Clinical trial NCT03645434
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: Moderate to severe COPD Muscarinic receptor antagonist β2 adrenoceptor agonist (MABA) Long-acting muscarinic antagonist (LAMA) Long-acting β2-agonist (LABA) Inhaled long-acting bronchodilator Small airways disease (obstructive bronchiolitis) Parenchymal destruction (emphysema),
Sponsor: AstraZeneca
Start date: 2018-10-10; Completion date: 2019-08-07
Enrollment: 73 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will evaluate the efficacy and safety data of AZD8871 in patients with moderate to severe chronic obstructive pulmonary disease (COPD). This study will determine the 24-hour efficacy (lung function) profile of AZD8871 600 μg relative to placebo dry powder inhaler (DPI) based on trough forced expiratory volume in 1 second (FEV1) following repeated dosing (2 weeks). Anoro® Ellipta® (umeclidinium/vilanterol) once daily is included as an active control. This study aims at providing a novel approach to the treatment of COPD with greater efficacy than single-mechanism bronchodilators, equivalent to long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) administered as free- or fixed-dose combination therapies, with an equivalent or superior safety and tolerability profile.

Detailed description:
This randomized, double-blind, placebo and active-controlled crossover study will be conducted at 5 sites in Germany and the United Kingdom (UK). Approximately 180 patients will be screened in order to randomize 72 patients into the study. Based on previous studies estimate, it is anticipated that 54 patients will be evaluable (study completers) assuming an approximate 25% dropout rate. A subset of 36 patients, who will have specifically consented for pharmacokinetics (PK), will undergo PK assessments. The study will consist of -

* A Screening period: Will last up to 28 days and consists of 2 Screening visits (Visit 1 and Visit 2) and a run-in period (between a minimum of 14 and a maximum of 28 days; from Visit 2 to Visit 3).
* Three treatment periods (Visit 3; 14 days each; each separated by a wash-out period of 42 to 49 days) and
* A Follow-up Visit: 42 days (up to 49 days) after last investigational product (IP) administration.

Patients will be requested to stop their usual COPD therapy after signing the informed consent form (ICF) at Visit 1 and will be maintained on a mono-component inhaled corticosteroid (ICS) therapy, if required. Patients that were taking any LAMA will be maintained with ipratropium (34 µg × 2 puffs 4 times per day) between Visit 1 and Visit 2. In addition, salbutamol 100 µg will be provided as rescue medication during the study as needed (rescue medication has to be discontinued 6 hours before any pulmonary function test). Visit 1 and Visit 2 could be performed on the same day if no wash-out of prior medication is required and the patient visits the site in fasting condition. In case any wash-out of prior medication is required, then Visit 2 will be performed after the wash-out is complete. If reversibility criteria and forced expiratory volume in 1 second (FEV1) predicted values are fulfilled according to inclusion criteria, the patient will be started on run-in period to assess clinical stability. If reversibility criteria or FEV1 predicted values are not met, pulmonary function tests could be rescheduled at the latest, up to Day 14. During the run in period, all patients will receive ipratropium 34 µg × 2 puffs 4 times per day (must be discontinued 8 hours prior to previous any pulmonary function test). A paper diary will be used to collect adverse events (AEs) and concomitant medication during run-in and wash-out periods.

Eligible patients will be randomized in 1:1:1:1:1:1 ratio to 1 of 6 treatment sequences and will receive orally 1 of the following 3 treatments sequence in the form of inhalation powder using DPI :

* AZD8871 600 µg once daily (double-blind).
* Anoro® Ellipta® (55 µg umeclidinium \[UMEC\]/ 22 µg vilanterol \[VI\]) once daily (double-blind).
* Placebo (double-blind). Study treatment administration during all the visits at the sites (Day 1, Day 2, Day 8, and Day 14 of each treatment period) will be supervised by study personnel.

During the treatment period Visits, safety and tolerability assessments and pulmonary function measurements will be taken pre-dose and up to 24 hours (Day 1) and up to 4 hours (Day 8) post-dose, respectively.

At Visits 3 to 11, a subset of 36 patients will undergo PK assessments. Blood samples will be collected pre-dose and up to 24 hours post dose.

In follow-up visit, AEs, safety laboratory, electrocardiogram (ECG), vital signs and physical examination will be assessed.

The study includes 12 visits and the entire study period is scheduled to take from a minimum of 6.5 months (182 days) to a maximum of 7.5 months (217 days) for each individual patient. The estimated study duration is 12 months.

Arms: arm 1: Randomized patients will receive multiple oral dose of inhalation powder via DPI as follow:

Treatment period 1: AZD8871 600 µg and Anoro® Ellipta® matching placebo.

Treatment period 2: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg.

Treatment period 3: Matching placebo of AZD8871 and Anoro® Ellipta® arm 2: Randomized patients will receive multiple oral dose of inhalation powder via DPI as follows:

Treatment period 1: AZD8871 600 µg and Anoro® Ellipta® matching placebo.

Treatment period 2: Matching placebo of AZD8871 and Anoro® Ellipta®

Treatment period 3: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg. arm 3: Randomized patients will receive multiple oral dose of inhalation powder via DPI as follows:

Treatment period 1: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg.

Treatment period 2: AZD8871 600 µg and Anoro® Ellipta® matching placebo.

Treatment period 3: Matching placebo of AZD8871 and Anoro® Ellipta® arm 4: Randomized patients will receive multiple oral dose of inhalation powder via DPI as follow:

Treatment period 1: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg.

Treatment period 2: Matching placebo of AZD8871 and Anoro® Ellipta®

Treatment period 3: AZD8871 600 µg and Anoro® Ellipta® matching placebo. arm 5: Randomized patients will receive multiple oral dose of inhalation powder via DPI as follow:

Treatment period 1: Matching placebo of AZD8871 and Anoro® Ellipta®

Treatment period 2: AZD8871 600 µg and Anoro® Ellipta® matching placebo.

Treatment period 3: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg. arm 6: Randomized patients will receive multiple oral dose of inhalation powder via DPI as follow:

Treatment period 1: Matching placebo of AZD8871 and Anoro® Ellipta®

Treatment period 2: AZD8871 matching placebo and Anoro® Ellipta® 55 μg / 22 μg.

Treatment period 3: AZD8871 600 µg and Anoro® Ellipta® matching placebo.
Interventions: intervention 1: AZD8871 intervention 2: Anoro® Ellipta®
Intervention descriptions: intervention 1: Randomized patients will receive 14 repeated daily doses of AZD8871 600 µg inhalation powder via DPI. intervention 2: Randomized patients will receive 14 repeated daily doses of Anoro® Ellipta® (55 µg/22 µg) inhalation powder via DPI.

Protocol documents:
Prot_000.pdf: 
Clinical Study Report Appendix 16.1.1 
AstraZeneca 
AZD8871 – D6640C00006 
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Clinical Study Report Appendix 16.1.1 
Drug Substance AZD8871 
Study Code 
D6640C00006 
Appendix 16.1.1 
Protocol and Protocol Amendments 
 


Clinical Study Report Appendix 16.1.1 
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VERSION OF PROTOCOL OR PROTOCOL AMENDMENT 
Global Document Name 
Version No 
Version Date 
First final version of the protocol prior to any amendments 
1.0 
29 May 2018 
Amended CSP 
2.0 
13 Jun 2018 
Amended CSP 
3.0 
13 Sep 2018 
Amended CSP 
4.0 
11 Dec 2018 
Local Document Name 
Country Name: United Kingdom 
Version No 
Version Date 
First final version of the protocol prior to any amendments 
1.0 
08 Aug 2018 


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Clinical Study Protocol 
Drug Substance
AZD8871
Study Code
D6640C00006
Version
4.0
Date
11 December 2018
A Phase IIa, Randomised, Multi-centre, Double-blind, Placebo and Active-controlled, 
3 Periods, Crossover Study to Investigate the Efficacy, Pharmacokinetics, Safety and 
Tolerability of Inhaled AZD8871 Administered Once Daily for 2 Weeks in Patients with 
Moderate to Severe COPD
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
EudraCT number: 2018-001722-25
This document contains trade secrets and confidential commercial information, disclosure of which is prohibited 
without providing advance notice to AstraZeneca and opportunity to object.


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VERSION HISTORY
Version 1.0, 29 May 2018
Initial creation
Version 2.0, 13 June 2018
Changes to the protocol are summarised below.
Removal of reversibility criterion for study eligibility as it is an unnecessary constraint for 
the conduct of this study. Reversibility testing will continue to take place but will not 
impact a patient’s eligibility for entering the study.
The screening failure rate has been revised downwards from 60% to 50% due to removal of 
the reversibility criterion for study eligibility; the number of patients to be screened is 
revised downwards from 180 to 145 patients.
The ipratropium dose has been changed from 34 µg to 20 µg.
The ECG parameters have been updated to remove QRS complexes.
Version 3.0, 13 September 2018
Changes to the protocol are summarised below. Added text is shown in italic font and 
deleted text is shown with strikethrough. 
Version 3.0 implements changes requested by the UK Medicines and Healthcare products 
Regulatory Agency (MHRA) and the German Federal Institute for Drugs and Medical 
Devices (BfArM).
In response to MHRA feedback the following changes have been made:
Section 5.1: Inclusion criterion #12:
Male patients should use a condom and spermicide (or sexual abstinence*) to prevent 
pregnancy and drug exposure of a partner, regardless of the gender or childbearing potential 
of the partner from the day of the first administration of the IP until 3 months after the last 
administration of the IP.  In addition to a condom with spermicide, a second highly effective 
method of contraception (oral, intravaginal or transdermal hormonal contraceptives, 
intrauterine device, or intrauterine hormone-releasing system, or sexual abstinence until 
3 months after the last administration of the IP) should be used with female partners of 
childbearing potential.  Double barrier methods (a combination of male condom with either 
a cap, diaphragm or sponge with spermicide) are not considered to be highly effective 
methods of contraception. Male patients with a pregnant partner should use a condom and 
spermicide or sexual abstinence*.
*True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
(periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], 


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declaration of abstinence for the duration of a trial, and withdrawal are not acceptable 
methods of contraception).
Section 6.3 Measures to minimise bias: randomisation and blinding:
The IVRS/IWRS will be programmed with blind-breaking instructions.  The blind may be 
broken if, in the opinion of the Investigator, it is in the patient’s best interest for the 
Investigator to know the study treatment assignment.  The Sponsor must be notified before 
the blind is broken unless identification of the study treatment is required for a medical 
emergency in which the knowledge of the specific blinded study treatment will affect the 
immediate management of the patient’s condition (eg, antidote available). In case of an 
emergency, the Investigator has the sole responsibility for determining if unblinding of a 
patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the Investigator decides that unblinding is 
warranted, the Investigator is asked to contact the Sponsor prior to unblinding a patient’s 
treatment assignment unless this could delay emergency treatment of the patient.
In response to BfArM feedback the following change has been made:
Section 5.2: Exclusion criteria: 
12. Patient with a heart rate <50 or >120 >100 beats per minute (bpm).
13. Patient has clinically significant uncontrolled hypertension (>180 >160 mmHg) as 
assessed by the Investigator.
Section 7.3: Withdrawal from the study
When a patient does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study 
Physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the Investigator regarding whether to continue or discontinue the patient from 
treatment.  Any patient that has been initiated on treatment and subsequently found not to 
meet all the eligibility criteria must stop the treatment and be excluded from the study.  The 
AstraZeneca Study Physician must ensure all decisions are appropriately documented.
Version 4.0, 11 December 2018
Changes to the protocol are summarised below. 
Heart Rate for pre-dose time points on visits 4, 7 and 10 will be taken from Vital 
Signs. 
As per protocol there is no pre-dose ECG for visits 4, 7 and 10. 
ECGs will be done as single measurements and not as triplicates. 
8.2.4 Electrocardiogram: Triple 12-lead ECG will be obtained as specified in the SoA 
(Table 1) using an ECG machine that automatically calculates the heart rate and measures 


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PR, QRS, QT, and QTc intervals. Table 1 does not specify any triplicate ECG time points 
and therefore the section on triplicate ECG measurement is also irrelevant. Single 
measurement has been confirmed by sponsor.
ECGs and Vital signs will be measured after 5min rest in a supine position (as flat as 
possible and what is comfortable for the patient) to ensure consistency between 
measurements. 
Use of supine position (as flat as possible and what is comfortable for the patient) for 
the ECG and vital signs. The same position should be used for all time-points. 
Vital Signs will be done as single measurement and not as triplicates. 
8.2.3 Vital signs: Vital signs will be measured in a supine position after 5 min rest and 
will include temperature, SBP and diastolic blood pressure (DBP). Three readings of BP 
will be taken. The first reading should be rejected. The second and third readings should 
be averaged to give the measurement to be recorded in the eCRF. 
Clinical Stability Check will be done at Screening and before the start of each 
period. 
This is to confirm that stability check will be done before the start of each treatment 
period. 
Drugs of abuse and Alcohol 
Screening results for Drugs of abuse and Alcohol will be used to determine Exclusion 
criterion #21 prior to randomisation due to the logistically accessibility of the results. 
Cough Monitoring for Visits 5, 8 and 11 will start on Day 14, just before dosing at 
site, for 24hours recording 
The recording for Visits 3, 6 and 9 are home recordings and will start at least 24 hours
before the dosing and will finish pre-dose. Table 1, footnote r. Cough monitoring for 
Visits 5, 8, and 11 will start on Day 14, just before, for 24 hours recording. 
Table 8: “Laboratory safety variables” in section 8.2.1 
Clinical safety laboratory assessments of the protocol the following parameters were 
omitted in the table by error: aPTT=Activated partial thromboplastin time, 
INR=International normalised ratio; PTT=Partial thromboplastin time. 
These parameters are only mentioned in the footnote but will be considered as part of the 
lab analysis in the table. 


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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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TABLE OF CONTENTS
1.
PROTOCOL SUMMARY ................................................................................. 10
1.1
Schedule of Activities (SoA).............................................................................. 10
1.2
Synopsis ............................................................................................................ 16
1.3
Schema .............................................................................................................. 21
2.
INTRODUCTION ............................................................................................. 23
2.1
Study rationale................................................................................................... 23
2.2
Background........................................................................................................ 23
2.3
Benefit/risk assessment ...................................................................................... 24
3.
OBJECTIVES AND ENDPOINTS.................................................................... 27
4.
STUDY DESIGN............................................................................................... 29
4.1
Overall design.................................................................................................... 29
4.2
Scientific rationale for study design ................................................................... 31
4.3
Justification for dose.......................................................................................... 32
4.4
End of study definition....................................................................................... 32
5.
STUDY POPULATION .................................................................................... 32
5.1
Inclusion criteria ................................................................................................ 33
5.2
Exclusion criteria ............................................................................................... 35
5.3
Lifestyle restrictions........................................................................................... 38
5.3.1
Meals and dietary restrictions............................................................................. 38
5.3.2
Caffeine, alcohol, and tobacco............................................................................ 39
5.3.3
Activity.............................................................................................................. 39
5.3.4
Medication and other restrictions ....................................................................... 40
5.4
Screen failures ................................................................................................... 40
6.
STUDY TREATMENTS................................................................................... 40
6.1
Treatments administered .................................................................................... 41
6.1.1
Investigational products ..................................................................................... 41
6.2
Preparation/handling/storage/accountability....................................................... 41
6.3
Measures to minimise bias: randomisation and blinding..................................... 42
6.4
Treatment compliance........................................................................................ 45
6.5
Concomitant therapy.......................................................................................... 45
6.5.1
Background medication...................................................................................... 47
6.5.2
Other concomitant treatment .............................................................................. 47
6.5.3
Rescue medication ............................................................................................. 48
6.6
Dose modification.............................................................................................. 48


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6.7
Treatment after the end of the study ................................................................... 48
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL ............................................................................................... 48
7.1
Discontinuation of study treatment..................................................................... 48
7.1.1
Temporary discontinuation................................................................................. 50
7.1.2
Rechallenge ....................................................................................................... 51
7.1.3
Procedures for discontinuation of study treatment .............................................. 51
7.2
Lost to follow-up ............................................................................................... 51
7.3
Withdrawal from the study................................................................................. 51
8.
STUDY ASSESSMENTS AND PROCEDURES............................................... 52
8.1
Efficacy assessments.......................................................................................... 53
8.1.1
Clinical outcome assessments ............................................................................ 53
8.1.2
FEV1 and clinical stability check........................................................................ 55
8.1.3
Reversibility testing ........................................................................................... 56
8.2
Safety assessments............................................................................................. 56
8.2.1
Clinical safety laboratory assessments................................................................ 56
8.2.2
Physical examinations........................................................................................ 58
8.2.3
Vital signs.......................................................................................................... 59
8.2.4
Electrocardiograms ............................................................................................ 59
8.3
Collection of adverse events............................................................................... 61
8.3.1
Method of detecting AEs and SAEs ................................................................... 61
8.3.2
Time period and frequency for collecting AE and SAE information ................... 61
8.3.3
Follow-up of AEs and SAEs .............................................................................. 61
8.3.4
Adverse event data collection............................................................................. 62
8.3.5
Causality collection............................................................................................ 62
8.3.6
Adverse events based on signs and symptoms.................................................... 63
8.3.7
Adverse events based on examinations and tests ................................................ 63
8.3.8
Hy’s law ............................................................................................................ 63
8.3.9
Disease under study (DUS) ................................................................................ 63
8.3.10
Disease progression............................................................................................ 64
8.4
Safety reporting and medical management ......................................................... 64
8.4.1
Reporting of serious adverse events ................................................................... 64
8.4.2
Pregnancy .......................................................................................................... 64
8.4.2.1
Maternal exposure.............................................................................................. 65
8.4.2.2
Paternal exposure............................................................................................... 65
8.4.3
Overdose............................................................................................................ 66
8.4.4
Medication error ................................................................................................ 66
8.5
Pharmacokinetics ............................................................................................... 66
8.5.1
Derivation of the pharmacokinetic parameters.................................................... 67
8.5.2
Determination of drug concentration.................................................................. 68
8.5.3
Storage and destruction of pharmacokinetic samples.......................................... 68
8.6
Pharmacodynamics ............................................................................................ 68


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8.7
Genetics............................................................................................................. 69
8.9
Health economics............................................................................................... 69
9.
STATISTICAL CONSIDERATIONS................................................................ 69
9.1
Statistical hypotheses ......................................................................................... 69
9.2
Sample size determination.................................................................................. 69
9.3
Populations for analyses..................................................................................... 69
9.4
Statistical analyses ............................................................................................. 71
9.4.1
Efficacy analyses ............................................................................................... 72
9.4.2
Safety analyses................................................................................................... 73
9.4.3
Pharmacokinetic analysis ................................................................................... 75
9.4.4
Exploratory analysis........................................................................................... 76
9.4.5
Methods for multiplicity control......................................................................... 76
9.5
Interim analyses.................................................................................................76
10.
REFERENCES .................................................................................................. 77
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS......................................................................................... 78
LIST OF TABLES
Table 1
Schedule of Assessments.......................................................................11
Table 2
Study objectives and endpoints..............................................................28
Table 3
Study Treatments ..................................................................................41
Table 4
Treatment sequences.............................................................................43
Table 5
Restricted medications ..........................................................................46
Table 6
Prohibited medications..........................................................................46
Table 7
Rescue medication ................................................................................48
Table 8
Laboratory safety variables ...................................................................57
LIST OF FIGURES
Figure 1
Study design .........................................................................................22
CCI


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LIST OF APPENDICES
Appendix A
Regulatory, Ethical and Study Oversight Considerations.......................78
Appendix B
Adverse Event Definitions and Additional Safety Information ..............82
Appendix C
Handling of Human Biological Samples................................................86
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ........................................................................89
Appendix E
Breathlessness, Cough, Sputum Scale Questionnaire.............................95
Appendix F
COPD Assessment Test.........................................................................96
Appendix G
Cough Visual Analogue Scale...............................................................97
Appendix H
Abbreviations........................................................................................98


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1.
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)


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Table 1
Schedule of Assessments
Screening
Treatment periods (Period 1-Period 3)
Follow-up or 
Discontinuation
Details in CSP section 
or Appendix
Period 1
Period 2
Period 3
Visit
1a
2a
3 b,d
4 c
5 b
6 b,d
7 c
8 b
9 b,d
10 c
11 b
42 days after Visit 11 
(or last IP admin)
Day 
-28 to -14 -28 to -14
1
8
14
1
8
14
1
8
14
Informed consent 
X
Section 5.1
Inclusion/exclusion criteria
X
X
X e
Section 5.1 and 5.2
Routine clinical procedures
Demography
X
Section 5.1
Smoking history
X
Section 5.1
Physical examination f
X
X
X
X
X
X
X
X
Section 5.1
Medical/surgical history
X
Section 5.1
Vital signs (BP) g
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.3
Height
X
Section 8.2.2
Weight
X
X
Section 8.2.2
12-lead ECG h
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.4
Previous and concomitant medication
X
X
At every visit and may be conducted by phone if not tied 
to a visit
Section 6.5
Routine safety measurements
Adverse events and COPD exacerbations
X
X
At every visit and may be conducted by phone if not tied 
to a visit
X
Section 8.3
Pregnancy test (urine)
X w
X
X
X
X
Section 5.1
Drugs of abuse and alcohol screen i
X
X
X
X
Section 5.1
Safety laboratory assessments (clinical 
chemistry, haematology and urinalysis) j
X
X
X
X
X
X
X
X
Section 8.2.1


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Table 1
Schedule of Assessments
Screening
Treatment periods (Period 1-Period 3)
Follow-up or 
Discontinuation
Details in CSP section 
or Appendix
Period 1
Period 2
Period 3
Visit
1a
2a
3 b,d
4 c
5 b
6 b,d
7 c
8 b
9 b,d
10 c
11 b
42 days after Visit 11 
(or last IP admin)
Day 
-28 to -14 -28 to -14
1
8
14
1
8
14
1
8
14
i-STAT measurement k
X
X
X
X
X
X
Section 8.2.1
Pharmacokinetic measurements m
Pre-dose PK blood sample
X
X
X
X
X
X
X
X
X
Section 8.5
30 min post-dose PK blood sample
X
X
X
X
X
X
Section 8.5
1 hour post-dose PK blood sample
X
X
X
X
X
X
X
X
X
Section 8.5
2 hours post-dose PK blood sample
X
X
X
X
X
X
Section 8.5
4 hours post-dose PK blood sample
X
X
X
X
X
X
Section 8.5
6 hours post-dose PK blood sample
X
X
X
X
X
X
Section 8.5
8 hours post-dose PK blood sample
X
X
X
X
X
X
Section 8.5
12 hours post-dose PK blood sample
X
X
X
X
X
X
Section 8.5
24 hours post-dose PK blood sample
X
X
X
X
X
X
Section 8.5
Efficacy measurements
Reversibility testing n
X
Section 8.1.3
Clinical stability check
X
X
X
X
Section 8.1.2
FEV1 stability check o
X
X
Section 8.1.2
Spirometry p
X
X
X
X
X
X
X
X
X
X
Section 8.1.1
BCSS questionnaire 
X
X
X
X
X
X
X
X
X
X
Section 8.1.1
CCI
CCI


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Table 1
Schedule of Assessments
Screening
Treatment periods (Period 1-Period 3)
Follow-up or 
Discontinuation
Details in CSP section 
or Appendix
Period 1
Period 2
Period 3
Visit
1a
2a
3 b,d
4 c
5 b
6 b,d
7 c
8 b
9 b,d
10 c
11 b
42 days after Visit 11 
(or last IP admin)
Day 
-28 to -14 -28 to -14
1
8
14
1
8
14
1
8
14
COPD assessment test (CAT)
X
X
X
X
X
X
X
X
X
X
Section 8.1.1
Cough VAS q
X
X
X
X
X
X
X
X
X
Section 8.1.1
Cough monitoring r
X
X
X
X
X
X
Section 8.1.1
Study treatment administration
Ipratropium dispensed s
X
X
X
X
Salbutamol dispensed
X
X
X
X
X
X
X
X
X
X
Randomisation
X
Section 6.3
Inhaler training t
X
X
X
Study treatment kit dispensed 
(daily dosing) u
X
X
X
Dispense/Check e-Diary/paper diaries v
X
X
X
X
X
X
X
X
X
X
AE=Adverse event; BCSS=Breathlessness, Cough, Sputum Scale; BP=Blood Pressure; COPD= Chronic Obstructive Pulmonary Disease; CSP=Clinical Study 
Protocol; ECG=Electrocardiogram; e-Diary= Electronic Diary; 
 FEV1=Forced Expiratory Volume in 1 second; 
IP=Investigational Product; PK=Pharmacokinetics; 
. 
a.
All the Screening assessments can be performed at Visit 1 or Visit 2, based on the site’s preference, except for the following:
(i)
Informed Consent Form (ICF) must be completed at Visit 1 before any study-specific assessments are performed. 
(ii)
Reversibility test with salbutamol and spirometry (to confirm inclusion criterion #6) must be performed at Visit 2 after wash-out is completed.
Visit 1 and Visit 2 could be performed on the same day if no wash-out of prior medication is required and the patient visits the site in fasting condition.  In 
case any wash-out of prior medication is required, then Visit 2 will be performed after the wash-out is complete. 
b.
Visits 3, 6 and 9 and Visits 5, 8 and 11 will be overnight stay visits; 6 overnight visits are required per patient.
c.
Visits 4, 7 and 10 will be outpatient visits with duration of approximately of 5 hours.
d.
Interval between randomised treatment periods (wash-out period) will be 42 to 49 days (from the last IP administration). 
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e.
Eligibility for study inclusion will be assessed from Screening Visit data for exclusion criterion #17. 
f.
Physical examination will be a complete examination at Screening and at the Follow-up Visit.  Brief physical examinations will be performed pre-dose at 
Visits 3, 6, 9, and 24 hours post-dose at Visits 5, 8 and 11.
g.
Vital signs: Blood pressure will be assessed pre-dose and 1, 2, 4, and 24 hours post-dose at Visits 3, 5, 6, 8, 9 and 11.  On Visits 4, 7 and 10 blood pressure 
will be measured at pre-dose, 1 and 4 hours post-dose.  Body temperature will be measured at Screening and at the Follow-up Visit. Heart rate will be 
assessed by ECG (except pre-dose on Visits 4, 7 and 10, which will be taken from Vital Signs).
h.
12-Lead ECG measurements will be done pre-dose and 1, 2, 4, and 24 hours post-dose on Visits 3, 5, 6, 8, 9 and 11.  At Visits 4, 7 and 10 ECG measurements 
will be done at 1 and 4 hours post-dose.  ECG should be performed before spirometry.
i.
The alcohol screen may be performed using a urine sample or a breath test. Screening results for drugs of abuse will be used to determine exclusion criterion 
#21 prior to randomisation due to the logistically accessibility of the results.
j.
Safety laboratory tests will be done at Visit 1, pre-dose at Visits 3, 6, 9 and at 24 hours post-dose at Visits 5, 8, 11 and at Follow-up Visit.  Safety laboratory 
tests will be done after 8 hours of fasting.  Serology parameters will be measured at Visit 1 only.
k.
i-STAT for glucose and potassium measurements will be done pre-dose and 1, 2, 4 and 24 hours post-dose on Visits 3, 5, 6, 8, 9 and 11.  i-STAT will be 
done after at least 4 hours of fasting.
 
m.
PK blood samples will be collected from patients who will have specifically consented to the PK assessments at pre-dose and at 30 minutes (min), 1, 2, 4, 
6, 8, 12, and 24 hours post-dose at Visits 3, 5, 6, 8, 9 and 11.  At Visits 4, 7 and 10 measurements will be done pre-dose and 1 hour post-dose.
n.
Reversibility test includes a pre-salbutamol spirometry and then at 20-30 min post-salbutamol.
o.
FEV1 stability will be done at Visits 6 and 9 based on the pre-best test review (BTR).
p.
Spirometry measurements will be done at -1 h and -15 min pre-dose and then 15 min, 30 min, 1, 2, 4, 8, 12, 23, and 23:45 hours post-dose on Visits 3, 5, 6, 
8, 9 and 11.  At Visits 4, 7 and 10 spirometry measurements will be done at -1 h and -15 min pre-dose and at 15, 30 min, 1, 2, and 4 hours post-dose.
q.
Cough VAS will be done pre-dose at Visits 3, 4, 6, 7, 9, and 10, and 24 hours post-dose at Visits 5, 8, and 11.
r.
Cough monitoring will be done starting 24 hours prior to dosing on Visits 3, 6, and 9, and pre-dose at Visits 5, 8, and 11.  The recording for Visits 3, 6 and 
9 are home recordings and will start at least 24 hours before the dosing and will finish pre-dose. Cough monitoring for Visits 5, 8 and 11 will start on Day 
14, just before dosing at site, and will finish 24 hours later.  Patients may attend the site between visits to collect the cough monitor prior to the recording
start.
s.
All patients will receive ipratropium (20 µg × 2 puffs 4 times per day) during the run-in and wash-out periods.  In addition, those patients that were taking 
any LAMA and/or LABA will be maintained with ipratropium between Visit 1 and Visit 2.  Ipratropium should be held at least 8 hours before Visits 3, 6 
and 9 (before any pulmonary function test) and during all treatment periods (until last pulmonary function test at Visits 5, 8 and 11).
t.
Inhaler training will be done before starting IP treatment on Day 1 at each treatment period.
u.
The first dose of IP is to be taken at the clinic at 9:00 AM±2 hours on Day 1 of each treatment period (Visits 3, 6 and 9) after the pre-dose specified procedures 
(and randomisation for Visit 3).  On subsequent days of each treatment period, IP is to be taken within ±1 hour of dosing time of Day 1 (and between 7 AM
and 11 AM). IP administration will be at the site on Day 1, 2, 8 and 14 of each treatment period.  This will be supervised at the clinic.  Day 3 to Day 7 and 
Day 9 to Day 13 of each treatment period - doses will be taken at home.
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v.
E-Diary will be used to collect daily BCSS and daily use of rescue medication (salbutamol 100 µg as needed) during the run-in and treatment periods. 
E-Diary will be used to collect CAT once at screening and daily during treatment periods. In addition, during treatment period daily IP intake will be 
recorded in the e-Diary. Paper diary will be used to collect AEs and concomitant medication during run-in and wash-out periods.  Paper diary is also used 
to collect rescue medication intake during the wash-out phase.
w.
Pregnancy results at Screening will be used to check the eligibility of the patient for participation in the study.
Note: For assessments occurring at the same time points, the recommended order of assessments is as follows: 1. ECG; 2. Vital signs; 3. i-STAT; 4. PK; and 
5. Spirometry (on the actual time points).


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1.2
Synopsis
International co-ordinating Investigators:
Protocol Title: 
A Phase IIa, Randomised, Multi-centre, Double-blind, Placebo and Active-controlled, 3 
Periods, Crossover Study to Investigate the Efficacy, Pharmacokinetics, Safety and 
Tolerability of Inhaled AZD8871 Administered Once Daily for 2 Weeks in Patients with 
Moderate to Severe COPD
Rationale: 
AZD8871 is a new chemical entity with the combined properties of a long-acting muscarinic 
antagonist (LAMA) and a long-acting β2-agonist (LABA) in a single molecule.  AZD8871 is 
being developed as an inhaled long-acting bronchodilator for the maintenance treatment of 
chronic obstructive pulmonary disease (COPD), formulated as an inhalation powder and 
delivered by dry powder inhaler (DPI).
Objectives and Endpoints
Primary objective:
Endpoint/variable:
To evaluate the efficacy of 
inhaled AZD8871 600 µg in 
patients with moderate to severe 
COPD
Primary
•
Change from baseline in Trough FEV1 on Day 15.
Secondary
•
FEV1 AUC(0-4)/4h (area under the curve for the change in FEV1 from 
baseline to 4h, normalised by the time window) at Day 1, Day 8, and 
Day 14.
•
FEV1 AUC(0-8)/8h, AUC(0-12)/12h, and AUC(0-24)/24h at Day 1 and Day 14.
•
Change from baseline in Trough FEV1 on Day 2, and Day 8.
•
Change from baseline in Peak FEV1 on Day 1, Day 8 and Day 14.
•
Change from baseline in Trough FEV1 over treatment duration.
•
Change from baseline in Peak FEV1 over treatment duration.
•
Change from baseline in Total Score of Breathlessness, Cough Sputum 
Scale (BCSS) questionnaire and cough, breathlessness and sputum 
individual domain scores from Day 1 to Day 8, from Day 9 to Day 14 
and during the whole treatment duration.
•
Change from baseline in CAT from Day 1 to Day 8, from Day 9 to 
Day 14 and during the whole treatment duration.
•
Rescue medication use from Day 1 to Day 8 and from Day 9 to Day 14.
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Objectives and Endpoints
Secondary objective:
Endpoint/variable:
To investigate the PK of 
AZD8871 600 µg and its
primary metabolite after 
multiple dose administration of 
inhaled AZD8871 in patients 
with moderate to severe COPD
On serial PK sampling days, the following PK parameters will be 
calculated for AZD8871 and its primary metabolite LAS191861 when 
applicable:
•
Day 1: Maximum plasma concentration (Cmax), time to reach maximum 
plasma concentration (tmax), area under the plasma concentration-curve 
from time 0 to the time of last quantifiable concentration (AUClast), area 
under the plasma concentration-curve from time 0 to 24 hours 
post-dose AUC(0-24).
•
Day 14: Cmax, tmax, AUClast, AUC(0-24), average plasma concentration 
during a dosing interval (Cavg,), fluctuation index during a dosing 
interval (%Fluctuation), accumulation ratio for Cmax [Rac(Cmax)] and 
accumulation ratio for AUC(0-24) [Rac(AUC(0-24))].
Additional parameters may be determined where appropriate.
Safety objective:
Endpoint/variable:
To evaluate the safety and 
tolerability of inhaled 
AZD8871 600 µg in patients 
with moderate to severe COPD
•
Adverse events (AEs)/Serious Adverse Events (SAEs).
•
Vital signs.
•
Electrocardiogram (ECG).
•
Clinical laboratory assessments.
Exploratory objective:
Endpoint/variable:
To evaluate patient’s response 
to inhaled AZD8871 600 µg in 
patients with moderate to severe 
COPD
•
COPD exacerbations.
•
Cough VAS.
•
Cough monitoring.
•
Overall design: 
This is a randomised, placebo-controlled, double-blind, 3-way complete crossover William’s 
design, international, multi-centre Phase IIa multiple dose study of 1 dose level of AZD8871, 
an active comparator (Anoro® Ellipta®) and placebo administered by DPI devices. 
The study will be performed in adult male and non-childbearing female patients aged 40 to 
85 years (both inclusive) with moderate to severe COPD as per the Global Initiative for 
Chronic Obstructive Lung Disease (GOLD 2018) guidelines.
The study will be conducted at approximately 5 sites in Germany and the United Kingdom 
(UK). Estimated study duration is 12 months.
Treatment will be assigned via a computer generated randomisation schedule after the 
Screening period (at Visit 3).
The study will consist of a Screening period, 3 treatment periods (each separated by a 
wash-out period), and a Follow-up Visit.
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Study Period:
Estimated date of first patient enrolled: Q3 2018
Estimated date of last patient completed: Q3 2019
Number of Patients: 
Approximately 145 patients will be screened in order to randomise 72 patients into the study
(previous studies estimate the screening failure rate to be approximately 50%). Screening 
failures are defined as patients who signed the informed consent form (ICF) to participate in 
the clinical trial but are not subsequently randomly assigned to study treatment.  It is 
anticipated that 54 patients will be evaluable (study completers) assuming an approximate 
25% dropout rate. A subset of 36 patients, who will have specifically consented for 
pharmacokinetics (PK), will undergo PK assessments.  
Treatments and treatment duration:
The entire study period is scheduled to take from a minimum of 6.5 months (182 days) to a 
maximum of 7.5 months (217 days) for each individual patient.
Screening period: This will last up to 28 days and consists of 2 Screening visits (Visit 1 and 
Visit 2) and a run-in period. 
Patients will be requested to stop their usual COPD therapy after signing the ICF at Visit 1 
and will be maintained on a mono-component inhaled corticosteroid (ICS) therapy, if 
required. Patients that were taking any LAMA and/or LABA will be maintained with 
ipratropium (20 µg × 2 puffs 4 times per day) between Visit 1 and Visit 2. In addition, 
salbutamol 100 µg will be provided as rescue medication during the study as needed (rescue 
medication has to be discontinued 6 hours before any pulmonary function test). Visit 1 and 
Visit 2 could be performed on the same day if no wash-out of prior medication is required and 
the patient visits the site in fasting condition. In case any wash-out of prior medication is 
required, then Visit 2 will be performed after the wash-out is complete. 
All the screening assessments can be performed at Visit 1 or Visit 2, based on the site’s 
preference, except for the following:

ICF: This must be completed at Visit 1 before any study-specific assessments are 
performed.

Reversibility test with salbutamol and spirometry (to confirm inclusion criterion
#6); this must be performed at Visit 2 due to wash-out requirements. 
If the forced expiratory volume in 1 second (FEV1) predicted value is fulfilled according to 
inclusion criteria, the patient will be started on run-in period to assess clinical stability.  If the 
FEV1 predicted value is not met, pulmonary function tests could be rescheduled at the latest, 
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The duration of run-in period will be between a minimum of 14 and a maximum of 28 days 
(from Visit 2 to Visit 3). During the run-in period, all patients will receive ipratropium 
20 µg × 2 puffs 4 times per day (must be discontinued 8 hours prior to previous any 
pulmonary function test). A paper diary will be used to collect AEs and concomitant 
medication during run-in and wash-out periods.
Treatment periods: After the screening period, patients must fulfil all inclusion and none of 
the exclusion criteria prior to being randomised at Visit 3. Eligibility results will be used from 
the Screening period for any assessments that cannot be completed within Visit 3 (eg, 
laboratory assessments).
The duration of each treatment period will be 14 days.  In each treatment period, patients will 
receive 1 of the following 3 treatments according to a William’s design with 3 periods and 6
sequences, using a balanced randomisation ratio per treatment sequence:

AZD8871 600 µg once daily (double-blind).

Anoro® Ellipta® (55 µg UMEC/ 22 µg VI) once daily (double-blind).

Placebo (double-blind).
Each of the 3 treatment periods will include 2 overnight stays at the study site and 
1 ambulatory visit at the study site. 
Visits 3, 6 and 9 (corresponding to Treatment Day 1 in each period) and Visits 5, 8 and 11 
(corresponding to Treatment Day 14 in each period) will include an overnight stay in the unit.  
At these visits, safety and tolerability assessments and pulmonary function measurements will 
be taken pre-dose and up to 24 hours post-dose.
Visits 4, 7 and 10 (corresponding to Treatment Day 8 in each period) will have duration of 
approximately 5 hours where safety and tolerability assessments as well as spirometry 
measurements will be performed pre-dose and up to 4 hours post-dose.
Study treatment administration during all the visits at the sites (Day 1, Day 2, Day 8, and 
Day 14 of each treatment period) will be supervised by study personnel.
At Visits 3 to 11, a subset of 36 patients will undergo PK assessments.  Blood samples will be 
collected pre-dose and up to 24 hours post-dose. 
On Day 1 of treatment periods 2 and 3, a FEV1 stability test will be performed pre-dose.  
FEV1 stability check will be based on the pre-best test review (BTR).  At Visits 6 and 9 the 
mean of the pre-dose FEV1 (mean of the 2 measured values) should be within (±)20% or 
(±)200 mL compared to the pre-dose FEV1 (mean of the 2 measured values) of the first 
treatment period (Visit 3). 
Study treatment administration compliance will be recorded in the e-Diary of the patient when 
the patient is not at the site. No dose modification is planned for this study.  


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Wash-out periods: Between each treatment period, there will be a wash-out period of 42 to 
49 days. During this period, all patients will receive ipratropium 20 µg × 2 puffs 4 times per 
day (must be discontinued 8 hours before any pulmonary function test).  A paper diary will be 
used to collect AEs and concomitant medication during run-in and wash-out periods.
Follow-up Visit: Patients will come to the site for a Follow-up Visit, 42 days (up to 49 days) 
after the last IP administration, for AE assessment, safety laboratory, ECG, vital signs and 
physical examination.
Statistical methods:
The analysis of all the efficacy variables will be performed on the Full Analysis Set (FAS) 
population.  In addition, the primary efficacy variable will be also analysed using the 
Per-Protocol population.
All demographic and baseline characteristics, safety outcomes and other variables will be 
analysed using the safety population. 
Pharmacokinetic parameters will be analysed in the PK population on the subset of 36 patients 
who will have specifically consented to participation in the PK assessments.
Analysis of the primary efficacy variable: The primary efficacy variable is the change from 
baseline in Trough FEV1 at Day 15 (ie, after 14 days of treatment).
Baseline for FEV1 will be defined as the mean of the 2 measured values for the corresponding 
variable (2 measurements 45 min apart, at -1 hour and -15 min), prior to the morning IP 
administration on Day 1 of each treatment period.  If both are missing, the Visit 2 
pre-bronchodilator value will be used instead.
Trough is defined as the mean of the FEV1 values obtained at 23 hours and 23 hours and 
45 min after the morning IP administration on Day 1 and Day 14 (ie, obtained on Day 2 and 
Day 15).  On Day 8, Trough is defined as the mean of the FEV1 pre-dose values (-1 hour 
and -15 min).  If one of the values is missing, the available value will be used as Trough.
This variable will be analysed by means of a mixed model with fixed effects for treatment, 
sequence, and period.  The patient will be fitted as a random effect and the pre-dose FEV1 of 
each period will be included as a covariate.
Analyses of secondary efficacy variables: All continuous variables defined as change from 
baseline or observed values will be analysed using similar mixed models as for the primary 
efficacy variable adjusted for the corresponding baselines. Modifications compared to the 
primary analysis model to covariance structures and included covariates may be done as 
appropriate. Peak FEV1 will be defined as the maximum value from 0 to 4 hours. 
All baselines will be the pre-dose values of each treatment period except for the Total BCSS 
questionnaire score where the run-in period baseline will be used for all treatments in each 
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Categorical variables will be analysed descriptively.
Pharmacokinetic analyses: Plasma concentrations and PK parameters will be listed and 
summarised for AZD8871 and its primary metabolite LAS191861 per day using appropriate 
descriptive statistics.
Safety analyses: Safety will be assessed by descriptive analysis of AEs, vital signs, ECGs and 
clinical laboratory assessments. Heart rate and QT data will be analysed using mixed models.
The study will be powered to demonstrate superiority of AZD8871 600 µg versus 
Anoro® Ellipta® for the primary efficacy endpoint. With a total of 54 patients, there is 90% 
power to detect a difference between AZD8871 and Anoro® Ellipta® treatments for the change 
from baseline to Trough FEV1 at Day 15 equal to 100 mL, assuming a standard deviation (SD) 
of differences of 220 mL, 2-sided 5% significance level and a normal distribution.
1.3
Schema
The general study design is summarised in Figure 1.


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Figure 1
Study design
d: day; FU: Follow-up; V: Visit.


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2.
INTRODUCTION
2.1
Study rationale
AZD8871 is a new chemical entity, a muscarinic receptor antagonist and β2 adrenoceptor 
agonist (MABA), with the combined properties of a LAMA and a LABA in a single molecule.  
AZD8871 is being developed as an inhaled long-acting bronchodilator for the maintenance 
treatment of COPD, formulated as an inhalation powder and delivered by DPI. By combining 
the activities of a LAMA and a LABA in to a single molecule, AZD8871 aims at providing a 
novel approach to the treatment of COPD with greater efficacy than single-mechanism 
bronchodilators, equivalent to LAMA and LABA administered as free- or fixed-dose 
combination therapies, with an equivalent or superior safety and tolerability profile.
The purpose of this study is to provide efficacy and safety data for AZD8871 in subjects with 
moderate to severe COPD. This study will determine the 24-hour efficacy (lung function) 
profile of AZD8871 600 μg relative to placebo DPI based on Trough FEV1 following repeated 
dosing (2 weeks). Anoro® Ellipta® once daily is included as an active control.
2.2
Background
Chronic obstructive pulmonary disease is a significant cause of morbidity and mortality 
worldwide (Global Initiative for Chronic Obstructive Lung Disease [GOLD 2018]).  It is a 
common, preventable and treatable disease characterised by persistent airflow limitations.  It 
is primarily regarded as a heterogeneous lung disease, where the chronic airflow limitation 
characteristic of COPD is caused by a mixture of small airways disease (obstructive 
bronchiolitis) and parenchymal destruction (emphysema), the relative contribution of which 
vary from person to person. There are also significant extrapulmonary effects and associated 
comorbidities.  The most common risk factor worldwide is smoking.
Chronic inflammation causes structural changes and narrowing of the small airways.  
Destruction of the lung parenchyma, also by inflammatory processes leads to the loss of 
alveolar attachments to the small airways and decreases elastic recoil; in turns these changes 
diminish the ability of the airway to remain open during expiration.  The lung pathology 
typically results in an airflow limitation that is not fully reversible and is usually progressive, 
reflected in a decline in the forced expiratory volume in 1 second (FEV1) that is more rapid 
than that normally seen with increasing age.  The characteristic clinical symptoms of COPD 
are chronic and progressive dyspnoea, cough and sputum production.  Exercise tolerance and 
health-related quality of life are increasingly affected as the disease progresses, particularly in 
association with exacerbations (ie, acute worsening). 
Long-acting bronchodilators are an established therapeutic class to control symptoms in 
COPD; LABAs and LAMAs are preferred over short-acting formulations (GOLD 2018
categories B, C, D).  The GOLD guidelines propose to combine LABA and LAMA treatments 
as possible initial treatment for patients of Group D (among first choices), B and C (among 
alternative choice).  Combining bronchodilators with different mechanisms allows increasing 


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the degree of bronchodilation for equivalent or lesser side effects than increasing the dose of a 
single component (Tashkin and Ferguson 2013).  
By combining the activities of a LAMA and a LABA in to a single molecule, AZD8871 aims 
at providing a novel approach to the treatment of COPD with greater efficacy than 
single-mechanism bronchodilators, equivalent to LAMA and LABA administered as free- or 
fixed-dose combination therapies, with an equivalent or superior safety and tolerability 
profile. This will also be evaluated by directly comparing AZD8871 to the best-in-class once
daily LAMA and LABA fixed-dose combination, Anoro® Ellipta®. Out of 3 fixed-dose 
combination products available on the market for the treatment of COPD, Anoro® Ellipta® was 
shown to be the most effective and will serve as the benchmark for this study (Feldman et al, 
2017).
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD8871 is 
provided in the Investigator’s Brochure (IB).
2.3
Benefit/risk assessment
Currently, no single molecule with dual β2-agonist and muscarinic antagonist properties is 
licensed for medical use, though similar molecules are currently in development (Wielders et 
al, 2013;Bateman et al, 2013).  However, there is extensive and increasing experience from 
clinical practice regarding products with effect on each of these receptors separately and in 
free and fixed combination.  The most commonly cited AEs of β2-agonists are palpitations, 
headache and tremor.  At higher doses, tachycardia, hyperglycaemia, hypokalaemia and an 
increased corrected QT interval (QTc) may be seen.  These effects can be monitored in 
clinical studies using standard safety monitoring.  Examples of systemically mediated AEs 
caused by muscarinic antagonists are: dryness of mouth, dilated pupils, glaucoma, increased 
heart rate, urinary retention and constipation.  However, systemic availability after inhalation 
is limited and the most frequently reported side effect after inhalation of the LAMAs is 
dryness of mouth, with irritation in the upper airways and cough reported as potential local 
side effects.
Findings in non-clinical toxicology and safety pharmacology studies with AZD8871 reflect 
the dual antimuscarinic and β2-adrenoreceptor agonist activities associated with the primary 
pharmacology of this compound and are summarised in the IB.  PR prolongation and atrio-
ventricular blocks were recorded in the dog single dose cardiovascular safety study at 
0.36 mg/kg, a dose above those causing tachycardia. This dose was associated with a 
systemic peak plasma concentration of 5.14 ng/mL (4 times higher than the values observed at 
the highest dose tested in Part 1 of the study D6640C00001 in asthma patients). These 
changes can be monitored and a higher dose was not associated with any unexpected cardiac 
toxicity with AZD8871 in Part 1 of study D6640C0001 and during the 12 consecutive days of 
treatment with the first dose in study D6640C00003.
Study D6640C00001 was a 2-part, randomised, placebo-controlled, safety, tolerability,
pharmacokinetic and pharmacodynamic study of AZD8871 delivered by inhalation in
asthmatic and COPD patients. In Part 1, single doses of AZD8871 from 50 up to 2100 µg 
were administered to asthma patients. Efficacy of the compound was apparent with Peak and 


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Trough FEV1 ranging from 427-694 mL to 267-414 mL at doses of 200-2100 μg
(respectively). AZD8871 was safe and well tolerated, no SAEs were reported during this part 
of the study; no AEs led to study discontinuation or met any of the stopping criteria.
In Part 2, single doses of AZD8871 of 400 and 1800 µg were administered to COPD patients
in a randomised crossover design. The evaluation of FEV1 showed that AZD8871 at 400 and
1800 µg induced bronchodilation in COPD patients with a quick onset and the effect was
sustained up to 36 hours. Both doses of 400 and 1800 µg AZD8871 were observed to be safe
and well tolerated, and no deaths were observed.
Study D6640C00003 reported data on multiple doses of 300, 600 and 900 µg in healthy
subjects. Neither SAEs, nor AE leading to discontinuation were reported in this study. No
clinically relevant laboratory or ECG results were reported. With the exception of heart rate,
no dose response effects were seen in any of the other safety outcomes. This effect needs
further exploration in future studies. Overall, multiple doses of AZD8871 administered to
healthy male subjects in this study were well tolerated and no safety concerns were noted for
any of the dosages investigated, and stopping criteria were not met.
Study D6640C00004 was a proof-of-concept, randomised, double-blind, placebo-controlled, 
3-way, complete crossover William’s design, multiple dose study to investigate the efficacy, 
PK, safety, and tolerability of 2 dose levels of AZD8871 (100 and 600 μg) and placebo, 
administered using a DPI device once daily, for 2 weeks, in patients with moderate to severe 
COPD. A total of 42 patients were randomised; 31 completed all 3 treatments periods and the 
relevant follow up assessments.  Both dose levels of AZD8871 had a positive, dose dependent 
effect on FEV1 at Day 14-15 of treatment compared with placebo, with the highest effect 
observed for the AZD8871 600 µg dose level. Overall, AZD8871 was well tolerated in 
COPD patients and no safety concerns were raised in the study.
Study D6640C00005 was a Phase I, randomised, multiple ascending dose (MAD) study to 
investigate safety, tolerability and PK of AZD8871 in healthy male Japanese subjects. This 
study entailed 3 dose levels: 300 µg (cohort 1), 600 µg (cohort 2) and 900 µg (cohort 3). In 
this study, the administration schedule for AZD8871 or placebo was a single dose on Day 1, 
followed by once daily dosing from Day 5 to Day 16 (12 consecutive daily doses). Safety 
stopping criteria or pre-set exposure limits were not reached. Overall, single and multiple 
doses of AZD8871 administered to healthy male subjects in this study were well tolerated and 
no safety concerns were noted for any of the dosages investigated.
To limit the risks for the patients enrolled in this study D6640C00006 and who will be 
required to stop their usual COPD therapy and to assess IP efficacy, patients will be 
maintained on a mono-component ICS, if required.  They will also be provided with 
salbutamol 100 µg to be used as rescue medication. In addition, patients that were taking any 
LAMA and/or LABA will be maintained with ipratropium between Visit 1 and Visit 2.  All 
patients will receive ipratropium (20 µg × 2 puffs 4 times per day) during run-in and wash-out 
period to ensure stability of the patient. 
Potential risks have been evaluated through review of the literature regarding β2-agonists and 
muscarinic antagonists, AZD8871 non-clinical studies, and data from completed or ongoing 


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AZD8871 clinical studies.  Relevant potential risks include cardiac effects (such as 
tachycardia, PR interval prolongation and 1st and 2nd degree atrio-ventricular blocks); other 
potential risks are metabolic effects (such as hyperglycemia and hypokalaemia) and 
hypersensitivity.  No treatment-related serious or severe AEs have been reported in the 
completed or ongoing clinical studies.  No clinically significant ECG abnormalities or
laboratory abnormalities were observed to date in human trials.  Thus, AZD8871 was well 
tolerated in firsts in human trials and its safety profile is acceptable for continuing further 
investigations. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of AZD8871 may be found in the IB.


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3.
OBJECTIVES AND ENDPOINTS


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Table 2
Study objectives and endpoints
Primary Objective:
Endpoint/Variable:
To evaluate the efficacy of 
inhaled AZD8871 600 µg 
in patients with moderate 
to severe COPD
Primary
•
Change from baseline in Trough FEV1 on Day 15.
Secondary
•
FEV1 AUC(0-4)/4h (area under the curve for the change in FEV1
from baseline to 4h, normalised by the time window) at Day 1, 
Day 8, and Day 14.
•
FEV1 AUC(0-8)/8h, AUC(0-12)/12h, and AUC(0-24)/24h at Day 1 and 
Day 14.
•
Change from baseline in Trough FEV1 on Day 2, and Day 8.
•
Change from baseline in Peak FEV1 on Day 1, Day 8 and Day 14.
•
Change from baseline in Trough FEV1 over treatment duration.
•
Change from baseline in Peak FEV1 over treatment duration.
•
Change from baseline in Total Score of BCSS questionnaire and 
cough, breathlessness and sputum individual domain scores from 
Day 1 to Day 8, from Day 9 to Day 14 and during the whole 
treatment duration.
•
Change from baseline in CAT from Day 1 to Day 8, from Day 9 to 
Day 14 and during the whole treatment duration.
•
Rescue medication use from Day 1 to Day 8 and from Day 9 to 
Day 14.
Secondary Objective:
Endpoint/Variable:
To investigate the PK of 
AZD8871 600 µg and its 
primary metabolite after 
multiple dose 
administration of 
AZD8871 in patients with 
moderate to severe COPD
On serial PK sampling days, the following PK parameters will be 
calculated for AZD8871 and its primary metabolite LAS191861 when 
applicable:
•
Day 1: Maximum plasma concentration (Cmax), time to reach 
maximum plasma concentration (tmax), area under the plasma 
concentration-curve from time 0 to the time of last quantifiable 
concentration (AUClast), area under the plasma concentration-curve 
from time 0 to 24 hours post-dose AUC(0-24).
•
Day 14: Cmax, tmax, AUClast, AUC(0-24), average plasma 
concentration during a dosing interval (Cavg,), fluctuation index 
during a dosing interval (%Fluctuation), accumulation ratio for 
Cmax [Rac(Cmax)] and accumulation ratio for AUC(0-24) [Rac(AUC(0-
24))].
Additional parameters may be determined where appropriate.
Safety Objective:
Endpoint/Variable:


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To evaluate the safety and 
tolerability of inhaled 
AZD8871 600 µg in 
patients with moderate to 
severe COPD
•
AEs/SAEs.
•
Vital signs.
•
ECG.
•
Clinical laboratory assessments.
Exploratory objective:
Endpoint/variable:
To evaluate patient’s 
response to inhaled 
AZD8871 600 µg in 
patients with moderate to 
severe COPD
•
COPD exacerbations.
•
Cough VAS. 
•
Cough monitoring. 
•
4.
STUDY DESIGN
4.1
Overall design
This is a randomised, placebo-controlled, double-blind, 3-way complete crossover William’s 
design, international, multi-centre Phase IIa multiple dose study of 1 dose level of AZD8871, 
an active comparator (Anoro® Ellipta®) and placebo administered by DPI devices.
Approximately 72 eligible male and non-childbearing female patients with moderate to severe 
COPD before randomisation and fulfilling all of the eligibility criteria will be randomised in a 
1:1:1:1:1:1 to 1 of 6 treatment sequences.  The study includes 12 visits and the entire study 
period is scheduled to take from a minimum of 6.5 months (182 days) to a maximum of 
7.5 months (217 days) for each individual patient. The aim is to ensure at least 54 patients 
complete the study.
A subset of 36 patients, who will have specifically consented for pharmacokinetics (PK), will 
undergo PK assessments.  
The study will be conducted at approximately 5 sites in Germany and the UK.  Estimated 
study duration is 12 months. 
The study will consist of a Screening period, 3 treatment periods (each separated by a 
wash-out period), and a Follow-up Visit, as described below.
Screening period: This will last up to 28 days and consists of 2 Screening visits (Visit 1 and 
Visit 2) and a run-in period. 
Patients will be requested to stop their usual COPD therapy after signing the ICF at Visit 1
and will be maintained on a mono-component ICS therapy, if required. Patients that were 
taking any LAMA will be maintained with ipratropium (20 µg × 2 puffs 4 times per day) 
between Visit 1 and Visit 2. In addition, salbutamol 100 µg will be provided as rescue 
medication during the study as needed (rescue medication has to be discontinued 6 hours 
before any pulmonary function test).  Visit 1 and Visit 2 could be performed on the same day 
if no wash-out of prior medication is required and the patient visits the site in fasting 
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condition. In case any wash-out of prior medication is required, then Visit 2 will be 
performed after the wash-out is complete. 
All the screening assessments can be performed at Visit 1 or Visit 2, based on the site’s 
preference, except for the following:

ICF: This must be completed at Visit 1 before any study-specific assessments are 
performed.

Reversibility test with salbutamol and spirometry (to confirm inclusion criterion 
#6); this must be performed at Visit 2 due to wash-out requirements. 
If the FEV1 predicted value is fulfilled according to inclusion criteria, the patient will be 
started on run-in period to assess clinical stability.  If the FEV1 predicted value is not met, 
pulmonary function tests could be rescheduled at the latest, up to Day -14.
The duration of run-in period will be between a minimum of 14 and a maximum of 28 days 
(from Visit 2 to Visit 3). During the run-in period, all patients will receive ipratropium 
20 µg × 2 puffs 4 times per day (must be discontinued 8 hours prior to previous any 
pulmonary function test). A paper diary will be used to collect AEs and concomitant 
medication during run-in and wash-out periods.
Treatment periods: After the screening period, patients must fulfil all inclusion criteria and 
no exclusion criteria prior to being randomised at Visit 3. Eligibility results will be used from 
the Screening period for any assessments that cannot be completed within Visit 3 (eg, 
laboratory assessments).
The duration of each treatment period will be 14 days.  In each treatment period, patients will 
receive 1 of the following 3 treatments according to a William’s design with 3 periods and 6
sequences, using a balanced randomisation ratio per treatment sequence:

AZD8871 600 µg once daily (double-blind).

Anoro® Ellipta® (55 µg UMEC/ 22 µg VI) once daily (double-blind).

Placebo (double-blind).
Each of the 3 treatment periods will include 2 overnight stays at the study site and 
1 ambulatory visit at the study site. 
Visits 3, 6 and 9 (corresponding to Treatment Day 1 in each period) and Visits 5, 8 and 11 
(corresponding to Treatment Day 14 in each period) will include an overnight stay in the unit.  
At these visits, safety and tolerability assessments and pulmonary function measurements will 
be taken pre-dose and up to 24 hours post-dose.


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Visits 4, 7 and 10 (corresponding to Treatment Day 8 in each period) will have duration of 
approximately 5 hours where safety and tolerability assessments as well as spirometry 
measurements will be performed pre-dose and up to 4 hours post-dose.
Study treatment administration during all the visits at the sites (Day 1, Day 2, Day 8, and 
Day 14 of each treatment period) will be supervised by study personnel.
At Visits 3 to 11, a subset of 36 patients will undergo PK assessments.  Blood samples will be 
collected pre-dose and up to 24 hours post-dose. 
On Day 1 of treatment periods 2 and 3, a FEV1 stability test will be performed pre-dose.  
FEV1 stability check will be based on the pre-BTR.  At Visits 6 and 9 the mean of the pre-
dose FEV1 (mean of the 2 measured values) should be within (±)20% or (±)200 mL compared 
to the pre-dose FEV1 (mean of the 2 measured values) of the first treatment period (Visit 3). 
Study treatment administration compliance will be recorded in the e-Diary of the patient when 
the patient is not at the site.  No dose modification is planned for this study.
Wash-out periods: Between each treatment period, there will be a wash-out period of 42 to 
49 days.  During this period, all patients will receive ipratropium 20 µg × 2 puffs 4 times per 
day (must be discontinued 8 hours before any pulmonary function test).
A paper diary will be used to collect AEs and concomitant medication during run-in and 
wash-out periods.
Follow-up Visit: Patients will come to the site for a Follow-up Visit, 42 days (up to 49 days) 
after the last IP administration, for AE assessment, safety laboratory, ECG, vital signs and 
physical examination.
For an overview of the study design see Figure 1, Section 1.3. For details on treatments given 
during the study, see Section 6.1 Treatments Administered.  
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives 
and Endpoints.  
4.2
Scientific rationale for study design
The objective of the study is to assess the efficacy, safety and pharmacokinetics (PK) of 
AZD8871 600 µg after a 14-day treatment period in patients with moderate to severe COPD.  
The target population includes male and female (non-childbearing potential) adult patients 
with clinical diagnosis of moderate to severe COPD as per the criteria of the GOLD 
guidelines.
A double-blinded, double-dummy design has been chosen to limit the occurrence of conscious 
and unconscious bias in the conduct and interpretation of a clinical study arising from the 
influence which the knowledge of treatment may have on the recruitment and allocation of 
patients.  It is considered the optimal approach according to International Conference on 
Harmonisation (ICH) E9 “Statistical principles in clinical studies.”


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The crossover design has been chosen to avoid inter-patient variability and optimize sample 
size.  Based on the information of terminal elimination half-lives observed for AZD8871 and 
LAS191861 from previous clinical studies, the wash-out period proposed for this current 
study is a minimum of 42 days and up to 49 days in order to avoid any carry-over effect 
between periods.
By randomly assigning treatment sequence, differences in baseline characteristics of the 
treatment groups will be minimised.  The inclusion of a placebo arm is considered the most 
reliable method to minimise patient and Investigator bias according to ICH Topic E10 (Choice 
of control group in clinical trials) ICH/364/96 guideline adopted by the Committee for 
Proprietary Medicinal Products (CPMP), CPMP/EWP/562/98 and Food and Drug 
Administration (FDA).
AZD8871 will be evaluated by directly comparing it against Anoro® Ellipta®; the best-in-class 
once daily LAMA and LABA fixed-dose combination (Feldman et al, 2017).
Since COPD patients present with multiple comorbidities, a placebo arm has been added to 
better characterise the safety profile of the product. The inclusion of a placebo treatment will 
enhance the interpretation of the difference in safety and efficacy outcomes between active 
arms. This is due to the limited available data for Anoro® Ellipta® in this specific COPD 
patient population and the endpoints that will be assessed.
4.3
Justification for dose
The proposed dose level of AZD8871 in this study is 600 µg of AZD8871 given by inhalation 
once daily during 14 days through a multi-dose DPI device.  The dose has been selected based 
on the safety, tolerability, efficacy, and PK information generated in previous clinical studies. 
The study drug released in this study will differ to previous trials due to the addition of 
Magnesium Stearate – required in multi-dose device setting - and slight changes in production 
processes. It is estimated these changes will have limited impact to the clinical outcome.
4.4
End of study definition
The end of study is defined as the last expected visit/contact of the last patient undergoing the 
study.
A patient is considered to have completed the study when he/she has completed his/her last 
scheduled visit.
See Appendix A 6 for guidelines for the dissemination of study results.
5.
STUDY POPULATION
Patients will be recruited from early phase clinical unit sites via internal databases and local 
advertisement. Investigator(s) should keep a record, the patient screening log, of patients who 
entered pre-study screening.


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Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomised to a study treatment.  Under no circumstances can 
there be exceptions to this rule. Patients who do not meet the entry requirements are screen 
failures, refer to Section 5.4.
In this protocol, “enrolled” patients are defined as those who sign informed consent.  
“Randomised” patients are defined as those who undergo randomisation and receive a 
randomisation number.
For procedures for withdrawal of incorrectly enrolled patients see Section 7.3.
5.1
Inclusion criteria
Patients are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply:
Informed consent
1.
Provision of signed and dated, written ICF prior to any study-specific procedures, 
sampling, and analyses. 
The ICF process is described in Appendix A 3.
Age
2.
Patient must be 40 to 85 years of age (both inclusive) at the time of signing the ICF
(Screening; Visit 1).
Type of patient and disease characteristics
3.
COPD Diagnosis: Patient with an established clinical history of moderate to severe 
COPD for more than 1 year at Screening, according to the GOLD COPD 
guidelines.
4.
Tobacco Use: Patient is a current or former smoker with a history of ≥10 pack-years 
of cigarette smoking [Number of pack-years=(number of cigarettes per day/20)* 
number of years smoked (eg, 1 pack-year=20 cigarettes smoked per day for 
1 year)].  A former smoker is defined as one who has stopped smoking for at least 
6 months prior to Screening.

Patient smoking other tobacco types (including e-cigarettes) will not be 
allowed, unless he/she meets the cigarette criterion as well.
5.
Patient with post-bronchodilator FEV1/forced vital capacity (FVC) ratio <70% 
based on the value reached after inhalation of salbutamol (400 µg) at Visit 2.  If 
criterion is not met, the test can be repeated at the latest, up to Day -14.


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6.
Patient with post-bronchodilator FEV1 that must be ≥40% and <80% predicted 
normal value at Visit 2.  If the criterion is not met, the test can be repeated at the 
latest, up to Day -14.
7.
Patient is willing and, in the opinion of the Investigator, able to change current 
COPD therapy as required by the protocol and willing to use ipratropium following 
the approved dosage and regimen (during run-in and wash-out periods) with or 
without ICS for maintenance therapy of COPD and rescue medication salbutamol 
(as needed) from Visit 1 to Visit 11.
8.
Patient must be able to read, speak and understand local language, and be willing to 
remain at the study centre as required per-protocol to complete all visit assessments.
Weight
9.
Body mass index (BMI) <40 kg/m2 at the time of Screening.
Sex
10.
Male and/or females of non-childbearing potential who are not pregnant or 
lactating.
Reproduction
11.
Female patients must be of non-childbearing potential defined as:

Permanently or surgically sterilised, including hysterectomy and/or bilateral 
oophorectomy and/or bilateral salpingectomy.

Post-menopausal; aged <50 years and amenorrhoeic for 12 months or more 
following cessation of exogenous hormonal treatments and with luteinizing 
hormone (LH) and follicle stimulating hormone (FSH) levels in the 
post-menopausal range of the local laboratory.

Post-menopausal; aged ≥50 years and amenorrhoeic for 12 months or more, 
following cessation of all exogenous hormonal treatments.
12.
Male patients should use a condom and spermicide (or sexual abstinence*) to 
prevent pregnancy and drug exposure of a partner, regardless of the gender or 
childbearing potential of the partner from the day of the first administration of the 
IP until 3 months after the last administration of the IP.  In addition to a condom 
with spermicide, a second highly effective method of contraception (oral, 
intravaginal or transdermal hormonal contraceptives, intrauterine device, or
intrauterine hormone-releasing system until 3 months after the last administration of 
the IP) should be used with female partners of childbearing potential.  Double 
barrier methods (a combination of male condom with either a cap, diaphragm or 
sponge with spermicide) are not considered to be highly effective methods of 
contraception. Male patients with a pregnant partner should use a condom and 
spermicide or sexual abstinence*.


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*True abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. (periodic abstinence [eg, calendar, ovulation, symptothermal, post-
ovulation methods], declaration of abstinence for the duration of a trial, and 
withdrawal are not acceptable methods of contraception).
5.2
Exclusion criteria 
Medical conditions
1.
Patient has significant diseases other than COPD, (ie, clinically relevant disease or 
condition or an abnormality in prior ECGs, medical history or physical 
examinations) which, in the opinion of the Investigator, may put the patient at risk 
because of participation in the study or may influence either the results of the study 
or the patient's ability to participate in the study (eg, severe hepatic impairment).
2.
Patient has alpha-1 antitrypsin deficiency as the cause of COPD (laboratory results 
will be used in combination with smoking and medical history).
3.
Patient has other active pulmonary disease such as predominant asthma, active 
tuberculosis, lung cancer, bronchiectasis, sarcoidosis, idiopathic interstitial 
pulmonary fibrosis, primary pulmonary hypertension, or uncontrolled sleep apnoea.  
Allergic rhinitis is not exclusionary.
4.
Lung surgery for volume reduction or lung transplantation: Patient has undergone 
lung volume reduction surgery, lobectomy, or bronchoscopic lung volume reduction 
(endobronchial blockers, airway bypass, endobronchial valves, thermal vapour 
ablation, biological sealants, massive pulmonary embolism and airway implants) 
within 1 year of Screening (Visit 1).
5.
Patient is using nocturnal positive pressure (eg, continuous positive airway pressure 
or bi-level positive airway pressure).  Patient is using any non-invasive positive 
pressure ventilation device.
Note: A patient using continuous positive airway pressure or bi-level positive 
airway pressure for Sleep Apnoea Syndrome is allowed in the study. 
6.
Patient who had 2 or more exacerbations of COPD (moderate or severe in intensity) 
within the last year prior to Screening (see Section 7.1 for definition of exacerbation 
of COPD).
7.
Patient has been hospitalised due to poorly controlled COPD within 3 months of the 
Screening period.
8.
Patient has acute worsening of COPD that requires treatment with corticosteroids or 
antibiotics in the 6 week interval prior to or during the Screening period.
9.
Patient has had lower respiratory tract infection(s) that required antibiotics within 
6 weeks prior to the Screening period.


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Cardiac disease:
10.
Patient has significant cardiovascular disease that may be vulnerable to 
cardiovascular instability.
Note: Some examples of clinically significant cardiovascular conditions are:

Myocardial infarction within the 6 months prior to Screening Visit (Visit 1).

Unstable angina or unstable arrhythmia which has required changes in the 
pharmacological therapy or other intervention within 12 months prior to 
Screening (Visit 1), or newly diagnosed arrhythmia within the previous 
3 months prior to Screening (Visit 1).

Second degree atrio-ventricular block.

Use of pacemaker.

Hospitalisation within 12 months prior to Screening (Visit 1) for heart failure 
functional classes III (marked limitation of activity and only comfortable at 
rest) and IV per the “New York Heart Association”.
11.
Patient with a QT interval corrected using Fridericia's formula (QTcF) value 
>450 ms for male and >470 ms for female or an ECG that is not suitable for QT 
measurements (eg, poorly defined termination of the T wave).
12.
Patient with a heart rate <50 or >100 beats per minute (bpm).
13.
Patient has clinically significant uncontrolled hypertension (>160 mmHg) as 
assessed by the Investigator.
Neurological:
14.
Patient has seizures or a history of seizures requiring anticonvulsants within 
12 months prior to Screening.
15.
Patient is taking selective serotonin reuptake inhibitors or serotonin-norepinephrine 
reuptake inhibitors whose dose has not been stable for at least 4 weeks prior to 
Screening, or exceeds the maximum recommended dose.
Renal/Urogenital:
16.
Patient has a symptomatic bladder neck obstruction, acute urinary retention or 
symptomatic non-stable prostate hypertrophy.


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Other:
17.
Any laboratory abnormality or suspicion of any clinically relevant disease or 
disorder (on history or examination), including uncontrolled diabetes or 
hypokalaemia (serum potassium <3.5 mmol/L), which, in the opinion of the 
Investigator, may either put the patient at risk because of participation in the study, 
or influence the results or the patient’s ability to participate in the study (eg, severe 
hepatic impairment) or any other safety concerns in the opinion of the Investigator.
Note: Potassium replacement and re-test is allowed once if serum potassium 
concentration was <3.5 mmol/L at Screening or prior to randomisation. 
18.
Patient has known human immunodeficiency virus (HIV) infection or chronic 
hepatitis B or C infection.
19.
History of malignancy of any organ system, treated or untreated within the past 
5 years, with the exception of localised basal cell carcinoma of the skin.
20.
Patient has known narrow-angle glaucoma.
21.
Patient has a history of drug of abuse within the past 2 years or consuming more 
than 14 (female patients) or 21 (male patients) units of alcohol a week, or shows 
positive for drugs of abuse and alcohol tests at Screening and prior to 
randomisation. 
Note: If a patient tests positive to any drugs of abuse tests, which cannot be 
explained by use of prescription medication, he/she will be excluded from the study. 
Unit=1 glass of wine (125 mL)=1 measure of spirits=½ pint of beer.
22.
Patient has a history of hypersensitivity (including paradoxical bronchospasm) to 
β2-agonists, muscarinic anticholinergics or lactose/milk protein.  Lactose 
intolerance is not an exclusion criterion.
Prior/concomitant therapy
23.
Patient has received a live attenuated vaccination within 30 days prior to Screening.
Note: Inactivated influenza vaccination, pneumococcal vaccination, or any other 
inactivated vaccine is acceptable provided it is not administered within 7 days prior 
to Screening or randomisation (Visit 3).
24.
Patient who, in the opinion of the Investigator, is unable to abstain from protocol-
defined prohibited medications during the study.
Prior/concurrent clinical study experience
25.
Patient was treated with an investigational drug or device in another clinical trial 
within the last 30 days or 5 half-lives (whichever is longer) prior to Screening.


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Note: Patient participation in observational studies (ie, studies that do not require 
change to medication or an additional intervention) is not exclusionary.
26.
Previous participation or prior screen failure in the present study. 
Other exclusions
27.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).
28.
Patient has changed their smoking status (ie, restarted or stopped smoking) or 
initiation of a smoking cessation program within 6 weeks of Screening.
29.
Patient has participated in the acute phase of a pulmonary rehabilitation program 
within 4 weeks prior to Screening or who will enter the acute phase of a pulmonary 
rehabilitation program during the study.  A patient in the maintenance phase of a 
pulmonary rehabilitation program is not to be excluded.
30.
Judgment by the Investigator that the patient should not participate in the study if 
the patient is unlikely to comply with study procedures, restrictions and 
requirements. Inability to comply with requirements includes having an e-Diary 
completion rate of <70% during the run-in period.
31.
Patient who have donated or lost >500 mL of blood and/or plasma within the 
previous 3 months prior to Screening.
32.
Vulnerable patients (who has been placed in an institution due to a regulatory or 
court order).
Procedures for withdrawal of incorrectly enrolled patients see Section 7.3.
5.3
Lifestyle restrictions
5.3.1
Meals and dietary restrictions
Patients enrolled in the study should adhere to the following fasting conditions for the 
duration of the study.  Any event likely to interfere with the objectives of the study will be 
communicated to the Investigator and reported without delay to the Sponsor.
1.
Patients should eat and drink only the standardised meals and drinks provided 
according to the study centre’s standard practice during their entire stay at the study 
centre each treatment visit.  Meals should not include any xanthine-containing 
compounds (ie, caffeine) or grapefruit-containing foods or beverages.  No food 
intake will be allowed between meals.
2.
On Day 1, Day 8, and Day 14 of each treatment period, patients will be required to 
undergo an 8-hour overnight fast before IP administration and will maintain a fasted 
condition for an additional 4 hours following IP administration on Day 1 and 
Day 14. On Day 8 a fasted condition of 1 hour after IP administration should be 


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observed.  During other treatment days, there are no fasting requirements prior to IP 
administration.
3.
Patient should fast for 4 hours before i-STAT (potassium and glucose 
measurements) and for 8 hours before routine safety laboratory testing.  During 
patients’ stays at the study centre, standardised meals will be served according to 
the study centre’s standard practice.
4.
Intake of water will not be allowed 1 hour prior to administration of the IP and 
1 hour post-administration of the IP on Day 1, Day 8, and Day 14 of each treatment 
period.
5.
Patients must abstain from consuming any of the following: 

Poppy seeds (eg, found in bread) from time of consent until the final Follow-up 
Visit at the end of the study.

Grapefruit or grapefruit juice, or Seville orange (also called bitter orange, 
including marmalade) consumption from 48 hours prior to administration of the 
IP at Visit 3 until the final Follow-up Visit at the end of the study.
5.3.2
Caffeine, alcohol, and tobacco
1.
Patients must abstain from any of the following:

Alcohol from 72 hours before each visit to the study centre and during the 
entire stay at the study centre.

Smoking should be avoided for 1 hour prior to the pulmonary function tests.

Energy drinks containing taurine or glucuronolactone (eg, Red Bull) from 
72 hours prior to administration of the IP at Visit 3 until the Follow-up Visit at 
the end of the study.

Caffeine-containing food and drinks for 24 hours prior to each visit to the study 
centre and during the entire stay at the study centre.  Decaffeinated drinks will 
be acceptable to be consumed during the study.
5.3.3
Activity
1.
Patients should avoid exposure to dust or polluted air for at least 1 hour before 
conducting any respiratory procedures.
2.
Patients must abstain from strenuous physical activity, which is not within the 
patient’s normal daily routine, from 72 hours before the Screening Visit until the 
Follow-up Visit at the end of the study.


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5.3.4
Medication and other restrictions
1.
Salbutamol should be withheld at least 6 hours before each visit where spirometry is 
performed up to the last spirometry procedure on that visit. However, patients are 
permitted to use salbutamol if its use is absolutely necessary during the visit, and 
with the approval of the Investigator.
2.
Ipratropium should be withheld at least 8 hours before Visits 3, 6 and 9 and during 
all treatment periods. This medication is to be used during the run-in and wash-out 
periods.
3.
Patients must abstain from any of the following: 

Blood or plasma donation from Screening (Visit 1) until 3 months after the 
Follow-up Visit at the end of the study.

Scheduled in-patient surgery or hospitalisation during the course of the study 
(patients are not required to abstain from emergency treatment).

Restrictions on medications (prescribed or over-the-counter products) are 
defined in Section 6.5.
5.4
Screen failures
Screening failures are defined as patients who signed the ICF to participate in the clinical 
study but are not subsequently randomly assigned to study treatment.  A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure patients to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
Individuals may be rescreened only if the patient has not failed any assessment but was not 
randomised within the screening window (28 days of their first assessment).  Individuals who 
do not meet the eligibility criteria (despite the repeated tests) will be screen failed.  Repetition 
of the entire Screening Visit is not allowed.  Rescreened patients should be assigned the same 
patient number as for the initial screening.  However, rescreening should be documented so 
that its effect on study results, if any, can be assessed.
These patients should have the reason for study withdrawal recorded in the electronic Case 
Report Form (eCRF).
6.
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study 
participant according to the study protocol. Study treatment in this study refers to AZD8871, 
Anoro® Ellipta®, and placebo.


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6.1
Treatments administered
6.1.1
Investigational products
Table 3
Study Treatments
Treatment 1
Treatment 2
Treatment 3
Treatment 4
Study treatment name:
AZD8871 (as 
saccharinate) 
inhalation powder
in SD3FL DPI
Anoro® Ellipta®
(umeclidinium 
[UMEC]/ 
vilanterol [VI])
Placebo to 
AZD8871 in 
SD3FL DPI
Placebo to 
Anoro® Ellipta®
Dosage formulation:
600 μg 
Predispensed: 
UMEC 62.5 μg, 
VI (as trifenatate) 
25 μg. 
Delivered dose: 
UMEC 55 μg, VI 
(as trifenatate) 
22 μg.
N/A
N/A
Route of administration 
Oral inhalation
Oral inhalation
Oral inhalation
Oral inhalation
Dosing instructions:
1 inhalation per 
day
1 inhalation per 
day
1 inhalation per 
day
1 inhalation per 
day
Packaging and labelling
Study treatment will be provided in individual patient kit labelled with study-
specific label.  Each kit will be labelled in accordance with Good 
Manufacturing Practice (GMP) Annex 13 and per country regulatory 
requirement.  Label text will be translated into local language.  The planned 
dose of AZD8871, Anoro® Ellipta®, or placebo will be administered via 
multi-dose DPI device.  Each DPI device will be packed in an aluminium 
pouch including desiccant.
Further information will be provided in the Investigator drug manual.
For training purposes, each patient will receive an empty DPI device for 
SD3FL (a variant of the commercially available Genuair® or Pressair® DPI) 
that will be used on Visit 3, 6 and 9, if considered necessary.
DPI: Dry powder inhaler; UMEC: umeclidinium; VI: vilanterol
6.2
Preparation/handling/storage/accountability
Study treatment will be provided in individual patient kit labelled with study-specific label.  
All IP should be kept in a secure place under appropriate storage conditions.  The label on the 
IP specifies the appropriate storage.
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.


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Only patients enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment.  All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the Investigator and authorised site staff.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
To allow drug reconciliation and dispensation control, research personnel will record patient 
ID on the labels of the patient kit, every period kit dispensed, as well as on the aluminium 
pouch labels and inhaler labels.
The manufacturing, labelling, packaging and release of AZD8871 and placebo to AZD8871
will be conducted following GMP by AstraZeneca.  Batch numbers will be indicated in the 
Clinical Study Report (CSR).
Further guidance and information for the final disposition of unused study treatment are 
provided in the Investigator drug manual.  
6.3
Measures to minimise bias: randomisation and blinding
PAREXEL will be responsible for generating the randomisation scheme through the AZRand
programme. The randomisation schedule will describe the link between the randomly 
assigned sequences of 3 treatments to each randomisation number. 
At Visit 3, approximately 72 patients will be randomly assigned to 1 of the 6 possible 
treatment sequences, according to a William’s design for crossover studies and using a 
balanced 1:1:1:1:1:1 randomisation ratio.  Thus, 12 patients will be assigned to each treatment 
sequence (Table 4).  To ensure random allocation, each patient will be given the IP bearing 
the lowest available randomisation number at the site.


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Table 4
Treatment sequences
Treatment Period 
1
Treatment Period 
2
Treatment Period 
3
Sequence 
A (n=12)
AZD8871
600 µg 
Placebo
Placebo
Anoro® Ellipta®
Placebo
55 μg / 22 μg
Placebo
Sequence 
B (n=12)
AZD8871
600 µg
Placebo
Placebo
Anoro® Ellipta®
Placebo
Placebo
55 μg / 22 μg
Sequence 
C (n=12)
AZD8871
Placebo
600 µg
Placebo
Anoro® Ellipta®
55 μg / 22 μg
Placebo
Placebo
Sequence 
D (n=12)
AZD8871
Placebo
Placebo
600 µg
Anoro® Ellipta®
55 μg / 22 μg
Placebo
Placebo
Sequence E 
(n=12)
AZD8871
Placebo
600 µg
Placebo
Anoro® Ellipta®
Placebo
Placebo
55 μg / 22 μg
Sequence F 
(n=12)
AZD8871
Placebo
Placebo
600 µg
Anoro® Ellipta®
Placebo
55 μg / 22 μg
Placebo
The Investigator(s) will:
1.
Obtain signed informed consent from the potential patient before any study-specific 
procedures are performed.
2.
Assign each patient a unique patient identification number.  This number will be 
composed of 2 parts: the first 4 digits (fixed) representing the site identifier.  The 
next 3 digits (ascending) which will be assigned sequentially within each site, 
starting with 001. The patient identification number will be used to identify the 
patient throughout the study and will be recorded in the eCRF.
3.
Determine patient eligibility; see Section 5.
4.
For patients fulfilling the eligibility criteria at Visit 3, the Investigator will assign a 
unique randomisation number following chronological ascending order.
Randomisation codes will be assigned strictly sequentially as patients become eligible for 
randomisation. The randomisation numbers will be grouped in blocks at an overall level.  The 
block size will not be communicated to the Investigators.
All patients will be centrally assigned to randomised study treatment using an interactive 
voice/web response system (IVRS/IWRS).  Before the study is initiated, the telephone number 
and call-in directions for the IVRS and/or the log-in information and directions for the IWRS 
will be provided to each site. 


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Randomisation data will be kept strictly confidential. The randomisation list will only be 
provided to AstraZeneca personnel responsible for study IP preparation and to Covance 
Bioanalytical group responsible for PK analyses.
When the study is completed and the data verified and locked and the populations defined, the 
randomisation codes will be made available for data analysis.
If a patient withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused.  Withdrawn patients will not be replaced.
This study will be performed in a double-blind manner.  All IPs will be supplied in identical 
packaging to enable double-blind conditions.
AZD8871 and Anoro® IPs will be provided in the SD3FL (a variant of the commercially 
available Genuair® or Pressair® DPI) and Ellipta® DPI devices, respectively. Placebos will be 
provided in both the SD3FL and Ellipta® DPI devices with the same external appearance and 
containing lactose monohydrate; the Ellipta® placebo DPI device will also contain Magnesium 
Stearate.
For each treatment period patients will be provided with one SD3FL DPI device and one 
Ellipta® DPI device for daily administration of one of the 3 following combinations: 
AZD8871-placebo, placebo-Anoro®, or placebo-placebo.
Supplies of salbutamol and ipratropium will be open-label.
The IVRS/IWRS will provide to the Investigator(s) or pharmacists the kit identification 
number to be allocated to the patient at the dispensing visit.
Routines for this will be described in the IVRS/IWRS user manual that will be provided to 
each centre.
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the patient requires knowledge of the treatment randomisation.  
The Investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to the patient to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities.  Randomisation codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual patient have been 
made and documented.
The IVRS/IWRS will be programmed with blind-breaking instructions.  In case of an 
emergency, the Investigator has the sole responsibility for determining if unblinding of a 
patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the Investigator decides that unblinding is 
warranted, the Investigator is asked to contact the Sponsor prior to unblinding a patient’s 


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treatment assignment unless this could delay emergency treatment of the patient.  In this case, 
the Sponsor must be notified within 24 hours after breaking the blind.  The date and reason 
that the blind was broken must be recorded in the source documentation and eCRF, as 
applicable. Study unblinding should not occur until database lock and all decisions on the 
evaluability of the data from each individual patient have been made and documented.
6.4
Treatment compliance
Investigators will record patients’ IP intake in the eCRF during site visits. For IP use between 
visits, patients will be provided with an e-Diary to record their intake of the IP on a daily 
basis. Any change from the dosing schedule, dose interruptions, dose reductions, dose 
discontinuations should be recorded in eCRF.
The Investigational Product Storage Manager is responsible for managing the IP from receipt 
by the study site until the destruction or return of all unused IP.  The Investigator(s) is 
responsible for ensuring that the patient has returned all unused IP.
6.5
Concomitant therapy
Any treatment taken during the 2 weeks prior to signing of the ICF must be recorded in the 
Previous and Concomitant Medication eCRF page to ensure proper wash-out of prohibited 
medications.
Patients will be withdrawn from their usual COPD therapy after signing the ICF and will be 
maintained on a mono-component ICS therapy, if required.  Ipratropium will be provided 
during run-in and wash-out periods but should be held at least 8 hours before Visits 3, 6 and 9 
(before any pulmonary function test) and during all treatment periods.  In addition, salbutamol 
will be provided as rescue medication for the duration of the study.
From the first IP administration, any new treatments taken or any change in ongoing 
medications during the participation in the study, apart from the IP, will be transcribed onto 
the corresponding eCRF page by the Investigator or designee.
Patients must be instructed to inform the Investigator of plans to take any new treatment 
during the participation in the study, including over-the-counter medicinal and herbal 
products.
In the interest of patient safety and acceptable standards of medical care, patients may be 
allowed to take any medications not listed as either permitted or not permitted (see below) at 
the discretion of the Investigator.  All treatments must be recorded in the patients’ eCRF.  Any 
medication taken for medical reasons deemed acceptable by the Investigator prior to study 
entry will be continued at the same dose and conditions until completion of the Follow-up 
Visit.
Table 5 and Table 6 summarise different possible treatments for COPD and other indications 
which are allowed and prohibited, respectively, with example of medication and applicable 
restrictions.


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Table 5
Restricted medications
Medications:
Usage (including limits for duration 
permitted and special situations in which 
it’s allowed):
Oral anti-histamines, intranasal corticosteroids 
and sympathomimetics and intranasal 
anticholinergics
Allowed but avoid for 24 hours prior and up to 
36 hours post-IP dosing at each period
ICSs mono-component
Allowed but if taken, dosage and regimen must be 
stable during the study duration. Avoid for 
12 hours prior to any spirometry test 
Rescue medication: Salbutamol 100 µg
Allowed but avoid for 6 hours prior to any 
spirometry test for the study
Ipratropium 20 µg × 2 puffs 4 times per day
Mandatory during run-in and wash-out periods but 
should be held at least 8 hours before Visits 3, 6 
and 9 (before any pulmonary function test) and 
during all treatment periods (until last pulmonary 
function test at Visits 5, 8 and 11)
ICS=Inhaled corticosteroid.
Table 6
Prohibited medications
Drug Class
Restrictions
ANTICHOLINERGICS
Oral or parenteral
Wash-out of 72 hours required before Visit 2
Inhaled short-acting, SAMAs
Wash-out of 8 hours required before Visit 2
Inhaled long-acting, LAMAs
Wash-out of 72 hours before Visit 2
Β2-ADRENERGIC AGONISTS
Inhaled short-acting, SABAs (except 
Salbutamol rescue medication)
Wash-out of 6 hours before starting first 
pulmonary function test at each study visit
Inhaled long-acting, LABAs (BID or QD)
BID: Wash-out of 48 hours required before 
Visit 2
QD: Wash-out of 7 days required before Visit 2
Oral short-acting
Wash-out of 24 hours required before Visit 2
COMBINATIONS (INHALED)
Inhaled long-acting LABA/LAMA 
combinations (BID or QD)
BID: Wash-out of 48 hours required before 
Visit 2
QD: Wash-out of 7 days required before Visit 2
LABA + ICS fixed-dose combinations
Stop combination at least 48 hours before Visit 2 
and switch to ICS mono-component at Visit 1


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Table 6
Prohibited medications
Drug Class
Restrictions
SABA + anticholinergic agent 
Wash-out of 72 hours required before Visit 2 
CORTICOSTEROIDS
Continuous oral or parenteral
Wash-out of 6 weeks required before Visit 2
OTHERS
Methyl-xanthines
Patients with these medications should not be 
enrolled into the study
Mast cell stabilisers
Wash-out of 5 days required before Visit 2
Leukotriene modifiers
Wash-out of 48 hours required before Visit 2
Selective and non-selective β-blocking agents 
(oral or topical including eye drops)
Patients with these medication should not be 
enrolled into the study
Phosphodiesterase IV inhibitors
Wash-out of 4 weeks required before Visit 2
Anti-IgE and anti-IL-5 antibody therapies
Wash-out of 6 months required before Visit 2
Medications that prolong the QT/QTc interval 
(other than inhaled β2 agonist) eg, 
anti-arrhythmics, anti-psychotics and 
fluoroquinolones
Stable at least 4 weeks prior to Visit 2
“Experimental”, non-approved medications
Wash-out of 3 months before Visit 1
Strong inhibitors of carboxyl esterase 2
Wash-out of 5 days required before Visit 2
Live attenuated vaccine
Wash-out of 30 days before screening
Inactivated vaccine
Wash-out of 7 days before screening or 
randomisation (Visit 3)
Wash-out of 7 days before each treatment period
Inactivated vaccines are not allowed during the 
treatment periods
BID=Twice a day; ICS=Inhaled corticosteroid; IgE=Immunoglobulin E; IL-5=Interleukin-5; LABA=Long-
acting β2-agonist; LAMA=Long-acting muscarinic antagonist; QD=Once a day; SABA=Short-acting β2-
agonist; SAMA=Short-acting muscarinic antagonist.
6.5.1
Background medication
The IP will not be given as an “add-on” to another medication or class of medication.
6.5.2
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.


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6.5.3
Rescue medication
The study site will supply salbutamol rescue medication (Table 7) that will be provided by the 
Sponsor or PAREXEL. Patients will be provided with an e-Diary to collect their daily use of 
rescue medication during the run-in and treatment periods.
Although the use of rescue medications is allowable at any time during the study, the use of 
rescue medications should be delayed, if possible, for at least 6 hours before any pulmonary 
function test.  The date and time of rescue medication administration as well as the dosage 
regimen of the rescue medication must be recorded.
Table 7
Rescue medication
Rescue drug:
Usage:
Salbutamol 100 µg
As needed but avoid for 6 hours prior to any spirometry 
test for the study
6.6
Dose modification
N/A.
6.7
Treatment after the end of the study
N/A.
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
7.1
Discontinuation of study treatment 
Patients may be discontinued from IP in the following situations.

Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.

Adverse Event.

Severe non-compliance with the Clinical Study Protocol.

Failure to meet randomisation criteria: Violations of inclusion and/or exclusion 
criteria detected after randomisation.  See Section 7.3 for patients not fulfilling 
inclusion/exclusion criteria but detected after randomisation.

Lost to follow-up: See Section 7.2 for details.

Pregnancy: In case of pregnancy the female patient will be immediately 
discontinued from study treatment.


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
Clinical/FEV1 stability criteria not fulfilled during the treatment periods.

Development of study-specific withdrawal criteria: These criteria are listed below; 
in the event that any of these conditions are reported as an AE, then this AE should 
be reported as the primary reason for discontinuation in the eCRF.

Withdrawal of consent to the use of donated biological samples.
(a) Vital signs (any time after randomisation; the test must be repeated to confirm that 
withdrawal criterion has been met)

Systolic blood pressure (SBP) increase of >40 mmHg from pre-dose at Day 1 of 
each treatment period AND SBP >180 mmHg at any time within the 12-hour 
interval after taking study treatment.
(b) Laboratory findings (any time after randomisation; the test must be repeated to 
confirm that withdrawal criterion has been met)

Haematologic toxicity defined as 1 or more of:

Confirmed leucocyte count <2.0×109/L.

Confirmed neutrophil count <1.0×109/L.

Confirmed platelet count <75×109/L.

Confirmed lymphocyte count <0.5×109/L. 

Hepatic toxicity defined as 1 or more of:

Confirmed alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
increase to >3×the upper limit of normal (ULN). 

Confirmed isolated total bilirubin (TBL) increase to >2×ULN. 

Confirmed ALT or AST increase to >2×ULN concurrent with an increase in TBL to 
>1.5×ULN.

Serum potassium, checked within 4 hours post-dose on the days tested, 
<3.0 mmol/L, will be treated appropriately by the Investigator, and the patient will 
be withdrawn from study treatment.
(c) ECG (within 4 hours of post-IP dosing; the test must be repeated to confirm that 
withdrawal criterion has been met): 

Symptomatic bradycardia defined as heart rate <45 bpm or asymptomatic 
bradycardia defined as resting supine pulse <30 bpm while awake, persisting for at 
least 10 min.


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
Heart rate of >120 bpm and an increase of >40 bpm during the first 4 hours 
post-dose, persisting for at least 10 min.

QTcF interval prolongation exceeding >500 ms during the treatment period OR
>60 ms change from pre-dose at Day 1 of each treatment period (within 4 hours 
post-dose), persisting for at least 5 min.
(d) Lung function

FEV1 decrease by>20% from pre-dose at Day 1 of each treatment period (ie, before 
first dose of study treatment) on 2 consecutive spirometry assessments obtained at 
least 15 min apart AND with associated symptoms of dyspnoea at any time within 
the first 2-hour interval after taking study treatment.
(e) Moderate to severe COPD exacerbation

COPD exacerbation of moderate or severe intensity.
Note: A COPD exacerbation is defined as a change in the patient’s baseline 
dyspnoea, cough, and/or sputum (increase in volume or change in colour towards 
purulence) that lasts ≥3 days, is beyond normal day-to-day variations, is acute in 
onset, and may warrant a change in regular medication.  The severity of COPD 
exacerbations is classified as follows:

Mild: Exacerbations that do not require systemic steroids or antibiotics and do not 
result in hospitalisation or death.

Moderate: Exacerbations that require treatment with systemic steroids and/or 
antibiotics, and do not result in hospitalisation or death.

Severe: Exacerbations that result in hospitalisation or death.
(f) Other

Study cancellation or any other reason not described above.

Patient withdrawal due to death.
Generally, before discontinuation of a patient from the study, a discussion between Sponsor’s 
Study Physician and Investigator is encouraged, as much as feasible.
See the SoA (Table 1) for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.1.1
Temporary discontinuation 
Temporary discontinuation will not be permitted in this study. 


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7.1.2
Rechallenge
N/A.
7.1.3
Procedures for discontinuation of study treatment
The Investigator should instruct the patient to contact the site before or at the time if study 
treatment is stopped.  A patient that decides to discontinue study treatment will always be 
asked about the reason(s) and the presence of any AEs.  The date of last intake of study 
treatment should be documented in the eCRF.  All study treatment, the e-Diary, and paper 
diary should be returned by the patient at their next on-site study visit or unscheduled visit.  
Patients permanently discontinuing study treatment should be given locally available standard 
of care therapy, at the discretion of the Investigator.
A patient that has discontinued study treatment, for any reason, does not need to complete all 
planned visits for this study, however, they must attend a discontinuation Follow-up Visit 
42 days (up to 49 days) after the last IP administration.
7.2
Lost to follow-up
A patient will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:

The site must attempt to contact the patient and reschedule the missed visit as soon 
as possible and counsel the patient on the importance of maintaining the assigned 
visit schedule.

Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient or next of kin by eg, repeat telephone 
calls, certified letter to the patient´s last known mailing address or local equivalent 
methods. These contact attempts should be documented in the patient’s medical 
record. 

Efforts to reach the patient should continue until the end of the study.  Should the 
patient be unreachable at the end of the study the patient should be considered to be 
lost to follow-up with unknown vital status at end of study and censored at latest 
follow-up contact.
7.3
Withdrawal from the study
A patient may withdraw from the study (eg, withdraw consent), at any time (IP and
assessments) at his/her own request, without prejudice to further treatment.
If a patient withdraws from the study they must attend a discontinuation Follow-up Visit 
42 days (up to 49 days) after the last IP administration.


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If the patient withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a patient withdraws from the study, he/she may request destruction of any samples taken, 
and the Investigator must document this in the site study records.  
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE.  The Investigator will follow up patients as medically indicated. The patient will 
return the e-Diary and paper diary.
AstraZeneca or its delegate will request Investigators to collect information on patients’ vital 
status (dead or alive; date of death when applicable) at the end of the study from publicly 
available sources, in accordance with local regulations.  Knowledge of the vital status at study 
end in all patients is crucial for the integrity of the study. 
See SoA, Table 1, for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. All study treatment should be 
returned by the patient.
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
randomised or receive study IPs.  There can be no exceptions to this rule.  Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be randomised 
or initiated on treatment, and must be withdrawn from the study.
When a patient does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study 
Physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the Investigator. Any patient that has been initiated on treatment and 
subsequently found not to meet all the eligibility criteria must stop the treatment and be 
excluded from the study.  The AstraZeneca Study Physician must ensure all decisions are 
appropriately documented.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA (Table 1).  
The Investigator will ensure that data are recorded on the eCRF.  The Web Based Data 
Capture (WBDC) system will be used for data collection and query handling.  
The Investigator ensures the accuracy, completeness, legibility 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 eCRF
will be archived at the study site.


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Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed at Visit 1 or Visit 2 and reviewed to confirm that 
potential patients meet all eligibility criteria.  The Investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable.  
Procedures conducted as part of the patient’s routine clinical management (eg, blood count)
and obtained before signing of the ICF may be utilised for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
The maximum amount of blood collected from each patient over the duration of the study, 
including any extra assessments that may be required, will not exceed 375 mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples.
8.1
Efficacy assessments 
Planned time points for all efficacy assessments are provided in the SoA (Table 1).
8.1.1
Clinical outcome assessments
Pulmonary function test (spirometry)
The pulmonary function test uses a spirometer that will measure:

FVC (maximal volume of air exhaled with maximally forced expiratory effort from 
a position of maximal inspiration). 

FEV1 (volume of air expressed in litres exhaled during the first second of 
performance of the FVC).
A centralised spirometry company (ERT) will provide the spirometers, all necessary 
equipment (computer, calibration syringe, printer, paper, ink, etc.), a detailed study manual 
and training to the technicians and Investigators (as needed) in charge of conducting the 
spirometry for this clinical study.  
The circumstances of patient’s tests should be similar on all occasions with respect to time of 
the day, temperature as well as the technician, as much as possible.
The American Thoracic Society (ATS) and European Respiratory Society (ERS) guidelines 
should be followed to provide accurate and comparable spirometric data. Spirometer will be 
configured to meet ATS/ERS recommendations for accuracy and precision (Miller et al, 


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2005). The computerised spirometer will check the consistency between tests and some of the 
requirements set out in the ATS/ERS spirometry guidelines, and will automatically alert the 
technician to the presence of deviations from some ATS/ERS requirements. However, the 
technician must ensure that tests are performed with the correct technique, manually 
deselecting efforts which do not meet minimum standards. The technician must use their 
judgment to ensure that the optimum spirometry data is gained from the patient at each test 
session. 
These data will be electronically transmitted by the Investigator to ERT typically at the end of 
each patient protocol visit. Throughout the study, a centralised reading of spirometric values 
will be performed by an independent spirometric expert at ERT, blinded to patient’s IP 
allocation and patient’s identity, in a 2-step quality control:

“Over-Read” process: The first review of the spirometry data (including review of 
tests rejected by the technician) qualifies spirometric curves according to ATS/ERS 
criteria. No changes are made to the data.

“Best Test Review” process: During this procedure, the acceptability of tests is 
assessed first followed by repeatability. If quality problems are encountered on the 
spirometric curve pre-identified as the “best test”, ERT will check if there is another 
curve that is acceptable. If a better “best test” is identified, site will be queried. If 
the site accepts the proposed new “best test” (as indicated by the Investigator 
signing a query form), this newly accepted measure will represent the “best test” in 
all analysis and reporting. No change on “best test” will be made without the 
approval of the Investigator. 
Inclusion of patient in the study will be based on the post-BTR values from Visit 2. 
FEV1 stability check will be based on the pre-BTR.
Prior to the first spirometry, the trained technician should demonstrate the procedure to the 
patient by using a detached mouthpiece and then allow the patient some practice attempts. 
Demonstration should be repeated and the patient should practise the procedure as many times 
during the study course as deemed necessary.
Patients who are unable to produce acceptable spirometry tests must not be included in the 
study. The patient should be at rest for 10 min prior to the test and comfortable; tight clothing 
should be loosened to allow the thorax to move freely. Each manoeuvre comprises one “set of 
tests”: 3 measurements (curves) technically adequate are needed according to the acceptability 
and repeatability criteria of the ATS/ERS spirometry guidelines. If both the acceptability and 
repeatability criteria are met, the manoeuvre session can conclude after 3 measurements. If 
one or both of these criteria are not met a maximum of 5 additional tests (up to a total of 8
tests) should be performed until either both criteria are met or patient is fatigued and could not 
provide any further useful data.
The operator performing the spirometry must print every spirometry test, sign and date them.
Breathlessness, cough, and sputum scale


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The BCSS (Leidy et al, 2003) questionnaire is a 3-item, patient-reported outcome (PRO) 
measure (see Appendix E).  On a daily basis, patients are asked to evaluate each of their 
3 symptoms (breathlessness, cough, and sputum) on a 5-point Likert scale ranging from 0 to 4, 
with higher scores indicating a higher severity of the symptom.  The BCSS questionnaire is 
expressed as a daily total score, which is the sum of the 3 symptom scores, ranging from 0 to 
12.
Patients will be provided with an e-Diary to collect their assessments of their 3 symptoms in 
the evening on a daily basis.
COPD Assessment Test 
The CAT (Jones et al, 2009) is an 8-item self-administered PRO designed to assess the 
condition of the patient and the overall impact of COPD (see Appendix F). Studies have 
shown the CAT to have good repeatability and discriminative properties, suggesting that it is 
sensitive to treatment effects at a group level. On a daily basis, patients are asked to evaluate 
the impact of COPD on their wellbeing and daily life on a 6-point Likert scale ranging from 0 
to 5, with higher scores indicating a higher impact of COPD. The CAT is expressed as a total 
score, which is a sum of the 8 questions, ranging from 0 to 40.  Patients will be provided with 
an e-Diary to collect their assessment in the evening on a daily basis.
Cough VAS
The VAS is a simple and reproducible PRO tool for the assessment of cough intensity as it 
provides an easy and rapid estimation (see Appendix G).  It is a 10-cm long line (oriented 
horizontally or vertically) on which patients indicated the intensity of cough by crossing the 
line at the point that corresponded to their cough severity.  The beginning of the scale refers to 
no cough (0 cm) and the end refers to the most severe cough they could imagine (10 cm).
Cough monitoring
Cough monitoring will be performed using the VitaloJAK wearable vitalograph device.  
Patients will be monitored for 24 hours, starting 24 hours prior to dosing on Day 1 and starting
at pre-dose on Day 14.  The VitaloJAK records coughs via an air-coupled Electret Condenser 
Microphone capacitive Cough Sensor on a single channel.  A second channel uses a 
microphone to sense audio data to provide a monitoring or supervisory channel in order to 
determine the validity of the data recorded from the Cough Sensor channel. Patients will be 
trained on how to use the device after all pulmonary function tests have been completed at 
Visit 2.
8.1.2
FEV1 and clinical stability check
This is not an outcome measure.  FEV1 stability check will be performed at Visits 6 and 9 
(Day 1 of treatment periods 2 and 3).  FEV1 stability check will be based on the pre-BTR 
values.  FEV1 at these visits will be calculated as the mean of the 2 pre-dose values and 
compared with the mean of the pre-dose FEV1 values measured at Visit 3.  This should be 
within (±)20% or (±)200 mL compared to the pre-dose FEV1 (mean of the 2 measured values) 
of the first treatment period (Visit 3).  If the FEV1 stability criterion is not met, an additional 


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measurement could be taken within 30 min of the second pre-dose measurement, and the 
mean of the last 2 measurements will be considered for the FEV1 stability criterion.
If the FEV1 stability criterion is still not met, the test can be rescheduled as soon as possible
(up to a maximum of 3 times), and if the FEV1 stability criterion is not met after re-testing, the 
patient should be withdrawn.
Patient’s clinical stability will be assessed at Visit 2 and before the start of each treatment 
period and defined as follows:

No relevant respiratory signs/symptoms that modify the patient’s baseline daily
activities.

Not meeting the criteria of COPD exacerbation (as per Investigator’s clinical 
judgment).

No ongoing SAEs.

No relevant AEs that potentially modify the absorption, distribution, metabolism, 
and excretion of IP.
8.1.3
Reversibility testing
Airflow reversibility is not an outcome variable.  Baseline reversibility testing will be 
performed at Visit 2.
Reversibility testing will include a pre-salbutamol spirometry, followed by administration of 
salbutamol by oral inhalation (100 µg×4 puffs).  Spirometry will be performed 20 to 30 min 
post-salbutamol.  Both percentage and absolute improvement will be captured.
8.2
Safety assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1).
8.2.1
Clinical safety laboratory assessments
See Table 8 for the list of clinical safety laboratory tests to be performed and to the SoA
(Table 1) for the timing and frequency.  All protocol-required laboratory assessments, as 
defined in the table, must be conducted in accordance with the laboratory manual and the 
SoA. The results of tests performed at Screening (Visit 1 or Visit 2) will be regarded as 
baseline data.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables. 
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.  Additional safety samples may be collected if clinically indicated at the 


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discretion of the Investigator.  The date, time of collection and results (values, units and 
reference ranges) will be recorded on the appropriate eCRF.
The clinical chemistry, haematology and urinalysis will be performed at a central laboratory.  
The central laboratory will provide the centre with the necessary material and instructions for 
the sampling.  In exceptional circumstances and upon discussion with the Sponsor, local 
laboratory assessments may have to be undertaken to collect key information supporting an 
AE or SAE. Information will be collected in eCRF as appropriate.
Table 8
Laboratory safety variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haematocrit
S/P-Glucose (fasting)
B-Haemoglobin
S/P-Cholesterol, total
B-Erythrocytes (red blood cells)
S/P-Triglycerides
B-MCV
S/P-Creatinine
B-MCH
S/P-Bilirubin, total
B-MCHC
S/P-Protein, total
B-Leukocyte count (white blood cells)
S/P-Albumin
B-differential blood count (neutrophils, lymphocytes, 
monocytes, eosinophils and basophil)
S/P-Uric acid and BUN
B-thrombocytes 
S/P-Sodium
B-Platelet
S/P-Potassium
aPTT
S/P-Calcium, total
INR
S/P-Chloride
PTT
Alpha-1 antitrypsin
Urinalysis (standard dipstick as a minimum)
S/P-Phosphorus, inorganic
U-pH
S/P-AST
U-Blood
S/P-ALT
U-leucocytes
S/P-ALP
U-Protein
S/P-GGT
U-Glucose
S/P-LDH
U-Bilirubin
S/P-Creatine kinase
U-Urobilinogen
S/P- Bicarbonate
U-Ketones
S/P- Magnesium
U-Nitrites
ALP=Alkaline phosphatase; ALT=Alanine transaminase; AST=Aspartate transaminase; BUN=Blood urea nitrogen; 
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haemoglobin concentration; MCV=Mean corpuscular volume; aPTT=Activated partial thromboplastin time; 
INR=International normalised ratio; PTT=Partial thromboplastin time.
NB. In case a patient shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN 
please refer to Appendix D ‘Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law’ for further instructions.
The following laboratory tests will be performed only at the Screening Visit (Visit 1 or 
Visit 2) to check the eligibility of the patient for participation in the study:

Serology tests:

HIV I and II antibodies.

Hepatitis B surface antigen.

Hepatitis B core (HBc) immunoglobulin antibodies (IgM).

Hepatitis C antibodies.

Urine pregnancy test in women.

Women aged less than 50 years (see inclusion criterion #11): Serum/plasma FSH 
and LH.
See the SoA (Table 1) for the timing and frequency of i-STAT measurements.
Drugs of abuse and alcohol screen (Table 9) will be performed as specified in the SoA 
(Table 1). The alcohol screen may be performed using a urine sample or a breath test.
Table 9 Drugs of abuse and alcohol parameters
Drugs of Abuse (10 mL fresh urine sample) and Alcohol (breath or urine test)
Amphetamine/Ecstasy 
Benzodiazepines
Ethanol/Alcohol 
Methadone
Cannabinoids/Tetrahydrocannabinol 
Barbiturates
Cocaine 
Urine Creatinine
Opiates 
Phencyclidine
Tricyclic anti-depressants
If a patient tests positive for any drugs of abuse tests, which cannot be explained by use of prescription 
medication, he/she will be excluded from the study.
8.2.2
Physical examinations
A complete physical examination will be performed at Screening (Visit 1 or Visit 2) and at the 
Follow-up Visit and include an assessment of the following: general appearance, respiratory, 


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cardiovascular, abdomen skin, head and neck (including ears, eyes, nose and throat), lymph 
nodes, thyroid, musculo-skeletal (including spine and extremities) and neurological systems.
A brief physical examination will be performed at other visits which include an overnight stay 
and will include an assessment of the following: skin, lungs, cardiovascular system, and 
abdomen (liver and spleen).
Body weight and height will be measured at Screening (Visit 1 or Visit 2) for calculation of 
BMI.  Patients should be in light indoor clothes without shoes.
Physical examination will be performed as specified in the SoA (Table 1), Investigators 
should pay special attention to clinical signs related to previous serious illnesses; new or 
worsening abnormalities may qualify as AEs, see Section 8.3.7 for details.
8.2.3
Vital signs

Temperature and blood pressure will be assessed by national standard methods.

Blood pressure measurements will be assessed with a completely automated device.  
Manual techniques will be used only if an automated device is not available.

Blood pressure measurements should be preceded by at least 5 min of rest for the 
patient in a quiet setting without distractions (eg, television, cell phones).

Vital signs will be measured in a supine position (as flat as possible and what is 
comfortable for the patient) after 5 min rest. The same position should be used for 
all timepoints and will include temperature, SBP and diastolic blood pressure
(DBP).  Vital Signs will be done as single measurement and are to be recorded in 
the eCRF.  Heart rate will be assessed by ECG (except pre-dose on Visits 4, 7 and 
10, which will be taken from Vital Signs).
8.2.4
Electrocardiograms
ECGs will be done as single measurement and will be obtained as specified in the SoA 
(Table 1) using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals.  Refer to Section 7.1 for QTcF withdrawal criteria and any 
additional QTcF readings that may be necessary.
Standard 12-lead ECG evaluations will be recorded after approximately 5 min resting in 
supine position before any blood sampling and spirometry test. 12-lead ECGs will be recorded 
preferably always by the same technician for each patient.
Electrocardiogram will be performed with the regular 12-lead ECG equipment at each site 
included in the study.
Electrode preparation to prevent interference in the ECG signal will be performed according 
to the recommendations of the supplier.


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Individual ECG analysis will be performed locally by the Investigator at each of the sites.  
Results will be collected and included in the eCRF.
The Investigator will review the reports to assess the clinical relevance of any abnormal 
findings and/or to decide if the patient is or remains eligible for the study.
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).  
The following ECG parameters will be recorded:

Time and date of the ECG.

Heart rate (beats per minute). Except pre-dose on Visits 4, 7 and 10, which will be 
taken from Vital Signs.

RR interval: Duration in milliseconds between 2 R peaks of 2 consecutive 
measurements.

PR interval: Duration in milliseconds from the beginning of wave P to onset of 
ventricular depolarisation (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: QT interval corrected by heart rate:

QTcF interval: QT interval corrected using Fridericia’s formula 
(QT[msec]/RR[sec]1/3).

Sinus rhythm (yes/no).

Overall evaluation (normal/abnormal).
At Screening (Visit 1 or Visit 2), the 12-lead ECG should be recorded at a similar time to that 
to be obtained pre-dose during the course of the study.  Investigators will assess patients’ 
eligibility according to the manual reading report at screening.
Any abnormal finding in the ECG tracing (rhythm, ectopy, conduction, morphology, 
myocardial infarction, ST segment, T wave and U wave observations) will be evaluated by the 
Investigator and will be specifically documented and registered on eCRF.
Throughout the study, clinically relevant new findings or worsening of a pre-existing finding 
in the ECGs (parameters or abnormal findings in the tracing) must be considered an 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 8.3.7.


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In case of technical problems, the Investigator considers any result is clinically relevant or 
doubtful, additional 12-lead ECGs may be performed, using the same equipment, within a 
reasonable time.
8.3
Collection of adverse events
The Principal Investigator (PI) is responsible for ensuring that all staff involved in the study 
are familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
AEs will be reported by the patient (or, when appropriate, by a caregiver or surrogate).  
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs 
see Section 8.3.3.  
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.  
8.3.2
Time period and frequency for collecting AE and SAE information 
Adverse Events will be collected from time of signature of ICF throughout the treatment 
period and including the follow-up period (42 to 49 days after last dose of IP).
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix B.  The Investigator will submit any updated SAE data to the Sponsor
within 24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study patients. However, 
if the Investigator learns of any SAE, including a death, at any time after a patient’s last visit 
and he/she considers the event to be reasonably related to the study treatment or study 
participation, the Investigator may notify the Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient
at subsequent visits/contacts.  All AEs will be followed until resolution, stabilisation, the 
event is otherwise explained, or the patient is lost to follow-up.
Any AEs that are unresolved at the patient’s last AE assessment in the study are followed up 
by the Investigator for as long as medically indicated (until resolution of a short-duration SAE 
or until chronic treatment is established in the scenario of a long-lasting SAE), but without 


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further recording in the eCRF.  AstraZeneca retains the right to request additional information 
for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
Adverse event data collection
'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 IP(s) (yes or no).

Action taken with regard to IP(s).

AE caused patient’s withdrawal from study (yes or no).

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE.

Date Investigator became aware of serious AE.

AE is serious due to.

Date of hospitalisation.

Date of discharge.

Probable cause of death.

Date of death.

Autopsy performed.

Causality assessment in relation to study procedure(s).

Causality assessment to other medications.
8.3.5
Causality collection
The Investigator will assess causal relationship between the IP and each AE, and answer ‘yes’ 
or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the 
event may have been caused by the investigational product?’


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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 B.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol-mandated laboratory tests and vital signs will be 
summarised in the CSR.  Deterioration as compared to baseline in protocol-mandated 
laboratory values, vital signs, ECGs and physical examination should therefore only be 
reported as AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of 
treatment with the IP.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study (DUS), see Sections 8.3.9 and 8.3.10.
8.3.8
Hy’s law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3xULN together with TBL ≥2xULN may need to be 
reported as SAEs.  Please refer to Appendix D for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law (HL).
8.3.9
Disease under study (DUS)
Symptoms of DUS are those which might be expected to occur as a direct result of COPD. 
Events which are unequivocally due to DUS should not be reported as an AE during the study 
unless they meet SAE criteria or lead to discontinuation of the IP.


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8.3.10
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied.  It may be an increase in the severity of the DUS
and/or increases in the symptoms of the disease.  
All COPD exacerbations (see Section 7.1 for definition of exacerbation of COPD) will be 
captured using a COPD exacerbation eCRF and will not be reported as AEs unless considered 
an SAE.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day ie, immediately but no later than 24 hours of when he or she becomes 
aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the electronic data 
capture (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 staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.
For further guidance on the definition of a SAE, see Appendix B.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study patient has received any study 
treatment.


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If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
Women of childbearing potential are not allowed to be included in this study.  Should a 
pregnancy still occur, the IP should be discontinued immediately and the pregnancy reported 
to AstraZeneca.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the patient
was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day (ie, immediately but no 
later than 24 hours) of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.2) 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 PREGOUT is 
used to report the outcome of the pregnancy.
8.4.2.2
Paternal exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
3 months after the last administration of the IP.
In case of pregnancy of the patient’s partner, the participant will not be necessarily 
discontinued from the study 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. 
Pregnancy of the patient’s partners is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality), occurring from the date of the first dose until 3 months after 
the last administration of the IP and as indicated by previous studies (pre-clinical and clinical) 
should, if possible, be followed up and documented in the Pregnancy Report Form. Consent 
from the partner must be obtained before the Pregnancy Report Form is completed.


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8.4.3
Overdose
For this study, any dose of AZD8871 greater than 600 μg within 1 day will be considered an 
overdose.
AstraZeneca recommends symptomatic treatment and monitoring of vital functions should be 
performed in the event of an overdose; according to routine clinical practice.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
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.
For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 8.3.2.  For other overdoses, reporting must occur within 30 days.
8.4.4
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors.
The definition of a medication error can be found in Appendix B.
8.5
Pharmacokinetics
PK parameters will be derived using non-compartmental methods. 
Definitions for the PK parameters are:

Cmax - Observed maximum concentration, taken directly from the individual 
concentration-time curve.

tmax - Time to reach maximum concentration, taken directly from the individual 
concentration-time curve.


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
AUClast - Area under the plasma concentration-curve from time 0 to the time of last 
quantifiable concentration.

AUC(0-24) - Area under the plasma concentration-curve from time 0 to 24 hours
post-dose.

Cavg - Average plasma concentration during a dosing interval, estimated as AUC0-
24/24.

%Fluctuation - Fluctuation index during a dosing interval estimated as 100*(Cmax -
Cmin)/Cavg (%), where Cmin is the minimum concentration at the end of the dosing 
interval.

Rac (Cmax) - Accumulation ratio for Cmax estimated as (Cmax on Day 14/Cmax on 
Day 1).

Rac (AUC0-24) - Accumulation ratio for AUC0-24 estimated as (AUC0-24 on 
Day 14/AUC0-24 on Day 1).
Additional parameters may be determined where appropriate. 
Blood samples of approximately 4 mL will be collected for measurement of plasma
concentrations of AZD8871 and its primary metabolite LAS191861 as specified in the SoA 
(Table 1).  Instructions for the collection and handling of biological samples will be provided 
by the Sponsor or analytical test site. The actual date and time (24-hour clock time) of each 
sample will be recorded.
Samples will be collected, labelled, handled, stored and shipped as detailed in the laboratory 
manual.
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
Sponsor and site study files, but will not constitute a protocol amendment.  The independent 
ethics committee (IEC) will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the ICF.
8.5.1
Derivation of the pharmacokinetic parameters
The PK analyses of the plasma concentration data for AZD8871 and its primary metabolite 
LAS191861 will be performed at Covance 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 6.2, 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. 


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For AUC derivation, 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 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.
AUC 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.
If an entire concentration-time profile is BLQ, the profile is excluded from the PK analysis.
8.5.2
Determination of drug concentration
For placebo and active comparator treatments immediately following an AZD8871 treatment 
period, only Day 1 pre-dose samples will be analysed unless specified. For any other placebo 
and active comparator treatments, samples will not be analysed unless specified.
Samples for determination of AZD8871 and its primary metabolite LAS191861
concentrations in plasma will be analysed by Covance on behalf of AstraZeneca, using an 
appropriate bioanalytical method.  Full details of the analytical method used will be described 
in a separate Bioanalytical Report.
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 CSR but 
separately in a Bioanalytical Report.
8.5.3
Storage and destruction of pharmacokinetic samples
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalisation or 
6 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.
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.


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8.7
Genetics
Genetic testing is not evaluated in this study.
 
 
 
 
 
 
 
8.9
Health economics
Health economic parameters are not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS 
9.1
Statistical hypotheses
The main comparison for the primary efficacy variable and for the key secondary efficacy 
variables is the efficacy of AZD8871 600 μg versus Anoro® Ellipta®.  Due to the exploratory 
nature of this study, no adjustments for multiple testing will be made.
9.2
Sample size determination 
The study will be powered to demonstrate superiority of AZD8871 600 µg versus 
Anoro® Ellipta® for the primary efficacy endpoint. With a total of 54 patients, there is 90% 
power to detect a difference between AZD8871 and Anoro® Ellipta® treatments for the change 
from baseline to Trough FEV1 at Day 15 equal to 100 mL, assuming a SD of differences of 
220 mL, 2-sided 5% significance level and a normal distribution.  Assuming an approximate 
25% dropout, the total sample size will be approximately 72 (multiple of 6 sequences).  From 
previous studies, the screening failure rate is estimated to be approximately 50%; therefore 
approximately 145 screened patients will be required to achieve the goal of approximately 
72 randomised patients.
9.3
Populations for analyses
For purposes of analysis, the following populations are defined: 
CCI


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Population
Description
Full Analysis Set (FAS)
The FAS population is defined as all patients randomised and 
receiving IP, irrespective of their protocol adherence and 
continued participation in the study.  Patients will be assigned 
according to their randomised treatment, irrespective of 
whether or not they have prematurely discontinued.  Patients 
who withdraw consent to participate in the study will be 
included up to the date of their study termination.  All efficacy 
analyses will be based on the FAS population and analysed 
according to the intent to treat principle.
Pharmacokinetic (PK) 
The PK population is defined as all randomised patients 
participating in the subset of PK patients, who took at least 1
dose of IP and have at least 1 of the parameters, Cmax, AUC or 
AUClast evaluable and are assumed not to be affected by factors 
such as protocol deviations (eg, disallowed medication, or 
incorrect IP received).  All protocol deviations that occur 
during the study will be considered for their severity/impact 
and will be taken into consideration when patients are assigned 
to the PK population.
The exclusion of any patients or time points from the 
calculation of the PK parameters will be documented by the PK 
scientist including the reason(s) for exclusion.  The available 
concentration data and PK parameter data for any patients 
excluded from the PK population will be listed only, and 
presented in the individual figures of concentration-time plots.
Per-Protocol (PP)
The PP population is defined as a subset of FAS population 
constituted by those patients who did not present important 
deviations of the protocol that may affect efficacy (eg, met all 
inclusion/exclusion criteria liable to affect the efficacy 
assessment).
Safety Population
The safety population consists of all randomised patients who 
received at least 1 dose of IP.  Patients will be analysed 
according to the randomised treatment assignment in each 
period.  Any important deviations from the randomised 
treatment assignment will be listed and considered when 
interpreting the safety data.


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9.4
Statistical analyses
Analyses will be performed by PAREXEL except the derivation of the PK parameters, which 
will be performed by Covance.  A comprehensive statistical analysis plan (SAP) will be 
developed and finalised before database lock and will describe the patient populations to be 
included in the analyses, and procedures for accounting for missing, unused, and spurious 
data.  This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints.  Any deviations from this plan will be reported in the CSR.
All results will be presented by treatment with descriptive statistics appropriate to the nature 
of the variables.  Demographic and baseline characteristics will be presented.  For continuous 
variables, the number of non-missing observations, mean, SD, standard error (SE) of the 
mean, 95% confidence interval (CI) of the mean (except safety data), median, first and third 
quartiles, minimum and maximum will be presented.  For categorical variables: counts (n) and 
percentages (%) [where specified] will be presented.  These summaries will be provided by 
time point of assessment as appropriate. 
The SAS® version 9.3 or later will be used for the data analysis.  A complete set of raw data 
listings will be appended to the final CSR.  All tables, figures and listings will be presented in 
Word and Portable Document Format documents without any manual editing, (ie, they will 
appear unmodified as programmed by means of the statistical package).
In general, there will be no imputation of missing data for the safety or efficacy analyses.  
Additional details will be provided in the SAP.
All personnel involved with the analysis of the study will remain blinded until database lock 
and Clinical Study Protocol deviations identified.  
Deviations from the protocol will be assessed as “important” or “not-important”.  Important 
deviations from the protocol may lead to the exclusion of patients from the PP population
and/or other populations.  Deviations will be defined before database hard lock and 
unblinding.  Important deviations will include the following: 

Violation of inclusion and/or exclusion criteria.

Administration of prohibited concomitant medications that are expected to influence 
the measurement of the primary endpoint. 
All important protocol deviations will be listed by patient for all randomised patients.  Further 
details will be described in the SAP.
A Blind Data Review Meeting (BDRM) will be held before opening randomisation codes in 
order to assign the patients to the different analysis populations according to the specified 
definitions.  The precise reasons for excluding patients from the study populations will be 
fully defined in the SAP and documented in the BDRM Report.


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9.4.1
Efficacy analyses
The analysis of all efficacy variables will be performed on the FAS population.  In addition, 
the primary efficacy variable will also be analysed using the PP population, and on the FAS
population with a model including covariates to capture potential carry-over effects.
Analysis of the primary efficacy variable
The primary efficacy variable is the change from baseline in Trough FEV1 at Day 15 (ie, after 
14 days of treatment).
Baseline for FEV1 will be defined as the mean of the 2 measured values for the corresponding 
variable (2 measurements 45 min apart, at -1 hour and -15 min), prior to the morning IP 
administration on Day 1 of each treatment period.  If both are missing, the Visit 2 
pre-bronchodilator value will be used instead.
Trough is defined as the mean of the FEV1 values obtained at 23 hours and 23 hours and 
45 min after the IP administration on Day 1 and Day 14 (ie, obtained on Day 2 and Day 15).  
On Day 8, Trough is defined as the mean of the FEV1 pre-dose values (-1 hour and -15 min).  
If 1 of the values is missing, the available value will be used as Trough.
This variable will be analysed by means of a mixed model with fixed effects for treatment, 
sequence, and period.  The patient will be fitted as a random effect and the pre-dose FEV1 of 
each period will be included as a covariate.
Each treatment effect and treatment differences will be estimated by the Least Square (LS) 
means along with their SE and 95% CI, and the p-value corresponding to the 
between-treatment group difference.
The main treatment comparisons that will be evaluated are:

AZD8871 600 µg versus Anoro® Ellipta®.

AZD8871 600 µg versus Placebo.
A treatment comparison for Anoro® Ellipta® versus placebo will also be explored.
A sensitivity analysis will be performed for the primary efficacy variable; computing the 
baseline for FEV1 as the mean of the 2 measured values for the corresponding variable 
(2 measurements 45 min apart, at -1 hour and -15 min), prior to the morning IP administration 
on Day 1 of the first treatment period.  If both are missing, the Visit 2 pre-bronchodilator 
value will be used instead.
This “modified” primary efficacy variable (change from first period baseline in trough FEV1) 
will be analysed by means of a mixed model; a random effects model with fixed effects for 
treatment, sequence, and period.  The patient will be fitted as a random effect and the pre-dose 
FEV1 of first period will be included as a covariate.


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Analyses of secondary variables:
All continuous variables defined as change from baseline or observed values will be analysed 
using similar mixed models as for the primary efficacy variable adjusted for the corresponding 
baselines. Modifications compared to the primary analysis model to covariance structures and 
included covariates may be done as appropriate.
Peak FEV1 will be defined as the maximum value from 0 to 4 hours.
All baseline values will be the pre-dose values of each treatment period except for the CAT 
and Total BCSS questionnaire score, where the run-in period baseline will be used for all 
treatments in each sequence.
The same treatment comparisons as those for the primary variable will be performed for the 
secondary variables.
9.4.2
Safety analyses
All demographic and baseline characteristics, safety outcomes and other variables will be 
analysed using the safety population. 
Safety will be assessed by descriptive analysis of AEs, vital signs, ECGs and clinical 
laboratory assessments.
All analyses of safety and tolerability outcomes will be performed on the safety population.  
Individual safety and tolerability data will be provided in data listings and summarised as 
appropriate by treatment.  Continuous variables (laboratory parameters [including i-STAT], 
vital signs and ECG) will be summarised using descriptive statistics (n, mean, SD, minimum, 
median, and maximum) as appropriate by scheduled assessment time point.  Where 
applicable, data will be summarised for the observed value, and for the corresponding change 
from baseline/screening.  Categorical variables will be summarised in frequency tables 
(counts and percentage).  Change from baseline will be calculated as the differences between 
the post-dose value at each time point and the morning value prior to administration of the IP.
For all variables, 12-lead ECG parameters, vital signs and laboratory tests (including i-STAT), 
baseline values will be defined as the values obtained prior to the morning IP administration 
on Day 1 of Visit 3.
Any clinically relevant new physical examination findings or worsening of a pre-existing 
physical examination finding that were to be recorded as an AE will be presented with the 
AEs.
AEs: The number and percentage of patients who experienced 1 or more treatment-emergent 
AEs (TEAEs), and the number of TEAE occurrences will be tabulated by treatment group.  
Adverse events occurring before administration of IP (ie, not treatment-emergent) and the 
number of occurrences will be reported in the same way as TEAEs.  An AE will be considered 
a TEAE if it was not present prior to the date of the first dose of IP or was present prior to the 
date of the first dose of IP, but increased in severity after IP administration.  A TEAE that 


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occurs during a wash-out period will be associated to the last treatment taken.  An AE that 
occurs more than 42 days after the last IP administration will not be counted as a TEAE.  
TEAE tables will be tabulated by system organ class, preferred term, intensity, causality, 
action taken, outcome, seriousness criteria and treatment group using descriptive statistics.
12-lead ECG: Descriptive statistics will be produced at each schedule assessment time point 
for all quantitative ECG parameters (heart rate, PR, RR, QRS, QT, QTcB and QTcF intervals) 
for both observed absolute values and changes from baseline.
For the QT, QTcB and QTcF parameters, the normalised AUC(0-4), and AUC(0-24) will be 
calculated as the value of each AUC (computed using the trapezoidal rule) divided by its 
corresponding time (4 hours, and 24 hours, respectively) on Day 1 and Day 14 (no AUCs will 
be computed for Day 8).  Heart rate and QT data will be analysed using mixed models for 
repeated measures.  More details will be given in the SAP.
Electrocardiogram findings in rhythm, ectopy, conduction, morphology, myocardial 
infarction, ST segment, T wave, and U wave will be presented with counts and percentages by 
treatment.
Electrocardiogram findings will also be listed.  A listing of AEs for patients with abnormal 
ECG findings will also be performed.
An analysis of potentially clinically significant ECG values on QT, QTcB, QTcF, QRS and 
PR interval, and heart rate will be performed.  The number and percentage of patients with 
potentially clinically significant ECG values will be tabulated across time and treatment 
group.  The criteria based on severity will be defined in the SAP.
Blood Pressure: SBP and DBP (mmHg) will be analysed at each scheduled assessment time 
point using descriptive statistics for both observed absolute values and changes from baseline.
Additionally, the number and percentage of patient with notable changes from pre-dose at 
each post-dose time point for SBP and DBP will be presented by treatment group.  The criteria 
for notable changes in blood pressure will be detailed in the SAP.
Laboratory tests (including i-STAT): Observed absolute values and changes from baseline 
in haematology, serum biochemistry and urinalysis parameters, will be summarised by 
treatment group using descriptive statistics at each scheduled assessment time point.
Out of range values will be flagged in the data listings and a list of clinically significantly 
abnormal values will be presented.
Additionally, treatment-emergent abnormalities, defined as newly occurring or worsening as 
well as notable abnormalities in laboratory parameters will be summarised by means of shift 
contingency tables comparing the values (post-dose versus pre-dose Day1 and follow-up 
versus pre-dose Day 1).  Newly occurring or worsening of abnormalities in laboratory 
parameters will be identified using the expanded normal ranges that will be specified in the 
SAP.


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9.4.3
Pharmacokinetic analysis
Pharmacokinetic parameters will be analysed in the PK population on the subset of 36 patients 
who will have specifically consented to participation in the PK assessments.
PK analyses will be described in the finalised SAP before database lock. 
Plasma concentrations and PK parameters will be listed and summarised for AZD8871 and its 
primary metabolite LAS191861 per day using appropriate descriptive statistics.
The PK analyses described herein will be included in the CSR. Any additional analysis, such 
as PK population analyses, will be presented separately from the CSR.  
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, AZD8871 and primary 
metabolite concentrations, and comments will be provided.
Plasma concentrations of AZD8871 will be summarised by using descriptive statistics (n, 
geometric mean, geometric SD, geometric coefficient of variation [CV%], arithmetic mean, 
arithmetic SD, minimum, median and maximum) based on the PK population.
For descriptive statistics for plasma concentrations that are BLQ will be handled as follows:

At a time point where less than or equal to 50% of the values are BLQ, all BLQ 
values will be set to 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 patients excluded from the PK population 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 patient for Day 1 and Day 14 (where 
applicable) overlaid on the same plot.


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Figures for the geometric mean (± geometric SD) concentration-time data will be presented 
for all doses overlaid on the same plot, in both a linear and semi-logarithmic scale (SD only 
on the linear scale).
All plots will be provided for AZD8871 and its primary metabolite LAS191861.
Additional graphical presentations of PK data may be added at the discretion of the PK 
scientist.  More details will be provided in the SAP.
9.4.4
Exploratory analysis
A composite endpoint for exacerbations (moderate or severe) in COPD (COPDCompEx) will 
be derived and analysed. COPDCompEx combines exacerbations with events defined from 
patient daily diaries. The definitions for both types of events are as follows:

Exacerbations: episodes leading to one or more of the following; hospitalisation, 
emergency room visit, treatment with oral corticosteroids, or treatment with 
antibiotics. 

Diary events: defined by threshold and slope criteria using the following diary 
variables: individual domains of the breathlessness, cough, and sputum scale and 
rescue medication use.
The analysis of this endpoint will primarily be time to first COPDCompEx event, but the 
events may also be analysed with models addressing event rates or time to recurrent event. 
More details on the derivation and analysis of this variable will be given in the SAP.
9.4.5
Methods for multiplicity control
Due to the exploratory nature of the study, there will be no adjustment for multiple 
comparisons.
9.5
Interim analyses 
No interim analysis is planned for this study. 


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10.
REFERENCES
Bateman et al, 2013
Bateman ED, Kornmann O, Ambery C, Norris V.  Pharmacodynamics of GSK961081, a bi-
functional molecule, in patients with COPD.  Pulm Pharmacol Ther. 2013; 26(5):581–7.
Feldman et al, 2017
Feldman GJ, Sousa AR, Lipson DA, Tombs L, Barnes N, Riley JH, et al.  Comparative 
Efficacy of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol Therapy in 
Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study.  Adv Ther. 
2017; 34(11):2518-2533
GOLD 2018
Global strategy for the diagnosis, management and prevention of chronic obstructive lung 
disease updated 2018.  Available from http://www.goldcopd.org.  Accessed on 27 March
2018.
Jones et al, 2009 
Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first 
validation of the COPD assessment test. Eur Respir J. 2009; 34(3):648-54.
Miller et al, 2005
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation 
of spirometry. Eur Respir J. 2005;26(2):319-38.
Leidy et al, 2003
Leidy NK, Schmier JK, Jones MKC, Lloyd J, Rocchiccioli K.  Evaluating symptoms in 
chronic obstructive pulmonary disease: validation of the Breathlessness, Cough and Sputum 
Scale.  Resp Med. 2003; 97(Suppl. A): S59-S70.
Tashkin and Ferguson 2013
Tashkin DP, Ferguson GT.  Combination bronchodilator therapy in the management of 
chronic obstructive pulmonary disease.  Respir Res. 2013; 14:49.
Wielders et al, 2013
Wielders PL, Ludwig-Sengpiel A, Locantore N, Baggen S, Chan R, Riley JH.  A new class of 
bronchodilator improves lung function in COPD: a trial with GSK961081.  Eur Respir J. 
2013; 42(4):972–81.


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Appendix A
Regulatory, Ethical and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines.

Applicable ICH Good Clinical Practice (GCP) Guidelines.

Applicable laws and regulations.
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an independent ethics committee (IEC) by the 
Investigator and reviewed and approved by the IEC before the study is initiated.  
Any amendments to the protocol will require IEC approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to 
study patients.  
The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IEC.

Notifying the IEC of SAEs or other significant safety findings as required by IEC 
procedures.

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations.
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
A 2
Financial Disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.


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A 3
Informed Consent Process
The Investigator or his/her representative will explain the nature of the study to the patient and 
answer all questions regarding the study.  
Patients must be informed that their participation is voluntary.  Patients will be required to 
sign a statement of informed consent that meets the requirements of local regulations, ICH 
guidelines, where applicable, and the IEC or study centre.  
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date and time the written consent was 
obtained.  The authorised person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
A copy of the ICF(s) must be provided to the patient.  
If a patients’ partner becomes pregnant during the study, the partner is asked to sign the 
"Adult Study Informed Consent Form for Pregnant Partners of Study Subjects" and provide 
information about the pregnancy accordingly.
Patients who are rescreened (only if the patient has not failed any assessment but was not 
randomised within the screening window) are required to re-sign the same ICF.
A 4
Data Protection
Each patient will be assigned a unique identifier by the Sponsor.  Any patient records or data 
sets transferred to the Sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred.  
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the patient.  
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the Sponsor, by 
appropriate IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
There will be no steering committee, data monitoring committees or scientific advisory 
committee as this is a study of a drug intended to provide short-term symptom relief. 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and 
letters to Investigators.


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A 6
Dissemination of Clinical Study Data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical trial and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the main study is 
conducted.
A 7
Data Quality Assurance
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data).  The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The Investigator must permit study-related monitoring, audits, IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the Sponsor.  No records may be 
transferred to another location or party without written notification to the Sponsor. 
A 8
Source Documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected.  Source documents are filed at the Investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  The Investigator may need to 
request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available.
Definitions of what constitutes source data can be found in the source data agreement and 
computerised data check list for electronic source data.


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A 9
Study and Site Closure
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the Investigator

Discontinuation of further study intervention development
A 10
Publication Policy
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission.  This allows the Sponsor to protect proprietary information and to provide 
comments.  
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multi-centre studies only in their entirety and not as individual site data.  In this 
case, a co-ordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.


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Appendix B
Adverse Event Definitions and Additional Safety Information
B 1
Definition of Adverse Events
An adverse event is the development of any untoward medical occurrence in a patient or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or wash-out periods, even if no study treatment has been administered.
B 2
Definitions of Serious Adverse Event
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
wash-out, follow-up), that fulfils 1 or more of the following criteria:

Results in death.

Is immediately life-threatening.

Requires in-patient hospitalisation or prolongation of existing hospitalisation.

Results in persistent or significant disability or incapacity.  

Is a congenital abnormality or birth defect.

Is an important medical event that may jeopardise the patient or may require 
medical treatment to prevent 1 of the outcomes listed above.
B 3
Life-threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).
B 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.


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B 5
Important Medical Event or Medical Treatment
Medical and scientific judgment 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 jeopardise the patient or may require 
medical treatment to prevent 1 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 
judgment must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment.

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine.

Intensive treatment in an emergency room or at home for allergic bronchospasm.

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation.

Development of drug dependency or drug abuse.
B 6
Intensity Rating Scale:
1.
mild (awareness of sign or symptom, but easily tolerated).
2.
moderate (discomfort sufficient to cause interference with normal activities).
3.
severe (incapacitating, with inability to perform normal activities).
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 7
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.

Time Course.  Exposure to suspect drug.  Has the patient actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?


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
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.

Rechallenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge.

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 recognised 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 DUS has deteriorated due to lack of effect should be 
classified as no reasonable possibility.
B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant.  
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.


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
was identified and intercepted before the participant received the drug.

did not occur, but circumstances were recognise that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion.

Dispensing error eg, 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 eg, tablet dissolved in water when it should be taken as 
a solid tablet.

Drug not stored as instructed eg, kept in the fridge when it should be at room 
temperature.

Wrong participant received the medication (excluding IVRS/IWRS errors).

Wrong drug administered to participant (excluding IVRS/IWRS errors).
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those which lead to 1 of 
the above listed events that would otherwise have been a medication error.

Participant accidentally missed drug dose(s) eg,  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 AZ product.
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody of Biological Samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
patients while in storage at the centre until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the patient is 
withdrawn from further study participation.
The Investigator:

Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented and the signed document returned to the study site

Ensures that the patient and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.


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C 3
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 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
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 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm)

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable

Samples routinely transported by road or rail are patient to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 


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containment standards are encouraged wherever possible when road or rail transport 
is used.


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Appendix D
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
1
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 subject meets 
potential 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 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Serious Adverse Events (SAEs) and Adverse Events (AEs) according to the 
outcome of the review and assessment in line with standard safety reporting processes.
2
DEFINITIONS
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase
(ALP). 
Hy’s Law (HL)
AST or ALT ≥3x ULN together with TBL ≥2xULN, where no other reason, other than the 
IMP, 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.
3
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:
ALT ≥3xULN
AST ≥3xULN
TBL ≥ 2xULN
When a subject meets any of the PHL identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the Investigator will:

Notify the AstraZeneca representative 

Request a repeat of the test (new blood draw) by the central laboratory
without delay

Complete the appropriate unscheduled laboratory CRF module(s) with 
the original local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the subject meets PHL criteria (see Section 2 within 
this Appendix for definition) by reviewing laboratory reports from all 
previous visits (including both central and local laboratory results)


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4
FOLLOW-UP
4.1 Potential Hy’s Law Criteria not met
If the subject does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the subject has not met PHL 
criteria

Perform follow-up on subsequent laboratory results according to the 
guidance provided in the Clinical Study Protocol
4.2 Potential Hy’s Law Criteria met
If the subject 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.

For subjects that met PHL criteria prior to starting IMP, the investigator 
is not required to submit a PHL SAE unless there is a significant change 
in the subject’s condition

The Study Physician contacts the Investigator, to provide guidance, 
discuss and agree an approach for the study subjects’ follow-up 
(including any further laboratory testing) and the continuous review of 
data

Subsequent to this contact the Investigator will:

Monitor the subject 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 aetiology of the event and perform diagnostic 
investigations as discussed with the Study Physician This includes 
deciding which tests available in the Hy’s law lab kit should be 
used

Complete the three Liver CRF Modules as information becomes 
available 


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5
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES
The instructions in this Section should be followed for all cases where PHL criteria are met.
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 CRF

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. 

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 


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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.
6
LABORATORY TESTS
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended when using a central laboratory. For individual studies, the list may be 
reduced to a subset of tests after consultation with the Hepatic Safety Knowledge Group.
Some of the tests may also be considered for use with local laboratories that have 
respective testing capabilities. Any test results need to be recorded in the CRF.
Hy’s Law lab kit for central laboratories
Additional standard chemistry and 
coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgM and IgG anti-HCV
HCV RNA
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-
LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron


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Ferritin
Transferrin
Transferrin saturation
References
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’


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Appendix E
Breathlessness, Cough, Sputum Scale Questionnaire


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Appendix F
COPD Assessment Test 


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Appendix G
Cough Visual Analogue Scale
     
No cough
Worse possible cough


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Appendix H
Abbreviations 
Abbreviation or 
special term
Explanation
%Fluctuation
Fluctuation index during a dosing interval
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATS
American Thoracic Society
AUC
Area under the plasma concentration-curve
AUC(0-24)
Area under the plasma concentration-curve from time 0 to 24 hours post-dose
AUClast
Area under the plasma concentration-curve from time 0 to the time of last 
quantifiable concentration
BCSS
Breathlessness, cough, sputum scale
BDRM
Blind Data Review Meeting
BID
Twice a day (bis in die)
BLQ
Below the lower limit of quantification
BMI
Body mass index
BP
Blood pressure
Bpm
Beats per minute
BTR
Best test review
BUN
Blood urea nitrogen
Cavg
Average plasma concentration during a dosing interval 
CI
Confidence interval
Cmax
Maximum plasma concentration
COPD
Chronic obstructive pulmonary disease
COPDCompEx
Composite endpoint for Exacerbations (moderate or severe) in COPD
CPMP
Committee for Proprietary Medicinal Products
CSR
Clinical study report
CV%
Coefficient of variation
DBP
Diastolic blood pressure
DPI
Dry powder inhaler
DUS
Disease under study
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
ERS
European Respiratory Society


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Abbreviation or 
special term
Explanation
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GMP
Good Manufacturing Practice
HBc
Hepatitis B core
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
ICS
Inhaled corticosteroid
IEC
Independent ethics committee IEC
IgM
Immunoglobulin antibodies
International 
Co-ordinating Investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the Investigators and/or activities 
internationally  
IP
Investigational product
IVRS
Interactive voice response system
IWRS
Interactive web response system
LABA
long-acting β2-agonist
LAMA
Long-acting muscarinic antagonist
LDH
Lactate dehydrogenase
LH
Luteinizing hormone
LLOQ
Lower limit of quantification
LS
Least square
MABA
Muscarinic receptor antagonist and β2 adrenoceptor agonist
MCH
Mean cell haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
μg
Microgram


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Abbreviation or 
special term
Explanation
min
Minutes
NA
Not applicable
ND
Not determined
PHL
Potential Hy’s Law
PI
Principal Investigator 
PK
Pharmacokinetics
PP
Per-Protocol
PRO
Patient-reported outcome
QD
Once a day (quaque die)
QTc
Corrected QT interval
QTcB
QT interval corrected using Bazett formula
QTcF
QT interval corrected using Fridericia's formula
Rac
Accumulation ratio
Rac(AUC(0-24))
Accumulation ratio for AUC(0-24)
Rac(Cmax)
Accumulation ratio for Cmax
SABA
Short-acting β2-agonist
SAE
Serious adverse event 
SAMA
Short-acting muscarinic antagonist
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Standard deviation
SE
Standard error
SoA
Schedule of Activities
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
Tmax
Time to reach maximum plasma concentration 
UK
United Kingdom
ULN
Upper limit of normal


SIGNATURE PAGE
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Document Name: d6640c00006-csp-v4
Document Title:
D6640C00006 Clinical Study Protocol version 4
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PPD
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SAP_001.pdf: 
Clinical Study Report Appendix 16.1.9 
AstraZeneca 
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CONFIDENTIAL AND PROPRIETARY 
1 of 2 
 
Clinical Study Report Appendix 16.1.9 
Drug Substance AZD8871 
Study Code 
D6640C00006 
Appendix 16.1.9 
Documentation of Statistical Methods and Supporting Statistical 
Analysis 
 
 
 


Clinical Study Report Appendix 16.1.9 
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AZD8871 - D6640C00006 
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Statistical Analysis Plan Number 
Date 
Page Number 
Statistical Analysis Plan, Version 2.0 
08 Feb 2019 
3 
Data Review Meeting Report Minutes 
29 Aug 2019 
60 
Files embedded in the Data Review Meeting Report Minutes are archived in the Trial Master 
File and available upon request. 


Statistical Analysis Plan  
Drug Substance AZD8871 
Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
Page 1 of 57 
 
 
Statistical Analysis Plan 
 
Drug Substance 
AZD8871 
 
Study Code 
D6640C00006 
 
Date 
08 February 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Phase IIa, Randomised, Multi-centre, Double-blind, Placebo and Active-
controlled, 3 Periods, Crossover Study to Investigate the Efficacy, 
Pharmacokinetics, Safety and Tolerability of Inhaled AZD8871 
Administered Once Daily for 2 weeks in Patients with Moderate to Severe 
COPD 
 
 
 
 
 
 


Statistical Analysis Plan 
Drug Substance 
Study Code D6640C00006 
Vmion Final 2.0 
Date 08 February 2019 
A Phase Ila, Randomised, Multi-centre, Double-blind, Placebo and Active-
controlled, 3 Periods, Crossover Study to Investigate the Efficacy, 
Pharmacokinetics, Safety and Tolerability of Inhaled AZD8871 
Administered Once Daily for 2 weeks in Patients with Moderate to Severe 
COPD 
Study Statistician 
Page 2 of 57 
PPD


Statistical Analysis Plan
Drug Substance
study Code D6640C00006
Version Final 2 0
Date 08 February 2019
A Phase Ila, Randomised, Multi-centre, Double-blind, Placebo and Active-
C
controlled, 3 Periods, Crossover Study to Investigate the Efficacy,
Pharmacokinetics, Safety and Tolerability of Inhaled AZD8871
Administered Once Daily for 2 weeks in Patients with Moderate to Severe
COPD
Global Product Statistician
l
Page 3 of57
PPD


Statistical Analysis Plan 
Drug Substance 
Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
A Phase Ha, Randomised, Multi-centre, Double-blind, Placebo and Active-
controlled, 3 Periods, Crossover Study to Investigate the Efficacy, 
Pharmacokinetics, Safety and Tolerability of Inhaled AZD8871 
Administered Once Daily for 2 weeks in Patients with Moderate to Severe 
COPD 
PK Specialist 
Page 4 of57 
PPD


Statistical Analysis Plan  
Drug Substance  
Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
Page 5 of 57 
 
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ............................................................................................................................ 1 
SIGNATURE OF STUDY STATISTICIAN ........................................................................... 2 
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN .................................................... 3 
SIGNATURE OF STUDY STATISTICIAN ........................................................................... 4 
TABLE OF CONTENTS ......................................................................................................... 5 
LIST OF ABBREVIATIONS .................................................................................................. 8 
AMENDMENT HISTORY .................................................................................................... 11 
1. 
STUDY DETAILS ................................................................................................. 12 
1.1 
Study objectives ..................................................................................................... 12 
1.1.1 
Primary and secondary objective ........................................................................... 12 
1.1.2 
Safety objectives .................................................................................................... 13 
1.1.3 
Exploratory objectives ........................................................................................... 13 
1.2 
Study design ........................................................................................................... 14 
1.3 
Number of patients ................................................................................................. 17 
2. 
ANALYSIS SETS ................................................................................................. 17 
2.1 
Definition of analysis sets ...................................................................................... 17 
2.1.1 
Full analysis set ...................................................................................................... 17 
2.1.2 
Safety analysis set .................................................................................................. 17 
2.1.3 
Pharmacokinetic analysis set ................................................................................. 17 
2.1.4 
Per-Protocol Analysis Set ...................................................................................... 18 
2.2 
Violations and deviations ....................................................................................... 18 
3. 
PRIMARY AND SECONDARY VARIABLES ................................................... 21 
3.1 
General definitions ................................................................................................. 21 
3.1.1 
Handling of missing or partial dates ...................................................................... 22 
3.1.1.1 
Imputation for concomitant medication start and stop dates ................................. 22 
3.1.1.2 
Imputation for adverse event start dates ................................................................ 24 
3.1.1.3 
Imputation for adverse event stop dates ................................................................. 25 
3.1.2 
Repeated and unscheduled visits............................................................................ 25 
3.1.2.1 
Spirometry variables .............................................................................................. 26 
3.2 
Assessment of study population ............................................................................. 26 
3.2.1 
Demographic and baseline characteristic variables ............................................... 26 
3.2.2 
Surgical and medical history .................................................................................. 26 
3.2.3 
Prior and concomitant medications ........................................................................ 26 
3.2.4 
Duration of exposure .............................................................................................. 27 


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Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
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3.2.5 
Treatment compliance ............................................................................................ 27 
3.3 
Efficacy variables ................................................................................................... 27 
3.3.1 
Pulmonary function variables ................................................................................ 27 
3.3.1.1 
Primary outcome variable ...................................................................................... 29 
3.3.1.2 
Secondary FEV1 -related variables ........................................................................ 29 
3.3.1.3 
Other FEV1 -related variables ................................................................................ 29 
3.3.2 
Other efficacy variables ......................................................................................... 29 
3.3.2.1 
Total Breathlessness, Cough Sputum Scale (BCSS) score questionnaire 
and cough, breathlessness and sputum individual domain scores ......................... 29 
3.3.2.2 
COPDCompEx, Cough VAS and Cough Monitoring ........................................... 30 
3.3.2.3 
COPD Assessment Test (CAT) ............................................................................. 30 
3.3.2.4 
Rescue medication use (Salbutamol) ..................................................................... 30 
3.4 
Pharmacokinetic variables ..................................................................................... 30 
3.5 
Safety variables ...................................................................................................... 32 
3.5.1 
Adverse events ....................................................................................................... 32 
3.5.2 
Serious adverse events ........................................................................................... 33 
3.5.3 
COPD exacerbations .............................................................................................. 33 
3.5.4 
Laboratory variables .............................................................................................. 34 
3.5.5 
ECG ........................................................................................................................ 36 
3.5.6 
Vital signs .............................................................................................................. 36 
 
 
4. 
ANALYSIS METHODS ....................................................................................... 37 
4.1 
General principles .................................................................................................. 37 
4.1.1 
Statistical testing .................................................................................................... 37 
4.1.2 
Presentation of results ............................................................................................ 37 
4.2 
Analysis methods ................................................................................................... 38 
4.2.1 
Analyses of study population ................................................................................. 38 
4.2.1.1 
Patient disposition .................................................................................................. 38 
4.2.1.2 
Demographic and baseline characteristics ............................................................. 38 
4.2.1.3 
Exposure ................................................................................................................ 40 
4.2.1.4 
Treatment compliance ............................................................................................ 40 
4.2.2 
Analysis of the primary variable: change from baseline in Trough FEV1 at 
Day 15 .................................................................................................................... 41 
4.2.3 
Analysis of the FEV1-related secondary variables ................................................. 41 
4.2.4 
Analysis of the other FEV1-related variables ......................................................... 42 
4.2.5 
Analysis of the other efficacy variables ................................................................. 42 
4.2.6 
Exploratory outcome variables .............................................................................. 43 
4.3 
Analysis of pharmarcokinetic variables ................................................................. 44 
4.3.1.1 
Descriptive statistics .............................................................................................. 44 
4.3.1.2 
Statistical analysis of accumulation in AZD8871 exposure (Cmax and 
AUC(0-24)) following multiple doses ...................................................................... 47 
4.4 
Safety ..................................................................................................................... 48 
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Drug Substance  
Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
Page 7 of 57 
 
4.4.1.1 
Adverse events ....................................................................................................... 48 
4.4.1.2 
Laboratory data ...................................................................................................... 50 
4.4.1.3 
ECG ........................................................................................................................ 53 
4.4.1.4 
Vital signs .............................................................................................................. 55 
 
 
5. 
INTERIM ANALYSES (NOT APPLICABLE) .................................................... 56 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 56 
7. 
REFERENCES (NOT APPLICABLE) ................................................................. 56 
8. 
APPENDIX ............................................................................................................ 57 
 
LIST OF TABLES 
Table 1 
Major protocol deviations and population classification .......................... 19 
Table 2 
Laboratory safety variables ...................................................................... 35 
Table 3 
Expanded normal ranges and notable abnormalities for laboratory 
parameters ................................................................................................. 51 
Table 4  
PCS ECG criteria: QTcF exceeding ICH boundaries ............................... 54 
Table 5 
PCS ECG criteria: Heart Rate and QRS interval ...................................... 54 
Table 6 
PCS vital sign criteria ............................................................................... 55 
 
LIST OF FIGURES 
Figure 1 
Study flow chart ....................................................................................... 16 
 
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Statistical Analysis Plan  
Drug Substance  
Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
Page 8 of 57 
 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase, also named SGPT 
AST 
Aspartate aminotransferase, also named SGOT 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the plasma concentration-time curve 
AUC(0-24h) 
Area under the plasma concentration-time curve from time zero to 24 
hours post-dose 
AUC0-t/th 
Area under curve from time zero to specified time t hours normalized 
by t hours 
AUClast 
Area under the plasma concentration-time curve from time zero to 
time of last quantifiable concentration 
BCSS 
Breathlessness, Cough, Sputum Score 
BDR 
Blind data review 
BLQ 
Below the limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
Cavg 
Average plasma concentration during a dosing interval 
Cmax 
Maximum plasma concentration 
COPD 
Chronic obstructive pulmonary disease 
CV% 
Coefficient of variation 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
 
 
ENR 
Expanded normal range 
FAS 
Full analysis set 
FEV1 
Forced expiratory volume in 1 second 
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Statistical Analysis Plan  
Drug Substance  
Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
Page 9 of 57 
 
Abbreviation or 
special term 
Explanation 
%Fluc 
Fluctuation index 
FVC 
Forced vital capacity 
gCV(%) 
Geometric coefficient of variation 
GGT 
Gamma glutamyl transferase 
gmean 
Geometric mean 
gSD 
Geometric standard deviation 
ICF 
Informed consent form 
ICS 
Inhaled Corticosteroids 
IP 
Investigational product 
LABA 
Long-Acting Beta2-Agonists 
LAMA 
Long-Acting Muscarinic Antagonist 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
max 
Maximum value 
min 
Minimum value 
MRAUC(0-24) 
Metabolite to parent ratio for AUC(0-24) 
MRAUClast 
Metabolite to parent ratio for AUClast 
MRCmax 
Metabolite to parent ratio for Cmax 
N 
Total number of subjects 
n 
Total number of values 
NA 
Not applicable 
NC 
Not calculated 
NQ 
Not quantifiable 
NR 
Not reported 
NS 
No sample 


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Drug Substance  
Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
Page 10 of 57 
 
Abbreviation or 
special term 
Explanation 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetic  
PKS 
Pharmacokinetic analysis set 
PP 
Per protocol analysis set 
PR interval 
Duration in milliseconds from the beginning of wave P to onset of 
ventricular depolarization (Q and R) 
PT 
Preferred term 
QRS interval 
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 
QTcF interval 
QT interval corrected, Fridericia formulae 
Rac(AUC(0-24)) 
Accumulation ratio for AUC(0-24)  
Rac(Cmax) 
Accumulation ratio for Cmax 
REML 
Restricted maximum likelihood 
RR interval 
Duration in milliseconds between two R peaks of two consecutive 
QRS complexes 
SAE 
Serious adverse event 
SAMA 
Short-Acting Muscarinic Antagonist 
SD 
Standard deviation 
SE 
Standard error 
SGOT 
Serum glutamic oxalacetic transaminase, also named AST 
SGPT 
Serum glutamic pyruvic transaminase, also named ALT 
SI 
International system of units 
SOC 
System organ class 
SS 
Safety set 
TEAE 
Treatment-emergent adverse event 
tlast 
Time to reach last quantifiable plasma concentration 
tmax 
Time to reach maximum plasma concentration 
ULN 
Upper limit of normal 
WHO 
World Health Organization 


Statistical Analysis Plan  
Drug Substance  
Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
Page 11 of 57 
 
AMENDMENT HISTORY 
Date 
Brief description of change 
25 Jan 2019 
Text updated as per Protocol Amendment 4 
 
Values for the CompEx algorithm corrected  
 
 


Statistical Analysis Plan  
Drug Substance  
Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
Page 12 of 57 
 
1. 
STUDY DETAILS 
1.1 
Study objectives 
1.1.1 
Primary and secondary objective 
Primary objective: 
Endpoints: 
To evaluate the efficacy of inhaled 
AZD8871 600 μg in patients with 
moderate to severe COPD 
Primary 
• Change from baseline in Trough FEV1 on Day 
15. 
Secondary 
• FEV1 AUC(0-4)/4h (area under the curve for the 
change in FEV1 from baseline to 4h, normalised 
by the time window) at Day 1, Day 8, and Day 
14. 
• FEV1 AUC(0-8)/8h, AUC(0-12)/12h, and AUC(0-24)/24h 
at Day 1 and Day 14. 
• Change from baseline in Trough FEV1 on Day 
2, and Day 8. 
• Change from baseline in Peak FEV1 on Day 1, 
Day 8 and Day 14. 
• Change from baseline in Trough FEV1 over 
treatment duration. 
• Change from baseline in Peak FEV1 over 
treatment duration. 
• Change from baseline in Total Score of 
Breathlessness, Cough Sputum Scale (BCSS) 
questionnaire and cough, breathlessness and 
sputum individual domain scores from Day 1 to 
Day 8, from Day 9 to Day 14 and during the 
whole treatment duration. 
• Change from baseline in CAT from Day 1 to 
Day 8, from Day 9 to Day 14 and during the 
whole treatment duration. 
• Rescue medication use from Day 1 to Day 8 and 
from Day 9 to Day 14. 
 
 


Statistical Analysis Plan  
Drug Substance  
Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
Page 13 of 57 
 
Secondary objective: 
Endpoints: 
To investigate the PK of AZD8871 
600 μg and its primary metabolite 
after multiple dose administration of 
inhaled AZD8871 in patients with 
moderate to severe COPD 
On serial PK sampling days, the following PK 
parameters will be calculated for AZD8871 and its 
primary metabolite LAS191861 when applicable: 
• Day 1: Maximum plasma concentration (Cmax), 
time to reach maximum plasma concentration 
(tmax), time to reach last quantifiable plasma 
concentration (tlast), area under the plasma 
concentration-curve from time 0 to the time of 
last quantifiable concentration (AUClast), area 
under the plasma concentration-curve from time 
0 to 24 hours post-dose AUC(0-24). 
• Day 14: Cmax, tmax, tlast, AUClast, AUC(0-24), 
average plasma concentration during a dosing 
interval (Cavg,), fluctuation index during a 
dosing interval (%Fluc), accumulation ratio for 
Cmax [Rac(Cmax)] and accumulation ratio for 
AUC(0-24) [Rac(AUC(0-24))]. 
Additional parameters may be determined where 
appropriate (e.g. metabolite to parent ratios). 
 
1.1.2 
Safety objectives 
Safety objectives: 
Endpoints: 
To evaluate the safety and tolerability of 
inhaled AZD8871 600 μg in patients with 
moderate to severe COPD 
• Adverse events (AEs)/Serious Adverse 
Events (SAEs). 
• Vital signs. 
• Electrocardiogram (ECG). 
• Clinical laboratory assessments. 
 
1.1.3 
Exploratory objectives 
Exploratory objectives: 
Endpoints: 
To evaluate patient’s response to inhaled 
AZD8871 600 μg in patients with 
moderate to severe COPD 
• COPD exacerbations. 
• Cough VAS. 
• Cough monitoring. 
• 
 
 
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Statistical Analysis Plan  
Drug Substance  
Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
Page 14 of 57 
 
1.2 
Study design 
This is a randomised, placebo-controlled, double-blind, 3-way complete crossover William’s 
design, international, multi-centre Phase IIa multiple dose study of 1 dose level of AZD8871, 
an active comparator (Anoro® Ellipta®) and placebo using a DPI device once daily, for 
2 weeks, in patients with moderate to severe COPD. This multi-centre study will be conducted 
at approximately 5 sites in Germany and United Kingdom (UK). It is planned that 
approximately 72 men and non-childbearing female aged 40 to 85 years (both inclusive) with 
moderate to severe COPD will be randomised in a 1:1:1:1:1:1 ratio to 1 of 6 treatment 
sequences. A subset of 36 patients, who will have specifically consented for pharmacokinetics 
(PK), will also undergo PK assessments. The study includes 12 visits and the entire study 
period is scheduled to take from a minimum of 6.5 months (182 days) to a maximum of 
7.5 months (217 days) for each individual patient. The aim is to ensure at least 54 patients 
complete the study. 
Screening period: This will last up to 28 days and consists of a Screening Visit (Visit 1 and 
Visit 2) and a run-in period.  
Patients will be requested to stop their usual COPD therapy after signing the ICF at Visit 1 
and will be maintained on a mono-component ICS therapy, if required. Patients that were 
taking any LAMA and/or LABA will be maintained with ipratropium (20 µg × 2 puffs 4 times 
per day) between Visit 1 and Visit 2.  In addition, salbutamol 100 µg will be provided as 
rescue medication during the study as needed (rescue medication has to be discontinued 
6 hours before any pulmonary function test).  The study will consist of a Screening period, 3 
treatment periods (each separated by a wash-out period), and a Follow-up Visit.  
Visit 1 and Visit 2 could be performed on the same day if no wash-out of prior medication is 
required and the patient visits the site in fasting condition. In case any wash-out of prior 
medication is required, then Visit 2 will be performed after the wash-out is complete. All the 
screening assessments can be performed at Visit 1 or Visit 2, based on the site’s preference, 
except for the following: 
• ICF: This must be completed at Visit 1 before any study-specific assessments are 
performed 
• Reversibility test with salbutamol and spirometry: This must be performed at Visit 2 
due to wash-out requirements. 
Only patients who fulfil FEV1 predicted values (FEV1 ≥40% and <80% from predicted normal 
value and FEV1/forced vital capacity (FVC) ratio <70%) postsalbutamol at Visit 2, will be 
started on the run-in period to assess clinical stability. 
If the FEV1 predicted values is not met, pulmonary function tests may be repeated at the latest, 
up to Day-14. 


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Drug Substance  
Study Code D6640C00006 
Version Final 2.0 
Date 08 February 2019 
Page 15 of 57 
 
The duration of run-in period will be between a minimum of 14 and a maximum of 28 days 
(from Visit 2 to Visit 3). During the run-in period, all patients will receive ipratropium 20 µg 
x 2 puffs 4 times per day (must be discontinued 8 hours before any pulmonary function test). 
A paper diary will be used to collect AEs and concomitant medications during run-in and 
wash-out periods. 
 
Treatment periods: After the screening period, patients must fulfil all inclusion criteria and 
no exclusion criteria prior to being randomised at Visit 3. Eligibility results will be used from 
the Screening period for any assessments that cannot be completed within Visit 3 (eg, 
laboratory assessments). 
 
The duration of each treatment period will be 14 days. During the treatment periods, patients 
will receive all 3 possible treatments, with every patient receiving placebo in one of the 
periods in addition to their ICS mono-component therapy, if any. In each period, patients will 
receive two devices to ensure the double blindness of the study. Patients will receive one of 
the 3 following possible treatments in any given period, in a randomised manner: 
 
• 
AZD8871 600 µg once daily 
• 
Anoro® Ellipta® (55µg UMEC/ 22 µg VI) once daily 
• 
Placebo once daily 
Each of the 3 treatment periods will last for 14 days and will include 2 overnight stays at the 
study site and one ambulatory visit at the study site. 
Each 14-day treatment period (except the last one) will be followed by a wash-out period of 
42 to 49 days, during which patients will receive ipratropium 20 µg x 2 puffs 4 times per day 
(must be discontinued 8 hours before any pulmonary function test), in addition to their usual 
ICS therapy, if any.  
From treatment period 2 onwards, on Day 1 of a new treatment period, a FEV1 stability test 
will be performed pre-dose. FEV1 stability check will be based on the prebest- test review. At 
Visit 6 and 9 the mean of the predose- FEV1 (mean of the 2 measured values) should be 
within (±)20% or (±)200 mL compared to the predose- FEV1 (mean of the 2 measured values) 
of the first treatment period (Visit 3). If the FEV1 stability criterion is not met, an additional 
measurement could be taken within 30 min of the second predose- measurement, and the 
mean of the last 2 measurements will be considered for the FEV1 stability criterion. If the 
FEV1 stability criterion is still not met, the test can be rescheduled as soon as possible (up to a 
maximum of 3 times), and if the FEV1 stability criterion is not met after re-testing, the patient 
should be withdrawn. 
There will be a Follow-up Visit scheduled to take place 42 up to 49 days after last 
administration of the IP. 
 


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Drug Substance  
Study Code D6640C00006 
Version 4.0 
Date 08 February 2019 
Page 16 of 57 
 
Figure 1 
Study flow chart 
 
d=day; FU=follow-up; V=visit. 
During treatment periods 1 to 3, each patient will randomly receive one of the 3 possible treatments (AZD8871 600 µg, Anoro® Ellipta® or placebo). 


Statistical Analysis Plan  
Drug Substance  
Study Code D6640C00006 
Version 4.0 
Date 08 February 2019 
Page 17 of 57 
 
 
1.3 
Number of patients 
The study was powered to demonstrate superiority of AZD8871 600 µg versus Anoro® 
Ellipta® for the primary efficacy endpoint. With a total of 54 patients, there is 90% power to 
detect a difference between AZD8871 and Anoro® Ellipta® treatments for the change from 
baseline to Trough FEV1 at Day 15 equal to 100 mL, assuming a SD of 220 mL, 2-sided 5% 
significance level and a normal distribution. Assuming an approximate 25% dropout, the total 
sample size required is 72 (multiple of 6 sequences). From previous studies, the screening 
failure rate is estimated to be approximately 50%; therefore approximately 145 screened 
patients will be required to achieve the goal of approximately 72 randomised patients. 
 
No adjustment of the Type I error for multiple comparisons will be made in the study due to the 
exploratory nature of the study.  
2. 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
2.1.1 
Full analysis set 
The Full Analysis Set (FAS) is defined as all patients randomised and receiving IP, 
irrespective of their protocol adherence and continued participation in the study. Patients will 
be assigned according to their randomised treatment, irrespective of whether or not they have 
prematurely discontinued. Patients who withdraw consent to participate in the study are 
included up to the date of their study termination. All efficacy analyses are based on the FAS 
and analysed according to the intent to treat principle. 
2.1.2 
Safety analysis set 
The Safety Analysis Set (SS) consists of all randomised patients who receive at least one dose 
of IP. For summaries based on the SS, patients are included for a treatment only if they 
received at least one dose of that treatment (e.g. a patient who discontinues prior to taking the 
study treatment for period 2 will not be included in the safety set for that treatment). 
The SS will be used for all summaries of safety data, and patients will be analysed according 
to the randomised treatment assignment for a given study period. Any important deviations 
from the randomised treatment assignment and any patients who received IP without being 
randomised for a given study period will be listed and considered when interpreting the safety 
data. Relevant safety summaries presented by actual treatment received will be considered if 
there are a considerable number of patients receiving another treatment than the one they were 
randomised to. 
2.1.3 
Pharmacokinetic analysis set 
The Pharmacokinetic (PK) Analysis Set (PKS) will consist of all patients participaiting in the 
subset of the PK patients, who received at least 1 dose of AZD8871 and have at least 1 of the 


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parameters Cmax, AUC(0-24) or AUClast evaluable for AZD8871 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). 
 
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when patients are assigned to the PK analysis sets. The 
exclusion of any patients or time-points from the calculation of the PK parameters and/or from 
the PK summary statistics will be agreed at the blinded data review meeting and it will be 
documented by the PK Scientist including the reason(s) for exclusion. The available 
concentration data and PK parameter data for any patients excluded from the PK analysis set 
for a given study period will be listed only. Concentration data for patients excluded from the 
PK analysis set will be presented in the individual figures of concentration versus time plots. 
2.1.4 
Per-Protocol Analysis Set 
The Per-Protocol Analysis Set (P-PS) is defined as a subset of FAS population constituted by 
those patients who did not present important deviations of the protocol that may affect 
efficacy (eg, met all inclusion/exclusion criteria liable to affect the efficacy assessment).  
2.2 
Violations and deviations 
Only important protocol deviations that may greatly impact the completeness, accuracy, 
and/or reliability of the study data or that may significantly affect a patient’s rights, efficacy, 
safety, or well-being will be summarised and listed. 
Important protocol deviations include: 
• Key eligibility criteria not fulfilled but patient randomised  
• Disallowed concomitant medication taken during the study 
• Developed discontinuation criteria but not withdrawn from study or discontinued 
investigational product, as appropriate  
• Received incorrect study drug 
A sensitivity analysis based on the P-PS will be conducted for internal validity purposes, 
whereby patients with important deviations from protocol deemed to affect efficacy will be 
excluded from the analysis.  
Table 1 shows the protocol deviations which will lead to exclusion from P-PS, PKS, SS, or 
FAS. During the blind data review (BDR) the final list of the important protocol deviations 
affecting efficacy will be finalyzed and documented prior to unblinding of the study data. 
 
 


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Table 1 
Major protocol deviations and population classification 
 
 
Excluded from analysis set 
Item 
# 
Event description 
P-PS  
SS 
PKS 
FAS 
1. Provision of informed consent not performed before any study specific procedures. 
Yes 
No 
No 
No 
2. ICF source document not available at site, or any issue with the ICF document. 
Yes 
No 
No 
No 
3. Subject must be able to read, speak and understand local language. 
Yes 
No 
No 
No 
4. Female Patient has childbearing potential 
Yes 
No 
No 
No 
5. Male patient did not prevent pregnancy and drug exposure of a partner. 
Yes 
No 
No 
No 
6. Patient has alpha-1 antitrypsin deficiency as the cause of COPD (laboratory results 
will be used in combination with smoking and medical history). 
Yes 
No 
No 
No 
7. Patient is less than 40 or more than 85 years of age 
Yes 
No 
No 
No 
8. Patient has no established clinical history of moderate to severe COPD for more than 
1 year at Screening 
Yes 
No 
No 
No 
9. Patient is not current or former smoker with a history of ≥10 pack-years of cigarette 
smoking and/or not smoking other types of tobacco (including e-cigarettes). 
Yes 
No 
No 
No 
10 Patient has post-bronchodilator FEV1/FVC ratio is >=70% based on the value 
reached after inhalation of salbutamol (400 µg) at Visit 2 
Yes 
No 
No 
No 
11 Patient with post-bronchodilator FEV1 <40% or > =80% predicted normal value at 
Visit 2.  
Yes 
No 
No 
No 
12 Patient with body mass index (BMI) >=40 kg/m2 at the time of Screening 
Yes 
No 
No 
No 
13 Patient has a clinically significant disease, other than COPD, that may impact study 
outcome, as determined by medical history, physical examination, laboratory testing, 
and 12-lead ECG findings, at Screening. 
Yes 
No 
No 
No 
14 Patient has other active pulmonary disease such as predominant asthma, active 
tuberculosis, lung cancer, bronchiectasis, sarcoidosis, idiopathic interstitial 
pulmonary fibrosis, primary pulmonary hypertension, or uncontrolled sleep apnoea.  
Yes 
No 
No 
No 
15 Patient has undergone lung volume reduction surgery, lung transplantation, 
lobectomy, or bronchoscopic lung volume reduction within 1 year of Screening. 
Yes 
No 
No 
No 
16 Patient is using nocturnal positive pressure 
Yes 
No 
No 
No 
17 Patient has been hospitalised due to poorly controlled COPD within 3 months of 
Screening. 
Yes 
No 
No 
No 
18 Patient has acute worsening of COPD that required antibiotics or corticosteroids in 
the 6-week interval prior to Screening (Visit 1), or during the Screening Period 
(between Visits 1 and 2). 
Yes 
No 
No 
No 
19 Patient has lower respiratory tract infections that required antibiotics within 6 weeks 
prior to Screening. 
Yes 
No 
No 
No 
20 Patient has changed their smoking status (ie, restart or stop smoking) or initiation of a 
smoking cessation program within 6 weeks of Screening. 
Yes 
No 
No 
No 
21 Subject with significant cardiovascular disease that may be vulnerable to 
cardiovascular instability. 
Yes 
No 
No 
No 
22 Patient with QT interval corrected using Fridericia's formula (QTcF) value at 
Screening >450 ms for male and >470 ms for female or an ECG that is not suitable 
for QT measurements (eg, poorly defined termination of the T wave). 
Yes 
No 
No 
No 
23 Patient with heart rate <50 or >100 bpm at Screening. 
Yes 
No 
No 
No 
24 Patient has clinically significant uncontrolled hypertension as assessed by the 
investigator. 
Yes 
No 
No 
No 
25 Patient with seizures or history of seizures requiring anticonvulsants within 
12 months prior to Screening. 
Yes 
No 
No 
No 
26 Patient is taking selective serotonin reuptake inhibitors or serotonin-norepinephrine 
reuptake inhibitors whose dose has not been stable for at least 4 weeks prior to 
Screening, or exceeds the maximum recommended dose. 
Yes 
No 
No 
No 


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Excluded from analysis set 
Item 
# 
Event description 
P-PS  
SS 
PKS 
FAS 
27 Patient with symptomatic bladder neck obstruction, acute urinary retention or 
symptomatic non-stable prostate hypertrophy. 
Yes 
No 
No 
No 
28 Patient has a serum potassium value <3.5 mmol/L at Screening and on repeat testing, 
uncontrolled diabetes and any clinically relevant lab abnormality. Note: however 
potassium replacement and rescreening is allowed once if serum potassium 
concentration was <3.5 mmol/L at Screening.  
Yes 
No 
No 
No 
29 History of malignancy of any organ system, treated or untreated within the past 
5 years, with the exception of localised basal cell carcinoma of the skin. 
Yes 
No 
No 
No 
30 Patient has known narrow-angle glaucoma. 
Yes 
No 
No 
No 
31 Patient has a history of hypersensitivity to β2-agonists, muscarinic anticholinergics or 
lactose/milk protein. Lactose intolerance is not an exclusion criterion.  
Yes 
No 
No 
No 
32 The patient has a history of drug of abuse within the past 2 years or consuming more 
than 14 (female patients) or 21 (male patients) units of alcohol a week, or shows 
positive for drugs of abuse and alcohol tests at Screening and/or prior to 
randomisation. 
Yes 
No 
No 
No 
33 Patient received a live attenuated vaccination within 30 days prior to Screening. 
Yes 
No 
No 
No 
34 Patient donated or lost >500 mL of blood and plasma within the previous 3 months 
prior to Screening 
Yes 
No 
No 
No 
35 Vulnerable patients (who has been placed in an institution due to a regulatory or 
court order) 
Yes 
No 
No 
No 
36 Patient is unlikely to co-operate with the requirements of the study, instructions of 
the Principal Investigator (PI), or have e-dairy completion rate of <70% during the 
run-in period.. 
Yes 
No 
No 
No 
37 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). 
Yes 
No 
No 
No 
38 Patient previously enrolled in the present study 
Yes 
Yes 
Yes 
Yes 
39 Patient has participate in the acute phase of a pulmonary rehabilitation program 
within 4 weeks prior to Screening or who will enter the acute phase of a pulmonary 
rehabilitation program during the study. 
Yes 
No 
Yes 
Yes 
40 Patient non-compliance with study procedures, unable to change current COPD 
therapy as required by the protocol and not willing to use ipratropium following the 
approved dosge and regimen – as judged by the investigator. 
Yes 
No 
Yes 
Yes 
41 Patient is unwilling to remain at the study centre as required per protocol to complete 
all visit assessments. 
Yes+++ 
No 
 Yes+++ 
No 
42 Participation in another clinical study with investigational drug or device within the 
last 30 days or 5 half-lives (whichever is longer) prior to Screening. 
Yes+++ 
No 
 Yes+++ 
No 
43 Patient with known human immunodeficiency virus (HIV) infection or chronic 
hepatitis B or C infection. 
Yes 
No 
No 
No 
44 Patient did not fulfill fasting requirements on Day 1, 8, and 14 before IP 
administration and following dose administration. 
Yes++ 
No 
No 
No 
45 Salbutamol not withheld at least 6 hours prior to any spirometry test for the study. 
Yes 
No 
No 
No 
46 Ipratropium not withheld at least 8 hours before visits 3, 6, and 9 and during all 
treatment periods. 
Yes 
No 
No 
No 
47 Patient could not abstain from list in protocol section 5.3 
Yes 
No 
No 
No 
48 Patient who had 2 or more exacerbations of COPD within the last year prior to 
Screening 
Yes 
No 
No 
No 
49 Patient unable to abstain from protocol-defined prohibited medications during the 
study, in the opinion of the investigator. 
Yes++ 
No 
Yes ++ 
No 
50 Patient is screening failure, but received study drug. 
Yes 
Yes 
Yes 
Yes 
51 Incorrect study medication received. 
Yes++ 
No 
Yes++ 
No 


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Excluded from analysis set 
Item 
# 
Event description 
P-PS  
SS 
PKS 
FAS 
52 Incorrect dose of study medication received. 
Yes++ 
No 
Yes++ 
No 
53 Patient did not take any IP  
Yes++ 
Yes 
Yes++ 
Yes++ 
54 IP not taken at the study site at 9:00 AM±2 hours on Day 1 (Visits 3, 6 and 9). 
Yes++ 
No 
Yes+++ 
No 
55 IP not taken within ±1 hours of dosing time of Day 1 and between 7 AM and 11AM 
on subsequent days of each treatment period. 
Yes++ 
No 
Yes+++ 
No 
56 Patient has taken any of the restricted medications on a different regim than the 
described in the protocol (Table 5, section 6.5). 
 
Yes++ 
No 
Yes+++ 
No 
57 Procedure not performed (missing PK samples to prevent calculation of PK 
parameters). 
 
No 
No 
Yes++ 
No 
58 Study assessments (For example cough monitoring, spirometry, 
 i-Stat, 12 Lead 
ECG and/or vital signs) are not performed at the scheduled timepoints. 
No 
No 
No 
No 
59 Missing baseline data for the spirometry (FEV1 main variable) 
Yes++ 
No 
No 
No 
60 FEV1 and FVC measurements performed outside tolerance window 
No 
No 
No 
No 
61 Fulfilling withdrawal criteria during the study but not withdrawn. 
 
Yes 
No 
No 
No 
62 Fatal or life-threatening AE was not reported to the appropriate AstraZeneca 
representatives within 1 calendar day of initial receipt. 
No 
No 
No 
No 
63 Non-fatal, and non-life-threatening SAE was not reported to the appropriate 
AstraZeneca representatives within 5 calendar days of initial receipt. 
No 
No 
No 
No 
64 Date of Screening Visit 1 is after date of Screening Visit 2. 
No 
No 
No 
No 
65 Visit date is after the Completed date. 
No 
No 
No 
No 
66 Any of the study visits not performed within the allowed time as per protocol. 
No 
No 
No 
No 
67 Other protocol deviations 
Yes+++ 
No 
Yes+++ 
No 
++Excluded from the specific timepoint or period only. +++ To be confirmed at the DRM; timepoint specific, global P-PS/PKS exclusion or 
no exclusion. 
3. 
PRIMARY AND SECONDARY VARIABLES 
3.1 
General definitions  
Baseline for FEV1 will be defined as the mean of the 2 measured values for the corresponding 
variable (2 measurements 45 min apart, at -1 hour and -15 min), prior to the morning IP 
administration on Day 1 of each treatment period. If both are missing, the Visit 2 pre-
bronchodilator value will be used instead. If one of the values is missing, the available value 
will be used as baseline.  
All baseline values for efficacy analysis will be the pre-dose values of each treatment period 
except for the Total BCSS questionnaire score, where the last 14 days of the run-in period 
baseline will be used for all treatments in each sequence. 
CCI


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The baseline for daily rescue medication use will be the daily average of puffs recorded in the 
e-Diary during the last 14 days of the run-in period; this baseline will be used as baseline for 
all treatment periods.  
For vital signs, laboratory variables (including i-STAT)  and 12-lead ECG variables, baseline 
is defined as the values obtained prior to the morning IP administration on Day 1 of Visit 3. 
 
The cough VAS measurement done at pre-dose on Day 1 of each treatment period will be 
used as a baseline. For cough monitoring, the assessment done starting 24 hours prior to 
dosing on Day 1 will be regarded as a baseline of each treatment period.  
 
For COPD assessments (CAT), baseline is defined as the value obtained at Screening (Visit 1 
or Visit 2). 
 
3.1.1 
Handling of missing or partial dates 
For date of COPD diagnosis, partial dates will be imputed as follows. 
• For dates with missing day and month (year is present), January 1 will be assigned to 
the missing fields. 
• For dates with missing day only (month and year are present), the first day of the 
month will be assigned to the missing day. 
For date of most recent COPD exacerbation, partial dates will be imputed as follows.  
• For dates with missing day and month (year is present), December 31 will be assigned 
to the missing fields provided it does not result in a date post screening visit, in which 
case last day of month preceding month of screening visit will be used. 
• For dates with missing day only (month and year are present), the last day of the 
month will be assigned to the missing day. 
3.1.1.1 
Imputation for concomitant medication start and stop dates 
For prior or concomitant medications, including relief medications, incomplete (ie, partial or 
completely missing) start dates and/or stop dates will be imputed.  
When the start date and the stop date are both incomplete for a patient, impute the start date 
first.  
Incomplete start date  
The following rules will be applied to impute the missing numerical fields. In addition, if the 
stop date is complete and the imputed start date is after the stop date, then the start date will be 
imputed using the stop date. If the stop date is present and implies that the medication is 
concomitant (ie, stop date is on or after the date of first dose of IP in the study), but the start 
date is completely missing, then the start date of the medication will be imputed with the date 
of first dose of IP.  


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For start dates with missing day and month (year is present): 
• If the year of the incomplete start date is the same as the year of the date of the first 
dose of IP in the study, then the day and month of the date of the first dose will be 
assigned to the missing fields.  
• If the year of the incomplete start date is prior to the year of the date of the first dose of 
IP in the study, then December 31 will be assigned to the missing fields.  
• If the year of the incomplete start date is after the year of the date of the first dose of IP 
in the study, then January 1 will be assigned to the missing fields.  
For start dates with missing month only (day and year are present): 
• The day will be treated as missing and both month and day will be replaced according 
to the above procedure.  
For start dates with missing day only (month and year are present): 
• If the month and year of the incomplete start date are the same as the month and year 
of the date of the first dose of IP, then the day of the date of the first dose of IP will be 
assigned to the missing day; 
• If either the year of the incomplete start date is before the year of the date of the first 
dose of IP or if both years are the same but the month is before the month of the date 
of the first dose of IP, then the last day of the month will be assigned to the missing 
day;  
• If either the year of the incomplete start date is after the year of the date of the first 
dose of IP or if both years are the same but the month is after the month of the date of 
the first dose of IP, then the first day of the month will be assigned to the missing day.  
Incomplete stop date  
The following rules will be applied to impute the missing numerical fields. If the stop date is 
completely missing, replace it with the last dose date. If the imputed stop date is before the 
start date (imputed or non-imputed start date), then the imputed stop date will be equal to the 
start date.  
For stop dates with missing day and month (year is present): 
• If the year of the incomplete stop date is the same as the year of the date of the last 
dose of IP, then the day and month of the date of the last dose will be assigned to the 
missing fields.  
• If the year of the incomplete stop date is prior to the year of the date of the last dose of 
IP, then December 31 will be assigned to the missing fields.  
• If the year of the incomplete stop date is after the year of the date of the last dose of IP, 
then January 1 will be assigned to the missing fields.  


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For stop dates with missing month only (day and year are present): 
• The day will be treated as missing and both month and day will be replaced according 
to the above procedure.  
For stop dates with missing day only (month and year are present): 
• If the month and year of the incomplete stop date are the same as the month and year 
of the date of the last dose of IP, then the day of the date of the last dose will be 
assigned to the missing day.  
• If either the year of the incomplete stop date is before the year of the date of the last 
dose of IP or if both years are the same but the month is before the month of the date 
of the last dose of IP, then the last day of the month will be assigned to the missing 
day.  
• If either the year of the incomplete stop date is after the year of the date of the last dose 
of IP or if both years are the same but the month is after the month of the date of the 
last dose of IP, then the first day of the month will be assigned to the missing day.  
Incomplete time in start or stop date  
Note that when dates are recorded using time (from 00:00 until 23:59) and if time is missing 
in a start date record, time = 00:01 will be assigned; if time is missing in a stop date record, 
then time = 23:59 will be assigned. 
3.1.1.2 
Imputation for adverse event start dates 
The following imputation rules apply to cases in which the start date is incomplete (ie, partial 
or completely missing) for adverse events. 
In addition to the following rules, if the stop date is complete and the imputed start date is 
after the stop date, then the start date will be imputed using the stop date. If the stop date is 
present and implies that the adverse event (AE) is treatment-emergent (ie, stop date is on or 
after the date of first dose of IP in the study), but the start date is completely missing, then the 
start date will be imputed with the date of first dose of IP. If the stop date is present and does 
not imply that the AE is treatment-emergent (ie, stop date is prior to the date of first dose of IP 
in the study), but the start date is completely missing, then the start date will be imputed with 
the stop date.  
For start dates with missing day and month (year is present): 
• If the year of the incomplete start date is the same as the year of the date of the first 
dose of IP, then the day and month of the date of the first dose of IP will be assigned to 
the missing fields.  
• If the year of the incomplete start date is prior to the year of the date of the first dose of 
IP, then December 31 will be assigned to the missing fields.  


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• If the year of the incomplete start date is after the year of the date of the first dose of 
IP, then January 1 will be assigned to the missing fields.  
For start dates with missing month only (day and year are present): 
• The day will be treated as missing and both month and day will be replaced according 
to the above procedure.  
For start dates with missing day only (month and year are present): 
• If the month and year of the incomplete start date are the same as the year and month 
of the date of the first dose of IP, then the date of the first dose of IP will be assigned 
to the missing day.  
• If either the year of the incomplete start date is before the year of the date of the first 
dose of IP or if both years are the same but the month is before the month of the date 
of the first dose of IP, then the last day of the month will be assigned to the missing 
day.  
• If either the year of the incomplete start date is after the year of the date of the first 
dose of IP or if both years are the same but the month is after the month of the date of 
the first dose of IP, then the first day of the month will be assigned to the missing day.  
For incomplete time in start date  
• Note that when dates are recorded using time (from 00:00 until 23:59) and if time is 
missing in a start date record, time = 00:01 will be assigned; if time is missing in a stop 
date record, then time = 23:59 will be assigned. 
3.1.1.3 
Imputation for adverse event stop dates 
• The following rules will be applied to partial stop dates: 
• If only the month and year are specified, then the last day of the month will be used. 
• If only the year is specified, then December 31 of the known year will be used. 
• If the stop date is completely unknown, the stop date will not be imputed. 
Missing or partially missing dates and/or times will be imputed as for the calculation of 
duration of each AE.  
3.1.2 
Repeated and unscheduled visits 
All repeated and unscheduled measurements will be presented in the listings. Repeated and 
unscheduled measurements will not be used for statistical analysis or summary tables, unless 
the repeated measurement was performed due to unreliable values/technical reasons, or the 
repeated measurement occurred prior to IP administration and is defined as the 'baseline'. The 
following general rules will apply to all repeated and unscheduled measurements (the below 
section describes a different approach for spirometry variables): 


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• For repeated measurements obtained prior to the first dose of IP in each period, the latest 
reliable value (which may be scheduled or unscheduled) will be used in the calculation of 
descriptive statistics 
• For repeated measurements obtained at the designated Baseline visit, the latest reliable 
value (which may be scheduled or unscheduled) will be defined as the Baseline in each 
period. Repeated measurements designated Baseline will be used in descriptive statistics 
rather than the planned measurement they replace 
• For repeated measurements obtained at any time point after the first dose of IP, the first 
reliable value of any repeated measurements will be used in the calculation of changes 
from Baseline and for the descriptive statistics.  
3.1.2.1 
Spirometry variables 
For repeated spirometry measurements that are taken on the same day and time as a scheduled 
visit and time point, the latest nonmissing- result will be used for that visit and time point. 
Spirometry data from unscheduled and End of Study visits for patients who discontinue from 
the study will not be included in the analyses, but all data (from scheduled and unscheduled 
visits) will be listed. 
3.2 
Assessment of study population 
3.2.1 
Demographic and baseline characteristic variables 
Demographic characteristics (including country, age, sex, race and ethnicity), baseline 
characteristics (including height, weight, body mass index [BMI]) and baseline disease 
characteristics (including COPD history, smoking history, time from diagnosis of COPD to 
randomisation, time from most recent exacerbation to randomisation, number of exacerbations 
in previous 12 months and FEV1, FVC variables defined in 4.2.1.2) will be assessed.  
3.2.2 
Surgical and medical history 
Surgical and medical histories will be coded using the latest version of the Medical Dictionary 
for Regulatory Activities (MedDRA, 21.0 or later).  
3.2.3 
Prior and concomitant medications 
All medications will be classified into anatomical therapeutic chemical (ATC) drug classes 
using the latest version of the World Health Organization (WHO DD+HD March 2017 or 
later) Drug Dictionary. 
Any medications taken by the patient between 15 days prior to signing the ICF and prior to the 
first dose date of IP will be considered prior medication. The medications taken by the patient 
more than 15 days before signing the ICF will be not considered prior medication but will be 
listed in the general listing of all medications for the patient.  


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Any medication taken by the patient at any time between the date of the first dose (including 
the date of the first dose) of IP up to 24h after the last IP administration of each treatment 
period will be considered concomitant medication.  
A medication is considered concomitant for a treatment if the start date of the medication is on 
or after the date of first dose in that treatment period and prior to or at 24h post last IP intake 
of the treatment period, or the start date is prior to the date of first dose in that treatment 
period and a stop date on or after the date of first dose in that treatment period (the medication 
is ongoing). If a medication is taken over multiple periods of treatment, it will be considered 
concomitant for all treatments taken in the different periods. 
A medication is considered to be taken during wash-out periods if it is taken after 24h of IP 
intake on Day 14 and before the following treatment period. 
Medications that start after one day post the date of last dose of IP during the overall study 
will not be considered concomitant.  
For the purpose of inclusion in prior or concomitant medication summaries, incomplete 
medication start and stop dates will be imputed as detailed in Section 3.1.1.1. 
Medications that start during the follow-up period (ie, that start after one day post the date of 
the last dose of IP during the study) will only be displayed in listings.  
3.2.4 
Duration of exposure 
Exposure (in days) will be calculated as the treatment duration, from the first dose to the last 
dose (inclusive), separately for each treatment:  
Treatment duration 
= (last dose date in treatment period
− first dose date in treatment period) +  1 
3.2.5 
Treatment compliance 
Treatment compliance will be calculated separately for each treatment received by a patient. 
For all treatments, treatment compliance will be calculated as follows, using the drug 
accountability data  
Treatment compliance (%) = 
Number of puffs taken during treatment period
Number of puffs expected during treatment period × 100. 
3.3 
Efficacy variables 
3.3.1 
Pulmonary function variables 
Pulmonary function will be assessed using spirometry performed as follows: 
• Pre-dose spirometry is performed before the morning daily dose at Day 1, Day 8, and 
Day 14 of each treatment period. Two sets of measurements will be performed during 


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the hour preceding the scheduled morning study drug administration, allowing 
approximately 45 min between them. 
• Trough FEV1 values are defined as the mean of the values obtained at 23 hours and 23 
hours 45 minutes after the morning IP administration on Day 1 and Day 14 (i.e. 
obtained on Day 2 and Day 15). On Day 8, TFEV1 value is defined as the mean of the 
FEV1 pre-dose values (-1 hour and -15 min).  
If one of the two measurements is missing, the non-missing measurement will be used 
as the trough value.  
 
• Definition above also applies to FVC measurements. 
 
• 4 hour serial spirometry is performed at Day 8 of each treatment period; spirometry 
will be performed post-dose at 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours. 
 
• 8 hour and 24 hour serial spirometry is performed at Day 1 and 14 of each treatment 
period; spirometry will be performed post-dose at 15 minutes, 30 minutes, 1 hour, 2 
hours, 4 hours, 8 hours, 12 hours, 23 hours and 23:45 hours. 
 
• The FEV1 peak value at a visit is defined as the highest value observed during the 
4 hour period immediately following the morning study drug administration at that 
visit (ie, the maximum value observed at 15 minutes, 30 minutes, 1 hour, 2 hours or 4 
hours post-dose). 
AUC is defined as the area under the curve.  
For t= 4, 8, 12 and 24 AUC is calculated from zero time to t hours (AUC0-t), using the 
trapezoidal method, divided by the corresponding duration (ie, 4, 8 and 24 hours, respectively) 
to give the AUC0-t/th values (where t is either 4, 8 or 24) in litres. Non-missing FEV1, at the 
following time points are required in order to calculate the normalised AUC0-4/4h: pre-dose; at 
least one value between 0 and 2 hours and the value at 4 hours post-dose. Similarly, 
nonmissing- FEV1 values at the following time points are required in order to calculate the 
normalised AUC0-8/8h: predose-; at least one value between 0 and 4 hours and the value at 8 
hours post-dose. For AUC0-24/24h , nonmissing- FEV1 values at the following time points are 
required in order to calculate the normalised AUC0-24/24h: predose-; at least one value between 
0 and 8 hours and at least one value post 8 hours post-dose; otherwise the normalised AUC0-t/th 
will be missing.  
Notice that in case that the 23:45 timepoint is missing and only the 23h timepoint is used, the 
AUC0-24 will still be normalized by 24 and AUC0-24/24h computed. The raw AUC will be used 
(rather than the logs), since the distribution of the FEV1 data is expected to approximate to a 
normal distribution. 


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3.3.1.1 
Primary outcome variable 
The primary variable to assess the primary objective is the change from baseline (pre-dose) in 
Trough FEV1 at Day 15 (ie, after 14 days of treatment). 
3.3.1.2 
Secondary FEV1 -related variables  
Secondary efficacy variables that will be assessed are the following: 
• 
Change from baseline in Trough FEV1 on Day 2, and Day 8 
• 
Change from baseline in Peak FEV1 on Day 1, Day 8, and Day 14 
• 
Change from baseline in Trough FEV1 over treatment duration (Day 1 to Day 15) 
• 
Change from baseline in Peak FEV1 over treatment duration (Day 1 to Day 14) 
 
3.3.1.3 
Other FEV1 -related variables  
• 
Change from baseline in FEV1 AUC(0-4/4h)  (area under the curve for the change in 
FEV1 from baseline to 4h, normalised by the time window) on Day 1, Day 8, and Day 
14 
• 
FEV1 AUC(0-8/8h) on Day 1, and Day 14 
• 
FEV1 AUC(0-12/12h) on Day 1, and Day 14 
• 
FEV1 AUC(0-24/24h) on Day 1, and Day 14  
3.3.2 
Other efficacy variables  
3.3.2.1 
Total Breathlessness, Cough Sputum Scale (BCSS) score questionnaire and cough, 
breathlessness and sputum individual domain scores  
The daily change from baseline obtained after treatment in Total BCSS score and cough, 
breathlessness and sputum individual domain scores will be averaged  
• 
over Day 1 to Day 8 to construct the Day 8 endpoints  
• 
over Day 9 to Day 14 to construct the Day 14 endpoints  
• 
over Day 1 to Day 14 to construct the Day 14 endpoints for the analysis of the whole 
treatment 


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3.3.2.2 
COPDCompEx, Cough VAS and Cough Monitoring  
A composite endpoint for exacerbations (moderate or severe) in COPD (COPDCompEx) will 
be derived and analysed. COPDCompEx combines exacerbations with events defined from 
patient daily diaries. The definitions for the different types of events are as follows: 
• 
Exacerbations: episodes leading to one or more of the following; hospitalisation, 
emergency room visit, treatment with oral corticosteroids, or treatment with 
antibiotics. 
• 
Diary events: defined by threshold and slope criteria using the following diary 
variables: individual domains of the breathlessness, cough, and sputum scale and 
rescue medication use. 
• 
Dropouts: Dropouts due to lack of efficacy (if possible to judge) occurring during 
treatment periods. 
The following COPD and cough variables will be assessed: 
• 
Change from baseline in cough VAS on Day 8 and Day 15 
• 
Change from baseline in number of coughs as measured by cough monitoring 
on Day 14 
• 
Time to first COPDCompEx.  
3.3.2.3 
COPD Assessment Test (CAT) 
Change from baseline in CAT from Day 1 to Day 8, from Day 9 to Day 14 and during the 
whole treatment duration will be described. 
3.3.2.4 
Rescue medication use (Salbutamol) 
The daily change from baseline obtained after treatment in rescue medication will be averaged  
• 
over Day 1 to Day 8 to construct the Day 8 endpoint  
• 
over Day 9 to Day 14 to construct the Day 14 endpoint  
3.4 
Pharmacokinetic variables 
The PK analyses of the plasma concentration data for AZD8871 and its primary metabolite 
LAS191861 will be performed by the Covance Clinical Pharmacology Alliance (CPKA) on 
behalf of AstraZeneca. 
The actual sampling times will be used in the plasma PK parameter calculations.  


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PK parameters will be derived using non-compartmental methods with Phoenix® WinNonlin® 
Version 6.4. or higher. PK 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. If 2 or more consecutive BLQ concentrations are followed by quantifiable 
concentrations in the terminal portion of the concentration-curve, the profile will be deemed to 
have terminated and therefore these quantifiable values will be set to missing for the 
calculation of the PK parameters unless there is a scientific rationale not to do so; this will be 
documented in the PK analysis notes. If an entire concentration-time profile is BLQ, the 
profile is excluded from the PK analysis. 
Area under the plasma concentration-curve will be calculated using trapezoidal methods when 
concentrations are 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 an AUC parameter to be determined, with at least one of these concentrations 
following Cmax. 
When possible, the following PK parameters will be determined for AZD8871 and its primary 
metabolite, LAS191861 from plasma concentration-time data: 
Day 1: 
Cmax - Maximum observed plasma concentration, taken directly from the individual 
concentration-time curve 
tmax - Time to reach maximum observed plasma concentration, taken directly from the 
individual concentration-time curve 
AUClast - Area under the plasma concentration-curve from time zero to the time of last 
quantifiable concentration 
tlast - Time to reach last quantificable concentration  
AUC(0-24) - Area under the plasma concentration-curve from time zero to 24 hours post-dose 
For metabolite LAS191861 only: 
MRCmax - Metabolite to parent ratio for Cmax 
MRAUC(0-24) - Metabolite to parent ratio for AUC(0-24)  


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MRAUClast - Metabolite to parent ratio for AUClast 
Day 14: 
Cmax - Maximum observed plasma concentration, taken directly from the individual 
concentration-time curve  
tmax - Time to reach maximum observed plasma concentration, taken directly from the 
individual concentration-time curve  
AUClast - Area under the plasma concentration-curve from time zero to the time of last 
quantifiable concentration 
tlast - Time to reach last quantificable concentration 
AUC(0-24) - Area under the plasma concentration-curve from time zero to 24 hours post-dose 
Cavg - Average plasma concentration during a dosing interval, estimated as AUC(0-24)/24 
%Fluc - Fluctuation index during a dosing interval estimated as 100*(Cmax - Cmin)/Cavg (%), 
where Cmin is the minimum concentration at the end of the dosing interval 
Rac (Cmax) - Accumulation ratio for Cmax estimated as (Cmax on Day 14 / Cmax on Day 1) 
Rac (AUC0-24) - Accumulation ratio for AUC0-24 estimated as (AUC(0-24) on Day 14 / AUC(0-24) 
on Day 1) 
For metabolite LAS191861 only: 
MRCmax - Metabolite to parent ratio for Cmax 
MRAUC(0-24) - Metabolite to parent ratio for AUC(0-24) 
MRAUClast - Metabolite to parent ratio for AUClast 
3.5 
 Safety variables 
3.5.1 
Adverse events 
AEs: The number and percentage of patients who experienced 1 or more treatment-emergent 
adverse event (TEAE), and the number of TEAE occurrences will be tabulated by treatment 
group. An AE is considered TEAE if the event occurs after first dose of IMP up to 42 days 
after the administration of the last dose of IMP or was present prior to the date of the first dose 
of IP, but increased in intensity after IP administration. All events present before first IMP are 
considered non-TEAEs. 
Adverse events occurring before administration of IP (ie, not treatment-emergent) and the 
number of occurrences will be reported in the same way as TEAEs in a different Table.  


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A TEAE that occurs during a wash-out period will be associated to the last treatment taken. 
An AE that occurs more than 42 days after the last IP administration will not be counted as a 
TEAE.  
3.5.2 
 Serious adverse events 
A serious AE (SAE) is an AE occurring at any time during the study (ie, during run-in, 
treatment, wash-out or follow-up) that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
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 jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above 
Any SAE occurring before the first dose of IP, or more than 42 days after the last dose of IP, 
is considered non-TEAE , it will be included in the data listings but will not be included in the 
summary tables of SAEs. 
3.5.3 
COPD exacerbations 
A COPD exacerbation is defined as a change in the patient’s baseline dyspnoea, cough, and/or 
sputum (increase in volume or change in colour towards purulence) that lasts ≥3 days, is 
beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular 
medication. The severity of COPD exacerbations is classified as follows: 
• 
Mild: Exacerbations that do not require systemic steroids or antibiotics and do not 
result in hospitalisation or death. 
• 
Moderate: Exacerbations that require treatment with systemic steroids and/or 
antibiotics, and do not result in hospitalisation or death. 
• 
Severe: Exacerbations that result in hospitalisation or death. 
All COPD exacerbations will be captured using a COPD exacerbation eCRF and will not be 
reported as AEs unless considered an SAE 


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3.5.4 
Laboratory variables  
Laboratory parameters will be recorded at Visit 1, pre-dose at visits 3, 6, 9, and at 24h 
post-dose at visits 5, 8, 11, and at follow-up. Safety laboratory tests will be done after 8 hours 
of fasting. Serology parameters will be measured at Visit 1 only. 
The laboratory variables detailed in Table 2 will be recorded. In addition, urine pregnancy 
tests will be performed for women of childbearing potential. Additional safety samples may 
be collected if clinically indicated at the discretion of the Investigator. This last values will not 
be transferred to the Sponsor, if there are relevant abnormalities it will be reported as TEAE.  
Laboratory values of the form of “< x” (ie, below the lower limit of quantification) or > x (ie, 
above the upper limit of quantification) will be imputed as “x” in the calculation of summary 
statistics, but the original value (ie, “< x” or “> x”) will be displayed in the listings. 


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Table 2 
Laboratory safety variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Haematocrit 
S/P-Glucose (fasting) 
B-Haemoglobin 
S/P-Cholesterol, total 
B-Erythrocytes (red blood cells) 
S/P-Triglycerides 
B-MCV 
S/P-Creatinine 
B-MCH 
S/P-Bilirubin, total 
B-MCHC 
S/P-Protein, total 
B-Leukocyte count (white blood cells) 
S/P-Albumin 
B- differential blood count (neutrophils, 
lymphocytes, monocytes, eosinophils and 
basophil) 
S/P-Uric acid and BUN 
B-thrombocytes  
S/P-Sodium 
B-Platelet 
S/P-Potassium 
aPTT 
S/P-Calcium, total 
INR 
S/P-Chloride 
PTT 
Alpha-1 antitrypsin 
Urinalysis (dipstick) 
S/P-Phosphorus, inorganic 
U-pH 
S/P-AST 
U-Blood 
S/P-ALT 
U-leucocytes 
S/P-ALP 
U-Protein 
S/P-GGT 
U-Glucose 
S/P-LDH 
U-Bilirubin 
S/P-Creatine kinase 
U-Urobilinogen 
S/P-Bicarbonate 
U-Ketones 
S/P-Magnesium 
U-Nitrites 
 
ALP=Alkaline phosphatase; ALT=Alanine transaminase; aPTT=Activate partial thromboplastin time; 
AST=Aspartate transaminase; BUN=Blood urea nitrogen; GGT=Gamma glutamyl transferase; 
INR=International normalised ratio; LDH=Lactate dehydrogenase; MCH=Mean cell haemoglobin; 
MCHC=Mean corpuscular haemoglobin concentration; MCV=Mean corpuscular volume; PT=Prothrombin 
time; PTT=Partial thromboplasma time. 
 
 


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3.5.5 
ECG  
Electrocardiogram will be performed during Screening Visit, and then at pre-dose and 1, 2, 4, 
and 24 hours post-dose on Visits 3, 5, 6, 8, 9 and 11. At Visits 4, 7 and 10 measurements will 
be done at 1 and 4 hours post-dose. ECG will also be performed at follow-up. ECG should be 
performed before spirometry.  
Number of ECG abnormalities in each category of conduction defects, rhythm, myocardial 
infarction and others will be reported at each timepoint from each day within each treatment. 
The following ECG parameters will be analyzed: 
• 
Heart rate (except pre-dose on Visits 4, 7 and 10, which will be taken from vital signs). 
• 
RR interval: Duration in milliseconds between two R peaks of two consecutive 
measurements 
• 
QRS complexes 
• 
PR interval: Duration in milliseconds from the beginning of wave P to onset of 
ventricular depolarisation (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: QT interval corrected by heart rate: 
− 
QTcF interval: QT interval corrected using Fridericia’s formula 
(QT[msec]/RR[sec]1/3) 
• 
Sinus rhythm 
• 
Overall evaluation (normal/abnormal) 
For HR, and QTcF parameters, between-group differences will be presented at each timepoint 
(day, timepoint (hours) within day).  
3.5.6 
Vital signs 
Systolic and diastolic blood pressure (BP) will be recorded at screening, pre-dose and 1, 2, 4, 
and 24 hours post-dose at Visits 3, 5, 6, 8, 9 and 11. On Visits 4, 7 and 10 blood pressure will 
be measured at pre-dose, 1 and 4 hours post-dose. BP will also be recorded at follow-up. Body 
temperature will be measured at Screening and at the Follow-up Visit. Heart rate will be 
assessed by ECG (except pre-dose on Visits 4, 7 and 10, which will be taken from vital signs). 


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4. 
ANALYSIS METHODS 
4.1 
General principles 
4.1.1 
Statistical testing 
This study is exploratory in nature. The main comparisons of interest are  
• 
AZD8871 600 µg versus Anoro® Ellipta® and 
• 
AZD8871 600 µg versus Placebo. 
No adjustment of the Type I error for multiple comparisons will be made in the study, as the 
primary purpose is estimation rather than hypothesis testing.  
4.1.2 
Presentation of results 
All analyses will use SAS® version 9.3 or higher. Unless otherwise specified, summary tables 
will be presented by treatment group, labelled as follows: AZD8871 600 µg, Anoro® Ellipta®, 
and Placebo.  
All data will be presented in listings, sorted by sequence, patient number, and treatment. 
Continuous variables will be summarised by the number of observations, mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized 
by frequency counts and percentages for each category. Unless otherwise stated, percentages 
will be calculated out of the population total for the corresponding treatment. 
The minimum and maximum will be reported to the same number of decimal places as the 
raw data recorded in the database. The mean, median and standard deviation will be reported 
to one more decimal place than the raw data recorded in the database. The maximum number 
of decimal places presented for any statistic shall be four, except for pulmonary function 
variables, where the maximum shall be three.  Decimals to be used for PK analysis is 
described in section 4.3. 
Percentages will be presented to one decimal place.  
All confidence intervals (CIs) will be two-sided 95% CIs, unless stated otherwise, and 
presented to one more decimal place than the raw data recorded in the database. If a model is 
used to estimate the treatment difference, the corresponding CI according to the model will be 
presented. Otherwise, the unadjusted CI will be used. Nominal p-values may also be 
presented. Care should be taken when interpreting CIs and p-values since no correction for 
CCI


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multiple testing is done for the endpoints.  The presentation of pvalues- will be to four decimal 
places unless a p-value is less than 0.0001, in which case “<0.0001” will be displayed. 
A month and a year are operationally defined to be 30.4 and 365.25 days respectively. 
4.2 
Analysis methods 
4.2.1 
Analyses of study population 
4.2.1.1 
Patient disposition 
The reason for screen failure (i.e., patients screened but not randomised) will be listed. 
The number and percentage of patients enrolled, randomised, receiving IP, completing the 
study and prematurely discontinuing from the study (as recorded on the End of Study eCRF 
page), including the reasons for premature discontinuation, in addition to the number of 
patients included in each analysis set, will be summarised overall and by treatment for 
enrolled patients.  
The number and percentage of patients completing the treatment period and prematurely 
discontinuing during the treatment period, including the reasons for premature 
discontinuation, will be summarised by treatment for the FAS. For patients who discontinue 
from the study, the discontinuation will be assigned to the last treatment period prior to their 
discontinuation. Patients who do not discontinue during a treatment period will be as counted 
as completing the treatment period.  
A summary of important protocol deviations will be provided. Important protocol deviations 
will be listed by centre and treatment.  
4.2.1.2 
Demographic and baseline characteristics  
Analyses of demographic and baseline characteristics will be performed on the FAS. 
Standard descriptive statistics will be presented for the continuous variables of: 
• 
Age (years) 
• 
Weight (kg) 
• 
Height (cm) 
• 
BMI (kg/m2), calculated as follows (where height is in metres): 
weight
height2 
• 
Time from diagnosis of COPD to randomisation (years), calculated as: 
date of randomisation −date of diagnosis of COPD
365.25
 


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• 
Time from most recent exacerbation to randomisation (months), calculated as: 
date of randomisation − date of most recent exacerbation 
30.4
 
• 
Number of exacerbations in previous 12 months 
• 
Pre-bronchodilator FEV1 at screening (L) 
• 
Pre-bronchodilator FEV1 % predicted at screening 
• 
Pre-bronchodilator FVC at screening (L) 
• 
Pre-bronchodilator FVC % predicted at screening 
• 
Post-bronchodilator FEV1 at screening (L) 
• 
Post-bronchodilator FEV1 % predicted at screening 
• 
Post-bronchodilator FVC at screening (L) 
• 
Post-bronchodilator FVC % predicted at screening 
• 
Post-bronchodilator FEV1/FVC (%) at screening 
• 
FEV1 absolute reversibility at screening (mL) 
• 
FEV1 percentage reversibility at screening  
The total counts and percentages of patients will be presented for the categorical variables of: 
• 
Age categorized (18-64 years, 65-84 years, 85 years and older) 
• 
Country 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Smoking status (Current smoker, Former smoker) 
• 
Smoking history (number of pack-years) 
• 
Severity of airflow limitation at screening, defined as: 


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• 
Stage II (moderate): post-bronchodilator FEV1/FVC < 70% and 
post-bronchodilator FEV1 % predicted ≥ 50% and < 80% 
• 
Stage III (severe): post-bronchodilator FEV1/FVC < 70% and 
post-bronchodilator FEV1 % predicted ≥ 30% and < 50% 
• 
Reversible at screening (Yes, No). A patient is defined as being reversible if the post-
salbutamol spirometry increases (post-bronchodilator FEV1) with at least 12% 
(percentage reversibility) and at least 200 mL (absolute reversibility) compared to the 
pre-salbutamol spirometry.  
Medical history will be listed and the number and percentage of patients with any relevant 
medical history will be summarised overall, by SOC and PT. Surgical history will be listed 
and summarised similarly. 
The following summaries will be produced: 
• Summary of prior medications received (15 days prior to signing the ICF), by ATC 
level 3 code and PT, overall. Prior medications that continue after the date of first dose 
will be reported as well and classified in both prior and concomitant medication 
groups.. 
• Summary of disallowed medications will be reported. 
Additionally, a subset of the previous summary will be produced presenting the number and 
percentage of patients who used any prior medication for COPD by the following therapeutic 
categories; Inhaled Corticosteroids (ICS), Long-Acting Beta2-Agonists (LABA), LABA+ICS 
combination, Long-Acting Muscarinic Antagonist (LAMA), Short-Acting Beta2-Agonists 
(SABA), SABA+ICS combination, Short-Acting Muscarinic Antagonist (SAMA), 
SABA+SAMA combination, Influenza Vaccine, Oxygen, Xanthines and PDE4 inhibitors. If a 
patient has LABA+ICS followed by ICS (as monotherapy), then this patient will be counted 
only once in the LABA+ICS category. 
 
Multiple records for a patient in the same ATC level 3 category and PT will be counted only 
once.  
All concomitant and other treatment data will be listed. 
4.2.1.3 
Exposure 
Treatment duration (days) will be summarised by treatment for the SS, using descriptive 
statistics.  
4.2.1.4 
Treatment compliance 
Treatment compliance (%) will be summarised by treatment for the FAS, using continuous 
type descriptive statistics.  


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Treatment compliance will also be presented using the following compliance status categories: 
<70%, >=70%-130%, >130%.  
4.2.2 
Analysis of the primary variable: change from baseline in Trough FEV1 at Day 15 
All analyses will be based on the FAS and P-PS populations.  
The primary efficacy variable will be analysed by means of a mixed model: fixed effects for 
treatment, sequence, and period and random effect for patient (nested within sequence), the 
pre-dose FEV1 of each period being included as covariate. 
Each treatment effect and treatment differences will be estimated by the Least Square means 
along with their standard errors (SE) and 95% CI, and the p-value corresponding to the 
between-treatment group difference. Differences between least squares means, the SE of the 
difference, 95% CIs, and the p-values corresponding to between-treatment differences will 
also be presented for each comparison of interest. 
The main treatment comparisons that will be evaluated are: 
• AZD8871 600 µg versus Anoro® Ellipta® 
• AZD8871 600 µg versus Placebo 
A treatment comparison for Anoro® Ellipta® versus placebo will also be explored. 
A sensitivity analysis will be performed using as baseline FEV1 the mean of the 2 measured 
values prior to the morning IP administration on Day 1 of the first treatment period (see 
Section 3.1 for the baseline FEV1 derivation on Day 1 of the first treatment period in case of 
missing value). This sensitivity analysis will be performed by means of a mixed model: fixed 
effects for treatment, sequence, and period and random effect for patient (nested within 
sequence), the pre-dose FEV1 of the first period being included as a covariate to capture carry-
over effects. 
For all mixed models, the estimation method used will be Restricted Maximum Likelihood 
(REML). The Kenward and Roger method for computing degrees of freedom will be used.  
 
4.2.3 
Analysis of the FEV1-related secondary variables  
• 
Change from baseline in Trough FEV1 on Day 2, and Day 8 
• 
Change from baseline in Peak FEV1 on Day 1, Day 8, and Day 14 
The analyses of the above endpoints will be performed using the FAS and will be based on the 
same model as described in 4.2.2. 
• 
Change from baseline in Trough FEV1 over treatment duration (Day 1 to Day 15) 
• 
Change from baseline in Peak FEV1 over treatment duration (Day 1 to Day 14) 


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The analyses of the 2 above endpoints will be performed using the FAS. These 2 efficacy 
variables will be analysed by means of a mixed repeated model: fixed effects for treatment, 
sequence, period, and day as a repeated factor within period (Day 1, Day 8 and Day 15 (Day 
14 for Peak FEV1)) and day-by-treatment interaction; a random effect for patient (nested 
within sequence) will be included also. The repeated covariance structure for day will be 
compound symmetry; the pre-dose FEV1 of each period being included as a covariate. 
For all mixed models, the estimation method used will be Restricted Maximum Likelihood 
(REML). The Kenward and Roger method for computing degrees of freedom will be used. 
The same treatment comparisons as those for the primary variable will be performed for the 
secondary variables.  
 
4.2.4 
Analysis of the other FEV1-related variables  
All analyses below will be based on the FAS and will be based on the same model as 
described in 4.2.2. 
• 
Change from baseline in FEV1 AUC0-4/4h (area under the curve for the change in FEV1 
from baseline to 4h, normalised by the time window) on Day 1, Day 8, and Day 14  
• 
FEV1 AUC0-8/8h on Day 1, and Day 14  
• 
FEV1 AUC0-12/12h on Day 1, and Day 14  
• 
FEV1 AUC0-24/24h on Day 1, and Day 14  
In addition, statistical analyses on the change from baseline in FEV1 15 min, 30 min, 1, 2, 4, 8, 
23, and 23:45 hours post-dose will be presented by treatment group at Day 1 and Day 15. 
Also, analyses on the change from baseline in FEV1 15 min, 30 min, 1, 2, and 4 hours post-
dose will be presented by treatment group at Day 8. All analyses will be using the FAS and 
will be based on the same model as described in 4.2.2. 
Mean changes from baseline for FEV1 will be displayed in a longitudinal plot by treatment 
group, where the least squares means and corresponding 95% CI from the mixed model at 
each time point will be displayed, separately for Day 1, Day 8, and Day 14. 
Absolute FEV1 values will be summarised by visit and time point, by treatment group using 
descriptive statistics. The same treatment comparisons as those for the primary variable will 
be performed for the secondary variables.  
 
4.2.5 
Analysis of the other efficacy variables 
The change from baseline in Total BCSS score and cough, breathlessness and sputum 
individual domain scores assessed at Day 8 and at Day 14 (see Section 3.3.2.1 for definition) 
will be analysed by means of a mixed model: fixed effects for treatment, sequence, and period 
and random effect for patient (nested within sequence); the baseline will be included as a 
covariate.  


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The change from baseline in use of rescue medication at Day 8, and at Day 14 (see Section 
3.3.2.4 for definition) will be analysed by means of a mixed model: fixed effects for treatment, 
sequence, and period and random effect for patient (nested within sequence); the baseline will 
be included as a covariate. 
Change from baseline in CAT from Day 1 to Day 8, from Day 9 to Day 14 and during the 
whole treatment duration will be analysed by means of a mixed model: fixed effects for 
treatment, sequence, and period and random effect for patient (nested within sequence); the 
baseline will be included as a covariate. The same treatment comparisons as those for the 
primary variable will be performed for the secondary variables. 
4.2.6 
Exploratory outcome variables 
The change from baseline in cough VAS at Day 8, and at Day 15 will be analysed by means 
of a mixed model: fixed effects for treatment, sequence, and period and random effect for 
patient (nested within sequence); baseline will be included as a covariate. The change from 
baseline in number of coughs as measured by cough monitoring at Day 14 will be analysed in 
a similar model after data transformation (a square root transformation will be applied to the 
counts). A summary of raw counts should also be produced.  
A composite endpoint for exacerbations (moderate or severe) in COPD (COPDCompEx) will 
be derived and analysed. COPDCompEx combines exacerbations with events defined from 
patient daily diaries and dropout events. 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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. 
 
The analysis of this composite endpoint for exacerbations will be time to first COPDCompEx 
event and, for each period, it will be calculated as follows: 
  
𝑇𝑖𝑚𝑒 𝑡𝑜 𝑓𝑖𝑟𝑠𝑡 𝐶𝑂𝑃𝐷𝐶𝑜𝑚𝑝𝐸𝑥 (𝑜𝑓 𝑒𝑎𝑐ℎ 𝑝𝑒𝑟𝑖𝑜𝑑) =
𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝐶𝑂𝑃𝐷𝐶𝑜𝑚𝑝𝐸𝑥 (𝑖𝑛 𝑡ℎ𝑎𝑡 𝑝𝑒𝑟𝑖𝑜𝑑) −𝐷𝑎𝑡𝑒 𝑜𝑓 𝐷𝑎𝑦 1 (𝑜𝑓 𝑒𝑎𝑐ℎ 𝑝𝑒𝑟𝑖𝑜𝑑)+1 
 
For each period, if a patient presents either an exacerbation as described above, or any diary 
event meeting the threshold and slope criteria, or drops out, COPDCompEx will be 1 (otherwise 
it will be 0). For those patients with COPDCompEx=1 the date when the event (either 
exacerbations, diary events or dropouts) occurred will be also recorded. Patients with 
COPDCompEx=0 in a particular period, will be considered as censored in that period. The date 
of censoring will be defined as last day of treatment in that period (or date of withdrawal if not 
judged to be a dropout due to lack of efficacy, whichever is sooner). 
 
Time to to first COPDCompEx event will be analysed using a Cox’s proportional hazards 
model with factors for treatment, sequence, and period. Patient will be fitted as as a clustering 
factor. Hazard ratios with 95% CIs will be presented, for the comparisons of AZD8871 600 
µg to Anoro® Ellipta® and to Placebo. 
 
Time to to first COPDCompEx event will be summarized in a table including the following 
summary statistics: the number of subjects in the analysis, the percentage of patients with 
events, the mean time to event, and the median time to event with 95% CI, for each treatment 
(AZD8871 600 µg Anoro® Ellipta® and Placebo). In addition, a Kaplan-Meier plot will be 
provided. 
 
4.3 
Analysis of pharmarcokinetic variables  
4.3.1.1 
Descriptive statistics 
All PK summary statistics and inferential statistics will be based on the PKS. 
A listing of all available PK blood sample collection times as well as derived sampling time 
deviations will be provided.  
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AZD8871 and LAS191861 plasma concentrations will be listed by subject and time-point for 
the relevant treatment period and treatment sequence.  
Plasma concentrations for AZD8871 and its primary metabolite (LAS191861) will be 
summarised after the first dose of AZD8871 on Day 1 and after QD multiple doses on Day 14 
using descriptive statistics (n, n below  LLOQ, geometric mean (gmean), gmean +gSD, gmean 
–gSD, geometric coefficient of variation [gCV%],  minimum, median and maximum) based 
on the PKS. 
The statistics for geometric mean, geometric mean+/-geometric SD and geometric CV% will 
be calculated as follows:  
Geometric mean: Calculated as exp[µ] 
Geometric mean +/- geometric SD: Calculated as exp[µ+/- s] 
Geometric CV% : Calculated as 100 x sqrt[exp(s2) – 1] 
For the geometric mean, geometric mean +/- geometric SD and geometric CV%, the following 
holds: 
• 
s is the arithmetic standard deviation of the natural log-transformed variable 
• 
µ is the arithmetic mean of the natural log-transformed variable 
• 
exp denotes the power function based on the natural base e 
Individual concentrations below the Lower Limit of Quantification (LLOQ) of the 
bioanalytical assay will be reported as NQ in the listings with the LLOQ defined in the 
footnotes of the relevant TFLs. Individual plasma concentrations that are Not Reportable will 
be reported as NR and those that are missing will be reported as NS (No Sample) in the 
listings. Plasma concentrations that are NQ, NR or NS will be handled as follows for the 
provision of descriptive statistics: 
• 
Any values reports as NR or NS will be excluded from the summary tables and figures. 
 
• 
At a time point where less than or equal to 50% of the values are NQ, all NQ 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 NQ, the gmean,  
gmean + gSD, gmean – gSD and gCV% will be set to Not Calculated (NC). The 
maximum value will be reported from the individual data, and the minimum and 
median will be set to BLQ. 
 


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• 
If all values are BLQ at a time point, no descriptive statistics will be calculated for that 
time point. The gmean, minimum, median and maximum will be reported as BLQ and 
the gCV% and gmean + gSD and gmean – gSD as NC. 
 
• 
The number of BLQ values (n below LLOQ) will be reported for each time point. 
 
Three observations > LLOQ are required as a minimum for a plasma concentration to be 
summarized. Two observations > LLOQ are presented as minimum and maximum with the 
other summary statistics as NC. 
Plasma conentrations that are NQ will be handled as follows for display in figures: 
• 
For gmean concentration-time plots: NQ concentrations will be handled as described 
for the descriptive statistics. If this handling results in a geometric mean of "NQ", then 
the value plotted at that time-point will be zero for linear plots and set to missing for 
semi-logarithmic plots. Any gmean±gSD error bar values that are negative will be 
truncated at zero on linear concentration-time plots and omitted from semi-logarithmic 
plots 
 
• 
For individual plots and combined individual plots: NQ values prior to the first 
quantifiable concentration in that profile will be set to zero (linear plots only); after the 
first quantifiable concentration of the profile any NQ values will be set to missing 
 
Subjects who reported Day 1 pre-dose concentrations > 5% of Cmax may 
be excluded from the Day 1 PK analysis and/or statistical analyses. 
 
Plasma PK parameters for AZD8871 and its primary metabolite (LAS191861) will be 
summarised using descriptive statistics as follows:  
• 
Cmax, Cavg, AUC(0-24) and AUClast: present n, gmean, gmean+gSD, gmean-gSD, 
gCV(%), median, min and max. 
 
• 
All parameter ratios (i.e. Rac values and metabolite to parent ratios): present n, gmean, 
gCV(%), mean, SD, median, min and max. 
 
• 
%Fluc: present n, mean, SD, median, min and max. 
 
• 
tmax and tlast : present n, median, min and max. 
 
Three values are required as a minimum for PK parameters to be summarized. Two values are 
presented as a min and max with the other summary statistics as NC. 


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For concentration data, the listings will be presented to the same number of significant figures 
as the data received from the bioanalytical laboratory; for PK parameters, the listings will be 
presented according to the following rules:  
• 
Cmax will be presented to the same number of significant figures as received from the 
bioanalytical laboratory.  
 
• 
tmax and tlast will be presented as received in the data, usually to 2 decimal places  
 
• 
AUClast,  AUC(0-24),  Cavg, accumulation ratios and metabolite to parent ratios and 
%Fluc and will be presented to 3 significant figures  
 
For concentration data all descriptive statistics will be presented to 4 significant figures with 
the exception of the minimum and maximum which will be presented to 3 significant figures.  
For PK parameter data the descriptive statistics will be presented according to the following 
rules:  
• 
Cmax, AUClast,  AUC(0-24), Cavg, Rac ratios, metabolite to parent ratios and 
%Flucdescriptive statistics will be presented to 4 significant figures with the exception 
of the minimum and maximum which will be presented to 3 significant figures  
 
• 
tmax  and tlast all descriptive statistics will be presented as received in the data, usually 
to 2 decimal places  
 
PK concentration and parameter data for patients excluded from the PKS will be included in 
the data listings, but not in the descriptive or inferential statistics or in mean figures or 
combined individual figures.  
Individual plasma concentrations versus actual elapsed time after dose will be plotted on both 
linear and semi logarithmic scales for AZD8871 and LAS191861 separately with the Day 1 
and Day 14 data overlaid on the same plot. Combined individual plasma concentrations will 
be presented on both linear and semi logarithmic scales with separate plots for each analyte 
and PK day (Day 1 and Day 14). 
Figures for the gmean concentration-time data (with gSD error bars) will be presented, on 
both a linear and semi-logarithmic scales by analyte, with Day 1 and Day 14 overlaid on the 
same plot.  
To evaluate any potential carryover effect in the study due to AZD8871 treatment, Day 1 
predose concentrations for AZD8871 and LAS191861 in those periods preceded by AZD8871 
treatment will be also listed. These data however, will not be summarized.   
4.3.1.2 
Statistical analysis of accumulation in AZD8871 exposure (Cmax and AUC(0-24)) 
following multiple doses 
AUC(0-24) and Cmax at Day 1 and Day 14 will be analysed by means of a linear mixed-effect 
model with the logarithm of the PK parameters as the response variable and sequence, period,  


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and day as fixed effects, random effect for patient nested within sequence and day being 
treated as a repeated effect within patient, the covariance structure being assumed to be 
compound symmetry. ADZ8871 accumulation will be evaluated by comparing AUC(0-24) 
(Day 14) with AUC(0-24) (Day 1) and Cmax (Day 14) with Cmax (Day 1) in the same model. 
From these models, least squares (LS) means together with 95% CI for Day 1 and Day 14, and 
LS means together with 90% CI for the difference for Day 14 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 14/Day 1 and 
corresponding CI. 
 
4.4 
Safety 
All safety summaries will be based on the SS. Any important deviations from the randomised 
treatment assignment will be listed and considered when interpreting the safety data.  
4.4.1.1 
Adverse events 
All reported AEs will be listed along with the date of onset, date of resolution (if AE is 
resolved), investigator’s assessment of intensity, outcome, action taken with IMP, and 
possible relationship to study drug.  
Any AE occurring before the first dose of IP, or more than 42 days after the last dose of IP, 
will be considered as non-TEAE, it will be included in the data listings but will not be 
included in the summary tables of AEs. 
Multiple occurrences of a TEAE in the same patient will only be counted once overall 
considering start date as the first day of first occurrence and stop date the last day of the last 
occurrence and the TEAE will assigned to the treatment of the first occurrence period study 
drug. Multiple occurrences of a TEAE in the same patient for the same treatment will only be 
counted once for that treatment.  
The number of patients/event will be tabulated also by preferred term, and treatment. 
In the case that, within a treatment period, a patient has more than one episode of the same 
preferred term with different levels of intensity, action taken, outcome causality or 
seriousness, then the maximum intensity level, action taken (i.e. withdrawn) and outcome (i.e. 
fatal), causality level (i.e. related), or seriousness level (i.e. serious), respectively will be used. 
The following ordering will be used to define maximum intensity level, action taken, outcome 
causality level, or seriousness level : 
• 
Intensity: Mild < Moderate < Severe 
• 
Causality: No < Yes 
• 
Seriousness: No < Yes 


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• 
Action taken: Unknown < Not applicable < Dose not changed < Drug interrupted < 
Drug withdrawn 
• 
Outcome: Unknown < Recovered/resolved < Recovered/resolved with sequelae < 
Recovering/resolving < Not recovered/not resolved < Fatal 
A general summary of all TEAEs will show the number and percentage of patients with  
• 
Any TEAE 
• 
Any TEAE with outcome = death 
• 
Any TESAE (including events with outcome = death) 
• 
Any TEAE leading to discontinuation of IP 
• 
Any TEAE leading to withdrawal from study 
The total number of TEAEs will be presented for the following categories; 
• 
All TEAE 
• 
All TEAE with outcome = death 
• 
All TESAE (including events with outcome = death) 
• 
All TEAE leading to discontinuation of IP 
• 
All TEAE leading to withdrawal from study 
The number and percentage of patients who experience one or more TEAEs will be tabulated 
by treatment and by: 
• 
SOC and PT . 
• 
PT, and maximum reported intensity 
• 
PT, and causality with the IP judged by investigator 
• 
SOC and PT with outcome of death 
Additionally, a subset with the number and percentage of patients with any non-serious 
treatment emergent adverse event (TEAE) by system organ class, and preferred term by 
treatment with common incidence >=5% will also be produced (ordered by frequency). 
Key patient information (age/sex/race) for patients experiencing SAEs and discontinuation of 
study drug due to AEs will be presented in a listing. 


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4.4.1.2 
Laboratory data 
All laboratory data recorded in the eCRF will be listed. Flags will be applied to values falling 
outside the expanded normal ranges (which will be explicitly noted on these listings where 
applicable). Individual patient data where ALT and/or AST and total bilirubin are elevated at 
any time will be listed (ie, ALT and/or AST ≥ 3 × the upper limit of normal [ULN] and total 
bilirubin ≥ 2 × ULN, at any time) to evaluate potential Hy’s Law cases. 
Change from baseline to 24h post-dose assessment will be calculated. 
For i-STAT glucose and potassium at Day 1 and 14, mean absolute values at baseline, 1, 2, 4, 
and 24 hours postdose as well as mean changes from baseline at 1, 2, 4, and 24 hours post-
dose will be will be presented by treatment.   
Mean absolute values and mean change from baseline for all clinical chemistry and 
haematology laboratory parameters (in international system of units [SI]) will be presented by 
treatment and timepoint. 
A figure summarizing the mean change from baseline (and SE) in i-STAT glucose and 
potassium by treatment and timepoint will also be provided. 
Shift from baseline tables will be presented by treatment overall and by timepoint, separately 
for haematology, clinical chemistry and iSTAT measurements, showing the number and 
percentage of subjects with shifts from baseline for each laboratory variable.  
Shift is defined as the change in category based on the expanded normal ranges (low, normal 
or high as above) at baseline to a post-baseline timepoint. The number and percentage of 
patients with laboratory test values:  
• 
lower than the lower limit of the expanded normal range (ENR), 
• 
within the ENR limits, and 
• 
larger than the upper limit of the ENR 
will be provided for post baseline timepoints, the ENR being calculated by multiplying the 
LLN and ULN of the laboratory by the factor shown in Table 3.  
Moreover, treatment-emergent abnormalities, defined as newly occurring or clinically relevant 
worsening, as well as notable abnormalities in laboratory parameters will be summarised by 
means of shift contingency tables comparing the values assessed at post-baseline timepoints to 
the baseline values; values at baseline are “Low”, “Normal”, “High” according to Table 3; 
values post-baseline are “New”, “Worsened”, “Notable”. Newly occurring or clinically 
relevant worsening laboratory abnormalities in laboratory parameters will be identified using 
the ENR. A laboratory result lying outside the ENR will be considered abnormal. 


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A laboratory parameter will be defined as showing a “New” abnormality if the observed lab 
test value is within the ENR at baseline but not at post-baseline timepoints, or it is outside the 
ENR at baseline and outside the ENR at endpoint at different extreme limits (from expanded 
lower limit to expanded upper limit, or vice versa).  
A laboratory parameter will be defined as “Worsened” if the baseline lab test value is above 
the expanded upper limit of the corresponding normal range (xULN) specified in Table 3 and 
the ratio of endpoint value to baseline value is also greater than the corresponding coefficient 
(multiplying factor) specified in Table 3, or alternatively if the baseline laboratory test value is 
below the expanded lower limit of the corresponding normal range (xLLN) specified in the 
above table and the ratio of endpoint value to baseline value is also lower than the 
corresponding coefficient specified in Table 3. 
The laboratory abnormality will be also classified as a “Notable” abnormality if it satisfies the 
criteria detailed in Table 3.  
A listing of all treatment-emergent AEs recorded for patients with laboratory parameters 
outside of the ENR limits (at baseline or post-baseline) will also be provided including the 
assessment of clinical relevance by investigator.  
Pregnancy test results will be listed only. 
Table 3 
Expanded normal ranges and notable abnormalities for laboratory 
parameters 
Laboratory Parameter 
Expanded Normal Ranges 
Notable Abnormalities 
Lower Limit 
Upper Limit 
Lower Limit 
Upper Limit 
HAEMATOLOGY 
Hemoglobin 
 0.85 × LLN 
 1.15 × ULN 
< 60 g/L 
> 230 g/L 
Hematocrit 
 0.85 × LLN 
 1.15 × ULN 
< 0.24 
NA 
Red Blood cells 
 0.85 × LLN 
 1.15 × ULN 
NA 
NA 
MCV 
 0.85 × LLN 
 1.15 × ULN 
NA 
NA 
MCH 
 0.85 × LLN 
 1.15 × ULN 
NA 
NA 
MCHC 
 0.85 × LLN 
 1.15 × ULN 
NA 
NA 
Platelets 
 0.85 × LLN 
 1.15 × ULN 
< 100 × 109/L 
NA 
White Blood cells 
 
 
Total 
 0.85 × LLN 
 1.15 × ULN 
< 1 × 109/L 
> 30 × 109/L 
Neutrophils 
 0.85 × LLN 
 1.15 × ULN 
< 0.5 × 109/L 
NA 
Eosinophils 
NA 
 1.15 × ULN 
NA 
NA 
Basophils 
NA 
 1.15 × ULN 
NA 
NA 
Lymphocytes 
 0.85 × LLN 
 1.15 × ULN 
NA 
NA 
Monocytes 
NA 
 1.15 × ULN 
NA 
NA 


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Table 3 
Expanded normal ranges and notable abnormalities for laboratory 
parameters 
Laboratory Parameter 
Expanded Normal Ranges 
Notable Abnormalities 
Lower Limit 
Upper Limit 
Lower Limit 
Upper Limit 
BIOCHEMISTRY 
Aspartate aminotransferase 
NA 
 1.15 × ULN 
NA 
> 3 × ULN 
Alanine aminotransferase 
NA 
 1.15 × ULN 
NA 
> 3 × ULN 
Alkaline phosphatase 
NA 
 1.15 × ULN 
NA 
> 3 × ULN 
Gamma-glutamyltranspeptidase 
NA 
 1.15 × ULN 
NA 
> 3 × ULN 
Total bilirubin 
NA 
 1.15 × ULN 
NA 
> 51.3 μmol/L 
Creatine-kinase 
NA 
 1.15 × ULN 
NA 
> 10 × ULN 
Lactate dehydrogenase 
NA 
 1.15 × ULN 
NA 
> 3 × ULN 
Blood urea nitrogen 
NA 
 1.15 × ULN 
NA 
> 17.9 mmol/L 
Creatinine 
NA 
 1.15 × ULN 
NA 
> 265 μmol/L 
Uric acid 
NA 
 1.15 × ULN 
NA 
> 714 μmol/L 
Total cholesterol 
NA 
 1.15× ULN 
NA 
NA 
Triglycerides 
NA 
 1.15× ULN 
NA 
NA 
Glucose 
 0.85 × LLN 
 1.15 × ULN < 2.22 mmol/L > 22.2 mmol/L 
Sodium 
 0.95 × LLN 
 1.05 × ULN 
<115 mmol/L 
> 165 mmol/L 
Potassium 
 0.95 × LLN 
 1.05 × ULN 
< 2.6 mmol/L 
> 6.9 mmol/L 
Calcium 
 0.85 × LLN 
 1.15 × ULN < 1.25 mmol/L > 3.25 mmol/L 
Chloride 
 0.95 × LLN 
 1.05 × ULN 
NA 
NA 
Inorganic phosphorus 
 0.85 × LLN 
 1.15 × ULN 
NA 
NA 
Total Protein 
 0.85 × LLN 
1.15 × ULN 
< 20 g/L 
> 90 g/L 
Albumin 
 0.85 × LLN 
 1.15 × ULN 
NA 
NA 
URINALYSIS 
 
 
 
 
pH 
 0.85 × LLN 
 1.15 × ULN 
NA 
> 1.15 × ULN 
MCH = mean corpuscular haemoglobin; MCHC = mean corpuscular haemoglobin concentration; 
MCV = mean corpuscular volume; LLN = lower limit of normal; ULN = upper limit of normal 
(LLN and ULN values are provided by the laboratory). NA = Not applicable 
 
 
 


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4.4.1.3 
ECG 
All ECG data collected will be listed. 
Mean absolute values and mean change from baseline for continuous ECG parameters will be 
summarised by treatment, day (Day 1, 8, and 14) and timepoint within day, 95% CIs for the 
change from baseline will be provided in addition to the usual descriptive statistics 
parameters. 
Graphical presentation of mean change from baseline (and SE) for ECG parameters by 
treatment and timepoint will also be pprovided. 
For HR, and QTcF parameters, change from baseline at each timepoint within Day 1, Day 8, 
and Day 14 will be analysed by means of a mixed model; a random effect model with fixed 
effects for treatment, sequence, and period. The patient will be fitted as a random effect and 
the pre-dose value of the parameter obtained at visit 3 will be included as a covariate. 
Between-groups difference in LSMeans will be provided with their 90% CI. A Figure 
presenting the LSMeans and 90% CI across time will be presented as well.  
QTcF exceeding ICH boundaries are defined in Table 4. Other ECG values (HR, QRS 
interval, and PR interval) are defined to be PCS if they meet criterion 1 or criterion 2 
displayed in Table 5. Number and percentages of patients with post-baseline QTcF exceeding 
ICH boundaries and PCS ECG values will be presented for each category, each criterion 
defined in Table 4 and Table 5.  
These numbers and percentages of patients with post-baseline QTcF exceeding ICH 
boundaries and PCS ECG values will be summarised by treatment overall and by timepoint 
within each day (Day 1, 8, and 14).  
A listing of individual data for all patients with PCS ECG values will be provided, and will 
include treatment sequence, patient number, and all ECG values (baseline and post-baseline 
values), clinical relevance of PCS assessed by the PI will also be in the listing.  
A listing of all treatment-emergent AEs recorded for patients with PCS ECG values (at 
baseline or post-baseline) will also be provided. 
The number and percentage of patients with post-baseline abnormal ECG findings (Rhythm, 
Extra Systoles, Conduction, ST-Changes, ST Segment, T Wave Observations, and U Wave 
Observations) will be summarised by treatment, overall and and by timepoint within each day 
(Day 1, 8, and 14).  
Percentages will be based on the number of patients with at least one post-baseline ECG 
assessment. 
A listing of all ECG abnormal findings will be provided. 
 
 


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Table 4  
PCS ECG criteria: QTcF exceeding ICH boundaries 
Category 1: QTcF value above the following cut-off at any time during 
treatment 
Criteria: 
   >450 (ms) 
   >480 (ms) 
   >500 (ms) 
  
 Category 2: QTcF increase by more than following cut-off at any time during 
treatment 
Criteria: 
   >30 (ms) 
   >60 (ms) 
   >90 (ms) 
 Category 3: QTcF value above cut-off and QTcF increase by more than cut-off 
at any time during treatment 
Criterions: 
  Value >450(ms) and Increase >30(ms)  
  Value >500(ms) and Increase >60(ms)  
 
 
Table 5 
PCS ECG criteria: Heart Rate and QRS interval  
ECG parameter 
Category 
Criterion 1 
Criterion 2 
Heart rate 
Tachycardia event 
≥ 110 bpm and an 
increase of ≥ 15% 
over baseline value 
≥ 120 bpm if 
baseline is < 100 
bpm 
Bradycardia event 
≤ 50 bpm and a 
decrease of ≥ 15% 
over baseline value 
≤ 40 bpm if 
baseline is > 40 
bpm 
QRS interval 
 
≥ 100 msec and an 
increase of ≥ 25% 
over baseline value 
≥ 150 msec if 
baseline is 
< 150 msec 
PR interval 
 
≥ 200 msec and an 
increase of ≥ 25% 
over baseline value 
≥ 250 msec if 
baseline is 
< 250 msec 
bpm = beats per minute. 
 


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4.4.1.4 
Vital signs 
All vital sign data collected will be listed. 
Mean absolute values and mean change from baseline for BP will be summarised by 
treatment, and time point; graphical presentation of mean change from baseline and SE will be 
provided also. 
High and low PCS vital signs values will be identified. Vital sign values will be PCS if they 
meet both the PCS criteria for the observed value and the PCS criteria for the change from 
baseline value for criterion 1, or if they meet the PCS criteria for the observed value for 
criterion 2; the 2 criteria should not be combined. The criteria for PCS vital signs values are 
displayed in Table 6. 
Table 6 
PCS vital sign criteria 
 
Criterion 1 
Criterion 2 
Vital sign 
 
Observed 
value 
Change from baseline Observed value 
Systolic BP 
(mmHg) 
High ≥ 180 
Increase of ≥ 20 
≥ 200, if baseline < 160 
Low 
≤ 90 
Decrease of ≥ 20 
≤ 75, if baseline > 75 
Diastolic BP 
(mmHg) 
High ≥ 105 
Increase of ≥ 15 
≥ 115, if baseline < 115 
Low 
≤ 50 
Decrease of ≥ 15 
≤ 40, if baseline > 40 
BP = Blood pressure. 
The number and percentage of patients with post-baseline PCS vital sign values will be 
summarised for each criteria by treatment, day and timepoint within day. Percentages will be 
based on the number of patients with baseline vital sign values and at least one post-baseline 
vital sign assessment.  
A listing of individual data for all patients with PCS vital sign values will be provided, and 
will include treatment sequence, patient number, and all vital sign values (baseline and 
post-baseline values).  
A listing of all treatment-emergent AEs recorded for patients with PCS vital sign values (at 
baseline or post-baseline) will also be provided. 
 
 
 
 
CCI


Statistical Analysis Plan  
Drug Substance  
Study Code D6640C00006 
Version Final 1.0 
Date 08 February 2019 
 
Page 56 of 57 
 
 
 
 
 
 
5. 
INTERIM ANALYSES (NOT APPLICABLE) 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL 
Change in the analysis set used: 
All demographic and baseline characteristics will be analysed using the full analysis set 
instead of the safety population.  
Change in definition of baseline for vital signs, laboratory variables including i-STAT glucose 
and potassium and ECG variables: 
Baseline is defined as the last assessment made before the first dose of IP in each period 
instead of the value obtained prior to the morning IP administration on day 1 of Visit 3 
 
For HR, and QTcF parameters:  
Analyses of change from baseline at each day and timepoint within day will be perfomed 
instead of the analysis of AUC0-4 at Day 1, Day 8, and Day 14 and AUC0-24 at Day 1 and Day 
14. No formal analysis of other ECG parameters will be performed.  
 
Dropouts due to lack-of-efficacy during treatment periods added as a COPDCompEx event. 
 
Additional analysis on FEV1: 
Statistical analyses on the change from baseline in FEV1 15 min, 30 min, 1, 2, 4, 8, 23, and 
23:45 hours post-dose will be presented by treatment group at Day 1 and Day 15.  
 
Also, analyses on the change from baseline in FEV1 15 min, 30 min, 1, 2, and 4 hours post-
dose will be presented by treatment group at Day 8.  
7. 
REFERENCES (NOT APPLICABLE) 
 
 
CCI


Statistical Analysis Plan  
Drug Substance  
Study Code D6640C00006 
Version Final 1.0 
Date 08 February 2019 
 
Page 57 of 57 
 
8. 
APPENDIX  
Appendix A Statistical supporting documentation 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
CCI