Clinical trial NCT03276052
Conditions: Healthy Volunteers
Keywords: Pharmacokinetics
Sponsor: AstraZeneca
Start date: 2021-10-14; Completion date: 2021-11-26
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
A Phase I, single centre, open-label study to investigate the pharmacokinetics (PK), safety and tolerability of single and multiple twice daily doses of inhaled Aclidinium Bromide in healthy Chinese male and female subjects.

Detailed description:
Screening will be performed within 21 days of dosing on Day 1. Eligible participants will be admitted to the trial center on Day -1.

Subjects will receive single dose on Day 1, twice daily regimen is from D5 to D8, and only morning dose will be given on Day 9.

During treatment period, from Day 1 through Day 11 at Visit 2, safety measurements (blood pressure, 12-lead ECG; and AE/SAE monitoring) and blood samples for PK assessments will be collected at predetermined time points.

Clinical laboratory tests (haematology, serum biochemistry and urinalysis) will be performed under fasting conditions at Day -1 at Visit 2.

A follow-up visit will be performed on Day 15.

Arms: arm 1: One inhalation from the 400 μg Aclidinium Bromide inhaler.
Interventions: intervention 1: Aclidinium Bromide 400 μg
Intervention descriptions: intervention 1: Aclidinium Bromide 400 μg BID inhalation powder. One oral inhalation via Genuair® dry powder inhaler (DPI)

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
A Phase I, Open-Label, Single and Multiple Dose (Twice-Daily), Clinical 
Trial to Evaluate the Pharmacokinetics, Safety and Tolerability of 
Aclidinium Bromide 400 μg Administered by Inhalation in Healthy Chinese 
Participants 
 
ClinicalTrials.gov Identifier: NCT03276052 
 
 
Date of Protocol: 05 Feb 2021 


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This document contains confidential commercial information, disclosure of which is 
prohibited without providing advance notice to AstraZeneca and opportunity to object.
Clinical Study Protocol D6572C00002
Drug Substance
Aclidinium bromide
Study Code
D6572C00002
M-AS273-01
Version
4.0  
Date
05 Feb 2021
A Phase I, Open-Label, Single and Multiple Dose (Twice-Daily), Clinical 
Trial to Evaluate the Pharmacokinetics, Safety and Tolerability of 
Aclidinium Bromide 400 μg Administered by Inhalation in Healthy Chinese 
Participants
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden




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Human immunodeficiency virus (HIV) antibody test is updated to include HIV type 2 and 
align with the common testing at sites which usually includes both HIV types, 1 and 2. 
Protocol synopsis, Pharmacokinetic Assessments 
The temperature storage range for the PK sample has been clarified to be -70 ±10°C. 
Protocol synopsis, statistical methods
Due to removal of the 200µg and 800µg treatment arms, frequency counts for qualitative 
variables and descriptive statistics for quantitative variables will be summarised across all 
participants and not by treatment (dose level of aclidinium bromide). 
The removal of the 200µg and 800µg doses means that dose proportionality of aclidinium 
bromide and its metabolites will no longer be analysed for PK parameters. Time 
dependency in PK will still be evaluated for aclidinium bromide 400µg.
Section 1.1 Background and rationale for conducting this study
-
Dates of marketing authorisations in the European union, Norway and Iceland, and in 
the United States are clarified to 20 Jul 2012 and 23 Jul 2012 respectively. The number 
of countries where the product is authorized (92) has also been updated, with Korea 
added to the list of authorized countries. 
-
Number of clinical trials and number of patients exposed to aclidinium bromide are 
updated per the Investigator’s Brochure. 
-
Inclusion of a clinical trial completed recently (D6560C00002) and an ongoing clinical 
trial (D6570C00002, also known as M-AS464-30 and part of the clinical development in 
China) with aclidinium bromide 400µg are added to the description to provide the most 
recent data in terms of safety. 
Section 1.4.1 Study Conduct Mitigation During Study Disruptions Due To Cases Of Civil 
Crisis, Natural Disaster, Or Public Health Crisis
Appendix D. Changes Related to Mitigation of Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis
The impact of COVID-19 has highlighted the risk to continuity of clinical trials during 
times of study disruption, whether by civil crisis, natural disaster or public health crisis. 
This section details the measures that may be implemented if a participant is not able to 
visit a study site to ensure that the clinical trial can continue, whilst minimizing risk to the 
participant, maintaining compliance with GCP, and minimizing risks to study integrity. 
These changes will only be initiated at a time of study disruption.    
Therefore, new wording was added, which would give guidance on how the study could 
continue in the event of a serious disruption with, details of mitigation that could be 
employed to ensure study continuity.
Section 3.1 Inclusion criteria


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Inclusion#2 explanatory note clarified that the method of birth control should be a non-
hormonal product, which ensure consistency with the medication restrictions (section 3.2 
exclusion#8 and section 7.8 Prior and concomitant medication).
Inclusion#3 body mass index (BMI) updated from ≤26 kg/m2 to ≥19 and ≤26 kg/m2 and 
body weight removed in order to ensure inclusion of participants with a BMI within the 
range expected for a healthy population.
Inclusion#4 Resting heart rate updated from 45 to 50 bpm as expected for healthy 
participants and aligned to the initial protocol submitted to the Regulatory Authority. 
Inclusion#6 Added a reference to section 7.4 to highlight the instruction about training on 
DPI inhaler use is followed and documented properly. 
Section 3.2 Exclusion criteria
Exclusion#4 QTcF criteria updated from ≥430 msec for male and ≥450msec for female to 
450msec and 460msec for male and female respectively. This change is aligned to 
AHA/ACCF/HRS recommendations for the standardization and interpretation of the 
electrocardiogram. 
Exclusion#13 is newly added to exclude participants with a previous history of COVID-19 
infection. 
Exclusion#19 is newly added to ensure any other condition not considered in the exclusion 
criteria, but relevant per the investigator’s opinion, can be considered exclusionary for the 
study. 
Exclusion#13 and #19 exploratory note is added to clarify that local guidance is to be 
followed for prevention of spreading and management of COVID-19 infection.
Section 3.2 Exclusion criteria, exclusion#8
Section 7.8 Prior and Concomitant medication
Exclusion #8, washout period for prior medication and restriction for concomitant 
medication are applicable to any medication, but it has been updated to include vaccines
and add clarity on the requirements.
Section 3.7 Methods of unblinding
This section is now considered as “not applicable” as randomisation is removed from this 
study. 
Section 3.8.1 Dietary and Fluid Restrictions
The instruction has been updated to provide some flexibility in relation to the 
documentation on the amount of food and low fat (<20g) is not a requirement any longer. 
The site can follow their own SOPs. 
Section 3.8.2 Other Restrictions


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Requirement on the blood or plasma donation post follow-up visit is removed, as that was 
required post-study completion, which may be out of the study scope.  
Section 3.9.1 Procedures for discontinuation of a subject from investigational product 
and from the study
Section removed from this CSP version as most of the instruction was covered by section 
3.9 and additional information was kept in that section (question about reasons to 
discontinuation, presence of adverse events, return of study drugs, reference to assessment 
to be conducted per table 1). 
Section 4, table 1 Schedule of Assessments 
Footnote b, definition of concomitant medication is updated per the latest version of the 
statistical analysis plan. 
Footnote j, inclusion of the full description for breakfast on treatment days is added to 
clarify on the requirements. 
Section 4.1. Enrolment/screening period
Day-1 is part of the enrolment/screening period therefore all details about Day-1 (Visit 2) 
are moved from section 4.2 to this section. 
Section 4.2.1 Treatment Period (Visit 2: Day 1 to Day 11)
The duration of this period has been clarified in the text (from Day 1 until completion of the 
48-hour PK sample collection and safety assessment on Day 11).
Section 5.1.2 Physical examination
Reference to “Medical History/Physical examination eCRF form” is replaced by “Medical 
History eCRF form” according to the eCRF standard design. 
Section 5.2.1 Collection of samples
In order to give more flexibility and improve the logistics at site, the accepted time window 
for PK pre-dose time point is updated from "±10 min" to "within 30 min prior to IP 
administration" on Day 1 and Day 9. It is also updated from "±10 min" to "within 10 min 
prior to IP administration" on Days 6-8.
Section 6.2 Definition of serious adverse event
New instruction on the reporting of and severity for malignant tumours have been added to 
the CSP in line with the latest CSP template. 
Section 6.6.1 Maternal exposure
A clarification on the type of CRF to be used is added: eCRF will be used for pregnancy 
reporting and paper based form will be used for reporting of pregnancy outcome.
Section 7.1 Identity of investigational product(s)
It has been clarified that the empty Genuair® for training can be used as needed to learn the 
correct technique for use of the device. 


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Section 7.2 Dose and treatment regimens
The treatment dose of 400 μg aclidinium bromide will be given as 1 inhalation, so “one 
inhalation” is added to the single morning dose description to make it clear.  
Section 7.3 Labelling
Instruction updated to clarify that Treatment period, Treatment dose and Randomisation 
number blank fields are not applicable to complete on the label as per current CSP. 
Section 7.4 Training on DPI inhaler use
The importance of the proper inhalation technique and training has been highlighted in this 
section, as well as the requirement on the distribution of the written instructions to the 
participant and documentation to be provided by PI. 
Section 7.8 Prior and concomitant medication
Description is updated to allow that medication for treating adverse event is given to the 
subjects without requiring further sponsor approval that may delay a timely treatment. 
Section 8. Statistical analyses
Due to removal of the 200µg and 800µg treatment arms, frequency counts for qualitative 
variables and descriptive statistics for quantitative variables will be summarised across all 
participants and not by treatment (dose level of aclidinium bromide). This affects tables 
related to participant disposition, demographic and baseline characteristics, prior and 
concomitant medication, pharmacokinetic data, adverse events, blood pressure, 12-Lead 
ECG and laboratory assessments. Additionally, for pharmacokinetic data, plots of geometric 
means (± geometric SD) will be presented based on all participants and not by dose level.
The removal of the 200µg and 800µg doses means that dose proportionality of aclidinium 
bromide and its metabolites will no longer be analysed for PK parameters. Time 
dependency in PK will still be evaluated for aclidinium bromide 400µg.
Section 10.3 Ethics and regulatory review
Regulatory Reporting Requirements for SAEs added according to the latest CSP template. 
Appendix A Additional Safety Information
Medication error language has been added for consistency with latest CSP template.
Appendix C Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law
This section has been updated to ensure consistency with the latest CSP template.
Some minor changes in the format, typo correction and update to terms such us subject(s) 
changed to participant(s), randomize replaced by randomise, center replaced by centre, 




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resting diastolic blood pressure ≥ 90 or ≤ 50 mmHg at Visit 1 (Screening) or Day -1 at Visit 
2.
Exclusion criteria 7 modified to delete HBc antibody IgM from serology as per PI request. 
Laboratory parameter also deleted from Table 2 in section 5.1.1 (Laboratory Safety 
Assessments)
Exclusion criteria 11 modified to “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 
screening (Visit 1).” as per site request to include blood/plasma donation maximum volume 
allowed.
Section 3.8.1 (Dietary and Fluid Restrictions)- Inclusion of sentence: “Time window 
allowance for each meal is ± 1 hour, except on Day 1/8 and Day15/22 where breakfast will 
not be served.”. 
Text regarding documentation of the percentage or amount of unconsumed food for each 
subject has been modified to clarify that the site should at least document this information 
for Day 1/15 and Day 8/22. 
The site is no longer required to provide a copy of the menu with the total nutritional 
content of each meal to the Sponsor. Relevant sentence has been deleted.
Section 4 (Study Plan and timing of procedures)- Study Plan and footnotes have been 
updated according to the below changes.
The blood pressure should be determined in sitting position after 5 minutes instead of 
supine position as per site standard procedures.
Inclusion of reference to section 5.2.1 for PK sample collection time window allowance.
Inclusion of time window allowance for ECG (± 15 min) and blood pressure (± 30 min) 
measurements post IP administration.
Urinalysis has been added to Day -1 and Day 10 to match the schedule for other safety lab 
tests as per site request.
Section 5.2.1 (Collection of samples)- Inclusion of recommended time window allowance 
for PK time points.
Section 5.6 (Total blood volume)- Table 3 footnote has been updated to include serum 
pregnancy test only to be performed for women of childbearing potential.
Section 6.3.1 (Time period for collection of adverse events)- Inclusion of sentence “In case 
an SAE is notified to the investigator after last follow up contact as per protocol, this should 




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PROTOCOL SYNOPSIS
A Phase I, Open-Label, Single and Multiple Dose (Twice-Daily), Clinical 
Trial to Evaluate the Pharmacokinetics, Safety and Tolerability of 
Aclidinium Bromide 400 µg Administered by Inhalation in Healthy Chinese 
Participants
Principal Investigator
The name and curriculum vitae of the investigator participating in the trial will be detailed in 
the Clinical Study Report of the trial.
Study site(s) and number of participants planned
Twenty (20) healthy volunteers are planned to be dosed in one centre in China.
Study period
Phase of development
Estimated date of first subject enrolled
Q2-Q3 2021
Phase I
Estimated date of last subject completed
Q4 2021
Study design
This is a Phase I, single centre, open-label study to investigate the pharmacokinetics (PK), 
safety and tolerability of single and multiple twice daily doses of inhaled aclidinium bromide 
400 μg in healthy Chinese male and female participants.
Twenty healthy Chinese participants, aged 18 to 45 years, will participate in the study. Site 
will be instructed to recruit the same number of males and females to try to get a balanced 
distribution by gender in the study as much as possible.  
Participants will be admitted to the trial centre on Day -1 and will be discharged on Day 11, 
48 hours after last IP administration on Day 9 and after the completion of the 48-hour PK 
sample collection and safety assessment on Day 11. A follow-up visit will be performed on 
Day 15 (±2). 
Safety measurements and blood samples for PK assessment will be collected at predetermined 
time points on Days 1 through 11.  


Clinical Study Protocol Synopsis
Drug Substance Aclidinium bromide
Study Code M-AS273-01 / D6572C00002
Version 4.0
Date 05 Feb 2021
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The treatment period will consist of a single dose of aclidinium bromide 400 μg followed by a 
96 hours wash out period and then the same treatment will be administered twice-daily for 
five consecutive days. 
Participants prematurely discontinued from the study will not be replaced with the exception 
of reasons related to study disruption due to cases of civil crisis, natural disaster, or public 
health crisis. 
Objectives
Primary Objective:
Outcome Measure:
To investigate the pharmacokinetics (PK) 
of aclidinium bromide and its metabolites 
after single and multiple doses (twice-daily 
[BID]) of aclidinium bromide 400 μg in 
Chinese Healthy volunteers
The following pharmacokinetic parameters will 
be determined when possible, for aclidinium 
bromide and its metabolites after single dose 
administration:
Cmax, tmax, λz, t½λz, AUClast, AUC, AUC(0-∞), Cmin, 
CL/F*, Vz/F* 
The following PK parameters will be calculated 
for aclidinium bromide after 5 days of repeated 
dose administration:
Css,max, tss,max, λz, t½λz, AUCss,, CL/F*, Vz/F*, 
Css,av, %Fluctuation, Css,min, Rac(Cmax), Rac(AUC) 
and Rac(Cmin).
Additional parameters may be determined where 
appropriate.
*only for aclidinium bromide
Secondary Objective:
Outcome Measure:
To evaluate the safety, and tolerability of 
aclidinium bromide 400 μg after single and 
multiple dose administration (twice-daily 
[BID]) in healthy Chinese participants.
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 participants will be screened within 21 days 
prior to the first investigational product (IP) dose administration on Day 1 at Visit 2. 


Clinical Study Protocol Synopsis
Drug Substance Aclidinium bromide
Study Code M-AS273-01 / D6572C00002
Version 4.0
Date 05 Feb 2021
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Eligibility screening will consist of inclusion and exclusion criteria evaluation; complete 
medical and surgical history; smoking history; prior medications; demographics; inhaler 
training; physical examination, body weight and height; blood pressure; 12-lead 
electrocardiogram (ECG); 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]); urine 
drugs of abuse and alcohol screen; and adverse event (AE) monitoring.
Upon admission to the trial centre on Day -1 at Visit 2 (the day preceding the first day of IP 
administration [Day 1]), the following safety procedures are to be performed: review of 
inclusion and exclusion criteria; inhaler training; 12-lead ECG; clinical laboratory tests 
(haematology and serum biochemistry); physical examination; blood pressure; serum 
pregnancy test for women of childbearing potential; urine drugs of abuse and alcohol screen; 
and AE monitoring.
Each eligible participant will enter on treatment period on Day 1. On that same day, 
participants will receive a single dose of aclidinium bromide in the morning (AM) via the 
Genuair® DPI, followed by a wash out period of 96 hours. On Day 5 through Day 8, 
participants will receive twice daily (BID) doses of aclidinium bromide (AM and PM) via the 
Genuair® DPI and on Day 9, participants will receive only the aclidinium bromide AM dose 
via the Genuair® DPI. Participants will be discharged on Day 11, 48 hours after last IP 
administration. 
From Day 1 through Day 11 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. 
Clinical laboratory tests (haematology, serum biochemistry and urinalysis) and serum 
pregnancy test for women of childbearing potential will be performed under fasting conditions 
on Day-1 at Visit 2 and 48 hours after last IP administration on Day 11. 
A follow up visit will be performed on Day 15 (±2). The following procedures are to be 
performed at the Follow-up Visit: recording of concomitant medications; physical 
examination; blood pressure; 12-lead ECG and AE monitoring.
Participants who prematurely discontinue from the study (withdrawal) will participate in a 
Premature Discontinuation Visit that will include physical examination, clinical laboratory 
tests (haematology, serum biochemistry and urinalysis), 12-lead ECG, blood pressure, serum 
pregnancy test for women of childbearing potential, and assessment of AEs and concomitant 
medication to ensure participant's safety.
For safety assessments, blood and urine samples tests will be sent to the site local laboratory 
for analysis. Drugs of abuse and alcohol screen will be performed locally at the site. 
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 


Clinical Study Protocol Synopsis
Drug Substance Aclidinium bromide
Study Code M-AS273-01 / D6572C00002
Version 4.0
Date 05 Feb 2021
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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. 
Pharmacokinetic Assessments 
Serial blood samples will be collected for PK assessments of aclidinium bromide and its 
metabolites (LAS34823 and LAS34850) in plasma at the following time points: 

Day 1: pre-morning dose, 5, 15, 30 min and 1h, 1.5h, 2, 3, 4, 6, 8, 12, 24, 36 
and 48 hours. (15 time points)

Day 6-8: pre-morning and pre-evening dose (6 time points)

Day 9: pre-morning dose, 5, 15, 30 min and 1h, 1.5h, 2, 3, 4, 6, 8, 12, 24, 36 
and 48 hours (15 time points)
All PK plasma specimens will be sent to Central laboratory 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 ±10°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 Central Laboratory 
Services.
Target population
Twenty (20) healthy Chinese male and non-pregnant, non-lactating female participants, 
between 18 and 45 years old, will be dosed.
Duration of treatment
The total duration of the trial for each participant will be approximately 5.5 weeks. There will 
be a run-in period of up to 21 days followed, by a treatment period, which will include a 
single dose of aclidinium bromide, followed by a 96 hours wash out period and then the same 
treatment being administered twice daily for four consecutive days, plus morning dose on day 
9, and a follow up visit that will be performed on Day 15 (±2).
Investigational product, dosage and mode of administration
Aclidinium bromide 400 μg BID inhalation powder will be administered via the Genuair®
device (dry powder inhaler, DPI) via oral inhalation (1 inhalation).
Statistical methods
No formal statistical hypothesis testing will be performed.  The analyses of PK, safety and 
tolerability data will be summarised descriptively including tables, listings and figures, as 
appropriate.


Clinical Study Protocol Synopsis
Drug Substance Aclidinium bromide
Study Code M-AS273-01 / D6572C00002
Version 4.0
Date 05 Feb 2021
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Pharmacokinetic outcomes: 
The time dependency will be evaluated by comparing AUCss,on Day 9 with AUC(0-∞) on Day 
1. Accumulation will be evaluated by comparing AUCss,on day 9 with AUCon Day 1 and 
Css,max on Day 9 with Cmax on Day 1.  
A linear mixed-effect model will be used with the logarithm of the PK parameters as the 
response variable and day as a fixed effect. Day will be treated as a repeated effect within 
participant. 
From these models, LS means together with 95% CI for Day 1 and Day 9, and LS means 
together with 90% CI for the difference for Day 9 versus Day 1 will be obtained.  The results 
will be transformed back to the original scale by exponentiation to provide estimates of 
geometric LS means, geometric LS mean ratios for Day 9/Day 1, and corresponding 90% CI. 
Safety Outcomes: The incidence and distribution of TEAEs will be summarized. 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, blood pressure and 
potentially clinical significant laboratory values will also be presented.


Clinical Study Protocol
Drug Substance Aclidinium bromide
Study Code M-AS273-01 /D6572C00002
Version 4.0
Date 05 Feb 2021
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TABLE OF CONTENT                                                                             
TITLE PAGE.......................................................................................................................1
VERSION HISTORY..........................................................................................................2
PROTOCOL SYNOPSIS................................................................................................... 10
TABLE OF CONTENT ..................................................................................................... 15
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................................... 19
1.
INTRODUCTION ............................................................................................. 23
1.1   Background and rationale for conducting this study.................................................... 23
1.2   Rationale for study design, doses and control groups .................................................. 25
1.3   Benefit/risk and ethical assessment ............................................................................. 25
1.4   Study Design .............................................................................................................. 26
1.4.1  Study Conduct Mitigation During Study Disruptions Due to  Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................. 27
2.
STUDY OBJECTIVES...................................................................................... 29
2.1
Primary objective............................................................................................... 29
2.2
Secondary objectives.......................................................................................... 29
3.
PARTICIPANT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 30
3.1
Inclusion criteria ................................................................................................ 30
3.2
Exclusion criteria ............................................................................................... 30
3.3
Enrolment and randomisation............................................................................. 33
3.4
Procedures for handling incorrectly enrolled or randomised participants ............ 33
3.5
Methods for assigning treatment groups............................................................. 33
3.6
Methods for ensuring blinding ........................................................................... 33
3.7
Methods for unblinding...................................................................................... 34
3.8
Restrictions........................................................................................................ 34
3.8.1
Dietary and Fluid Restrictions............................................................................ 34
3.8.2
Other Restrictions .............................................................................................. 34
3.9
Participants discontinuation of investigational product and from the study 
(withdrawal)....................................................................................................... 35
3.10
Criteria for withdrawal....................................................................................... 36
3.10.1
Screen failures ................................................................................................... 36
3.11
Premature Discontinuation of the study.............................................................. 36


Clinical Study Protocol
Drug Substance Aclidinium bromide
Study Code M-AS273-01 /D6572C00002
Version 4.0
Date 05 Feb 2021
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3.11.1
Replacement of participants ............................................................................... 37
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 37
4.1
Enrolment/screening period................................................................................ 40
Day -1 (Visit 2).................................................................................................. 41
4.2
Treatment period................................................................................................ 42
4.2.1
Treatment Period (Visit 2: Day 1 to Day 11) ...................................................... 42
Day 1 ................................................................................................................. 42
Day 2 to Day 4................................................................................................... 42
Day 5 to Day 9................................................................................................... 43
Day 10 to Day 11............................................................................................... 43
4.3
Follow-up period (Visit 3).................................................................................. 44
4.4
Premature discontinuation visit .......................................................................... 44
5.
STUDY ASSESSMENTS.................................................................................. 45
5.1
Safety assessments............................................................................................. 45
5.1.1
Laboratory safety assessments............................................................................ 45
5.1.1.1
Pregnancy Test................................................................................................... 46
5.1.1.2
Urinalysis........................................................................................................... 47
5.1.1.3
Drugs of Abuse Screen....................................................................................... 47
5.1.2
Physical examination ......................................................................................... 47
5.1.3
ECG................................................................................................................... 47
5.1.3.1
Resting 12-lead ECG ......................................................................................... 47
5.1.4
Vital signs.......................................................................................................... 49
5.1.4.1
Blood pressure ................................................................................................... 49
5.1.5
Adverse Events .................................................................................................. 49
5.1.6
Repeated Tests (re-test)...................................................................................... 49
5.1.7
Unscheduled Tests ............................................................................................. 50
5.2
Pharmacokinetics ............................................................................................... 50
5.2.1
Collection of samples......................................................................................... 50
5.2.2
Determination of drug concentration.................................................................. 51
5.2.3
Storage and destruction of pharmacokinetic samples.......................................... 51
5.3
Pharmacodynamics ............................................................................................ 51
5.4
Pharmacogenetics .............................................................................................. 51
5.5
Biomarker analysis............................................................................................. 51
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 51
6.1
Definition of adverse events............................................................................... 51
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


Clinical Study Protocol
Drug Substance Aclidinium bromide
Study Code M-AS273-01 /D6572C00002
Version 4.0
Date 05 Feb 2021
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6.3.3
Variables............................................................................................................ 53
6.3.4
Causality collection............................................................................................ 54
6.3.5
Adverse events based on signs and symptoms.................................................... 54
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
Management of IP related toxicities ................................................................... 58
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 58
7.1
Identity of investigational product(s).................................................................. 58
7.2
Dose and treatment regimens ............................................................................. 58
7.3
Labelling............................................................................................................ 59
7.4
Training on DPI inhaler use ............................................................................... 59
7.5
Storage............................................................................................................... 59
7.6
Compliance........................................................................................................ 60
7.7
Accountability.................................................................................................... 60
7.8
Prior and concomitant medication ...................................................................... 61
8.
STATISTICAL ANALYSES............................................................................. 61
8.1
Statistical considerations .................................................................................... 61
8.2
Sample size estimate .......................................................................................... 61
8.3
Definitions of analysis sets................................................................................. 61
8.3.1
Safety analysis set.............................................................................................. 62
8.3.2
PK analysis set................................................................................................... 62
8.3.3
Protocol deviations............................................................................................. 62
8.4
Outcome measures for analyses.......................................................................... 63
8.4.1
Pharmacokinetics Outcomes .............................................................................. 63
8.4.1.1
Pharmacokinetics parameters ............................................................................. 63
8.4.1.2
Calculation or derivation of the pharmacokinetic parameters.............................. 65
8.4.2
Safety and Tolerability Outcomes ...................................................................... 66
8.5
Methods for statistical analyses.......................................................................... 66
8.5.1
General principles.............................................................................................. 66
8.5.2
Missing data....................................................................................................... 67
8.5.3
Participant disposition........................................................................................ 67
8.5.4
Demographic and baseline characteristics .......................................................... 67


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8.5.5
Prior and concomitant medication ...................................................................... 67
8.5.6
Drug administration ........................................................................................... 68
8.5.7
Statistical analysis of the Pharmacokinetic data.................................................. 68
8.5.7.1
Analysis of time dependency in PK and accumulation........................................ 69
8.5.8
Analysis of safety data ....................................................................................... 69
8.5.8.1
Adverse events................................................................................................... 69
8.5.8.2
Blood Pressure................................................................................................... 70
8.5.8.3
Resting 12-lead electrocardiogram ..................................................................... 70
8.5.8.4
Physical examination ......................................................................................... 70
8.5.8.5
Laboratory assessments...................................................................................... 70
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA......................... 71
9.1
Training of study site personnel ......................................................................... 71
9.2
Monitoring of the study...................................................................................... 71
9.2.1
Source data ........................................................................................................ 72
9.2.2
Study agreements............................................................................................... 72
9.2.3
Archiving of study documents............................................................................ 72
9.3
Study timetable and end of study........................................................................ 72
9.4
Data management............................................................................................... 72
10.
ETHICAL AND REGULATORY REQUIREMENTS....................................... 74
10.1
Ethical conduct of the study ............................................................................... 74
10.2
Participant data protection.................................................................................. 74
10.3
Ethics and regulatory review .............................................................................. 74
10.4
Informed consent ............................................................................................... 75
10.5
Changes to the protocol and informed consent form........................................... 76
10.6
Audits and inspections ....................................................................................... 76
11.
LIST OF REFERENCES ................................................................................... 76
APPENDIX A
ADDITIONAL SAFETY INFORMATION............................. 78
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
APPENDIX D
CHANGES RELATED TO MITIGATION OF STUDY 
DISRUPTIONS DUE TO CASES OF CIVIL CRISIS, NATURAL 
DISASTER, OR PUBLIC HEALTH CRISIS..................................................... 86


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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
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AM
Morning (antemeridiam) 
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC(0-∞)
Area under the concentration-time curve from time zero extrapolated to infinity
AUCex
Percentage of AUC(0-∞) obtained by extrapolation, calculated as 
[(Clast(obs)/λz)/AUC(0-∞) * 100]
AUClast
Area under the plasma concentration-curve from time zero to the time of last 
quantifiable concentration
AUC(0-∞)/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
bpm
Beats per minute
Cav
Average steady state concentration
CI
Confidence Interval
CK
Creatine kinase
CL/F
Apparent clearance for parent drug estimated as dose divided by AUC(0-∞)
Cmax
Observed maximum concentration
Cmax/D
Observed maximum concentration divided by dose
Cmin
Observed minimum concentration within a dosing interval


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Abbreviation or special 
term
Explanation
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 9
Css,min
Observed minimum concentration, taken directly from the individual 
concentration-time curve on Day 9
Css,max /D
Observed maximum concentration divided by dose
COPD
Chronic Obstructive Pulmonary Disease
COVID-19
Corona Virus Disease 2019
CRF
Case Report Form
CRO
Clinical Research Organisation
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CV%
Geometric coefficient of variation
DAE
Discontinuation of Investigational Product due to Adverse Event
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
EU
European Union
FEV1
Forced Expiratory Volume in one second
GCP
Good Clinical Practice
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
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IP
Investigational Product 


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Abbreviation or special 
term
Explanation
λz
Terminal rate constant
LLOQ
Lower Limit of Qualification
LS
Least Square
MDI
Metered-dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
mmHg
Millimeters of mercury
msec
Milliseconds
MRT
Mean residence time calculated by AUMC/AUC(0-∞), 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
Premature discontinuation
PHL
Potential Hy’s Law
PI
Principal Investigator
PK
Pharmacokinetics
PM
Evening (Post meridiem)
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 
depolarization (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 9/Cmax on Day 1)
Rac(AUC)
Accumulation ratio for AUCestimated as (ratio of AUCss,on Day 9/AUCon Day 
1)
Rac(Cmin)
Accumulation ratio for Cmin estimated as (ratio of Css,min on Day 9/ Cmin on Day 1)
RR
Respiratory rate
RSq adj
Adjusted coefficient of determination for calculation of λz
SAE
Serious Adverse Event


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Abbreviation or special 
term
Explanation
SAP
Statistical Analysis Plan 
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SD
Standard Deviation
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
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)
%AUCex
Percentage of AUC(0-∞) obtained by extrapolation
%Fluctuation
Fluctuation index during a dosing interval estimated as 100*(Cmax- Cmin)/Cav (%)


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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Chronic Obstructive Pulmonary Disease (COPD), a common preventable and treatable 
disease, is 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 2020). Dyspnoea, chronic cough and sputum production are the most 
common clinical symptoms. Adrenergic and cholinergic pathways mediate 
bronchoconstriction in COPD.
Bronchodilators are central to the symptomatic management of COPD and may be given on 
an as-needed basis for acute symptomatic relief, or as a maintenance treatment for prevention 
or reduction of symptoms. Currently used bronchodilators include β2-agonists, 
anticholinergics, theophylline or a combination of these drugs.
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). 
Anticholinergic drugs decrease bronchoconstriction (increased FEV1) and thereby reduce 
dyspnoea and COPD exacerbations, increase exercise tolerance, and improve quality of life.
Aclidinium bromide is a novel long acting muscarinic antagonist that received its first 
marketing authorisations in the European Union (EU), Norway and Iceland for the treatment 
of COPD by a Centralised Procedure (Eklira® Genuair® and Bretaris® Genuair®) and in the 
United States (US; TudorzaTM Pressair™) on 20 Jul 2012 and 23 Jul 2012, respectively. Since 
then, aclidinium bromide has been authorised in 92 countries worldwide, including the 
countries of EU, the US, Switzerland, Canada, Australia, Japan and Korea.
Aclidinium bromide is indicated as a twice daily (BID) maintenance bronchodilator treatment 
to relieve symptoms of patients with COPD. The authorised metered dose is a single 
inhalation of aclidinium bromide 400 μg BID via a multidose breath-actuated device-metered 
dry powder inhaler (DPI; described herein as the Genuair® inhaler). Each delivered dose (the 


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dose leaving the mouthpiece) contains 375 μg of aclidinium bromide equivalent to 322 μg of 
aclidinium.
The clinical development programme for aclidinium BID comprised 13 Phase I/II studies that 
investigated the clinical pharmacology/pharmacokinetics of aclidinium bromide and 16 Phase 
II, Phase III and Phase IV studies that provided evidence of its efficacy and safety. 
Approximately 9207 participants have received aclidinium bromide 400 µg BID in clinical 
studies (Investigator’s Brochure - IB).   
The 3 pivotal clinical studies of aclidinium bromide BID 400 μg have demonstrated a 
clinically and statistically significant bronchodilatory effect when compared to the placebo 
throughout the 12 and 24 weeks treatment period; treatment with aclidinium bromide 400 μg 
BID was associated with an improvement in dyspnoea, disease-related health status (St. 
George's Respiratory Questionnaire [SGRQ]) and daily and night-time symptoms (Jones et al 
2012, Kerwin et al 2012). Furthermore, Phase II Studies M/34273/23 (Fuhr et al 2012) and 
M/34273/29 (Singh et al 2012) showed the overall bronchodilation of aclidinium bromide 400 
μg BID to be broadly comparable to that of commercially available bronchodilators, 
tiotropium and formoterol. Evidence of the benefits of aclidinium bromide on exercise 
endurance, lung hyperinflation, exertional dyspnoea and daily physical activity was observed 
in Study M/34273/40 (Beeh et al 2014).
To support registration of aclidinium bromide for patients with COPD in Japan and Korea, 
four studies in Asian patients were conducted by AstraZeneca’s co-development partners. A 
pharmacokinetic study (KRP-AB1102-D202), a Phase II study (KRP-AB1102-D201) and a 
long-term safety study (KRP-AB1102-D301) have been conducted in Japan and a Phase III 
bridging study, has been conducted in Korea (DW_EKL001). Overall, as in studies in Western 
patients, aclidinium bromide at a dose of 400 µg BID was more effective than lower doses 
tested (100 µg BID and 200 µg BID) in Asian patients with COPD.  In Japan, aclidinium 
approval was granted in 2015 and in 2014 in Korea.
Most recently, a Phase IV, randomised, double-blind, placebo-controlled study showed that 
Aclidinium bromide 400 µg BID does not increase the risk of cardiovascular events, even in a 
patient population at a higher risk of such events; and demonstrated the favourable effect of 
aclidinium bromide in reduction of COPD exacerbations. The safety profile of aclidinium 
bromide 400 µg BID in Study D6560C00002 was similar to that of the pooled safety 
populations, despite the treatment duration being longer in Study D6560C00002 (up to 3 
years, as compared to up to 6 months in the pooled safety populations), and the different 
characteristics of the patient populations.
One clinical study of aclidinium bromide is currently ongoing. This is a Phase III clinical trial 
of aclidinium/formoterol in patients with COPD that is being conducted in China and other 
Asian countries including India, Taiwan, Vietnam and Philippines (D6570C00002, also 
known as M-AS464-30). As this study includes an aclidinium bromide 400 μg BID
comparator arm, safety data from this study will contribute to the safety database for 
aclidinium bromide. Based on current data compiled from this ongoing trial, no concerns 
regarding the safety of aclidinium bromide 400 μg have been raised.


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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. 
Consistently with these arguments, similar systemic exposure parameters were observed in 
Japanese patients as in Western participants after 7 days of twice daily repeated administration 
of aclidinium bromide at doses of 200 µg and 400 µg to Japanese patients (KRP-AB1102-
D202). 
Common adverse events (≥1/100 to <1/10) which may be “expected” with aclidinium bromide 
treatment include sinusitis, nasopharyngitis, headache, cough, diarrhoea and nausea. 
Uncommon adverse events (≥1/1,000 to <1/100) are blurred vision, tachycardia, dysphonia, 
dry mouth, urinary retention, rash, stomatitis and pruritus.
Full pharmacological, toxicological and pharmacokinetic information is described in the IB.
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 400 µg after single and multiple dose administration (BID) from the 
Genuair® multidose dry powder inhaler in healthy Chinese participants.
Dosing aclidinium bromide twice-daily for 5 consecutive days is considered to be the 
adequate duration to reach steady state and to characterize the PK profile in Chinese 
participants. The dose strength of 400 µg BID corresponds to the currently registered product 
and the dose that is being considered for development and future marketing authorisation in 
China. 
Due to the known terminal elimination half-life of aclidinium bromide (~19h), a  96-hour 
washout period between single and multiple administration phase is considered enough to 
avoid a carry-over effect.
Twenty (20) healthy participants are to be enrolled in this study. This is considered to be a 
sufficient number to meet the objective of the study. Healthy participants are to be enrolled to 
avoid possible interference of concomitant medication or diseases with the primary objectives’ 
parameters.
1.3
Benefit/risk and ethical assessment
The current trial is a Phase I trial in healthy participants. Participants will not receive any 
known health benefit from participating in the trial. No known risks are applicable other than 


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those described in the aclidinium bromide IB. Still, investigators will ensure adequate medical 
care of the trial participants at all times throughout the course of the study.
1.4
Study Design 
This is a Phase I, single centre, open-label study to investigate the pharmacokinetics (PK), 
safety and tolerability of single and multiple twice daily doses of inhaled aclidinium bromide 
400 μg in healthy Chinese male and female participants.
All participants will sign an ICF before starting any study related procedures. 
The study will consist of a Screening Visit (Visit 1) conducted after signature of the ICF and 
maximum 21 days prior to Day 1, where medical history, physical examination, blood 
pressure assessment, laboratory analysis, 12-lead ECG will be conducted.
All participants fulfilling inclusion/exclusion criteria will be admitted to the clinical unit the 
day preceding the 1st dose( Day -1, Visit 2). 
On Day 1 (Visit 2) participants will receive a single dose of aclidinium bromide in the 
morning (AM) via the Genuair® DPI, followed by a wash out period of 96 hours. On Day 5 
through Day 8, participants will receive twice daily (BID) doses of aclidinium bromide (AM 
and PM) via the Genuair® DPI and on Day 9, participants will receive only the AM dose of 
aclidinium bromide via the Genuair® DPI. Participants will be discharged on Day 11, 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 11). 
A follow-up visit will take place on Day 15 (±2).
Participants who prematurely discontinue from the study (withdrawal) will participate in a 
Premature Discontinuation Visit that will include physical examination, clinical laboratory 
tests, 12-lead ECG, blood pressure, serum pregnancy test for women of childbearing potential, 
and assessment of AEs and concomitant medication to ensure participant´s safety. Participants 
prematurely discontinued from the study will not be replaced, with the exception of study 
disruption reasons as described in Appendix D.
The study flow chart for each treatment sequence is shown in Figure 1.  
A complete list of all procedures and assessments is provided in the Schedule of Assessments 
in Table 1 (Section 4).


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Figure 1
Study flow chart
Visit 1
Screening
Visit 2
Residential Period
Visit 3
Follow-up
Informed 
consent
Admission 
to study unit
Single Dose 
administration
Multiple Dose 
administration
Discharge 
from study 
unit
Follow-up
Screening period
Treatment period
Follow-up 
period
Day -21 
to Day -2
Day -1
Day 1
Day 5
Day 9
Day 11
Day 15 
(±2)
1.4.1         Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (e.g., 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study participants become infected with SARS-CoV-2 or similar pandemic 
infection), which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the participant’s ability to conduct the study. The 
investigator or designee should contact the study Sponsor to discuss whether the mitigation 
plans below should be implemented.  
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with Good Clinical Practice, and minimize risks to study integrity. 
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(e.g., hospital policies) or local government, these changes may include the following options: 
-
Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the Informed Consent Form (ICF) should be signed at the 
participant’s next contact with the study site).


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-
Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. 
The investigator should confirm this with the designated study physician. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix D.


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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To investigate the pharmacokinetics (PK)
of aclidinium bromide and its metabolites 
after single and multiple doses of 
aclidinium bromide 400 μg twice-daily 
(BID) in Chinese Healthy volunteers
The following pharmacokinetic parameters will 
be determined when possible, for aclidinium 
bromide and its metabolites after single dose 
administration:
Cmax, tmax, λz, t½λz, AUClast, AUC, AUC(0-∞), 
Cmin, CL/F*, Vz/F* 
The following PK parameters will be calculated 
for aclidinium bromide and after 5 days of 
repeated dose administration:
Css,max, tss,max, λz, t½λz, , AUCss,, CL/F*, Vz/F*, 
Css,av, %Fluctuation, Css,min, Rac(Cmax), Rac(AUC)
and Rac(Cmin).
Additional parameters may be determined where 
appropriate.
*only for aclidinium bromide
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To evaluate the safety, and tolerability of 
aclidinium bromide 400 μg twice-daily 
(BID) after single and multiple dose 
administration in healthy Chinese 
participants.
AEs/SAEs
Blood pressure
Clinical laboratory parameters (haematology, 
serum biochemistry and urinalysis)
12-lead ECG parameters


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3.
PARTICIPANT SELECTION, ENROLMENT, 
RANDOMISATION, RESTRICTIONS, DISCONTINUATION 
AND WITHDRAWAL 
Each participant should meet all of the inclusion criteria and none of the exclusion criteria for 
this study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study, participants 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 restrictions. 
2.
Healthy participants: Chinese men or non-pregnant, non-lactating women, 18 through 
45 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 show to 
have a negative serum pregnancy test at the Screening Visit (Visit 1) and a negative serum 
pregnancy test at Day -1 and are using, during the last two months before the Screening Visit 
and during the whole duration of the trial, at least one medically approved non-hormonal 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.
Have a body mass index (BMI) ≥19 kg/m2 and ≤ 26 kg/m2.
Explanatory note: [BMI (kg/m2) = Body weight (kg)/Height2 (m2)]. 
4.
Resting heart rate ≥ 50 beats per minute (bpm) and ≤ 100 bpm at Visit 1 (Screening) 
and at admission to the unit on Day -1 at Visit 2.
5.
Non-smoker (never smoked or has not smoked within 2 years prior to the first dose of 
investigational product [IP]).
6.
Demonstrate satisfactory technique in the use of the DPI at screening. See section 7.4
training on DPI inhaler use. 
3.2
Exclusion criteria
Participants should not enter the study if any of the following exclusion criteria are fulfilled:


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1.
History of any significant drug allergy or hypersensitivity to aclidinium bromide or 
other muscarinic antagonists.
Explanatory note: Significant drug allergy includes anaphylaxis or hepatotoxicity; a history of 
allergy to the test drug, formulation excipients, or any drug chemically similar to the drug 
under investigation.
2.
Have abnormal and clinically significant results on the physical examination, medical 
history, serum biochemistry, haematology, or urinalysis at Visit 1 (Screening).
3.
Sustained resting systolic blood pressure ≥ 140 or ≤ 90 mmHg and resting diastolic 
blood pressure ≥ 90 or ≤ 50 mmHg at Visit 1 (Screening) or Day -1 at Visit 2.
4.
Electrocardiogram (ECG) showing corrected QT interval (QTc) using Fridericia’s 
correction (QTcF) ≥ 450 msec for male participants and ≥460 msec for female participants as 
indicated in the centralised reading report assessed at Screening (Visit 1).
Explanatory note: In addition, participants with any other risk factors for QT/QTcF 
prolongation or any abnormality in the ECG that, in the opinion of the PI, increases the risk of 
participating in the trial will be excluded, such as sick sinus syndrome, second or third-degree 
atrioventricular block, any type of tachycardia, more than one premature ventricular 
contraction on a 12-lead ECG, incomplete or complete left bundle-branch block, nonsinus 
rhythm, or evidence of myocardial ischemia/infarction (either changes suggesting acute 
ischemia/infarction or changes from previous tracings compatible with an infarction during 
the preceding 6 months).
5.
Have a history of alcohol or substance abuse within the previous 5 years, as reported 
by the participants.
6.
Positive results for drugs of abuse at Visit 1 (Screening).
Explanatory note: Drugs of abuse including alcohol, cotinine, benzoylecgonine (cocaine), 
methadone, barbiturates, amphetamines, benzodiazepines, cannabinoids, opiates, and 
phencyclidine.
7.
Positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody and/or 
human immunodeficiency virus (HIV) antibodies at Visit 1 (Screening).
8.
Use of any medication within 2 weeks or within the equivalent time of 5 half-lives of 
taking the last dose (whichever is longer) before the first dose of IP, or hormonal drug 
products and traditional Chinese medicines within 30 days before the first dose of IP.
Explanatory note: Include any medication (prescription or over-the-counter [OTC]), health 
supplements, herbal/traditional remedies and vaccines. 
9.
Have consumed caffeine or any grapefruit-containing products within 48 hours or 
alcohol within 72 hours before Day -1.


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10.
Participation in any other clinical investigation using an experimental drug requiring 
repeated blood or plasma draws within 60 days of Day 1 at Visit 2.
11.
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 screening (Visit 1). 
12
Recent history of a disease or condition that would result in any residual upper 
respiratory airways/lung inflammatory process or residual limited lung function at the time of 
Day 1 at Visit 2.
Explanatory note: Upper respiratory infection with residual symptoms, pulmonary infection in 
the previous 3 months, thoracic surgery within the last 12 months.
13.
History of confirmed COVID-19 infection.
Explanatory note: Local guidance on precautions for prevention of spreading and management 
of COVID-19 infection must be followed. 
14.
Have any gastrointestinal, hepatic, or renal condition that might affect the absorption, 
distribution, biotransformation, or excretion of aclidinium bromide.
15.
Inability to be venipunctured or tolerate venous access as determined by the PI or 
designee.
16.
Participants unable to give their consent, or participants of consenting age but under 
guardianship, or vulnerable participants.
17.
In the opinion of the PI, participants who are unlikely to comply with the protocol 
requirements, instructions, and trial-related restrictions. 
Explanatory note: Examples include uncooperative attitude, inability to return for follow-up 
visits, and improbability of completing the clinical trial. This also includes participants who 
have problems understanding the protocol requirements; instructions and trial-related 
restrictions; the nature, scope and possible consequences of the clinical trial.
18.
Participant is a relative of the Investigator or any sub-investigator, research assistant, 
pharmacist, trial coordinator, or other staff or directly involved in the conduct of the clinical 
trial.
19.
Any other conditions that, in the Investigator’s opinion, might have indicated the 
participant to be unsuitable for the study (e.g. confirmed/suspected COVID-19)
Explanatory note: Local guidance on precautions for prevention of spreading and management 
of COVID-19 infection must be followed. 
Procedures for withdrawal of incorrectly enrolled participants see Section 3.4.


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3.3
Enrolment and randomisation
Investigator(s) should keep a record, the participant screening log, of participants who entered 
pre-study screening.
The Investigator(s) will:
1.
Obtain signed informed consent from the potential participant before any study 
specific procedures are performed.
2.
Assign potential participant a unique participant 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, 
starting with 001. The participant identification number will be used to identify the 
participant throughout the study and will be recorded in the electronic Case Report 
Form (eCRF).
3.
Determine participant eligibility (see Sections 3.1 and 3.2). Participant not meeting 
inclusion and exclusion criteria will be marked as “screen failures” and should have 
the final evaluation eCRF completed.
If a participant withdraws from participation in the study, then his/her ID code cannot be 
reused.
Randomisation is not applicable in this study.
3.4
Procedures for handling incorrectly enrolled or randomised 
participants
Participants 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.  Participants 
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 participant does not meet all the eligibility criteria but incorrectly started on 
treatment, the Investigator should inform the AstraZeneca study physician immediately, and a 
discussion should occur between the AstraZeneca study physician and the investigator 
regarding whether to continue or discontinue the participant 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 study is open-label.


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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 9 
where breakfast will not be served. 
Water is allowed as desired except for 1 hour before and 1 hour after IP administration. 
Participants will be instructed to consume the entire contents of each meal and snack, if 
possible. Trial centre personnel will document the percentage or the amount of food 
(consumed or unconsumed food according to the trial centre SOPs) for each participant, at 
least on Day 1 and Day 9.
Standard  meals and snacks during trial confinement will be provided according to the trial 
centre SOPs and in accordance with this protocol. Meals should not include any xanthine-
containing beverages or food (e.g., coffee, tea, cola, chocolate, diet pills, "energy drinks"), or 
caffeine.
On days that serum biochemistry samples will be drawn (Visit 1 [Screening], Day -1, Day 11, 
and Follow Up Visit), a fast of at least 8 hours will be observed.
Participants must abstain from caffeine, and xanthine-containing beverages or food (e.g., 
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 centre on Day -1 at Visit 2 until discharge from the trial centre.
Abstain from alcohol from 72 hours (3 days) prior to entry in the trial centre on Day -1 at Visit 
2 until discharge from the trial centre.
3.8.2
Other Restrictions
All participants will have to comply with the following general requirements:
•
Strenuous activity, sunbathing, and contact sports within 96 hours (4 days) prior to 
admission into the trial centre on Day -1 at Visit 2, and for the duration of the trial.


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3.9
Participants discontinuation of investigational product and from 
the study (withdrawal)
Any participant may withdraw from the trial at any time during the trial at the discretion of the 
Investigator or at the request of the participant.
If a participant is discontinued from IP, the participant will be withdrawn from further study 
procedures.
The date and main reason for such a premature discontinuation must be documented in the 
eCRF.
Participant may be prematurely discontinued from the trial by the Investigator for any of the 
following reasons:
1. Adverse Events: If a participant experiences an AE, premature discontinuation will be 
at the discretion of either the PI or the participant, independent of the relationship to 
the trial treatment. The appropriate AE eCRF form must be completed.
2. Protocol Deviation: After enrolment into the trial, any protocol violations detected 
should be corrected when possible and the participant should be allowed to continue. 
ONLY the following violations should lead to participant discontinuation: those which 
could affect participant safety (e.g., illness requiring treatment[s] which in the clinical 
judgment of the Investigator [or after discussion with the trial monitor might invalidate 
the trial by interfering with the IP) or which are due to participant unwillingness to 
comply with the trial activities.
3. Failure to meet eligibility criteria: Violations of inclusion and/or exclusion criteria 
detected after initiating on treatment.  See Section 3.4 for participants not fulfilling 
inclusion/exclusion criteria but detected after initiating on treatment.
4. 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 
participant, and to assure participant attendance as soon as possible. Every effort (at 
least 3 documented attempts in the medical records) should be made to contact the 
participant. A registered mail letter will be sent to the participant and documented in 
the medical records.
5. Withdrawal by participant: The participant 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.


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6. Pregnancy: In case of pregnancy, the female participant will be immediately 
discontinued from the trial.
7. "Other": at the Investigator’s request, study cancellation or any other reason not 
described above.
8. Participant withdrawal due to death.
All dosed participants who prematurely discontinue from the trial, regardless of cause, will be 
seen for a premature discontinuation visit AS SOON AS POSSIBLE. 
A participant that decides to discontinue 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 participant. Procedures/assessments for the premature 
discontinuation are indicated in the Schedule of Assessments (Table 1).
If there is a medical reason for withdrawal, the participant will remain under the supervision 
of the Investigator until satisfactory health has returned. 
3.10
Criteria for withdrawal
3.10.1
Screen failures
Screening failures are participants who do not fulfil the eligibility criteria for the study, and 
therefore must not enter on treatment. These participants should have the reason for study 
withdrawal recorded as ‘Screen Failure’ (i.e., participant does not meet the required 
inclusion/exclusion criteria). This reason for study withdrawal is only valid for screen failures 
(not participant on treatment).
3.11
Premature Discontinuation of the study
The “end of trial” is defined as the date when all participants 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. Certain 
circumstances may require the premature termination of the trial, such as the following:
•
The Investigator and the Sponsor feel that the type, the number and/or severity of AEs 
justifies discontinuation of the trial.
•
The Sponsor decides to discontinue the trial.
•
Data not known before become available and raise concerns about the safety of the IP 
so that continuation would pose potential risks to the participants.


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If the trial is terminated or suspended, the Sponsor will promptly inform the Investigator/trial 
centre and the Regulatory Authorities. The EC should be promptly informed and provided the 
reason(s) for the termination or suspension by the Investigator/Sponsor, as specified by the 
applicable regulatory requirement(s).
The Investigator will inform the participants 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 participant 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 participants' interests.
3.11.1
Replacement of participants
Participants prematurely discontinued from the study will not be replaced, with the exception 
of study disruption reasons as described in Appendix D. 
4.
STUDY PLAN AND TIMING OF PROCEDURES 


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Table 1
Schedule of Assessments
Screening period
Treatment period
Follow-up 
period
Visit 1a
Screening
Visit 2
Follow up Visit 
(Visit 3) or PD
Procedure/Study Day
-21 to -2
-1
1
2-4
5
6-8
9
10
11
15 (±2)
Sign informed consent
X
Demographics 
X
Inclusion/Exclusion criteria
X
X
Smoking history
X
Medical history
X
Prior and Concomitant Medicationsb
X
X
X
Inhaler Training
X
X
Admission to Trial Centre
X
Meals (provided by trial centre)j
X
X
X
X
X
X
X
X
Discharge from the Trial Centrec
X
Outpatient Visit
X
X
Physical examination, height and weightd
X
X
X
12-lead ECG and blood pressuree
X
X
X
X
X
X
X
Laboratory Tests (Haematology, Serum 
Biochemistry)f
X
X
X
Xi
Laboratory Test (Urinalysis)
X
X
X
Xi
Serum Pregnancy Test
X
X
Xi
Serologyg
X
Urine Drugs of Abuse and Alcohol Screen 
X
X
Dosing of IP
X
X
X
X


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Table 1
Schedule of Assessments
Screening period
Treatment period
Follow-up 
period
Visit 1a
Screening
Visit 2
Follow up Visit 
(Visit 3) or PD
Procedure/Study Day
-21 to -2
-1
1
2-4
5
6-8
9
10
11
15 (±2)
Blood sampling for pharmacokineticsh
X
X
X
X
X
X
Adverse event review (AEs and SAEs)
X
X
X
X
X
X
X
X
X
X
AE = adverse event; AM = morning; BMI = body mass index; DPI = dry powder inhaler; ECG = electrocardiogram; HIV = human immunodeficiency virus; ICF = Informed 
Consent Form; IP = investigational product; PI = Principal Investigator; PM = evening; PD= Premature Discontinuation; PK = pharmacokinetic
a. If the participant needs additional time to washout any prior medications, the ICF must be provided before Visit 1. Participants must discontinue medications after informed 
consent.
b. Prior medication will be defined as any hormonal product or any other medication/herbal remedies taken within 14 days of trial Screening at Visit 1 up to the first dose of 
aclidinium bromide. Concomitant medication will be defined as any medication taken at least once after the 1st IP administration until the time of the last PK sample on Day 11 
(48 hours post-last dose).
c. Participants will be discharged from the trial centre after the completion of the 48-hour PK blood sample collection and safety assessments.
d. Height and weight will be measured and BMI will be calculated at Visit 1 (Screening). 
e. Safety ECGs and blood pressure will be collected at Visit 1 (Screening); at Visit 2 on Day -1; and Days 1, Day 5 to 9 at 0 hour (pre AM dose) and at 2 hours post AM dose; 
and at the Follow-Up Visit or Premature Discontinuation Visit. ECGs and blood pressure measurements will be obtained after the patient has rested quietly for at least 5 
minutes. If an ECG is scheduled at the same time as a meal, the ECG must be obtained first.
f. If blood sampling, vital sign assessments, and ECG recordings are scheduled at the same time points, ECG recording and blood pressure assessments will need to be 
collected prior blood sampling, assuring that PK blood sampling occurs on the time point. Includes blood and serum samples. Participants are required to fast for at least 8 
hours prior to the collection of specimens.
g. Serum for hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) types 1 and 2 antibodies. Results must be available and 
reviewed prior to dosing on Day 1.
h. PK blood samples will be collected on Day 1 at pre-dose (approximately 15 minutes prior to the AM 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 (i.e. on Day 2), 36 hours (i.e. on Day 2) and 48 hours (i.e. on Day 3) post the AM dose after IP administration.
On Days 6-8, PK blood samples will be collected at pre-dose (approximately 5 minutes prior to the AM and PM dose) 
On Day 9, PK blood samples will be collected at pre-dose (approximately 5 minutes prior to the AM 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 (i.e. on Day 10), 36 hours (i.e. on Day 10) and 48 hours (i.e. on Day 11) post the AM dose after IP administration on Day 9. 
Time window allowances are indicated in section 5.2.1
i. Laboratory test (haematology, biochemistry and urinalysis) and serum pregnancy test to be performed only at Premature Discontinuation Visit.
j. On treatment days, breakfast will be served approximately 2 hours prior to IP, except on Day 1 and Day 9 where no breakfast will be served. 


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4.1
Enrolment/screening period
This period will start with the signature of the Informed Consent Form (ICF) at Visit 1 
(Screening), when Chinese male and female healthy volunteers 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 participants will be admitted to the trial centre on Day 
-1.     No study specific procedures will be performed prior to signing ICF.
Participants who require a washout period from prohibited concomitant treatments should be 
seen and sign the ICF prior to Visit 1, to ensure the necessary washout before this visit. No 
trial assessments will be performed that date, and Visit 1 will be scheduled later according to 
the wash-out length required for the specific medication stopped.
If no wash-out period is required, Visit 1 assessments will start after signing the ICF to ensure 
that they meet eligibility criteria. Any participant signing the ICF should be recorded in the 
eCRF and should be assigned a Participant ID number.
At Screening, to verify the eligibility of participants, the following evaluations will be 
performed:
Obtain informed consent.
Assess inclusion/exclusion criteria. 
Review medical/surgical history, demographic (age, sex and race) and smoking history.
Perform a complete physical examination including body weight (in light indoor clothes, 
without shoes) and height.
Collect blood pressure. 
Perform 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.
Train participants on Genuair® inhaler user instructions. See section 7.4.


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Record in the eCRF all medications the participant is currently taking and has taken during the 
previous 15 days before signature of the ICF. Remind the participant to avoid prohibited 
medications (see Section 7.8 for details). 
Document the participant participation in the study into the participant's medical records.
Only participants who meet all inclusion/exclusion criteria will be allowed to continue to Visit 
2.  
Day -1 (Visit 2)
The following procedures will be performed:
On Day -1, reassess the inclusion/exclusion criteria and review with participant if any AEs 
occurred.
Perform the 12-lead ECG.
Blood pressure assessment.  
Blood and urine sample collection for safety laboratory tests (haematology, biochemistry and 
urinalysis).  Participants should be fasting a minimum of 8 hours prior to safety laboratory test 
collection.
Perform a complete physical examination.
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.
Train the participant on how to use the DPI device.  The investigator/designee will evaluate 
proper use of the device by the participant and provide additional training if needed. See 
section 7.4. 
Provide meals according to Section 3.8.1.
Have the participant remain in the study centre overnight.
Only participants who meet all inclusion/exclusion criteria will be considered as enrolled in 
the study and continue to Day 1 at Visit 2.  
All participants will remain in the trial centre from Day -1 at Visit 2 until the completion of 
the 48-hour PK sample collection and safety assessments on Day 11.


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4.2
Treatment period
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.
If blood sampling, blood pressure assessments, and ECG recordings are scheduled at the same 
time points, ECG recording and vital sign assessments will need to be collected prior to 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
Treatment Period (Visit 2: Day 1 to Day 11)
This period will start on Day 1 at Visit 2 until the completion of the 48-hour PK sample 
collection and safety assessments on Day 11.
Participants will stay overnight at the trial centre for a total of 11 nights (from Day -1 to Day 
11). 
Day 1
Perform 12-lead ECG before IP administration (pre-dose). 
Blood pressure assessment before IP administration (pre-dose). 
Collect PK blood samples at pre-dose (approximately 15 minutes before the IP 
administration). Time window allowance in section 5.2.1
Administer the 1st single dose of AM IP approximately at 8:00 AM by inhalation from the 
Genuair ® DPI. The investigator or study personnel should check that the participant has used 
the inhaler correctly. Window allowance deviation for IP will be ±1h.
Collect PK blood samples at 5, 15, 30min 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. 
Blood pressure assessment at 2 hours (± 30min) post IP administration. 
Review with participant if any AEs occurred.
Provide lunch, dinner and snack according to the time schedule defined in section 3.8.1.
Have the participant remain in the study centre overnight.
Day 2 to Day 4
Collect PK blood samples at 24h, 36h and 48h post IP administration on Day 1. Time window 
allowance in section 5.2.1


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Review with participant if any AEs occurred.
Provide breakfast, lunch, dinner and snack according to the time schedule defined in section 
3.8.1.
Have the participant remain in the study centre overnight.
Day 5 to Day 9
Perform 12-lead ECG before morning IP administration (pre-dose). 
Blood pressure assessment before morning IP administration (pre-dose). 
From Day 5 to Day 8, administer AM IP at approximately 8:00h and IP PM dose at 
approximately 20:00 hours (12 hours after AM dose). On Day 9, only the AM dose 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 6, 7 and 8, 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.
On Day 9, 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 morning IP administration. 
Blood pressure assessment at 2 hours (± 30 min) post morning IP administration. 
Review with participant if any AEs occurred.
Provide breakfast, lunch, dinner and snack according to the time schedule defined in section 
3.8.1. No breakfast will be served on Day 9.
Have the participant remain in the study centre overnight.
Day 10 to Day 11
Collect PK blood samples at 24h, 36h and 48h post IP administration on Day 9. Time window 
allowance in section 5.2.1.
Have the participant remain in the study centre overnight on Day 10.
Blood and urine sample collection for haematology, biochemistry and urinalysis on Day 11.  
Participants should be fasting a minimum of 8 hours prior to safety laboratory test collection.
Review with participant if any AEs occurred.


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Provide a participant's diary for the participant to record any AE and/or concomitant 
medication used once discharged from the unit.
Provide breakfast, lunch, dinner and snack according to the time schedule defined in section 
3.8.1.
On Day 11 collect blood sample for serum β-human chorionic gonadotropin (β-hCG) 
pregnancy test only for women of childbearing potential.
Discharge the participant on Day 11 after all safety and PK assessments are completed.
4.3
Follow-up period (Visit 3)
Participants are required to return to the trial centre for a Follow-up Visit (performed on Day 
15 ±2).
The following procedures are to be performed at the Follow-up Visit: 

Assessment of AEs and concomitant medications.

Physical examination.

Perform 12-lead ECG.

Blood pressure assessment.
4.4
Premature discontinuation visit
If the participant is agreeable, the following procedures should be performed at this visit as 
soon as the participant has been discontinued from the trial:

Assessment of AEs and concomitant medications.

Physical examination.

Perform 12-lead ECG.

Blood pressure assessment.

Collect blood and urine samples for clinical laboratory tests (haematology, serum 
biochemistry, and urinalysis). Participants should be fasting a minimum of 8 hours 
prior to safety laboratory test collection.

Collect blood sample for serum β-human chorionic gonadotropin (β-hCG) pregnancy 
test only for women of childbearing potential.


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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 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.
The clinical chemistry, haematology, serology and urinalysis will be performed by the site 
local laboratory services which will provide the report to the investigator. Site specific 
procedures will be followed for the sampling analysis. 
Complete routine laboratory assessments will be performed under fasting conditions. 
Participants are required to fast for at least 8 hours prior to the collection of blood specimens.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be retained at centre as source data for 
laboratory variables. 
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 EDC form. 
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 6.3.
In case of technical problems, or if the investigator considers that a result is clinically relevant 
or doubtful, additional blood samples may be collected within a reasonable time and will be 
sent to the site local laboratory for analysis (see Sections 5.1.6 and 5.1.7 for Unscheduled and 
Repeated tests 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-Haematocrit
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)
Urinalysis
S/P-Albumin
U-Hb/Erythrocytes/Blood 
S/P-Potassium
U-Leukocytes
S/P-Calcium, total
U-Glucose 
S/P-Sodium
U-pH
S/P- Chloride
U-Protein/Albumin 
S/P- Inorganic phosphorous
U-Bilirubin
S/P-Glucose
U-Urobilinogen
S/P-Total cholesterol
U-Ketones
S/P- Triglycerides
U-Nitrites
S/P- Total protein
S/P- Uric acid 
Serology (serum or plasma)
S/P- Urea Nitrogen 
S/P- HBsAg
S/P-anti-HCV
S/P- anti-HIV types 1and 2
NB. In case a participant 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.
As per AstraZeneca standards, during the course of the study the Investigator will remain 
vigilant for increases in liver biochemistry. The Investigator is responsible for determining 
whether a participant meets potential Hy’s Law (PHL) criteria at any point during the trial.
Hy’s Law guidance for the Investigator is included in Section 6.3.7 and Appendix C.
5.1.1.1
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 Day 11 at Visit 3, or at Premature Discontinuation Visit.


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If pregnancy occurs during participation in the trial, the participant must immediately 
discontinue from the trial. The pregnancy should be reported as described in Section 6.6.
5.1.1.2
Urinalysis
The urine sample will be sent to the site local laboratory in China for urinalysis.
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: cotinine, 
benzoylecgonine (cocaine), methadone, barbiturates, amphetamines, benzodiazepines, 
cannabinoids, opiates and phencyclidine. Alcohol screen will be performed using a breath test. 
5.1.2
Physical examination
A medical history of screened participants will be obtained at the Visit 1 (Screening) (see 
Table 1), recording only the relevant demographic and medical data, as required in the 
Medical History/Physical examination eCRF form.
A complete physical examination will be performed at the Visit 1 (Screening), on Day -1 at 
Visit 2; and at the Follow-Up Visit (Table 1). At Visit 1 (Screening), only relevant findings 
will be recorded in the Medical History eCRF form. From Day -1 to 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.
Body weight and height will be measured only at the Visit 1 (Screening) (see Table 1), 
allowing the calculation of BMI. Participants should be in light indoor clothes without shoes.
For information on how AEs based on physical examination should be recorded and reported, 
see Section 6.3.
5.1.3
ECG
5.1.3.1
Resting 12-lead ECG
Standard 12-lead ECGs will be performed at time points detailed in Table 1 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 
participant.
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 participant's 
eligibility according to the centralized reading report 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 1.


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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 and 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 participant'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. 
The investigator will review the “manual reading” reports to assess the clinical relevance of 
any abnormal finding and/or to decide if the participant is or remains eligible for the study.
However, the responsibility for inclusion or continuation of the participant 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).


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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 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 Investigator 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 5.1.6 and 5.1.7).
5.1.4
Vital signs
5.1.4.1
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 1. Measurements will be carried out 
with participant in resting 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.
5.1.5
Adverse Events
Adverse events will be recorded throughout the trial, see Table 1. Procedures for recording 
and assessing AEs are included in Section 6.3.
5.1.6
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 
enrolment e.g., in case of impaired results (e.g., blood sample haemolysed) or results requiring 
confirmation (to ensure participant eligibility or results inconsistent with participant's known 
past medical conditions), etc. The full Visit 1 will not be repeated. If any of the specific tests 
of the Screening Visit need to be repeated, and more than 28 days has elapsed since first test 
date, the participant 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. 
The repeated tests will be called “re-test” and will be identified with the same visit identifier 
as the first attempt.


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5.1.7
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 of aclidinium bromide and its metabolites LAS34850 and 
LAS34823 in plasma will be taken at the following time points
Day 1:
0 hour (pre-dose; approximately 15 minutes prior to the AM 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 (i.e. Day 2), 36 hours (i.e. Day 2) and 48 hours (i.e. 
Day 3). 
Days 6-8:
0 hour (pre-dose; approximately 5 minutes prior to the AM and PM dose).
Day 9:
0 hour (pre-dose; approximately 5 minutes prior to the AM 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 (i.e. Day 10), 36 hours (i.e. Day 10) and 48 hours 
(i.e. Day 11) post the AM dose.
The recommended time windows allowance for PK blood collection are the following:
Day 1 and Day 9:
pre-dose:  within 30 min prior to IP administration
5 -30 min: ± 1 min
1-6 hours: ± 5 min
8-12 hours: ± 10 min
24-48 hours: ± 30 min
Days 6-8 :
pre-dose: within 10 min prior to IP administration
Samples will be collected, labelled, handled, stored and shipped as detailed in the Laboratory 
Manual.


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5.2.2
Determination of drug concentration
Samples for determination of aclidinium bromide and its metabolites, LAS34850 and 
LAS34823, in plasma will be analysed by Central Laboratory on behalf of AstraZeneca, using 
a validated bioanalytical method. 
Full details of the analytical method used will be described in a separate Bioanalytical Report.  
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, if any, 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
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
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 participants.
6.1
Definition of adverse events
An adverse event is the development of an undesirable medical condition, or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 


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can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout period, 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 participant 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.
Adverse Events (AEs) for malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed
and reported as a non-serious AE. For example, if the tumour is included as medical history 
and progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as non-serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy.


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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 
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 participant'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 participants 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
Date of discharge


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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 an 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 an 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).
AE will be collected only once with their 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.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the participant 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 


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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, blood pressure and physical 
examination will be summarised in the clinical study report.  
Medical disorders present at the time of signing the ICF that are part of the participant'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/blood pressure, ECGs will not be considered AEs if already known as part of the 
medical history or in relation to prior medical conditions, and will be recorded on the eCRF 
Medical History/physical examination form/page. However, abnormalities detected in 
screening/run-in/baseline tests, thought to be due to a study procedure, will be considered 
AEs.
During the trial, abnormalities (newly occurring or worsening of previously known 
abnormalities) detected in laboratory values, blood pressure, 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 participant 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 SAE eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day 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.


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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 (e.g., 
participant lives too far from the hospital or has no caregiver at home).
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the Investigator’s Brochure or and will notify the IRB/IEC, if appropriate 
according to local requirements.
6.5
Overdose
As participants 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.
If an overdose 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.


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For overdoses associated with an SAE, the standard reporting process and 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 participant becomes pregnant during the course of the study, the investigational product 
should be discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the participant 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 1 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 
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 eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.
6.6.2
Paternal exposure 
Provided that nonclinical data with aclidinium bromide based on conventional studies of 
safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential and 
toxicity to reproduction and development do not reveal special hazard for humans, male 
participants are not requested to use contraception methods during their participation on the 
trial.
In case of pregnancy of the participant'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 and consented, be obtained and documented.


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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
Powder for inhalation administered via 
multidose DPI (Genuair ® )  
400 µg/inhalation 
Industrias Farmacéuticas Almirall S.A 
(IFA).
Sant Feliu de Llobregat, Barcelona, 
Spain
DPI = dry powder inhaler
Single and multiple inhaled doses of aclidinium bromide powder will be administered via the 
multidose dry powder inhaler (DPI) Genuair®.
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 participant will receive an empty Genuair® DPI that will be used 
on Visit 1 (Screening) and on Day -1 at Visit 2  . As many practices as needed to learn the 
correct technique for use of the device will be allowed.
7.2
Dose and treatment regimens
Before taking the first dose of the IP the participant will be instructed by the study personnel 
on how to use the Genuair® DPI. Participant 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 participants in local language. 
Further information regarding IP preparation at site will be provided in the investigator drug 
manual.
Each participant will receive a single morning dose (one inhalation) of aclidinium bromide on 
Day 1.
The multiple dosing phase of the study will start on Day 5.  Morning and evening doses of 
aclidinium bromide will be administered for four days with a final morning dose on Day 9. 
The treatment dose of 400 μg aclidinium bromide will be given as 1 inhalation from the 400 
μg aclidinium bromide inhaler.  


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7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language.
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 and placed in a box.
In order to allow drug reconciliation and dispensation control, research personnel will record 
the participant number on the labels of every kit dispensed, as well as on the bags label and 
inhalers labels. 
The medication box, the Aluminium pouch and the Genuair® DPI labels will have blank fields 
for completion of Treatment period, Treatment dose, Subject ID, Randomisation number and 
Investigator name. The Subject ID and Investigator name will have to be completed by the 
investigator before the administration. Blank fields for Treatment period, Treatment dose and 
Randomisation number will not be applicable to complete according to the current CSP. 
Training DPI will be provided with the appropriate labelling but the participant number 
information will be completed by the investigator. All Genuair® DPIs for training will be 
clearly identified as TRAINING.
7.4
Training on DPI inhaler use
Training for the use of the DPI will be done at Screening and on Day -1; the participant will 
receive an empty Genuair® inhaler device for training. All participants will be trained on the 
use of the inhaler. 
The PK of inhaled products, either from a DPI or a metered-dose inhaler (MDI) is largely 
dependent upon proper inhalation technique, therefore training on the DPI inhaler use should 
be conducted carefully. As many practices as needed to learn the correct technique for use 
of the device will be allowed.
Participants will be provided written instructions on the use of the inhaler device.
The Investigator should ensure comprehension of the instructions by the participants and the 
correct use of the inhaler training devices. This task must be clearly documented and approved 
by the PI.
7.5
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.


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Further information regarding IP storage at site will be provided in the investigator drug 
manual.
7.6
Compliance
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the eCRF.
Participants will receive all IP doses under the direct supervision of trial centre personnel, 
which will guarantee compliance. The PI 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 PI.
Investigational product compliance will be assumed to be 100% when dosing has been 
recorded in the eCRF.
The trial centre will keep an accurate drug disposition record that specifies the amount of IP 
administered to each participant and the date of administration.
No IP will be administered out of the unit; therefore, no extra compliance method will be 
needed.
7.7
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The PI is responsible for the control of the IP under investigation. Adequate records of the 
receipt (e.g., 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 participant to whom the IP was dispensed. 

Date(s) and quantity of the IP administered to the participant.

Date(s) and quantity of the IP remaining after dosing completion.
The study personnel will account for all study drugs dispensed to the participant.
Study site personnel, if applicable, or the CRO 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 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 


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site monitor.  The completed Drug Dispensing Log and Drug Return Record(s) will be sent to 
the trial master file (TMF).
7.8
Prior and concomitant medication
No concomitant medications are permitted during the study. Participants will be instructed not 
to take any drugs for at least 14 days before the first day of dosing and during the course of 
the study. Participants will be specifically reminded that this includes over-the-counter 
medications such as aspirin, supplements, herbal remedies, tobacco products, illegal drugs, as 
well as medicines requiring a prescription and vaccines. No hormonal drug products or 
traditional Chinese medicines will be allowed 30 days before Day 1 and throughout the study. 
The Investigator or Sponsor reserves the right to exclude a participant from participation in 
the study if a medication taken 14 or more days before the study start may potentially interfere 
with the study outcome (e.g., a drug with prolonged half-life). The Sponsor may be contacted 
if there are questions about any possibly excluded substances.
Participants who take concomitant medication during the study other than the study drug may 
be withdrawn after discussion with the sponsor, unless for treatment of an adverse event. In 
the event medication is used, it will be recorded in the appropriate section of the eCRF and in 
the source documents.
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 Central Laboratory.
A comprehensive Statistical Analysis Plan (SAP) will be prepared by Parexel prior to first 
participant treated and any subsequent amendments will be documented, with final 
amendments completed prior to database lock.
8.2
Sample size estimate
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 studies 
with aclidinium bromide.
It is planned for 20 participants to enter on treatment in the study.
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 of participants in each analysis set will be summarized (except for Screening 
analysis set). The number and percentage of participants who complete the treatment period 


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and of participants who prematurely discontinue will be presented. The reasons for premature 
discontinuation from the treatment period, as recorded on the termination pages of the eCRFs, 
will be summarized. Additionally, the cause of screening failure should be tabulated for 
Screening analysis set.
8.3.1
Safety analysis set
The safety analysis set will include all participants who received at least 1 dose of IP and for
whom any safety post-dose data are available.
Unless otherwise stated, the safety analysis set will be used for the presentation of all 
demographic and disposition data, as well as all safety analyses.  Exposure to IP will also be 
presented using the safety analysis set.
8.3.2
PK analysis set
The PK analysis set will consist of all participants in the safety analysis set who received at 
least 1 dose of aclidinium bromide and have at least 1 of the parameters (Cmax, Css,max, AUC(0-
∞) AUClast or AUCss,) evaluable and are assumed not to be affected by factors such as 
protocol deviations (e.g., prohibited concomitant medications which are thought to impact on 
the PK data, or incorrect study medication received).
The exclusion of any participants 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 participants excluded from 
the PK analysis set will be listed only. Concentration data for participants excluded from the 
PK analysis set will be presented in the individual figures of concentration versus 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 windows allowance 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 participants from the PK 
analysis set. 
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;
•
Time window deviations for PK and safety assessments;


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•
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 participants for all participants who entered on 
treatment.  Further details will be described in the statistical analysis plan (SAP).
8.4
Outcome measures for analyses
8.4.1
Pharmacokinetics Outcomes
8.4.1.1
Pharmacokinetics parameters
The following PK parameters will be assessed for aclidinium bromide and its metabolites 
LAS34850 and LAS34823 on plasma concentrations: 
Day 1:
Cmax - Observed maximum concentration, taken directly from the 
individual concentration-time curve
Cmin – Observed minimum concentration, taken directly from the 
individual concentration-time curve within a dosing interval
tmax - Time to reach maximum concentration, taken directly from the 
individual concentration-time curve
λz - Terminal rate constant, estimated by log-linear least squares (LS) 
regression of the terminal part of the concentration-time curve
t½λz - Terminal half-life, estimated as (ln2)/ λz
AUClast  - Area under the plasma concentration-curve from time zero to 
the time of last quantifiable concentration
AUC- Area under the plasma concentration-curve from time zero to 12 
hours post-dose
AUC(0-∞) - Area under the concentration-time curve from time zero 
extrapolated to infinity.  AUC(0-∞) is estimated by AUClast + Clast/λz where 
Clast is the last observed quantifiable concentration
CL/F - Apparent clearance for parent drug estimated as dose divided by 
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Vz/F - Apparent volume of distribution for parent drug at terminal phase 
(extravascular administration), estimated by dividing the apparent 
clearance (CL/F) by λz
MRT – mean residence time calculated by AUMC/AUC(0-∞), where 
AUMC is the area under the first moment-time curve
Cmax/D - Observed maximum concentration divided by dose 
AUC/D - Area under the concentration-time curve zero to 12 h divided 
by the dose
AUC(0-∞) /D - Area under the concentration-time curve from time zero 
extrapolated to infinity divided by the dose
Day 9:
Css,max - Observed maximum concentration, taken directly from the 
individual concentration-time curve on Day 9 
Css,min – Observed minimum concentration, taken directly from the 
individual concentration-time curve within a dosing interval on Day 9
Tss,max  - Time to reach maximum concentration, taken directly from the 
individual concentration-time curve 
λz  - Terminal rate constant, estimated by log-linear LS regression of the 
terminal part of the concentration-time curve 
t½λz - Terminal half-life, estimated as (ln2)/ λz
AUCss,- Area under the plasma concentration-curve from time zero to 12 
hours post-dose
CL/F - Apparent clearance for drug estimated as dose divided by AUCss,
Vz/F - Apparent volume of distribution for parent drug at terminal phase 
(extravascular administration), estimated by dividing the apparent 
clearance (CL/F) by λz
Css,max /D - Observed maximum concentration divided by dose 
AUCss,/D - Area under the concentration-time curve zero to 12 h divided 
by the dose 
Css,av - Average plasma concentration during a dosing interval, estimated 
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%Fluctuation - Fluctuation index during a dosing interval estimated as 
100*(Cmax- Cmin)/Cav (%), where Cmin is the minimum concentration at 
the end of the dosing interval
Rac (Cmax) - Accumulation ratio for Cmax estimated as (ratio of Css,max on 
Day 9/Cmax on Day 1)
Rac (AUC) - Accumulation ratio for AUCestimated as (ratio of AUCss,
on Day 9/AUCon Day 1)
Rac (Cmin) - Accumulation ratio for Cmin estimated as (ratio of Css,min on 
Day 9/ Cmin on Day 1)
Time - dependency - estimated as ratio of AUCss,on Day 9/AUC(0-∞) 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 obs - Number of data points included in the log-linear regression 
analysis
AUCex - Percentage of AUC(0-∞) obtained by extrapolation, calculated as 
[(Clast(obs)/λz)/AUC(0-∞) * 100]
Additional PK parameters may be determined where appropriate.
8.4.1.2
Calculation or derivation of the pharmacokinetic parameters
The PK analyses of the plasma concentration data for aclidinium bromide and its metabolites, 
will be performed at Central Laboratory, on behalf of AstraZeneca.  The actual sampling 
times will be used in the plasma PK parameter calculations.  
PK parameters will be derived using non-compartmental methods with Phoenix® WinNonlin®
Version 6.3, or higher and/or SAS® Version 9.3 or later.  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 BLQ concentrations are followed by 
quantifiable concentrations in the terminal portion of the concentration-curve, the profile will 


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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.
8.4.2
Safety and Tolerability Outcomes
AEs
Clinical laboratory parameters (haematology, serum biochemistry, 
urinalysis)
Vital Signs (blood pressure)
12-lead ECG parameters
8.5
Methods for statistical analyses
8.5.1
General principles
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 
analyses in the sections below will be described in further detail in a study specific SAP.


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All original and derived parameters, as well as demographic and disposition data, will be 
listed and described using summary statistics.  Demographic and baseline data, 
pharmacokinetic data and safety and tolerability data will be summarised for all participants in 
the appropriate analysis set. All safety data (scheduled and unscheduled) will be presented in 
the data listings.
Frequency counts (number of participants[n] and percentages) will be made for each 
qualitative variable.  Descriptive statistics (n, mean, standard deviation [SD], median, 
minimum and maximum) will be calculated for each quantitative variable (unless otherwise 
stated).  All statistical analyses and production of tables, figures and listings will be performed 
using SAS® Version 9.3 or later.
8.5.2
Missing data
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 participant who withdraws prior to the last planned observation in a study period will be 
included in the analyses up to the time of discontinuation.  The handling of any missing 
dates/times in the AE or concomitant medication data will be described in the SAP.
8.5.3
Participant disposition
The assignment of participants to each of the analysis sets will be listed and summarised.  
Additional listings will be presented for participant discontinuations and informed consent. 
8.5.4
Demographic and baseline characteristics
Demographic variables (including age, sex, race, height, weight and BMI) will be listed and 
summarised for all participants in the safety analysis set.  
Medical history data will be listed by participant including description of the 
disease/procedure, Medical Dictionary for Regulatory Activities (MedDRA) System Organ 
Class (SOC) and MedDRA Preferred Term (PT).
8.5.5
Prior and concomitant medication
Prior medication is defined as any medication taken up to the 1st dose of IP. 
Concomitant medication is defined as any medication taken at least once after the 1st IP 
administration until the time of the last PK sample on Day 11 (48 hours post-last dose on Day 
9).
A medication that is started before the IP administration and continues afterwards is classified 
as both prior and concomitant medication.
Prior and concomitant medication will be coded using the WHO-Drug Enhanced plus Herbal 
Dictionary and will be listed by participant.


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The number and percentage of participants who used any prior and concomitant medication 
will be summarised separately by Anatomical Therapeutic Code (ATC) to a maximum of 3rd 
level, and preferred name.  Participants with multiple drug usage in the same preferred name 
will be counted only once.  Any medications taken before the first IP administration and 
continuing afterwards, will be included in tabulations for both prior and concomitant 
medications.
8.5.6
Drug administration
Drug administration dates and times will be listed for each participant.
8.5.7
Statistical analysis of the Pharmacokinetic data
A listing of PK blood sample collection times as well as derived sampling time deviations will 
be provided.  A listing of individual sample collection dates and times will be provided.
Plasma concentrations will be summarised using descriptive statistics (n, geometric mean, 
geometric mean+/-geometric SD, geometric coefficient of variation [CV%], arithmetic mean, 
arithmetic SD, minimum, median and maximum) based on the PK analysis set.
For descriptive statistics for plasma concentrations that are below the LLOQ will be handled 
as follows:
•
Where there is non-reportable concentration (NR), these will be set to missing.
•
At a time point where less than or equal to 50% of the values are BLQ, all BLQ values 
will be set to the LLOQ, and all descriptive statistics will be calculated accordingly.
•
At a time point where more than half (but not all) of the values are BLQ, the arithmetic 
mean, arithmetic SD, 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 median will 
be set to BLQ.
•
If all values are BLQ at a time point, no descriptive statistics will be 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 fields for arithmetic mean, geometric mean, minimum, 
median, and maximum.
•
The number of BLQ values (n above LLOQ) will be reported for each time point.
All plasma PK parameters will also be listed and summarised using similar descriptive 
statistics.  For tmax only n, median, minimum and maximum will be reported.
Data from participants excluded from the PK analysis set will be included in the data listings, 
but not in the summaries or in the inferential statistics.
Individual plasma concentrations versus actual time will be plotted in linear and semi-
logarithmic scale, with separate plots for each participant and concentrations for Day 1 and 


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Day 9 overlaid on the same plot.  Combined individual plasma concentration will also be 
presented in linear and semi-logarithmic scale with separate plots for each day (Day 1 and 
Day 9).
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).  
Geometric mean (± SD) plasma trough concentrations versus day profiles (pre-dose on Day 6 
to Day 9) will be presented in both linear and semi-logarithmic scale. 
All plots will be repeated for aclidinium bromide metabolites.
Additional graphical presentations of PK data may be added at the discretion of the PK 
Scientist.  More details will be provided in the SAP.
8.5.7.1
Analysis of time dependency in PK and accumulation
The time dependency will be evaluated by comparing AUCss,on Day 9 with AUC(0-∞) on Day 
1. Accumulation will be evaluated by comparing AUCss,on day 9 with AUCon Day 1 and 
Css,max on Day 9 with Cmax on Day 1.  
A linear mixed-effect model will be used with the logarithm of the PK parameters as the 
response variable and day as a fixed effect.  Day will be treated as a repeated effect within 
participant.  
From these models, LS means together with 95% CI for Day 1 and Day 9, and LS means 
together with 90% CI for the difference for Day 9 versus Day 1 will be obtained.  The results 
will be transformed back to the original scale by exponentiation to provide estimates of 
geometric LS means, geometric LS mean ratios for Day 9/Day 1, and corresponding 90% CI. 
8.5.8
Analysis of safety data
All analyses of safety data will be performed on the safety analysis set.
8.5.8.1
Adverse events
All AEs will be coded using MedDRA dictionary, and will be listed for each participant.  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 participants and the number of 
events where applicable.


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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.
8.5.8.2
Blood Pressure
The results of the blood pressure measurements will be listed by participant 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 participants with notable changes from pre-dose (baseline) will 
be tabulated by 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.
8.5.8.3
Resting 12-lead electrocardiogram
12-Lead ECG results performed for safety evaluation will be listed for each participant 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 time point including 
changes from baseline.  The baseline for the safety ECG parameters will be the results 
obtained on Day -1.
8.5.8.4
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.
8.5.8.5
Laboratory assessments
Haematology and clinical chemistry values will be listed by participant 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. 


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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 participants with shifts from baseline in each of these categories.
Urinalysis results will be listed.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first participant 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:

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 eCRFs with the 
participant's medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating participants. This 
will require direct access to all original records for each participant (e.g., clinic charts).

Ensure withdrawal of informed consent to the use of the participant's biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the participant.


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The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre need 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 participants and in all other respects, not relating to study conduct or treatment of 
participants, 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 participants are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA).
9.3
Study timetable and end of study
The end of the study is defined as the date when all participants who entered on treatment in 
the trial performed the last contact (either Visit 3 Follow-up or premature discontinuation 
visit).
The study is expected to start in Quarter 2 – 3, 2021 and to end by Quarter 4, 2021.
The study may be terminated at the centre 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.


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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 
have 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.
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.
An audit trail of all databases will be maintained in order to protect the authenticity and 
integrity of the clinical data.


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10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Participant 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 participants.  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 participant into the study. 
The Ethics Committee should approve all advertising used to recruit participants for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.
Before enrolment of any participant 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.
Regulatory Reporting Requirements for SAEs


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
Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

For all studies except those utilizing medical devices, investigator safety reports must 
be prepared for suspected unexpected serious adverse reactions (SUSAR) according to 
local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary.

European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the [Investigator’s Brochure or state other 
documents] and will notify the IRB/IEC, if appropriate according to local 
requirements.
10.4
Informed consent
The Investigator(s) at the centre will:

Ensure each participant is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study.

Ensure each participant is notified that they are free to discontinue from the study at 
any time.

Ensure that each participant is given the opportunity to ask questions and allowed time 
to consider the information provided.

Ensure each participant provides signed and dated informed consent before conducting 
any procedure specifically for the study.

Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File.

Ensure a copy of the signed Informed Consent Form is given to the participant.


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
Ensure that any incentives for participants who participate in the study, as well as any 
provisions for participants harmed as a consequence of study participation, are 
described in the informed consent form that is approved by 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 Investigator and 
AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
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
1.
Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalenceof 
COPD (the BOLD Study): a population-based prevalence study. Lancet. 2007; 370:741-50. 
2.
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.
3.
Jones PW, Singh D, Bateman ED, et al. Efficacy and safety of twice- daily aclidinium bromide 
in COPD patients: the ATTAIN study. Eur Respir J 2012; 40: 830-836.


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4.
Kerwin EM, D’Urzo AD, Gelb AF, et al. Efficacy and safety of a 12-week treatment with 
twice-daily aclidinium bromide in COPD patients (Accord COPD 1). COPD 2012; 9: 90-101.
5.
Fuhr R, Magnussen H, Sarem K et al. Efficacy of Aclidinium Bromide 400 µg Twice Daily 
Compared With Placebo and Tiotropium in Patients With Moderate to Severe COPD. Chest 
2012; 141(3):745–752.
6.
Singh D, Magnussen H, Kirsten AM et al. A randomised, placebo- and active-controlled dose-
finding study of aclidinium bromide administered twice a day in COPD patients. Pulmonary 
Pharmacology & Therapeutics 25 (2012) 248-253.
7.
Beeh K, Watz H, Puente-Maestu L et al. Aclidinium improves exercise endurance, dyspnea, 
lung hyperinflation, and physical activity in patients with COPD: a randomized, placebo-
controlled, crossover trial. BMC Pulmonary Medicine 2014, 14:209.
8.
Investigator’s Brochure Aclidinium Bromide edition number 18, 10Sep2019.
9.
WMA Declaration of Helsinki (18th WMA General Assembly 1964), revised at 59th World 
Medical Association General Assembly Seoul, October 2008. 
10. 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.


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     Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (e.g., hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant 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 participant or may 
require medical intervention to prevent one or more outcomes listed in the definition of 
serious.  These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.


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
Time Course.  Exposure to suspect drug.  Has the participant 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.
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 


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A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g., medication prepared incorrectly, even if it was not actually given 
to the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated e.g., tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed e.g., kept in the fridge when it should be at room 
temperature 

Wrong participant received the medication (excluding IRT/RTSM errors)

Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM - including those which lead to one of 
the above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) e.g., forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 


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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 e.g., 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 e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations.

Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging. 

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content.

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable.

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.


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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 Potential Hy's Law (PHL) cases and Hy’s Law (HL) cases. 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 participant meets 
potential Hy’s Law (PHL) criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Product (IMP). 
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 
IP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  


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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 participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative

Determine whether the participant meets PHL criteria by reviewing laboratory reports 
from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
Follow-up
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the participant 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 participant does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE 
of Potential Hy’s Law; serious criteria ‘Important medical event’ and causality 
assessment ‘yes/related’ according to CSP process for SAE reporting.


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• The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study participants' follow-up (including any further laboratory testing) and 
the continuous review of data. 
• Subsequent to this contact the Investigator will:

Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required. 

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. 

Complete the three Liver CRF Modules as information becomes available. 
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.
As soon as possible 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 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date PHL criteria was met.  The AstraZeneca Global Clinical Lead or equivalent and 
Global Safety Physician will also be involved in this review together with other subject matter 
experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where 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 eCRF.

If the alternative explanation is an AE/SAE, update the previously submitted Potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 


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
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply.

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days 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:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE 
reporting.

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 still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
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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Version 4.0
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Appendix D
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (e.g., during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the Sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.  
D 1  Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, e.g., remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections D 2 to D 4. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided. 
D 2   Rescreening of Participants To Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
study physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrolment into the study or commencing of dosing with IP. If this delay 
is outside the screening window specified in section 4.1 the participant will need to be 
rescreened to reconfirm eligibility before commencing study procedures. This will provide 
another opportunity to re-screen a participant. The procedures detailed in section 4.1 must be 
undertaken to confirm eligibility using the same participant ID number.
D 3  Telemedicine follow-up Visit to Replace On-site follow-up Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the participants 
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices.
During a civil crisis, natural disaster, or public health crisis, the on-site follow-up visits may 
be replaced by a telemedicine visit if allowed by local/regional guidelines. Having a 


Clinical Study Protocol Appendix D
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Version 4.0
Date 05 Feb 2021
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telemedicine contact with the participants will allow adverse events, concomitant medication, 
add other information where relevant to be collected according to study requirements to be 
reported and documented. Participants will be instructed to return to the trial centre to 
complete the on-site follow-up assessments (12-lead ECG and blood pressure assessment) as 
soon as possible. 
D 4   Data Capture During Telemedicine follow-up Visit
Data collected during telemedicine follow-up visit will be captured by the qualified HCP from 
the study site in the medical notes and recorded in the eCRF.
D 5  Replacement of participants
Participants who are withdrawn from the study due to study disruption will not be replaced 
unless fewer than 10 participants complete treatment.  Participants will be replaced only if the 
sponsor’s responsible physician and the Investigator agree it is safe to do so.
Screening failure participants will be replaced until the number of  participants on treatment is 
reached.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d657200002-csp-v4
Document Title:
D6572C00002 Eklira PK Clinical Study Protocol version 4
Document ID:
Version Label:
6.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
10-Feb-2021 11:00 UTC
Content Approval
10-Feb-2021 03:23 UTC
Content Approval
09-Feb-2021 13:47 UTC
Content Approval
09-Feb-2021 14:13 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
CCI
PPD
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SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
A Phase I, Open-Label, Single and Multiple Dose (Twice-Daily), Clinical 
Trial to Evaluate the Pharmacokinetics, Safety and Tolerability of 
Aclidinium Bromide 400 μg Administered by Inhalation in Healthy Chinese 
Participants 
 
ClinicalTrials.gov Identifier: NCT03276052 
 
 
Date of Statistical Analysis Plan: 27 Aug 2021 




 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 






 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
  
  
  
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
 
 
  
 
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
   
 
 
  
 
  
 
 
  
 
 
 
 
  
 
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 




 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 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