on the PK population. The available 
concentration data and PK parameter data for any patients excluded from the PK population 
will be listed only and presented in the individual figures of concentration, but not included in 
the descriptive statistics or in the inferential statistics.
A listing of PK blood sample collection times as well as derived sampling time deviations will 
be provided. 
Plasma concentrations for aclidinium bromide, LAS34823 and LAS34850 and formoterol will 
be summarised per day using appropriate descriptive statistics (n, geometric mean, geometric 
coefficient of variation, arithmetic mean, arithmetic standard deviation [SD], minimum and 
maximum). For tmax, only n, median, minimum, and maximum will be reported.
For descriptive statistics, plasma concentrations below the LLOQ will be handled as follows:
∀
At a time point where less than or equal to 50% of the values are BLQ, 
all BLQ values will be set to LLOQ, and all descriptive statistics will be 
calculated accordingly. 
∀
At a time point where more than 50% (but not all) of the values are BLQ, 
the arithmetic mean, geometric mean and CV% will be set to not 
determined (ND) The maximum value will be reported from the 
individual data and the minimum and maximum are set to BLQ.
∀
If all values are below LLOQ at a time point, no descriptive statistics are 
calculated for that time point. Not applicable (NA) will be written in the 
field for arithmetic SD and geometric CV% and BLQ will be written in 
mean, minimum, median and maximum in the table.
∀
The number of observations above the LLOQ (n>LLOQ) will be reported 
in the Table for each time-point.
Graphical presentations will include: individual/combined individual and mean plasma 
concentration vs time curves on both linear and semi-logarithmic scale. 
Additional graphical presentations of PK data may be added at the discretion of the PK 
scientist. More details will be provided in the SAP.
8.5.2
Analysis of safety data
All analyses of safety data will be performed on the safety analysis set.


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8.5.2.1
Adverse events
All AEs will be coded using MedDRA vocabulary, and will be listed for each subject.  A 
treatment-emergent adverse event (TEAE) is defined as an AE with onset (start date/time) 
after the 1st dose of IP.
Adverse events will be summarised including tabulations by causality and severity (mild, 
moderate and severe).  All tabulations will be presented by SOC and PT.  Furthermore, 
separate listings of SAEs, AEs that led to discontinuation (DAEs) and AEs that led to death 
will be presented.  The AEs that occur before 1st dosing (i.e., not treatment-emergent) will be 
excluded from the summary tables.
All tabulations will include the number and percentage of subjects and the number of events 
where applicable.
Finally, an overview of all AEs will be presented including categories for any AE, AEs with 
outcome of death, SAEs and AEs leading to discontinuation of study drug.
8.5.2.2
Blood Pressure
The results of the blood pressure measurements will be listed by subject and time point 
including the date/time of the assessment, changes from baseline and repeat/unscheduled 
measurements.  The baseline for blood pressure measurements will be the pre-dose assessment 
on Day 1.  Descriptive statistics will be presented by time point for both observed values and 
changes from baseline.
The number and percentage of subjects with notable changes from pre-dose (baseline) will be 
tabulated by treatment and time point based on the criteria provided in the table below:
Parameter
Flag
Criteria
Systolic blood pressure (mmHg)
High
≥180 and increase over baseline 
of ≥20 or ≥200 and baseline 
<200
Low
≤90 and decrease from baseline 
of ≥20 or ≤75 and baseline >75
Diastolic blood pressure 
(mmHg)
High
≥105 and increase over baseline 
of ≥15 or ≥115 and baseline 
<115
Low
≤60 and decrease from baseline 
of ≥15 or ≤40 and baseline >40
Abnormal values (based on the criteria above) will also be flagged in the listings.


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8.5.2.3
Resting (safety) 12-lead electrocardiogram
12-Lead ECG results performed for safety evaluation will be listed for each subject and will 
include the ECG parameters (where applicable) and changes from baseline, assessment by the 
Investigator (normal/abnormal not clinically significant/abnormal clinically significant) and 
details of any abnormalities.  ECG parameters will be summarised by treatment and time point 
including changes from baseline.  The baseline for the safety ECG parameters will be the 
results obtained on Day -1.
8.5.2.4
Physical examination
Any abnormalities in the physical examination will be listed as part of medical history at 
Screening and as AEs thereafter.  No separate listing of physical examination will be 
presented.
8.5.2.5
Laboratory assessments
Haematology and clinical chemistry values will be listed by subject and time point including 
changes from baseline (Day -1) and repeat/unscheduled measurements.
Summary tabulations will be presented by time point for the safety analysis set. 
Laboratory variables will be categorized as low, normal and high based on the reference 
ranges provided by the safety laboratory.  Shift tables will also be presented, showing the 
number and percentage of subjects with shifts from baseline in each of these categories.
Urinalysis results will be listed.
9.
STUDY AND DATA MANAGEMENT 
9.1
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and EDC system(s) 
utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:


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∀
Provide information and support to the Investigator(s).
∀
Confirm that facilities remain acceptable.
∀
Confirm that the investigational team is adhering to the protocol, that data 
are being accurately and timely recorded in the eCRFs, that biological 
samples are handled in accordance with the Laboratory Manual and that 
study drug accountability checks are being performed.
∀
Perform source data verification (a comparison of the data in the CRFs 
with the patient’s medical records at the hospital or practice, and other 
records relevant to the study) including verification of informed consent 
of participating patients. This will require direct access to all original 
records for each patient (e.g., clinic charts).
∀
Ensure withdrawal of informed consent to the use of the patient’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the patient.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.
9.2.2
Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA).
9.3
Study timetable and end of study
The “end of trial” is defined as the date when all patients enrolled in the trial performed the 
last contact (either Visit 3 Follow-up or Premature Discontinuation Visit).


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The study is expected to start in Quarter 3-4 2017 and to end by Quarter 1-2 2018.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with aclidinium bromide.
9.4
Data management 
Data Management (DM) of the study will be performed by Parexel and supervised by DM at 
AstraZeneca according upon agreed Standard Operating Procedures.
Main DM activities and procedures will be accurately described in the Data Management Plan 
(DMP), created by Parexel and meeting the sponsor requirements.
An EDC system will be used to collect and manage clinical data in electronic format (eCRF or 
electronic forms). Parexel will be responsible for EDC and database creation (including all 
data sources) according to the Sponsor structure specifications.
Consistency and structural checks to be run in the data and listings for Parexel data cleaning 
and review will be defined in a Data Validation Plan which will be created by Parexel to meet 
sponsor requirements and standards.
Interactive checks on the EDC will provide a first level of filters. Checks will run when data 
has been inserted, informing the research personnel through a flag when data must be verified. 
The need of additional queries may also be identified during the study as per the listings 
review by the Parexel DM staff, data coding, SAEs reconciliation process, etc.
Database, checks, programmes for data visualisation, listings programming (for data review 
and data visualisation) and any programming implying data conversions will be appropriately 
validated by Parexel.
Reconciliation of SAEs between the clinical database and Drug Safety database will be 
performed by Parexel DM on ongoing basis and before database soft lock. Procedures to 
follow will be detailed in the DMP.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA). Medications 
will be classified according to WHO DRUG Enhanced extended with Herbal. All coding will 
be performed by medical coding team at the CRO. MedDRA and WHO DRUG Enhanced
extended with Herbal will be used, version number of each dictionary will be documented in 
the DMP.
Data will be collected during the study execution and transferred to the study data repository 
at the CRO, where data will be mapped into SDTM datasets on an ongoing basis.


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
75 (85)
Transfers of SDTM datasets from the study data repository will be periodically received at 
AstraZeneca during the study and after Database lock. Frequency of these transfers will be 
agreed between AstraZeneca and the CRO.
All the processes will be carried out according to the specific pre-established processes and 
timelines documented in the DMP.
The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.
When all data have been coded, validated, locked and signed, clinical database lock will be 
declared. Any treatment revealing data (random, PK data, etc) may thereafter be added and 
after clinical database will has been locked.
An audit trail of all databases will be maintained in order to protect the authenticity and 
integrity of the clinical data.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
10.3
Ethics and regulatory review
An Ethics Committee should approve the final study protocol, including the final version of 
the Informed Consent Form and any other written information and/or materials to be provided 
to the patients.  The Investigator will ensure the distribution of these documents to the 
applicable Ethics Committee, and to the study site staff.
The opinion of the Ethics Committee should be given in writing. The Investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study. 
The Ethics Committee should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
76 (85)
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements.
10.4
Informed consent
The Principal Investigator(s) at each centre will:
∀
Ensure each patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the 
study
∀
Ensure each patient is notified that they are free to discontinue from the 
study at any time
∀
Ensure that each patient is given the opportunity to ask questions and 
allowed time to consider the information provided
∀
Ensure each patient provides signed and dated informed consent before 
conducting any procedure specifically for the study
∀
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File
∀
Ensure a copy of the signed Informed Consent Form is given to the 
patient
∀
Ensure that any incentives for patients who participate in the study as 
well as any provisions for patients harmed as a consequence of study 
participation are described in the informed consent form that is approved 
by an Ethics Committee.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
77 (85)
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
the Principal Investigator. For distribution to Ethics Committee see Section 10.3.
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements.  The Investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the centre.
11.
LIST OF REFERENCES
Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of 
COPD (the BOLD Study): a population-based prevalence study. Lancet. 2007; 370: 741-50.
CHMP Assessment report for Ultibro Breezhaler, EMA/CHMP/296722/2013, 25 July 2013 
CHMP Assessment report for Anoro, EMA/CHMP/163509/2014, 28 March 2014.
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use.
Duaklir® Genuair®, Summary of Product Characteristics. March 2015


Clinical Study Protocol
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
78 (85)
D’Urzo AD, Rennard SI, Kerwin EM et al. Efficacy and safety of fixed-dose combinations of 
aclidinium bromide/formoterol fumarate: the 24-week, randomised, placebo-controlled 
AUGMENT COPD study Respiratory Research 2014, 15:123.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the 
diagnosis, management and prevention of chronic obstructive pulmonary disease. Medical 
Communications Resources, Inc; 2016. Available from: http://www.goldcopd.org/.
Investigator’s Brochure Aclidinium bromide/ formoterol fumarate edition 10, 5 August 2015.
Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. Efficacy and safety of 
umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary 
disease: Results of a 24-week, randomized, controlled trial. Respir Med. 2014 Oct 
15;108(12):1752-1760. 
Maltais F, Singh S, Donald AC, Crater G, Church A, Goh AH, Riley JH.Effects of a 
combination of umeclidinium/vilanterol on exercise endurance in patients with chronic 
obstructive pulmonary disease: two randomized, double-blind clinical trials. Ther Adv Respir 
Dis. 2014 Dec;8(6):169-81. 
Pelaia Gl, Maselli R, Matera MG. Treatment of Chronic Obstructive Pulmonary Disease by 
Dual Bronchodilation with Coformulation of Indacaterol/Glycopyrronium. Pharmacology.
2014 Nov 28;94(5-6):249-258. 
Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault J-C. Lung volume 
and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, 
European Community for Steel and Coal. Official Statement of the European Respiratory 
Society. Eur Respir J 1993; 6: Suppl. 16, 5–40.
Singh D, Jones P, Bateman ED et al. Efficacy and safety of aclidinium bromide/formoterol 
fumarate fixed-dose combinations compared with individual components and placebo in 
patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. BMC Pulmonary 
Medicine 2014, 14:178.
WMA Declaration of Helsinki (18th WMA General Assembly 1964), revised at 59th World 
Medical Association General Assembly Seoul, October 2008.
Zhong N, Wang C, Yao W, et al. Prevalence of chronic obstructive pulmonary disease in
China a large, population-based survey. Am J Respir Crit Care Med. 2007; 176: 753-60


Clinical Study Protocol Appendix A
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
79 (85)
Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the patient or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
∀
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
∀
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine
∀
Intensive treatment in an emergency room or at home for allergic bronchospasm
∀
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation
Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.


Clinical Study Protocol Appendix A
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
80 (85)
∀
Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?
∀
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
∀
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?
∀
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
∀
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.
∀
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
∀
Is this a recognized feature of overdose of the drug?
∀
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


Clinical Study Protocol Appendix B
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
81 (85)
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:
∀
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:
∀
UN 3373 – Biological Substance, Category B
∀
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
∀
Clinical trial samples will fall into Category B or exempt under IATA regulations
∀
Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging 
∀
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
∀
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable
∀
Samples routinely transported by road or rail are patient to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.


Clinical Study Protocol Appendix C
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
82 (85)
Appendix C
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥ 3x ULN  together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
∀
ALT ≥ 3xULN


Clinical Study Protocol Appendix C
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
83 (85)
∀
AST ≥ 3xULN
∀
TBL ≥ 2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:
∀
Notify the AstraZeneca representative
∀
Request a repeat of the test (new blood draw) by the central laboratory
∀
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
∀
Determine whether the patient meets PHL criteria (see Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results)
Follow-up
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
∀
Inform the AstraZeneca representative that the patient has not met PHL criteria.
∀
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
∀
Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:


Clinical Study Protocol Appendix C
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
84 (85)
∀
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 
∀
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. This includes deciding which the tests available in the Hy’s 
law lab kit should be used. 
∀
Complete the three Liver CRF Modules as information becomes available 
∀
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IP.  
The AstraZeneca Medical Science Director and Global Safety Physician will also be involved 
in this review together with other patient matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
∀
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
∀
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP:
∀
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes. 
%
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
%
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.


Clinical Study Protocol Appendix C
Drug Substance Aclidinium bromide /Formoterol fumarate
Study Code M-AS464-01
Version 1.0
Date 24 March 2017
85 (85)
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
∀
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above
∀
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf


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SAP_000.pdf: 
Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
1
Statistical Analysis Plan
Study Code
D6572C00001 / M-AS464-01
Edition Number
2.0
Date
03 July 2018
A Phase IIa, Open-Label, Repeat-Dose Clinical Trial to Evaluate the 
Pharmacokinetics, Safety and Tolerability of Aclidinium Bromide / 
Formoterol Fumarate Fixed Dose Combination Administered Twice-Daily 
by Inhalation in Chinese Patients With Moderate to Severe Chronic 
Obstructive Pulmonary Disease


PPD


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
3
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
TABLE OF CONTENTS.....................................................................................3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS...........................5
AMENDMENT HISTORY..................................................................................8
1.
STUDY DETAILS...............................................................................................9
1.1
Study objectives...................................................................................................9
1.1.1
Primary objective.................................................................................................9
1.1.2
Safety objectives..................................................................................................9
1.2
Study design ........................................................................................................9
1.3
Number of subjects ............................................................................................13
2.
ANALYSIS SETS ............................................................................................. 13
2.1
Definition of analysis sets .................................................................................. 13
2.1.1
All Subjects Screened ........................................................................................ 13
2.1.2
Safety analysis set (SAF) ................................................................................... 13
2.1.3
Pharmacokinetic analysis set (PKS) ................................................................... 13
2.2
Protocol deviations............................................................................................. 13
3.
PRIMARY AND SECONDARY VARIABLES................................................. 15
3.1
Pharmacokinetic variables.................................................................................. 15
3.2
Safety variables..................................................................................................17
3.2.1
Adverse events...................................................................................................17
3.2.2
12-lead ECG parameters .................................................................................... 17
3.2.3
Blood pressure ................................................................................................... 18
3.2.4
Clinical laboratory variables...............................................................................18
3.2.4.1
Hy’s Law ........................................................................................................... 18
3.3
Other Variables..................................................................................................19
3.3.1
Demographic and baseline characteristics .......................................................... 19
3.3.2
Spirometry data and COPD characteristics at baseline........................................ 20
3.3.3
Prior and concomitant medication ...................................................................... 21
3.3.4
Drugs of abuse and alcohol ................................................................................21
3.3.5
Physical examination ......................................................................................... 21
4.
ANALYSIS METHODS....................................................................................21


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
4
4.1
General principles.............................................................................................. 21
4.1.1
Handling of repeated/unscheduled measurements...............................................22
4.2
Analysis and reporting ....................................................................................... 23
4.2.1
Subject disposition............................................................................................. 23
4.2.2
Protocol deviations.............................................................................................23
4.2.3
Demographic and baseline characteristics .......................................................... 23
4.2.4
Spirometry data and COPD characteristics at baseline........................................ 24
4.2.5
Prior and concomitant medication ...................................................................... 24
4.2.6
Drug administration ........................................................................................... 25
4.2.7
Pharmacokinetics............................................................................................... 25
4.2.7.1
Calculation or Derivation of the Pharmacokinetic parameters............................. 25
4.2.7.2
Pharmacokinetic data ......................................................................................... 26
4.2.8
Analysis of safety data ....................................................................................... 28
4.2.8.1
Adverse events...................................................................................................28
4.2.8.2
Vital signs and 12-lead electrocardiogram.......................................................... 30
4.2.8.3
Clinical laboratory assessments.......................................................................... 32
4.3
Data handling..................................................................................................... 36
4.3.1
Pharmacokinetic data below the lower limit of quantification (BLQ) or 
non-reportable (NR)........................................................................................... 36
4.3.2
Precision and rounding rules for pharmacokinetic data....................................... 37
4.3.3
Safety laboratory data with semi-qualitative results............................................ 38
4.3.4
Missing data for adverse events and medications................................................ 38
4.3.5
Computation of derived variables.......................................................................40
4.3.5.1
Definition of Baseline values ............................................................................. 40
4.3.5.2
Summary statistics ............................................................................................. 40
5.
INTERIM ANALYSES ..................................................................................... 40
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 40
7.
APPENDIX ....................................................................................................... 41
7.1
Appendix I – List of Tables, figures and listings................................................. 41
7.1.1
TABLES............................................................................................................ 41
7.1.2
FIGURES .......................................................................................................... 42
7.1.3
LISTINGS ......................................................................................................... 44


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
5
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this Statistical Analysis Plan (SAP).
Abbreviation or 
special term
Explanation
AB/FF 400/12
aclidinium bromide/formoterol 400/12 μg
AE
Adverse event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AM
Morning (antemeridiam) 
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area under curve (pg.h/mL)
AUC!
Area under the plasma concentration curve (pg.h/mL) during the first 
dosing interval, ! (first dose)
AUClast
Area under the plasma concentration-curve from time zero to the time of 
last quantifiable analyte concentration (pg.h/mL)
AUCss,τ
Area under the plasma concentration curve during the dosing interval, τ at 
steady state (pg.h/mL)
BID
Twice daily
BLQ
Below the lower limit of quantification
BMI
Body Mass Index
Cav
Average plasma concentration (pg/mL)
CK
Creatine kinase
CL/F
Apparent plasma clearance for parent drug (L/h)
Cmax
Observed maximum concentration (pg/mL)
Cmin
Observed minimum concentration (pg/mL)
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CSP
Clinical Study Protocol
CSR
Clinical Study Report
Css,max
Observed maximum concentration, taken directly from the individual 
concentration-time curve at steady state (pg/mL)
Css,min
Observed minimum concentration, taken directly from the individual 
concentration-time curve within a dosing interval (pg/mL)


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
6
Abbreviation or 
special term
Explanation
CV%
Geometric coefficient of variation
DDE
Drug Dictionary Enhanced
DPI
Dry Powder Inhaler
DRM
Data Review Meeting
ECG
Electrocardiogram
eCRF
Electronic Case Report Form 
FEV1
Forced Expiratory Volume in one second
%Fluctuation
Fluctuation index
FVC
Forced vital capacity
GGT
Gamma-glutamyl transferase
GOLD
Global Initiative for Chronic Obstructive Lung Disease
Hb
Haemoglobin
HBsAg
hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
ICF
Informed Consent Form
λz
Terminal rate constant (h-1)
LLN
Lower Limit of Normal
LLOQ
Lower Limit of Quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRCmax
Metabolite to parent ratio for Cmax
MRAUC!
Metabolite to parent ratio for AUC!
mmHg
Millimeters of mercury
msec
Milliseconds
n obs
Number of data points included in the log-linear regression analysis
NA
Not applicable
ND
Not determined
NR
Non-reportable 
PCS
Potentially Clinically Significant
PDS
protocol deviations specifications
PK
Pharmacokinetics
PKS
Pharmacokinetic analysis set


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
7
Abbreviation or 
special term
Explanation
PM
Evening (Post meridiem)
pMDI
pressurised metered-dose inhaler
PPS
Per protocol set
PR interval
Duration in milliseconds from the beginning of wave P to onset of 
ventricular depolarization (Q and R)
PT
Preferred Term
QRS interval
Onset of ventricular depolarization
QT interval
Duration in milliseconds from the beginning of Q wave to the end of the T 
wave
QTc interval
QT interval corrected by heart rate
QTcB interval
QT interval corrected, Bazett formula 
QTcF interval
QT interval corrected, Fridericia formula 
Rac(AUC!)
Accumulation ratio for AUC!
Rac(Cmax)
Accumulation ratio for Cmax
Rac(Cmin)
Accumulation ratio for Cmin
RR
Respiratory rate
RSq adj
Adjusted coefficient of determination for calculation of ∀z
SAE
Serious Adverse Event
SAF
Safety analysis set
SAP
Statistical Analysis Plan 
SD
Standard Deviation
SOC
System Organ Class
SOP
Standard Operating Procedure
t½λz
Terminal half-life (h)
TEAE
Treatment-Emergent Adverse Event
TESAE
Treatment-Emergent Serious Adverse Event
TFLs
Tables, Figures and Listings
tmax
Time to maximum concentration (h)
tss,max
Time to maximum concentration (h), taken directly from the individual 
concentration-time curve at steady state
ULN
Upper Limit of Normal
Vz/F
Apparent volume of distribution for parent drug at terminal phase (L)
WHO
World Health Organisation


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
8
AMENDMENT HISTORY
Date
Brief description of change
17 October 2017
Original Document (Final 1.0)
03 July 2018
Updated for formatting, PK trough concentration figures, concomitant 
medication definition and Spirometry revisions (Final 2.0)


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
9
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
The primary study objective is to evaluate the pharmacokinetics (PK) of aclidinium bromide,
its metabolites LAS34850 and LAS34823 and formoterol after administration of aclidinium 
bromide/formoterol 400/12 μg twice-daily (BID) for 5 days in Chinese patients with stable 
moderate to severe Chronic Obstructive Pulmonary Disease (COPD). The variables are given 
in Section 3.1.
1.1.2
Safety objectives
Secondary objectives are to evaluate the safety, and tolerability of aclidinium 
bromide/formoterol 400/12 μg twice-daily (BID) administered for 5 days in Chinese patients 
with stable moderate to severe COPD. The variables are given in the Section 3.2.
1.2
Study design
This is a Phase IIa, single centre, open-label, repeat-dose study to investigate the PK, safety 
and tolerability of single and multiple twice daily doses of inhaled aclidinium 
bromide/formoterol 400/12 μg (hereafter referred to as AB/FF 400/12) in Chinese male and 
female subjects with stable moderate to severe COPD.
Twenty COPD Chinese subjects of 40 years of age or older, will participate in the study. The 
target population is based on current or former smokers with a smoking history of ≥10 pack-
years, aged ≥40, COPD subjects with stable moderate to severe airflow obstruction (post-
bronchodilator FEV1 ≥30% and <80% and post-bronchodilator FEV1/FVC <70%). Refer to 
the clinical study protocol (CSP) for the full list of inclusion and exclusion criteria.
The study will consist of a Screening Visit (to check for eligibility) conducted after signature 
of the Informed Consent Form (ICF) and maximum 21 days before the first dose of AB/FF 
400/12, followed by a residential period from Day -1 to Day 7, of which treatment period is 
scheduled between Day 1 and Day 5 and a follow up period of 5 days after discharge. The 
whole study duration for each subject is expected to last approximately 5 weeks. The study 
flow chart for each treatment sequence is shown in Figure 1 below.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
10
Figure 1
Study flow chart
Subjects who meet all criteria at screening will be admitted to the study center on Day -1, the 
day prior to first AB/FF 400/12 administration. On Day 1 through Day 4, they will receive 
one inhalation of AB/FF 400/12 μg BID. The morning dose will be administered at 
approximately 08:00 hours, and the evening dose 12 hours after the morning dose (at 
approximately 20:00 hours) and the 12-hour PK sample collection.
On Day 5, at approximately 08:00 hours, subjects will receive one inhalation of AB/FF 400/12 
μg. There will be no PM dose administered. Subjects will be discharged on Day 7, 48 hours 
after last AB/FF 400/12 administration on Day 5 and after the completion of the 48-hour PK 
sample collection and safety assessment on Day 7.
Subjects who prematurely discontinue from the study (withdrawal) will participate in a 
Premature Discontinuation Visit.
Rescue medication (salbutamol pMDI 100 μg/puff) is to be provided to the subjects at Visit 1 
(Screening), and can be re-supplied throughout the study as necessary according to use.
Pharmacokinetic assessments will be conducted at specific time-points in the clinical unit 
during the residential period (from Day -1 to Day 7). Safety assessments will be performed at 
Screening, during the treatment period and follow-up or premature discontinuation visits, as 
presented in Table 1 below.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
11
Table 1 Schedule of Assessments
Procedure
Screening 
Day -21 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Follow-Up Visit Days 
8-12c or Premature 
Discontinuation2
Informed consent
X
Demographics 
X
Inclusion/Exclusion criteria
X
X
Medical/surgical and COPD
history
X
Prior and Concomitant 
Medications3
X
X
X
X
X
X
X
X
X
X
Spirometry12
X
Inhaler Training
X
X
Admission to Study Center
X
Meals (provided by study
center)13
X
X
X
X
X
X
X
X
Discharge from the Study
Center4
X
Outpatient Visit
X
X
Physical examination5
X
X
X
12-lead ECG and blood 
pressure 6
X
X
X
X
X
X
X
X
Laboratory Tests7
X
X
X
Pregnancy Test8
X
X
X
Serology9
X
Drug-of-abuse and Alcohol 
Screen
X
X
Dosing of AB/FF 400/1210
X
X
X
X
X
PK Blood samples11
X
X
X
X
X
X
X
Adverse Event review
X
X
X
X
X
X
X
X
X
X
AE = adverse event; AM = morning; BMI = body mass index; COPD= Chronic Obstructive Pulmonary Disease; DPI = dry powder inhaler; ECG = electrocardiogram; eC
form; HIV = human immunodeficiency virus; ICF = Informed Consent Form; PK = pharmacokinetic; PM = evening


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
12
1. If the subject needs additional time to washout any prior medications, the ICF must be provided before Visit 1. Subjects must discontinue medications after informed c
2. The premature discontinuation visit/assessments will be performed as soon as possible after subject discontinuation.
3. Any treatment administered during the 2 weeks before the ICF signature and during the Run-in Period must be recorded into the eCRF to ensure a proper washout of a
From Visit 1 (Screening) onwards, any new treatments taken or any change to the ongoing medications during the participation in the study, apart from AB/FF 400/12, w
eCRF by the investigator or designee.
4. Subjects will be discharged from the study center after the completion of the PK blood sample collection and safety assessments.
5. Height and weight will be measured and BMI will be calculated at Visit 1 (Screening) only. 
6. Safety ECGs (including heart rate) and blood pressure will be collected at Visit 1 (Screening), at Visit 2 (from Days -1 on admission to Day 5) and at the Follow-up V
Discontinuation Visit. On Visit 2 (from Day 1 to Day 5) the standard 12-lead ECG will be performed at 0h morning pre-dose and at 2 hours (± 15 min) post morning dos
after the subject has rested quietly in a seated position for at least 5 minutes. If blood sampling, blood pressure assessments, and ECG recordings are scheduled at the sam
sequence will be followed: 1) ECG recording; 2) blood pressure assessments; and 3) blood sampling, assuring that PK blood sampling occurs on the time-point. If an EC
time as a meal, the ECG must be obtained first. 
7. Includes blood, serum, and urine samples. Subjects are required to fast for at least 8 hours prior to the collection of specimens.
8. For women of childbearing potential, a serum pregnancy test will be done at visit 1 (Screening); on Day -1 (Visit 2), and at the Follow-up visit or Premature Discontin
must be available and reviewed prior to dosing on Day 1 on Visit 2.
9. Serum for anti-hepatitis C virus, hepatitis B surface antigen and anti-HIV type 1. Results must be available and reviewed prior to dosing on Day 1 (Visit 2).
10. On Day 5, only the morning dose of aclidinium bromide/formoterol 400/12 μg will be administered; no evening dose will be administered. At approximately 08:00 h
receive one inhalation of aclidinium bromide/formoterol 400/12 μg via the Genuair® multidose DPI. 
11. PK blood samples will be collected on Day 1 of Visit 2 at 0 hour (approximately 15 minutes prior to the morning dose), 5 minutes, 15 minutes, 30 minutes, 1 hour, 1
hours, 6 hours, 8 hours, and 12 hours post the morning dose (the 12-hour sample will be collected 5 minutes before the evening dose).
On Days 2-4 of Visit 2, PK blood samples will be collected at 0 hour (approximately 5 minutes prior to the morning and evening dose).
On Day 5 of Visit 2, PK blood samples will be collected at 0 hour (approximately 5 minutes prior to the morning dose), 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 ho
hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours and 48 hours post morning dose. Time window allowance for all PK time-points are indicated in Section 2.2.
12. Administer inhaled salbutamol (100 μg x 4 puffs) through a spacer device at a minimum of 10 minutes after the previous spirometry test. Ten (10) to 15 minutes after
perform the 1 set of spirometry forced manoeuvres again.
13. No breakfast will be served on Day 1 and Day 5.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
13
1.3
Number of subjects
Due to the exploratory nature of the study the sample size is not based on formal statistical 
considerations. The sample size is based on experience from previous similar Phase I and 
Phase II studies with aclidinium bromide and formoterol.
A total of 20 subjects are deemed sufficient to ensure appropriate characterization of the PK of
aclidinium bromide, LAS34823, LAS34850 and formoterol.
2.
ANALYSIS SETS
Subject dispositions will be summarized using All Subjects Screened. Descriptive statistics for 
demographics and other baseline characteristics as well as safety analyses will be provided
using the safety population. PK analysis will be done using the PK population.
2.1
Definition of analysis sets
2.1.1
All Subjects Screened
All subjects who have signed the Informed Consent form.
2.1.2
Safety analysis set (SAF)
All subjects who receive at least one dose of AB/FF 400/12 will be included in the safety 
population.
2.1.3
Pharmacokinetic analysis set (PKS)
All subjects who took at least one dose of AB/FF 400/12 and have at least one of the 
parameters (Cmax, Css,max, AUC, AUClast or AUCss, !) evaluable and are assumed not to be 
affected by factors such as important protocol deviations. All protocol deviations that occur 
during the study will be considered for their severity/impact and will be taken into 
consideration when subjects are assigned to the PK analysis sets.
The exclusion of any subjects from the PK analysis set will be documented by the PK scientist 
including the reason(s) for exclusion.
The available concentration data and PK parameter data for any subjects excluded from the 
PK analysis set will be listed only, and presented in the individual figures of concentration 
time plots.
2.2
Protocol deviations
The criteria for the assessment and reporting of protocol deviations will be stipulated in a
separate study specific protocol deviation specification document.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
14
Important deviations from the protocol may lead to the exclusion of subjects from the PK
analysis set. Data may be excluded from summary statistics and inferential analysis of 
concentrations at a specific time-point without excluding the subject from the PKS.
Important deviations and analysis sets will be defined before database hard lock at the data
review meeting.
Important deviations will include the following:
#
Violation of inclusion and/or exclusion criteria that may influence PK analysis;
#
Administration of prohibited concomitant medications that are expected to influence the 
measurement of the PK endpoints;
#
Missing dose, incomplete or interrupted administration.
Table 2 shows important protocol deviations that affect the assignment of subjects and/or 
specific data points to analysis sets.
The separate protocol deviations specifications (PDS) document provides details on specific 
checks and the formatting for reporting deviations.
Table 2
Important protocol deviations and analysis set classification
Excluded from 
analysis set
Event description
SAF
PKS
Subject met this exclusion criterion: Positive results for drugs of abuse at Visit 1 (Screening).
No
Yes+++
Subject met this exclusion criterion: Taken any medication within 14 days before the first dose of AB/FF 
400/12, or hormonal drug products and traditional Chinese medicines within 30 days before the first dose of 
AB/FF 400/12, with the exception of allowed medications listed in Section 7.9.
No
Yes+++
Subject met this exclusion criterion: Have any clinical condition that might affect the absorption, distribution, 
biotransformation, or excretion of aclidinium bromide/formoterol fumarate.
No
Yes+
Subject met this exclusion criterion: Have consumed any grapefruit-containing products within 48 hours or 
alcohol within 72 hours before Day -1 at Visit 2.
No
Yes+++
Subject has missing date/time for PK blood sampling 
No
Yes+++
Subject has missing sample for PK blood sampling 
No
Yes++
Subject received prohibited medication 
No
Yes+++
Subject did not adhere to dietary restrictions prior to or after dosing per protocol specification
No
Yes+++
Subject is missing dosing information (including completely missing record, missing date/time, dose) 
No
Yes+++
Subject received incorrect treatment.
No
Yes+++
Other protocol deviations
Yes++
+
Yes+++
+ Assessed at DRM and transcribed to protocol deviations log if assessed as important. ++Excluded from the specific time-point only. 
+++ To be confirmed at the DRM; time-point specific or global PPS/PKS exclusion.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
15
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Pharmacokinetic variables
Serial blood samples for PK assessments of aclidinium bromide, its metabolites (LAS34823 
and LAS34850) and formoterol in plasma will be collected at the following time-points:
#
Day 1: pre-dose, 5, 15, 30 min and 1h, 1.5h, 2, 3, 4, 6, 8 and 12h (12 time-points)
#
Day 2-4: pre-morning and pre-evening dose (6 time-points)
#
Day 5: pre-dose, 5, 15, 30 min and 1h, 1.5h, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours (15 
time-points)
The recommended time window allowance for PK blood collection is the following:
Day 1 and Day 5:
#
Pre-dose: -30 min for Day 1 and -10 min for Day 5
#
5-30 min: ± 1 min
#
1-6 hours: ± 5 min
#
8-12 hours: ± 10 min
#
24-48 hours: ± 30 min
Days 2 to 4:
#
Pre-dose: - 10 min
Where possible, the following PK parameters will be calculated for aclidinium bromide, its 
metabolites LAS34823 and LAS34850 and formoterol:
Day 1
#
Cmax – Observed maximum concentration (pg/mL), taken directly from the individual
concentration-time curve (first dose)
#
tmax – Time to maximum concentration (h), taken directly from the individual 
concentration-time curve (first dose) 
#
Cmin – Minimum plasma drug concentration (pg/mL) at the end of the dosing interval 
(first dose)


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
16
#
AUClast – Area under the plasma concentration-curve from time zero to the time of last 
quantifiable analyte concentration (pg.h/mL)
#
AUC! – Area under the plasma concentration curve during the first dosing interval, !
(first dose) (pg.h/mL)
#
MRCmax – Metabolite to parent ratio for Cmax, estimated by dividing the metabolites 
Cmax by the parent Cmax
#
MRAUC! – Metabolite to parent ratio for AUC!, estimated by dividing the metabolites 
AUC! by the parent AUC!
Day 5
#
Css,max – Observed maximum concentration (pg/mL), taken directly from the individual 
concentration-time curve at steady state
#
Css,min – Observed minimum concentration (pg/mL), taken directly from the individual
concentration-time curve within a dosing interval on Day 5
#
tss,max – Time to maximum concentration (h), taken directly from the individual 
concentration-time curve at steady state
#
∀z – Terminal rate constant (h-1), estimated by log-linear least square regression of the 
terminal part of the concentration-time curve
#
t½λz – Terminal half-life (h), estimated as (ln2)/∀z
#
AUCss,τ – Area under the plasma concentration curve during the dosing interval, τ at 
steady state (pg.h/mL)
#
CL/F* – Apparent plasma clearance for parent drug estimated as dose divided by 
AUCss,τ (L/h)
#
Vz/F* – Apparent volume of distribution for parent drug at terminal phase (L), estimated 
by dividing the apparent clearance (CL/F) by λz
#
Cav – Average plasma concentration (pg/mL) during a dosing interval, estimated as 
AUCss,τ /12
#
%Fluctuation – Fluctuation index during a dosing interval estimated as 100*(Cmax-
Cmin)/Cav (%)
#
Rac(Cmax) – Accumulation ratio for Cmax estimated as Css,max on Day 5/ Cmax on Day 1
#
Rac(Cmin) – Accumulation ratio for Cmin estimated as Css,min on Day 5/ Cmin on Day 1


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
17
#
Rac(AUC!) – Accumulation ratio for AUC! estimated as AUCss,τ on Day 5/ AUCτ on 
Day 1
#
MRCmax – Metabolite to parent ratio for Css,max, estimated by dividing the metabolites 
Css,max by the parent Css,max
#
MRAUC! – Metabolite to parent ratio for AUCss,!, estimated by dividing the metabolites 
AUCss,! by the parent AUCss,!
The following diagnostic parameters of the plasma PK analysis will be listed, but not
summarised:
#
∀z interval – Lower and upper limit of the time interval (h) of the log-linear regression to
determine ∀z
#
Rsq adj – Adjusted coefficient of determination for calculation of ∀z
#
λz,N – Number of data points included in the log-linear regression analysis
Additional parameters may be determined as appropriate.
*Only for Aclidinium bromide and formoterol
3.2
Safety variables
Safety and tolerability variables will include the following categories of variables:
#
Adverse events (AEs) and Serious adverse events (SAEs)
#
12-lead Electrocardiogram (ECG) parameters
#
Blood pressure parameters
#
Laboratory parameters
3.2.1
Adverse events
The definitions of AEs and SAEs are given in Sections 6.1 and 6.2 respectively of the CSP.
Adverse events will be recorded from the time of informed consent up to the follow-up visit or 
premature discontinuation visit.
3.2.2
12-lead ECG parameters
A 12-lead safety ECG will be obtained at the following time-points:
#
Screening


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
18
#
Day -1
#
Day 1 to Day 5; at pre-dose, 2 h post-dose
#
Follow-up or Premature Discontinuation visit in case of early termination.
At each time-point above, the Investigator will provide an overall interpretation of the safety 
ECG as normal, abnormal or borderline, and the result recorded in the CRF. If abnormal, the 
clinical significance (Yes or No), will also be recorded on the CRF.
The parameters determined will be heart rate, RR interval, PR interval, QRS interval, QT 
interval, QTc interval (including QTcB and QTcF).
3.2.3
Blood pressure
Measurements of blood pressure will be performed at the following time-points: 
#
Screening
#
Day -1 to Day 5; at pre-dose, 2 h post-dose
#
Follow-up or Premature discontinuation visit in case of early termination.
The following variables will be measured at each time-point: 
#
Systolic blood pressure (mmHg)
#
Diastolic blood pressure (mmHg)
3.2.4
Clinical laboratory variables
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
will be taken at the following time-points:
#
Screening
#
Day -1
#
Follow-up or Premature discontinuation visit in case of early termination.
Serology variables will be assessed at the Screening visit only.
For women of childbearing potential only, a serum pregnancy test will be done at Screening, 
Day -1, and at the Follow-up/Premature Discontinuation visit.
3.2.4.1
Hy’s Law
Hy's law provides an assessment of whether a drug is at high risk of causing a fatal drug-
induced liver injury (DILI) when given to a large population.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
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During the course of the study the investigator remains vigilant for increases in liver 
biochemistry and is responsible for determining whether a subject meets Potential Hy’s Law 
(PHL) criteria at any point during the study.
A review and assessment of cases to determine whether PHL cases agree with Hy’s Law (HL) 
criteria is performed. HL criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than DILI caused by AB/FF 400/12.
Potential Hy’s Law (PHL):
#
At least one event of aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) ≥ 3x upper limit of normal (ULN), together with total bilirubin (TBL) ≥ 2xULN 
at any point during the study following the start of study medication irrespective of an 
increase in Alkaline Phosphatase (ALP).
Hy’s Law (HL):
#
AST or ALT ≥ 3x ULN, together with TBL ≥ 2xULN, where no other reason, other than 
AB/FF 400/12, can be found to explain the combination of increases, e.g. elevated ALP 
indicating cholestasis, viral hepatitis, another drug.
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
3.3
Other Variables
Meal consumption data are collected but not included in the CSR.
3.3.1
Demographic and baseline characteristics
The following demographic and baseline characteristics variables will be derived at 
Screening:
#
Age group (≤65, 66-75, 76-85, ≥85)
#
Body Mass Index (BMI) is derived as continuous variable as weight in Kg divided by 
height in meter squared (Kg/m2) and categorized (BMI Group) as: Underweight (<18.5), 
Normal weight (≥18.5 and < 25), Pre-obese (≥25 and <30) and Obese (≥30).
#
History of Tobacco Use 
Duration of smoking (years) is calculated as follows:
For a former smoker:
	
 
 
	 =  
   –   + 1


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
20
For a current smoker:
	
 
 
	 = 	  –  
3.3.2
Spirometry data and COPD characteristics at baseline
Spirometry will be performed at screening, from which the following COPD Severity Stage 
classifications will be derived. 
#
COPD classification of airflow limitation based on the post-bronchodilator PFT at 
screening:
o
Stage I (mild): FEV1/FVC <0.70 and FEV1 >=80% predicted
o
Stage II (moderate): FEV1/FVC < 0.70 and 50% ≤ FEV1 < 80% predicted
o
Stage III (severe): FEV1/FVC < 0.70 and 30% ≤ FEV1 < 50% predicted
o
Stage IV (very severe): FEV1/FVC <0.70 and FEV1 <30% predicted 
Only subjects with Stage II and Stage III are eligible to be included in the study.
Derived spirometry parameters:
At each time point (screening pre- and post-bronchodilation), the maximum FEV1 and FVC 
value will be flagged from all repetitions obtained during the spirometry tests.  From these 
maximum values the associated derived spirometry parameters will be calculated and are 
given as follows:
Bronchodilator Reversibility Testing in COPD
#
pre-bronchodilator FEV1/ FVC
#
post-bronchodilator FEV1/FVC
Absolute bronchial reversibility value:
#
[(post −bronchodilator FEV1) – (pre −bronchodilator FEV1)]  
Percent bronchial reversibility value:
#
[(012345617891:;<=316 >?@A) – (06B45617891:;<=316 >?@A)]
(06B45617891:;<=316 >?@A)
∗100
The maximum post-bronchodilator FEV1 and the derived post-bronchodilator FEV1/ FVC
will be used for determining the COPD Severity Stage.
The following baseline COPD characteristics variables will be derived at Screening:


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
21
Time since diagnosis (years) is calculated as follows:
E	 	 	
	
= F 
 	 – F 
 GHI 	 	
  + 1
3.3.3
Prior and concomitant medication
Prior medication is defined as any medication other than AB/FF 400/12 with an end date that 
shows that the medication ended before the 1st dose of AB/FF 400/12.
Concomitant medication is defined as any medication other than AB/FF 400/12 with a start 
date indicating that the medication was taken at least once after the first AB/FF 400/12
administration through the last dose day.
Any medication taken after last dose day will be classified as post-treatment medication.
A medication that started before the AB/FF 400/12 administration and continues during 
treatment is classified as both prior and concomitant medication. It is classified as post-
treatment medication if continues after the end of treatment.
All medication will be coded using the latest version of the WHO-Drug Enhanced plus Herbal
Dictionary and will be listed by subject.
All medications will be marked as allowed or prohibited (according to Table 5 of the 
protocol).
3.3.4
Drugs of abuse and alcohol
Results for drugs of abuse and alcohol will not be reported as part of the clinical study report 
(CSR). 
3.3.5
Physical examination
Any abnormalities in the physical examination will be listed as part of medical history at 
Screening and as AEs thereafter. No separate listing of physical examination will be 
presented.
4.
ANALYSIS METHODS
4.1
General principles
This Statistical Analysis Plan (SAP) describes the statistical analyses of demographics, 
baseline characteristics, concomitant medication, PK, safety and tolerability and exploratory 
data planned in the study protocol. All data analyses will be performed by PAREXEL, except 


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
22
the derivation of PK parameters for aclidinium bromide, its metabolites LAS34823 and 
LAS34850 and formoterol which will be performed by Covance. SAS®version 9.3 (SAS 
Institute, Inc., Cary, North Carolina) will be used to create all datasets and all tables, figures 
and listings (TFLs).
Given the exploratory nature, no formal statistical hypothesis testing will be performed in this 
study. Since no formal testing is planned, and the confidence intervals (CIs) that will be 
calculated are only for descriptive purposes, no corrections for multiplicity will be used.
All TFLs that will be produced in the study are listed in Appendix 7.1.
Categorical variables will be summarised with counts (n) and percentages (%) and will be 
tabulated overall. For continuous variables, the number of non-missing observations, mean, 
standard deviation (SD), standard error of the mean, median, first and third quartiles, 
minimum and maximum will be tabulated overall. Refer to Section 4.2.7.2 for statistical 
analysis of the PK data. When applicable, these summaries will be provided by visit and 
time-point of assessment. As a rule (unless otherwise specified), mean, SD and median, will 
be reported to one decimal place more than the observed values, minimum and maximum with 
the same number of decimal places as the observed values. For PK concentrations and 
parameters please follow rules for standard statistics and significant figures in Section 4.2.7.2.
4.1.1
Handling of repeated/unscheduled measurements
Unless otherwise indicated, the following rules will apply to any repeated safety 
measurements for visit-based summary and analysis purposes: 
#
If the repeated measurement of a specific parameter occurs prior to AB/FF 400/12
administration on Day 1, then the last obtained value prior to dosing will be used in the 
descriptive statistics and in the calculation of changes from baseline
#
If the repeated measurement of a specific parameter occurs after AB/FF 400/12
administration on Day 1, then then the closest value to the target visit day will be used in 
descriptive statistics and in the calculation of changes from baseline. If the values are 
equidistant from the scheduled visit day, the later will be used. For the follow-up or 
premature discontinuation visit, no target day is defined and the last (non-missing) value 
will be selected. If the repeated measurement of a specific parameter occurs after AB/FF
400/12 administration on Day 1 and the reason for the repeat is a technical error/device 
error, then the second value will be used in descriptive statistics and in the calculation of 
changes from baseline
#
If a whole visit is repeated after AB/FF 400/12 administration on Day 1, then the 
repeated visit will be used in the descriptive statistics and in the calculation of changes 
from baseline


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
23
All measurements, both from scheduled and unscheduled visits, will be presented in the 
subject data listings, and in case of repeated measurements the value not selected for the 
analysis will be flagged in the listing.
4.2
Analysis and reporting
4.2.1
Subject disposition
Discontinuations from the study including screen failures will be listed, including date of 
informed consent, first and last dose, date of discontinuation and primary reason for 
discontinuation (inclusion and exclusion criteria not met for screen failures), and duration of 
treatment in days.
Subjects completing the study will be listed, including the date of informed consent, first and 
last dose and duration of treatment in days.
Subject disposition will be summarised overall. The tabulation will include the following 
information: number of subjects screened and screen-failures, number and percentage of 
subjects dosed, number and percentage of subjects completing the study, completed treatment 
and the number and percentage of subjects who were withdrawn (including reasons for 
withdrawal). Additionally, the cause of screening failure will be tabulated for all subjects 
screened.
Disposition data will be presented based on all subjects and the denominator for percentages 
will be all subjects screened.
Assignment of subjects to analysis sets will be listed by subject and summarised overall for all 
subjects screened. Reasons for subjects being excluded from the analysis sets will be 
listed/summarised in the same output.
4.2.2
Protocol deviations
All important protocol deviations will be listed for each subject in the SAF. Only important 
protocol deviations will be listed in the CSR.
4.2.3
Demographic and baseline characteristics
Demographic variable (including age, age group, sex, ethnic group, and race) will be listed 
and summarised for all subjects in the SAF. Subject characteristics (height, weight, BMI, and 
BMI group) will be listed and summarised for all subjects in the SAF. Percentages for 
categorical variables (sex, ethnic group, race, age group, BMI group) will have the number of 
subjects in the SAF as the denominator.
Medical and surgical history data will be listed in the SAF by subject and Medical Dictionary 
for Regulatory Activities (MedDRA version 20.1 or higher) by System Organ Class (SOC) 
and MedDRA Preferred Term (PT).


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
24
History of tobacco use will be listed by subject including the variables recorded as specified in 
Section 3.3.1. The number of pack years (cigarettes only), smoking status, and smoking 
duration will be summarised for all subjects in the SAF. Although collected on the CRF, 
smoking substance will not be summarised nor listed.
4.2.4
Spirometry data and COPD characteristics at baseline
Respiratory Disease History at baseline, including COPD Severity (GOLD categories, as 
determined by the post-bronchodilation assessment), number of exacerbations in previous 12 
months, and time since COPD diagnosis (years) will be listed and summarized in the SAF.
Spirometry results at Screening will be listed for each subject in the SAF. This will include all 
repetitions of FEV1 and FVC as actual and percent values at each time point as well as the 
derived parameters (ratio and reversibility) presented in Section 3.3.2. A flag will be included 
in the listing for the maximum FEV1 and FVC value at each time point to show the values 
used in the analysis. Derived parameters will be obtained only for the maximum FEV1 and 
FVC parameters. A summary of all the flagged and derived spirometry parameters will be 
presented.
4.2.5
Prior and concomitant medication
Any medications administered other than AB/FF 400/12 will be classified as prior,
concomitant or post-treatment based on the start and end dates of the medication as recorded 
in the CRF, in accordance with the definition in Section 3.3.3. Partially recorded start and end 
dates/times will be handled as described in Section 4.3.4.
Prior, concomitant and post-treatment medication will be listed by subject and will include the 
information as detailed in Section 3.3.3. In addition, the listings will include the preferred 
term (PT), Anatomical Therapeutic Code (ATC) to a maximum 3rd level and duration of 
administration.
Duration of medication will be calculated as the time between the start and end dates as:
	
 
 J		
 () =   −  + 1
For medications with partial or completely missing start date/times and/or end date/times, the 
duration will not be calculated.
The number and percentage of subjects who used any prior or concomitant medication will be 
summarised on the SAF, (separately for prior and concomitant medications) by ATC to a 
maximum of 3rd level and PT. Subjects with multiple drug usage in the same PT will be 
counted only once. 
Percentages will be calculated using the number of subjects in the SAF as the denominator.
Medications taken after last dose will not be included in the summary tables but will be 
identified in the listing for concomitant medication.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
25
All prohibited medications will be identified in the listing for concomitant medication.
4.2.6
Drug administration
Drug administration will be listed for each subject, which will cover everything collected in 
the CRF.
Drug overdose, drug accountability and rescue medication usage will also be listed.
4.2.7
Pharmacokinetics
4.2.7.1
Calculation or Derivation of the Pharmacokinetic parameters
Pharmacokinetic parameters will be derived using non-compartmental methods with Phoenix 
WinNonlin® Version 6.4, or higher and/or SAS® Version 9.3 or later.
The PK analyses of the plasma concentration data for aclidinium bromide, its metabolites and 
formoterol will be performed at Covance. PK analysis will, where possible, be carried out 
using actual elapsed times determined from the PK sampling and dosing times recorded in the 
database. If actual elapsed times are missing, nominal times may be used at the discretion of 
the PK Scientist with Sponsor approval.
For Day 1, plasma concentrations that are not quantifiable (NQ) from the time of pre-dose 
sampling (t=0) up to the time of the first quantifiable concentration will be set to a value of 
zero. After this time-point, NQ plasma concentrations will be set to missing for all 
concentration profiles. Where 2 or more consecutive concentrations are NQ at the end of a 
profile, the profile will be deemed to have terminated and therefore any further quantifiable 
concentrations will be set to missing for the calculation of the PK parameters unless it is 
considered to be a true characteristic of the profile of the drug.
If an entire concentration-time profile is NQ, the profile will be excluded from the PK
analysis.
Cmax, Cmin, Css,max, Css,min, tmax and tss,max will be determined by inspection of the concentration-
time profiles.
Where possible λz will be calculated by log-linear regression of the terminal portion of the
concentration-time profiles where there are sufficient data and t½λz will be calculated as ln2/λz. 
For the determination of λz, the start of the terminal elimination phase for each subject will be 
defined by visual inspection and will be the first time-point at which there is no systematic 
deviation from the log-linear decline in plasma concentrations (λz lower) and the last point (λz
upper) will be the time of the last measurable plasma concentration. The choice of data points 
used to estimate ∀z should follow the general guidelines:
#
If there is more than 1 phase, use only observations from the terminal phase.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
26
#
In general, the minimum data requirements are 3 measured concentrations spanning 3
half-lives. Where t½∀z is estimated over less than three half-lives, the values will be 
flagged in the data listings.
#
Include the last measurable concentration.
#
Include only observations after Cmax.
#
The adjusted correlation coefficient (Rsq adj) should be ≥0.80. Any ∀z with a Rsq adj of 
<0.8 will be flagged in the data listings along with any parameters derived from ∀z (ie.
t½∀z, CL/F, Vz/F).
Area under the plasma concentration-curve values will be calculated using trapezoidal 
methods when concentration is increasing and logarithmic trapezoidal method when 
concentrations are decreasing.
Three concentrations higher than the lower limit of quantification (LLOQ) are required as a 
minimum for the AUC parameter to be reported with at least one of these concentrations 
following Cmax.
For rules pertaining to LLOQ see Section 4.3.1.
4.2.7.2
Pharmacokinetic data
All PK summary statistics will be based on the PKS. All PK listings will be based on the SAF.
Data from subjects excluded from the PKS, and also data from subjects in the PKS that have 
been excluded by the PK scientist during the DRM, i.e. specific time-points/concentrations 
that won´t be used for the parameter calculation, will be included in the data listings and 
individual figures, but not in the summary statistics, mean figures or combined individual 
figures.
A listing of PK blood sample collection times, as well as derived sampling time deviations
(the calculated difference between actual sampling time and planned sampling time), will be 
presented. Any plasma concentration with sampling time that deviates more than 10% from 
the planned sampling time (20% for the 5-minute timepoint) will be excluded from the 
descriptive statistics and from the summary plots, but these concentration values will be used 
for the calculation of the parameters as that will use the actual sampling time. Individual 
aclidinium bromide, LAS34823 and LAS34850, formoterol plasma concentrations will be 
listed by subject and time-point. Concentrations that are not used in the summaries will still be 
included in the listings, with excluded concentrations flagged.
Plasma concentrations for aclidinium bromide, LAS34823, LAS34850 and formoterol will be 
summarised by Day and nominal time-point using descriptive statistics (geometric mean, 
geometric mean ± geometric SD, geometric coefficient of variation [CV%], arithmetic mean, 
SD, minimum, median and maximum). In addition, n and n<LLOQ will also be presented.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
27
If one or more values for a given parameter/time-point/ treatment is zero (or imputed with 
zero), then no geometric statistics can be calculated for that parameter/time-
point/analyte/treatment and the results for geometric statistics will be set to “NA” (not 
applicable).
Protocol scheduled times will be used for the PK summary tables and geometric mean figures 
of the plasma concentration-time data.
Descriptive statistics for plasma concentrations that are below the LLOQ will be handled as 
described in Section 4.3.1.
All plasma PK parameters will be listed for aclidinium bromide, LAS34823, LAS34850 and 
formoterol. All PK parameters will be summarised, except for the diagnostic parameters (Rsq 
adj, λz, N and λz upper/lower intervals) which will be listed only. PK parameters will be 
summarised by Day based on the PKS, as follows:
#
Cmax, Cmin, Css,max, Css,min, Cav, AUCτ, AUClast and AUCss,τ will present n, geometric 
mean, geometric mean ± geometric SD, geometric CV%, median, arithmetic mean, SD, 
minimum and maximum.
#
t½,λz, CL/F, Vz/F and %Fluctuation will present n, arithmetic mean, SD, median, 
minimum and maximum.
#
Rac ratios, metabolite to parent ratios and λz will present n, geometric mean, geometric 
CV%, arithmetic mean, SD, median, minimum and maximum.
#
tmax and tss,max will present only n, median, minimum and maximum.
The statistics:
#
geometric mean
#
geometric mean ± geometric SD and
#
geometric CV%
will be calculated as specified in Section 4.3.4.
Individual plasma concentrations versus actual time will be plotted in linear and 
semi-logarithmic scale, with separate plots for each subject and concentrations for Day 1 and 
Day 5 (where applicable) overlaid on the same plot.
Combined individual plasma concentrations will also be plotted in linear and semi-logarithmic 
scale with separate plots for Day 1 and Day 5, and concentrations for each subject overlaid on 
the same plot.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
28
Combined individual plasma trough concentration will be plotted over time/day with all 
individuals overlaid on the same plot, in linear scale only.
Figures for the geometric mean (± geometric SD) concentration-time data will be presented in 
both a linear and semi-logarithmic scale (SD only on the linear scale), with each Day (Day 1 
and Day 5) overlaid on the same plot.
Geometric mean (± SD) plasma trough concentrations versus day profiles (pre-dose on Day 1
to Day 5) will be presented in both linear and semi-logarithmic scale (SD only on the linear 
scale).
All plots will be produced for aclidinium bromide, LAS34823, LAS34850 and formoterol. All 
mean and combined individual plots will be based on the PK analysis set. All individual plots 
will be based on the SAF.
Concentrations that are below the LLOQ will be graphically displayed as described in
Section 4.3.4.
4.2.8
Analysis of safety data
All safety data (scheduled and unscheduled) will be presented in the data listings. For data 
summaries analysis visit windowing will be done, as outlined in Section 4.1.1.
4.2.8.1
Adverse events
Adverse events will be coded using MedDRA version 20.1.
A treatment emergent adverse event (TEAE) is defined as an AE that has started after first 
dose of AB/FF 400/12 or within 15 days from the last dose. AEs with missing start date/time 
will be handled as detailed in Section 4.3.4.
Listings will be presented for each of the following:
#
All AEs, with onset and resolution, including the AE number, including classification of 
the AE as pre-treatment, post-treatment or TEAE, SOC, PT and verbatim term, onset 
date/time, resolution date/time and time from the last dose of AB/FF 400/12
#
All AEs by relationship and causality, including the PT and verbatim term, severity, 
action taken with regards to AB/FF 400/12, outcome, causality, whether the AE was 
serious, and whether the AE resulted in the subject being withdrawn
Adverse events will be summarized based on the SAF, as number and percentage of subjects 
or where applicable the number of events, with the denominator for percentages being the 
number of subjects in the SAF 
The following tabulations will be presented for TEAEs only:
#
AEs in any category 


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
29
#
AEs by SOC class and PT
#
Number and percentage of subjects with AEs by causality and PT
#
AEs by maximum reported intensity and PT
#
SAEs, by PT and SOC
#
AEs leading to discontinuation of investigational product, by PT and SOC
#
Non-serious AEs occurring in >5% of subjects
Key information (including age and sex) on AEs leading to death, SAEs and AEs leading to 
discontinuation will be separately presented and contain the following information:
#
AEs leading to death: AE as reported, PT, date of death, time from start of treatment 
with AB/FF 400/12 to onset of AE, time from start of study treatment to death, time 
from last dose to death, whether there is a reasonable possibility that the AE was caused 
by AB/FF 400/12, and whether she/he received treatment for AE.
#
Serious AEs: AE as reported, PT, time from start of treatment to onset of AE, time from 
last dose of AB/FF 400/12 to onset of AE, time from start of treatment to becoming 
serious, the outcome, action taken with AB/FF 400/12 and whether there is a reasonable 
possibility that the AE was caused by AB/FF 400/12
#
Adverse events leading to discontinuation: AE as reported, PT, time from start of 
treatment to onset of AE, time from start of treatment to discontinuation, whether the 
AE is serious, the outcome and whether there is a reasonable possibility that the AE was 
caused by AB/FF 400/12
For AEs with incomplete start or end dates/time, the time to start of treatment will not be 
calculated.
Adverse events of special interest
SOC terms, along with Standard MedDRA Query (SMQs) and PTs used to identify the 
treatment emergent AEs of special interest (AESI) are included in Table 3.
The number and percentage of subjects with a treatment emergent anticholinergic and β2
adrenergic events will be tabulated by SOC and PT.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
30
Table 3 Definition of Treatment-Emergent Adverse Events of Interest
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, unequal 
pupils, visual impairment, 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
B2 adrenergic 
events
Hypertension
Hypertension (narrow search SMQ)
Hyperglycaemia
Hyperglycaemia/new onset diabetes mellitus (narrow 
search SMQ)
Tachyarrhythmias
Tachyarrhythmias (incl supraventricular and 
ventricular tachyarrhythmias) (SMQ) (narrow and 
broad search SMQ) plus
Additional PTs: tachycardia, heart rate increased, and 
palpitations
Tremor (excl congenital)
HLT
Additional PTs: Anxiety, Nervousness, Insomnia, Headache, Dizziness, Vision 
blurred, Mydriasis, Dysgeusia, Throat irritation, Cough, Hypokalemia, Myalgia, 
Muscle spasms, Urinary retention, Urinary tract infection, Constipation, Oedema 
peripheral, Electrocardiogram QT interval abnormal, Electrocardiogram QT 
prolonged.
4.2.8.2
Vital signs and 12-lead electrocardiogram
12-lead electrocardiogram:
12-Lead ECG results performed for safety evaluation will be listed for each subject and will
include the ECG parameters (where applicable) and changes from baseline, overall 
interpretation assessment by the Investigator (normal/abnormal not clinically 
significant/abnormal clinically significant) and details of any abnormalities (e.g. flags of the 
outliers presented in Table 4). ECG parameters will also be summarised by time-point
including changes from baseline. The baseline for the safety ECG parameters will be the pre-
dose results obtained on Day 1, if missing at Day -1 or screening.
The number and percentage of subjects with outliers with respect to 12-lead ECG parameters
will be presented for the following categories in Table 4 at each time-point (and any post-
baseline visit):


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
31
Table 4 Definition of potentially clinically significant (PCS) values in 12-lead ECG 
parameters
Criteria 1
Criteria 2
QTcF intervals
a) Absolute values
> 480 milliseconds (msec)
> 500 msec
b) Absolute change from 
baseline
> 30 msec
> 60 msec
QRS interval
≥ 100 msec and an increase of 
≥ 25% over baseline value
≥ 150 msec if baseline is < 
150 msec
PR interval
≥ 200 msec and an increase of 
≥ 25% over baseline value
≥ 250 msec if baseline is < 
250 msec
Heart Rate
a) Tachycardia event
≥ 110 beats per minute (bpm) 
and an increase of ≥ 15% over 
baseline value
≥ 120 bpm if baseline is < 
120 bpm
b) Bradycardia event
≤ 50 bpm and a decrease of ≥ 
15% over baseline value
≤ 40 bpm if baseline is > 40 
bmp
bpm = beats per minute; ECG = electrocardiogram; QTcF = QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)⅓).
For QTcF and heart rate, if either condition a) or condition b) are met for one of the two 
criteria, the value will be considered potentially clinically significant (PCS).
Descriptive statistics and outlier summary, and subject-level data listing will be based on the 
SAF. For the percentage of subjects, the denominator will be the number of subjects in the 
SAF.
Calculation of the ECG parameters
Derived ECG parameters, i.e. QTcB, QTcF, HR and others as applicable, will be calculated 
for each time-point, based on values for QT and RR.
QTcB will be calculated as: QTcB = QT/RRA/P where the QT interval is in msec and the RR 
interval is in seconds
QTcF will be calculated as: QTcF = QT/RRA/Q where the QT interval is in msec and the RR 
interval is in seconds
HR will be calculated as: HR = 60/RR interval, where the RR interval is in seconds
Blood pressure
The results of the blood pressure measurements will be listed by subject in the SAF and time-
point including the changes from baseline. The baseline for blood pressure measurements will 
be the assessment prior to first dose of study medication on Day 1, if missing Day -1 or 
screening will be used instead. Subjects with notable changes from baseline will be flagged in 
the listing as "high" or "low" according to criteria in Table 5.


Statistical Analysis Plan 
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Table 5 Blood pressure notable changes from baseline 
Parameter
Flag
Criteria
Systolic blood pressure 
(mmHg)
High
observed value ≥180 and increase over baseline of ≥20
or
observed value ≥200 and baseline observed value < 200
Low
observed value ≤90 and decrease from baseline ≥20
or
observed value ≤75 and baseline observed value > 75
Diastolic blood 
pressure
(mmHg)
High
observed value ≥105 and increase over baseline of ≥15
or
observed value ≥115 and baseline < 115
Low
observed value ≤60 and decrease from baseline of ≥15
or
observed value ≤40 and baseline > 40
Descriptive statistics will be presented by time-point for both observed values and changes 
from baseline, based on the SAF.
The number and percentage of subjects with notable changes from baseline as defined in
Table 5 will be tabulated by time-point (and any post-baseline visit) based on the criteria 
provided, based on the SAF with the denominator for percentages equal to the number of 
subjects in the SAF.
4.2.8.3
Clinical laboratory assessments
Haematology and clinical chemistry values will be listed by subject and time-point including 
changes from baseline (Day -1, if missing Screening) measurements.
Listings will include a flag for out of range values for both notable abnormalities as well as 
expanded normal ranges as defined in Table 6.
Each laboratory test value will be identified as:
#
Low: lower than the lower limit of the expanded normal range (ENR),
#
Normal: within the ENR limits, and
#
High: larger than the upper limit of the ENR
with the ENR being calculated by multiplying the LLN and ULN of the laboratory by the 
factor shown in Table 6.
Moreover, treatment-emergent abnormalities including the Follow-up Period, defined as 
newly occurring or worsening, as well as notable abnormalities in laboratory parameters will 
be identified.


Statistical Analysis Plan 
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Date 03 July 2018
33
Newly occurring or worsening laboratory abnormalities in laboratory parameters will be 
identified using the ENR. A laboratory result lying outside the ENR will be considered 
abnormal.
A laboratory parameter will be defined as showing a “New” abnormality if the observed lab 
test value is within the ENR at baseline but not at post-baseline time-points, or it is outside the 
ENR at baseline and outside the ENR at endpoint at different extreme limits (from expanded 
lower limit to expanded upper limit, or vice versa).
A laboratory parameter will be defined as “Worsened” if the baseline lab test value is above 
the expanded upper limit of the corresponding normal range (xULN) specified in Table 6 and 
the ratio of endpoint value to baseline value is also greater than the corresponding coefficient 
(multiplying factor) specified in Table 6, or alternatively if the baseline laboratory test value is 
below the expanded lower limit of the corresponding normal range (xLLN) specified in the 
above table and the ratio of endpoint value to baseline value is also lower than the 
corresponding coefficient specified in Table 6.
The laboratory abnormality will be also classified as a “Notable” abnormality if it satisfies the 
criteria detailed in Table 6, having a baseline value within the notable abnormality limits.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
34
Table 6 Expanded normal ranges and notable abnormalities for laboratory parameters
Laboratory Parameter
Expanded Normal Ranges
Notable Abnormalities
MFL
MFU
Lower Limit
Upper Limit
Lower Limit
Upper Limit
Haematology
Haemoglobin
0.85
1.15
MFL × 
LLN
MFU × ULN
< 60 g/L
> 230 g/L
Haematocrit
0.85
1.15
MFL × 
LLN
MFU × ULN
< 0.24
NA
Erythrocytes count
0.85
1.15
MFL × 
LLN
MFU × ULN
NA
NA
Platelets
0.85
1.15
MFL × 
LLN
MFU × ULN
< 100 × 109/L
NA
Leukocyte count
0.85
1.15
MFL×  
LLN
MFU × ULN
< 1 × 109/L
> 30 × 109/L
Neutrophils
0.85
1.15
MFL×  
LLN
MFU × ULN
< 0.5 × 109/L
NA
Eosinophils
NA
1.15
MFL×  
LLN
MFU × ULN
NA
NA
Basophils
NA
1.15
MFL×  
LLN
MFU × ULN
NA
NA
Lymphocytes
0.85
1.15
MFL×  
LLN
MFU × ULN
NA
NA
Monocytes
NA
1.15
MFL×  
LLN
MFU × ULN
NA
NA
Clinical chemistry
Aspartate 
aminotransferase (AST)
NA
1.15
NA
MFU × ULN
NA
> 3 × ULN
Alanine 
aminotransferase(ALT)
NA
1.15
NA
MFU × ULN
NA
> 3 × ULN
Alkaline phosphatase
NA
1.15
NA
MFU × ULN
NA
> 3 × ULN
Gamma-glutamyl 
transpeptidase
NA
1.15
NA
MFU × ULN
NA
> 3 × ULN
Total bilirubin (TBL)
NA
1.15
NA
MFU × ULN
NA
> 51.3 μmol/L
Creatine-kinase
NA
1.15
NA
MFU × ULN
NA
> 10 × ULN
Lactate dehydrogenase
NA
1.15
NA
MFU × ULN
NA
> 3 × ULN
Blood urea nitrogen?
NA
1.15
NA
MFU × ULN
NA
> 17.9 mmol/L
Creatinine
NA
1.15
NA
MFU × ULN
NA
> 265 μmol/L
Uric acid
NA
1.15
NA
MFU × ULN
NA
> 714 μmol/L
Total cholesterol
NA
1.15
NA
MFU × ULN
NA
NA
Triglycerides
NA
1.15
NA
MFU × ULN
NA
NA
Glucose
0.85
1.15
MFL×  
LLN
MFU × ULN
< 2.22
mmol/L
> 22.2 mmol/L


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
35
Laboratory Parameter
Expanded Normal Ranges
Notable Abnormalities
MFL
MFU
Lower Limit
Upper Limit
Lower Limit
Upper Limit
Sodium
0.95
1.05
MFL×  
LLN
MFU × ULN
<115 mmol/L
> 165 mmol/L
Potassium
0.95 
1.05
MFL×  
LLN
MFU × ULN
< 2.6 mmol/L
> 6.9 mmol/L
Calcium, total
0.85
1.15
MFL×  
LLN
MFU × ULN
< 1.25
mmol/L
> 3.25 mmol/L
Chloride
0.95
1.05
MFL×  
LLN
MFU × ULN
NA
NA
Inorganic phosphorus
0.85 
1.15
MFL×  
LLN
MFU × ULN
NA
NA
Total Protein
0.85
1.15
MFL×  
LLN
MFU × ULN
< 20 g/L
> 90 g/L
Albumin
0.85
1.15
MFL× 
LLN
MFU × ULN
NA
NA
LLN: lower limit of normal as provided by the safety laboratory; MFL: lower multiplying factor; MFU: upper multiplying factor; ULN: 
upper limit of normal as provided by the safety laboratory.
For the classification of laboratory values, calculation of changes from baseline and for the 
purposes of summary statistics, any laboratory parameter value that is given as ‘<xx.x’ or 
‘>xx.x’ in the database will be imputed according to rules stated in Section 4.3.2.
Urinalysis results will be listed.
Descriptive statistics for haematology and clinical chemistry will be presented separately by 
time-point for both observed values and changes from baseline. 
The number and percentage of subjects with potentially clinically significant values will be 
presented by time-point (and at any post-baseline visit), and by type of shift from baseline, 
separately for haematology and clinical chemistry measurements. Shift is defined as the 
change in category (low, normal or high as above) at baseline to a post-baseline time-point. 
The denominator for percentages will be the number of subjects in the SAF. The following 
shift categories will be shown:
#
New (Low/High/Total)
#
Worsening (Low/High/Total)
#
Notable (Low/High/Total)
Cases of potential Hy’s Law, (including PHL and/or HL) where a subject has occurrences of 
AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN will be listed for each subject, 
along with their demographic characteristics, day and time-point of treatment discontinuation.
Summary statistics by treatment group will be presented for the maximum post-baseline ALT 
and AST by TBL.  


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
36
Serum pregnancy test results will be listed but not summarised.
4.3
Data handling
Since the statistical analyses will be predominantly presentations in tables and individual data 
listings, no specific action will be taken to handle missing data. A subject who withdraws 
prior to the last planned observation in a study period will be included in the analyses up to 
the time of discontinuation. In general, missing data will result in a reduced sample size for 
the given parameter. No imputation of missing data will be performed except for the below 
cases. A subject who withdraws prior to the last planned observation in the study will be 
included in the analyses up to the time of discontinuation, if no important protocol deviations 
necessitate the exclusion of collected data from the analysis.
4.3.1
Pharmacokinetic data below the lower limit of quantification (BLQ) or 
non-reportable (NR)
The LLOQs are the following:
#
Aclidinium bromide (LAS34273): 2 pg/mL
#
LAS34823: 5 pg/mL
#
LAS34850: 50 pg/mL
#
formoterol: 0.5 pg/mL
Plasma concentrations that are BLQ will be reported as not quantifiable (NQ) for all listings.
For descriptive statistics of Plasma concentration summaries:
#
Where there is a NR, these will be set to missing.
#
At a time-point where less than or equal to 50% of the values are NQ, all NQ values will 
be set to the lower limit of quantification (LLOQ), and all descriptive statistics will be 
calculated accordingly.
#
If more than 50%, but not all, of the concentrations are NQ, the geometric mean, 
geometric mean ± geometric SD and geometric CV% will be reported as not calculable 
(NC). The maximum value is reported from the individual data, and the minimum and 
median are set as NQ.
#
If all concentrations are NQ at a time-point, the geometric mean, minimum, median and 
maximum are reported as NQ and the geometric CV% and geometric mean ± geometric 
SD as NC.
#
The number of values below the LLOQ (n<LLOQ) are reported for each time-point 
along with the total number of collected values (n).


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
37
Three observations >LLOQ are required as a minimum for a plasma concentration or PK 
parameter to be summarised. Two values are presented as a minimum and maximum with the 
other summary statistics as NC.
For display in figures:
#
For mean plots: BLQ values will be handled as described for the descriptive statistics. If 
this handling results in a geometric mean of "NA", "ND" or "NQ", then the value at that 
time-point will not be plotted (made missing)
#
For individual plots and combined individual plots: BLQ values will be set to zero on 
Day 1 pre-dose; at all other time-points, BLQ values will be set to missing.
4.3.2
Precision and rounding rules for pharmacokinetic data
For PK concentration data, the listings will be presented to the same number of significant 
figures as the data received from the bioanalytical laboratory; for PK parameters, the listings 
will be presented according to the following rules: 
#
Cmax, Cmin, Css,max, Css,min – will be presented to the same number of significant figures as 
received from the bioanalytical laboratory. 
#
tmax, tss,max, λz lower and upper time limit – will be presented as received in the data, 
usually to 2 decimal places 
#
AUCτ, AUCss,τ, AUClast, t1/2,λz, CL/F, Vz/F, Cav, Rac ratios, metabolite to parent ratios, 
%Fluctuation and Rsq adj – will be presented to 3 significant figures 
#
λz – will be presented to 4 significant figures 
#
λz, N – will be presented as an integer (no decimals) 
For PK concentration data all descriptive statistics will be presented to 4 significant figures 
with the exception of the minimum and maximum which will be presented to 3 significant 
figures. 
For PK parameter data the descriptive statistics will be presented according to the following 
rules: 
#
Cmax, Cmin, Css,max, Css,min, AUCτ, AUCss,τ, AUClast, t1/2λz, CL/F, Vz/F, Cav, Rac ratios, 
metabolite to parent ratios and %Fluctuation descriptive statistics will be presented to 4 
significant figures with the exception of the minimum and maximum which will be 
presented to 3 significant figures 
#
tmax, tss,max – all descriptive statistics will be presented as received in the data, usually to 
2 decimal places 


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
38
#
λz – all descriptive statistics will be presented to 5 significant figures with the exception 
of the minimum and maximum which will be presented to 3 significant figures 
Source data shall be used in all derived PK parameter calculations without prior rounding.
4.3.3
Safety laboratory data with semi-qualitative results
For the purposes of calculating changes from baseline and summary statistics:
#
Laboratory values reported as “<xx.x” will be imputed with half of the given xx.x
#
Laboratory values reported as “>xx.x” will be imputed with 1.5 times the given xx.x 
value
4.3.4
Missing data for adverse events and medications
All adverse events and prior/concomitant medication data will be listed as recorded on the 
CRF, unless stated otherwise. For the purposes of tabulations, the following rules will be 
followed.
Missing adverse event causality
#
A causality of “related” will be assigned to an AE if the relationship to AB/FF 400/12 is 
missing for an AE and the start date of the AE shows that the AE started on or after the 
first dose of AB/FF 400/12
#
A causality of “not related” will be assigned to an AE if the relationship to AB/FF 
400/12 is missing for an AE and the start date of the AE shows that the AE started 
before the first dose of AB/FF 400/12
Missing adverse event intensity and seriousness
#
An intensity of “severe” and seriousness of “serious” will be assigned to an AE if 
missing
Missing start date of AEs and medications
Adverse events and medications with incomplete (partially known or missing) start 
dates/times will be handled as follows for the purposes of the tabulations:
#
If the start date is completely missing but the known end date is on or after the first dose 
date, then the start date will be imputed as the first day of dosing; if the known end date 
is before the first dose date, then the screening date will be used for the start date. If the 
end date is non-informative (i.e. is missing or does not contain enough information), the 
start date will be imputed as the first date of dosing;


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
39
#
If only the start day is missing the day will be imputed as the first day on which a dose 
was given in that month unless the known end date is before a dose was given in that 
month; in which case, the date will be imputed as 01. If the end date is non-informative 
(i.e. is missing or does not contain enough information), the start date will be imputed as 
the first date of dosing in the known month. If the month is not a dosing month the date 
will be imputed as 01;
#
If the start day and month are missing the date will be imputed as the first day of dosing 
in the known year unless the known end date is before a dose was given in that year; in 
which case, the start day and month will be imputed as 01Jan or with the date of 
screening if this is later. If the end date is non-informative (i.e., is missing or does not 
contain enough information), the start date will be imputed as the first date of dosing in 
the known year. If the year is not a year of dosing then the date will be imputed as 01Jan 
or with the date of screening if this is later;
#
Missing times will be imputed as 00:00 h or with the time of AB/FF 400/12 dosing for 
events starting on a dosing day.
Missing end date of AEs and medications
Missing end date of AEs will not be imputed. 
For medication, when the start date and the end date are both incomplete, first impute the start 
date following the steps in the section above “Missing start date of AEs and medications”, and 
then impute the end date, with the following steps:
#
If the end date is completely missing or only the year is missing, it will be imputed with 
last visit date/year or the medication start date/year, whichever occurs later. 
#
If the end year is not missing but the month is missing, then the following will be 
imputed: 
o
if the end year is prior to the year of last dose, then December 31 will be used 
o
if the end year is equal to the year of last dose then the month and day of last dose 
will be assigned, 
o
otherwise, January 1 will be assigned to the missing fields
#
If only the end day is missing, then the following will be imputed: 
o
if the month and year are the same as the last dose, then the day of last dose will be 
assigned. 
o
if the year is prior to the last dose or the years are the same but the month is prior to 
last dose, then last day of the month will be used. 


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
40
o
If the year is after the last dose date or the years are the same but the month is after 
last dose, then first day of the month will be used.
4.3.5
Computation of derived variables
4.3.5.1
Definition of Baseline values
The Baseline value for all variables will be the last available value prior to the first AB/FF 
400/12 administration. Scheduled or unscheduled measurements can be used as the Baseline 
value.
Where available, change from Baseline will be listed and summarised for all numeric 
variables, and is calculated as:-
Gℎ 
 UV	 = WV −UV	 WV
4.3.5.2
Summary statistics
For the geometric mean, geometric mean +/- SD and geometric CV%, the following holds:
#
SDL is the arithmetic standard deviation of the natural log-transformed variable
#
ML is the arithmetic mean of the natural log-transformed variable
#
exp denotes the power function based on the natural base e
Geometric mean is calculated as exp[ML].
Geometric mean +/- geometric SD is calculated as exp[ML +/- SDL].
Geometric CV% is calculated as 100 x sqrt[exp(SDL2) – 1].
5.
INTERIM ANALYSES
No interim analysis will be performed.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
None.


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
41
7.
APPENDIX
7.1
Appendix I – List of Tables, figures and listings
7.1.1
TABLES
11. SUMMARY TABLES AND FIGURES, LISTINGS, AND NARRATIVES
SUBJECT DISPOSITION
Table 11.1.1.1.1
Subject disposition (All subjects screened)
Table 11.1.1.1.2
Screening failures – inclusion criteria (All subjects screened)
Table 11.1.1.1.3
Screening failures – exclusion criteria (All subjects screened)
Table 11.1.2.1.1
Analysis sets (All subjects screened)
DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Table 11.1.3.1.1
Demographic characteristics (SAF)
Table 11.1.3.1.2
Subject characteristics (SAF)
Table 11.1.3.1.3
History of tobacco use (SAF)
Table 11.1.3.1.4
COPD Characteristics at Baseline (SAF)
PRIOR AND CONCOMITANT MEDICATION
Table 11.1.4.1.1
Prior medication (SAF)
Table 11.1.4.1.2
Concomitant medication (SAF)
PHARMACOKINETICS
Table 11.2.1.1.1
Summary of plasma concentrations (pg/mL) for aclidinium bromide (PKS)
Table 11.2.1.1.2
Summary of plasma concentrations (pg/mL) for LAS34823 (PKS)
Table 11.2.1.1.3
Summary of plasma concentrations (pg/mL) for LAS34850 (PKS)
Table 11.2.1.1.4
Summary of plasma concentrations (pg/mL) for formoterol (PKS)
Table 11.2.7.1.1
Summary of plasma pharmacokinetic parameters for aclidinium bromide
(PKS)
Table 11.2.7.1.2
Summary of plasma pharmacokinetic parameters for LAS34823 (PKS)
Table 11.2.7.1.3
Summary of plasma pharmacokinetic parameters for LAS34850 (PKS)
Table 11.2.7.1.4
Summary of plasma pharmacokinetic parameters for formoterol (PKS)
ADVERSE EVENTS
Table 11.3.2.1.1
Adverse events in any category (SAF)
Table 11.3.2.1.2
Adverse events by system organ class and preferred term (SAF)
Table 11.3.2.1.3
Adverse events by preferred term and maximum reported intensity (SAF)
Table 11.3.2.1.4
Adverse events by preferred term and investigator’s causality assessment
(SAF)
Table 11.3.3.1.1
Adverse events with outcome of death – key subject information (SAF)
Table 11.3.4.1.1
Serious adverse events, by system organ class and preferred term (SAF)


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
42
Table 11.3.4.1.2
Serious adverse events – key subject information (SAF)
Table 11.3.5.1.1
Adverse events leading to discontinuation of investigational product, by 
system organ class and preferred term (SAF)
Table 11.3.5.1.2
Adverse events leading to discontinuation– key subject information (SAF)
Table 11.3.6.1.1
Non-serious adverse events occurring in >5% of subjects (SAF)
Table 11.3.6.2.1
Anticholinergic adverse events by system organ class, and preferred term 
(SAF)
Table 11.3.6.2.2
β2 adrenergic adverse events by system organ class, and preferred term 
(SAF)
LABORATORY VARIABLES
Table 11.3.7.1.1
Haematology laboratory variables over time (SAF)
Table 11.3.7.1.2
Haematology variables, shift table of treatment-emergent potentially 
clinically significant values (SAF)
Table 11.3.7.1.3
Clinical chemistry laboratory variables over time (SAF)
Table 11.3.7.1.4
Clinical chemistry variables, shift table of treatment-emergent potentially 
clinically significant values (SAF)
Table 11.3.7.1.5
Maximum post-baseline ALT and AST by maximum total bilirubin for
assessing Hy’s Law criteria (SAF)
Table 11.3.7.2.1
Subjects with potential Hy's Law combined ALT or AST, and TBL 
elevations - individual subject data (SAF)
VITAL SIGNS & ECG
Table 11.3.8.1.1
Vital signs variables over time (SAF)
Table 11.3.8.1.2
Number (%) of subjects with blood pressure notable changes from baseline
(SAF)
Table 11.3.8.2.1
ECG variables, over time (SAF)
Table 11.3.8.2.2
ECG variables treatment-emergent potentially clinically significant values 
(SAF)
7.1.2
FIGURES
Figure 11.2.3.1.1 Geometric mean (± geoSD) plasma concentration (pg/mL) of aclidinium 
bromide versus time (Linear scale) (PKS)
Figure 11.2.3.1.2 Geometric mean plasma concentration (pg/mL) of aclidinium bromide 
versus time (Semi-logarithmic scale) (PKS)
Figure 11.2.3.2.1 Geometric mean (± geoSD) plasma concentration (pg/mL) of LAS34823
versus time (Linear scale) (PKS)
Figure 11.2.3.2.2 Geometric mean plasma concentration (pg/mL) of LAS34823 versus time 
(Semi-logarithmic scale) (PKS)
Figure 11.2.3.3.1 Geometric mean (± geoSD) plasma concentration (pg/mL) of LAS34850 
versus time (Linear scale) (PKS)


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
43
Figure 11.2.3.3.2 Geometric mean plasma concentration (pg/mL) of LAS34850 versus time 
(Semi-logarithmic scale) (PKS)
Figure 11.2.3.4.1 Geometric mean (± geoSD) plasma concentration (pg/mL) of formoterol
versus time (Linear scale) (PKS)
Figure 11.2.3.4.2 Geometric mean plasma concentration (pg/mL) of formoterol versus time 
(Semi-logarithmic scale) (PKS)
Figure 11.2.4.1.1 Geometric mean (± geoSD) plasma trough concentration (pg/mL) of 
aclidinium bromide versus study day (Linear scale) (PKS)
Figure 11.2.4.1.2 Geometric mean plasma trough concentration (pg/mL) of aclidinium 
bromide versus study day (Semi-logarithmic scale) (PKS)
Figure 11.2.4.2.1 Geometric mean (± geoSD) plasma trough concentration (pg/mL) of 
LAS34823 versus study day (Linear scale) (PKS)
Figure 11.2.4.2.2 Geometric mean plasma trough concentration (pg/mL) of LAS34823 versus 
study day (Semi-logarithmic scale) (PKS)
Figure 11.2.4.3.1 Geometric mean (± geoSD) plasma trough concentration (pg/mL) of 
LAS34850 versus study day (Linear scale) (PKS)
Figure 11.2.4.3.2 Geometric mean plasma trough concentration (pg/mL) of LAS34850 versus 
study day (Semi-logarithmic scale) (PKS)
Figure 11.2.4.4.1 Geometric mean (± geoSD) plasma trough concentration (pg/mL) of 
formoterol versus study day (Linear scale) (PKS)
Figure 11.2.4.4.2 Geometric mean plasma trough concentration (pg/mL) of formoterol versus 
study day (Semi-logarithmic scale) (PKS)
Figure 11.2.5.1.1 Individual plasma concentrations (pg/mL) of aclidinium bromide for 
subject <E0001001> versus time (Linear scale) (SAF)
Figure 11.2.5.1.2 Individual plasma concentrations (pg/mL) of aclidinium bromide for 
subject <E0001001> versus time (Semi-logarithmic linear scale) (SAF)
Figure 11.2.5.2.1 Individual plasma concentrations (pg/mL) of LAS34823 for subject 
<E0001001> versus time (Linear scale) (SAF)
Figure 11.2.5.2.2 Individual plasma concentrations (pg/mL) of LAS34823 for subject 
<E0001001> versus time (Semi-logarithmic scale) (SAF)
Figure 11.2.5.3.1 Individual plasma concentrations (pg/mL) of LAS34850 for subject 
<E0001001> versus time (Linear scale) (SAF)
Figure 11.2.5.3.2 Individual plasma concentrations (pg/mL) of LAS34850 for subject 
<E0001001> versus time (Semi- logarithmic scale) (SAF)
Figure 11.2.5.4.1 Individual plasma concentrations (pg/mL) of formoterol for subject 
<E0001001> versus time (Linear scale) (SAF)
Figure 11.2.5.4.2 Individual plasma concentrations (pg/mL) of formoterol for subject 
<E0001001> versus time (Semi- logarithmic scale) (SAF)
Figure 11.2.6.1.1 Combined individual plasma concentrations (pg/mL) of aclidinium bromide 
versus time (Linear scale) (PKS) Treatment Day 1
Figure 11.2.6.1.2 Combined individual plasma concentrations (pg/mL) of aclidinium bromide 
versus time (Semi‑logarithmic scale) (PKS) Treatment Day 1


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
44
Figure 11.2.6.1.3 Combined individual plasma concentrations (pg/mL) of aclidinium bromide 
versus time (Linear scale) (PKS) Treatment Day 5
Figure 11.2.6.1.4 Combined individual plasma concentrations (pg/mL) of aclidinium bromide 
versus time (Semi‑logarithmic scale) (PKS) Treatment Day 5
Figure 11.2.6.2.1 Combined individual plasma concentrations (pg/mL) of LAS34823 versus 
time (Linear scale) (PKS) Treatment Day 1
Figure 11.2.6.2.2 Combined individual plasma concentrations (pg/mL) of LAS34823 versus 
time (Semi‑logarithmic scale) (PKS) Treatment Day 1
Figure 11.2.6.2.3 Combined individual plasma concentrations (pg/mL) of LAS34823 versus 
time (Linear scale) (PKS) Treatment Day 5
Figure 11.2.6.2.4 Combined individual plasma concentrations (pg/mL) of LAS34823 versus 
time (Semi‑logarithmic scale) (PKS) Treatment Day 5
Figure 11.2.6.3.1 Combined individual plasma concentrations (pg/mL) of LAS34850 versus 
time (Linear scale) (PKS) Treatment Day 1
Figure 11.2.6.3.2 Combined individual plasma concentrations (pg/mL) of LAS34850 versus 
time (Semi-logarithmic scale) (PKS) Treatment Day 1
Figure 11.2.6.3.3 Combined individual plasma concentrations (pg/mL) of LAS34850 versus 
time (Linear scale) (PKS) Treatment Day 5
Figure 11.2.6.3.4 Combined individual plasma concentrations (pg/mL) of LAS34850 versus 
time (Semi-logarithmic scale) (PKS) Treatment Day 5
Figure 11.2.6.4.1 Combined individual plasma concentrations (pg/mL) of formoterol versus 
time (Linear scale) (PKS) Treatment Day 1
Figure 11.2.6.4.2 Combined individual plasma concentrations (pg/mL) of formoterol versus 
time (Semi-logarithmic scale) (PKS) Treatment Day 1
Figure 11.2.6.4.3 Combined individual plasma concentrations (pg/mL) of formoterol versus 
time (Linear scale) (PKS) Treatment Day 5
Figure 11.2.6.4.4 Combined individual plasma concentrations (pg/mL) of formoterol versus 
time (Semi-logarithmic scale) (PKS) Treatment Day 5
Figure 11.2.6.5.1 Combined individual plasma trough concentrations (pg/mL) of aclidinium 
bromide versus time (Linear scale) (PKS)
Figure 11.2.6.5.2 Combined individual plasma trough concentrations (pg/mL) of LAS34823 
(Linear scale) (PKS)
Figure 11.2.6.5.3 Combined individual plasma trough concentrations (pg/mL) of LAS34850 
(Linear scale) (PKS)
Figure 11.2.6.5.4 Combined individual plasma trough concentrations (pg/mL) of Formoterol 
(Linear scale) (PKS)
7.1.3
LISTINGS
SUBJECT DISPOSITION
Appendix 12.2.1.1.1 Discontinued subjects (All subjects screened)
Appendix 12.2.1.1.2 Subject completing the study (All subjects screened)
Appendix 12.2.2.1.1 Subjects with important protocol deviations (All subjects screened)
Appendix 12.2.3.1.1 Subjects excluded from analysis sets (All subjects screened)


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
45
DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Appendix 12.2.4.1.1 Demographic and baseline subject characteristics (SAF)
Appendix 12.2.4.2.1 Medical and surgical history (SAF)
Appendix 12.2.4.3.1 History of tobacco use (SAF)
Appendix 12.2.4.3.2 COPD Characteristics at Baseline (SAF)
Appendix 12.2.4.3.3 Spirometry data (SAF)
Appendix 12.2.4.4.1 Prior medication (SAF)
Appendix 12.2.4.4.2 Concomitant medication (SAF)
DRUG ADMINISTRATION
Appendix 12.2.5.1.1 Administration of investigational product (SAF)
Appendix 12.2.5.2.1 Overdose of investigational product (SAF)
Appendix 12.2.5.3.1 Drug Accountability (SAF)
Appendix 12.2.5.4.1 Rescue Medication (SAF)
PHARMACOKINETIC DATA
Appendix 12.2.6.1.1 Individual pharmacokinetic sample collection times and deviations
(SAF)
Appendix 12.2.6.2.1 Individual plasma aclidinium bromide concentrations (pg/mL) (SAF)
Appendix 12.2.6.2.2 Individual plasma LAS34823 concentrations (pg/mL) (SAF)
Appendix 12.2.6.2.3 Individual plasma LAS34850 concentrations (pg/mL) (SAF)
Appendix 12.2.6.2.4 Individual plasma formoterol concentrations (pg/mL) (SAF)
Appendix 12.2.6.3.1 Individual plasma aclidinium bromide pharmacokinetic parameters
(SAF)
Appendix 12.2.6.3.2 Individual plasma LAS34823 pharmacokinetic parameters (SAF)
Appendix 12.2.6.3.3 Individual plasma LAS34850 pharmacokinetic parameters (SAF)
Appendix 12.2.6.3.4 Individual plasma formoterol pharmacokinetic parameters (SAF)
Appendix 12.2.6.4.1 Individual plasma aclidinium bromide lambda z related parameters 
(SAF)
Appendix 12.2.6.4.2 Individual plasma LAS34823 lambda z related parameters (SAF)
Appendix 12.2.6.4.3 Individual plasma LAS34850 lambda z related parameter (SAF)
Appendix 12.2.6.4.4 Individual plasma formoterol lambda z related parameter (SAF)
ADVERSE EVENT LISTINGS
Appendix 12.2.7.1.1 All adverse events – onset and resolution (SAF)
Appendix 12.2.7.2.1 All adverse events – relationship and causality (SAF)
LABORATORY LISTINGS
Appendix 12.2.8.1.1 Individual laboratory data – haematology (SAF)
Appendix 12.2.8.2.1 Individual laboratory data – clinical chemistry (SAF)
Appendix 12.2.8.3.1 Individual laboratory data – urinalysis (SAF)
Appendix 12.2.8.4.1 Individual laboratory data – Serum Pregnancy Test (SAF)
VITAL SIGNS AND ECG LISTINGS


Statistical Analysis Plan 
Study Code D6572C00001 / M-AS464-01
Edition Number 2.0
Date 03 July 2018
46
Appendix 12.2.9.1.1 Individual vital signs data (SAF)
Appendix 12.2.10.1.1 12-lead safety electrocardiogram data (SAF)